Darunavir/cobicistat

>10% (darunavir)

Increased total cholesterol (10-25%)

>10% (cobicistat)

Total bilirubin, >2.5 x ULN (65%)

Ocular icterus, all grades (15%)

Jaundice, all grades (13%)

Nausea, all grades (12%)

1-10% (darunavir)

Increased triglycerