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

Brand name: Symtuza
Drug class: HIV Protease Inhibitors
Chemical name: [(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate
Molecular formula: C₂₇H₃₇N₃O₇SC₄₀H₅₃N₇O₅S₂C₈H₁₀FN₃O₃SC₂₁H₂₉N₆O₅P
CAS number: 1097732-88-1

Medically reviewed by Drugs.com on Jul 20, 2023. Written by ASHP.

Introduction

The fixed combination of darunavir, an HIV-1 protease inhibitor, cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs), is an antiretroviral agent.

Uses for Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate has the following uses:

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is a four-drug combination of darunavir (DRV), an HIV-1 protease inhibitor, cobicistat (COBI), a CYP3A inhibitor, and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 NRTIs, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 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.

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

General

The fixed combination of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is available in the following dosage form(s) and strength(s):

Tablets: 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (equivalent to 11.2 mg of tenofovir alafenamide fumarate).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

• Testing: Prior to or when initiating darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, test patients for HBV infection. Prior to or when initiating darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients on a clinically appropriate schedule. In patients with chronic kidney disease, also assess serum phosphorus.

• Recommended dosage: One tablet taken once daily with food.

• Renal impairment: Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL/min.

• Hepatic impairment: Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with severe hepatic impairment.

Cautions for Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

Contraindications

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is contraindicated to be co-administered with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or which may lead to loss of therapeutic effect of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate and development of resistance.

Warnings/Precautions

Severe Acute Exacerbation of Hepatitis B in Patients Co-infected with HIV-1 and HBV

Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Patients coinfected with HIV-1 and HBV who discontinue darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. 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.

Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir, a component of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. 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.

Post-marketing cases of liver injury, including some fatalities, have been reported with darunavir. 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. A causal relationship with darunavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate and patients should be monitored during treatment as clinically appropriate. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate treatment.

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) should prompt consideration of interruption or discontinuation of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate.

Severe Skin Reactions

In patients receiving darunavir, a component of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, severe skin reactions may occur. These include conditions accompanied by fever and/or elevations of transaminases. Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%. During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported. Discontinue darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate immediately if signs or symptoms of severe skin reactions develop. 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.

Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate in the AMBER trial. Rash events were mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate was 2%.

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

The concomitant use of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate and other drugs may result in known or potentially significant drug interactions, some of which may lead to:

• Loss of therapeutic effect of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate and possible development of resistance.

• Possible clinically significant adverse reactions from greater exposures of concomitant drugs.

See Drug Interactions section in Full Prescribing Information for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate therapy; review concomitant medications during darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate therapy; and monitor for the adverse reactions associated with concomitant medications.

When used with concomitant medications, darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, which contains darunavir boosted with cobicistat, may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate interactions.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been 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.

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

New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, there were no cases of proximal renal tubulopathy (PRT), including Fanconi syndrome, reported in the darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate group through Week 48. Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with creatinine clearance below 30 mL per minute.

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

Prior to or when initiating darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate and during treatment with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Cobicistat, a component of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

Sulfa Allergy

Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. 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.

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 darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate should be suspended 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 have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. 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.

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. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

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). In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary: There are insufficient human data on the use of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate in pregnant individuals from the APR to inform on a potential 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 of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15–20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates pregnant individuals and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks' gestation.

In animal reproduction studies, no adverse developmental effects were observed when the components of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate were administered separately at darunavir exposures less than 1- (mice and rabbits) and 2.6-times (rats) higher, at cobicistat exposures 1.7- and 4.1-times higher (rats and rabbits respectively) at emtricitabine exposures 88- and 7.3- times higher (mice and rabbits, respectively), and tenofovir alafenamide exposures equal to or 85- times higher (rats and rabbits, respectively) than human exposures at the recommended daily dose of these components in darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.1 times the human exposure at the recommended therapeutic dose.

Clinical Considerations: Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy. Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate.

Darunavir/Cobicistat Human Data: Darunavir and cobicistat in combination with a background regimen was evaluated in a clinical trial of 7 pregnant individuals taking darunavir and cobicistat prior to enrollment and who were willing to remain on darunavir and cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals completed the trial. Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum. One out of 6 pregnant individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five pregnant individuals had sustained virologic response (HIV RNA <50 copies/mL) throughout the study period. There are no clinical data on the virologic response when darunavir and cobicistat are initiated during pregnancy.

Darunavir Human Data: Based on prospective reports to the APR of 679 live births following exposure to darunavir-containing regimens during pregnancy (including 425 exposed in the first trimester and 254 exposed in the second/third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.1% (95% CI: 1.0% to 4.0%) with first trimester exposure to darunavir-containing regimens and 2.4% (95% CI: 0.9% to 5.1%) with second/third trimester exposure to darunavir-containing regimens.

Cobicistat Human Data: Insufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects.

Emtricitabine Human Data: Based on prospective reports to the APR of 3749 exposures to emtricitabine-containing regimens during pregnancy (including 2614 exposed in the first trimester and 1135 exposed in the second/third trimester), there was no difference between emtricitabine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to emtricitabine-containing regimens and 2.1% (95% CI: 1.4% to 3.1%) with the second/third trimester exposure to emtricitabine-containing regimens.

Tenofovir Alafenamide Human Data: Insufficient numbers of pregnancies with exposure to tenofovir alafenamide have been reported to the APR to estimate the rate of birth defects.

Darunavir Animal Data: Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6–15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7–19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8–20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (2.6-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended daily dose of darunavir in darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate.

Cobicistat Animal Data: Cobicistat was administered orally to pregnant rats at doses up to 125 mg/kg/day on GD 6–17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.7 times higher than human exposures at the recommended daily dose of cobicistat in darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. In pregnant rabbits, cobicistat was administered orally at doses up to 100 mg/kg/day during GD 7–20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 4.1 times higher than human exposures at the recommended daily dose of cobicistat in darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses up to 75 mg/kg from GD 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.1 times the human exposures at the recommended daily dose of cobicistat in darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate.

Emtricitabine Animal Data: Emtricitabine was administered orally to pregnant mice and rabbits (up to 1000 mg/kg/day) through organogenesis (on GD 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 88 times higher and in rabbits approximately 7.3 times higher than human exposures at the recommended daily dose of emtricitabine in darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. In a pre/postnatal development study, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth in utero through sexual maturity at daily exposures of approximately 88 times higher than human exposures at the recommended daily dose of emtricitabine in darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate.

Tenofovir Alafenamide (TAF) Animal Data: TAF was administered orally to pregnant rats (up to 250 mg/kg/day) and rabbits (up to 100 mg/kg/day) through organogenesis (on GD 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures approximately similar to (rats) and 85 times higher (rabbits) than the exposure in humans at the recommended daily dose. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 51 (rats) and 80 (rabbits) times higher than human tenofovir exposures at the recommended daily dose of TAF in darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF (another prodrug of tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on GD 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposure in humans at the recommended daily dose of TDF.

Lactation

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

Based on published data, emtricitabine has been shown to be present in human breast milk. 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. Darunavir and cobicistat are present in the milk of lactating rats. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF. 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 darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate.

Darunavir Animal Data: Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is excreted in milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 66% of those obtained in humans at the recommended clinical dose of darunavir with ritonavir.

Cobicistat Animal Data: During the pre/postnatal developmental toxicology study, at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10.

Tenofovir Alafenamide Animal Data: Studies in rats and monkeys have demonstrated that tenofovir is excreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating rhesus monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.

Pediatric Use

The safety and effectiveness of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate in pediatric patients less than 18 years of age have not been established. Darunavir, a component of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.

Juvenile Animal Toxicity Data: In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.

Geriatric Use

Clinical trials of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate included 35 subjects aged above 65 years of which 26 received the fixed combination preparation. No differences in safety or efficacy have been observed between elderly subjects and those aged 65 years or less. In general, caution should be exercised in the administration and monitoring of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy.

Renal Impairment

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL per minute). No dosage adjustment of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is required in patients with creatinine clearance greater than or equal to 30 mL per minute.

Cobicistat has been shown to decrease creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosage adjustment for renal impairment when used in combination with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate.

Hepatic Impairment

No dosage adjustment of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is required in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate has not been studied in patients with severe hepatic impairment (Child Pugh Class C) and there are only limited data regarding the use of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate components in this population. Therefore, darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is not recommended for use in patients with severe hepatic impairment.

Common Adverse Effects

The most common adverse reactions (all grades, incidence greater than or equal to 2%) were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Co-administration of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate components. Consult the full prescribing information prior to and during treatment for potential drug interactions.

Actions and Spectrum

Mechanism of Action

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is a fixed-dose combination of antiretroviral drugs darunavir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide.

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

Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of CYP-P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates.

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate 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. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε, and mitochondrial DNA polymerase γ.

Tenofovir Alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.

Spectrum

Darunavir: Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human PBMCs, and human monocytes/macrophages with median EC₅₀ values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC₅₀ values ranging from less than 0.1 to 4.3 nM. The EC₅₀ value of darunavir increases by a median factor of 5.4 in the presence of human serum.

Cobicistat: Cobicistat has no detectable antiviral activity in cell culture against HIV-1.

Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary PBMCs. The EC₅₀ values for emtricitabine were in the range of 0.0013–0.64 µM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC₅₀ values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC₅₀ values ranged from 0.007–1.5 µM).

Tenofovir Alafenamide: The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), primary monocyte/macrophage cells, and CD4+ T lymphocytes. The EC₅₀ values for TAF ranged from 2.0 to 14.7 nM. TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F, and G (EC₅₀ values ranged from 0.10 to 12.0 nM) and strain specific activity against HIV-2 (EC₅₀ values ranged from 0.91 to 2.63 nM).

The combination of darunavir, emtricitabine, and tenofovir alafenamide was not antagonistic in cell culture combination antiviral activity assays. In addition, darunavir, emtricitabine, and tenofovir alafenamide were not antagonistic with a panel of representative agents from the major classes of approved HIV antivirals (PIs, NRTIs, NNRTIs, and INSTIs). The antiviral activity of approved HIV antivirals was not antagonized by cobicistat.

Resistance

Darunavir in Cell Culture: HIV-1 isolates with a decreased susceptibility to darunavir have been selected and obtained from subjects treated with darunavir co-administered with ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated substitutions resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC₅₀ values ranging from 125 nM to 3461 nM.

Emtricitabine in Cell Culture: HIV-1 isolates with reduced susceptibility to emtricitabine were selected in cell culture and in subjects treated with emtricitabine. Reduced susceptibility to emtricitabine was associated with M184V or I substitutions in HIV-1 RT.

Tenofovir Alafenamide in Cell Culture: HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions. In addition, a K70E substitution in HIV-1 RT was observed.

Individuals with Prior Antiretroviral Treatment in Clinical Trials: Darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, and L89V) in HIV-1 protease were derived from clinical trial data of antiretroviral therapy experienced patients, which were all protease inhibitor-experienced patients. Baseline International AIDS Society-USA (IAS-USA)-defined PI resistance substitutions confer reduced virologic response to darunavir.

Individuals with No Prior Antiretroviral Treatment History in Clinical Trials: In the AMBER clinical trial of subjects with no prior antiretroviral treatment history, there were 7 subjects with protocol-defined virologic failure and with HIV-1 RNA ≥400 copies/mL at failure or later timepoints who had post-baseline resistance data in the darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate arm. None of the subjects had detectable emergent darunavir resistance-associated substitutions or other primary protease inhibitor resistance substitutions and only one subject had emergent M184M/I/V, which confers resistance to emtricitabine and lamivudine. In the comparative PREZCOBIX + emtricitabine/tenofovir disoproxil fumarate arm, there were 2 protocol-defined virologic failures with post-baseline resistance data and neither had detectable resistance emergence.

Virologically Suppressed Individuals in Clinical Trials: In the EMERALD clinical trial of virologically-suppressed subjects who switched to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, 1 subject who rebounded and 2 subjects who discontinued early from the study had post-baseline resistance genotypes. None of the subjects had darunavir, primary protease inhibitor, emtricitabine, or tenofovir resistance substitutions. In the control arm, there were 3 subjects who rebounded with post-baseline genotypes and no resistance substitutions were observed.

Cross-Resistance

Darunavir: Cross-resistance among PIs has been observed. Darunavir has a less than 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir. A less than 10-fold decreased susceptibility was observed for the other PIs in 26% to 96% of these PI resistant clinical isolates [nelfinavir (26%), ritonavir (34%), lopinavir (46%), indinavir (57%), atazanavir (59%), saquinavir (64%), amprenavir (70%), and tipranavir (96%)]. Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, gp41 fusion inhibitors, CCR5 co-receptor antagonists, or integrase strand transfer inhibitors is unlikely because the viral targets are different.

Emtricitabine: Emtricitabine-resistant viruses with the M184V or I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

Tenofovir Alafenamide: Tenofovir resistance substitutions K65R and K70E result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 with multiple thymidine analog substitutions (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R) or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M substitution complex including K65R, showed reduced susceptibility to TAF in cell culture.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Instructions for Use

Advise patients to take darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate 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 darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate or discontinue therapy without consulting their physician. For patients who are unable to swallow tablets whole, darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate may be split using a tablet-cutter, and the entire dose should be consumed immediately after splitting.

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Co-Infection

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 TDF, and may likewise occur with discontinuation of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Advise the patient to not discontinue darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate without first informing their healthcare provider.

Hepatotoxicity

Inform patients that drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and liver injury, including some fatalities, could potentially occur with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Advise patients to contact their healthcare provider immediately if signs and symptoms of liver problems develop.

Severe Skin Reactions

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 darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Advise patients to contact their healthcare provider immediately if signs or symptoms of severe skin reactions develop, including but not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, and/or conjunctivitis.

Pregnancy

Advise patients that darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate.

Lactation

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

Drug Interactions

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate may interact with many drugs; therefore, inform patients of the potential serious drug interactions with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, and that some drugs are contraindicated with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate and other drugs may require dosage adjustment. 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.

Immune Reconstitution Syndrome

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.

Renal Impairment

Advise patients to avoid taking darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate 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.

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Advise patients that they should stop darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.

Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, and that the cause and long-term health effects of these conditions are not known at this time.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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

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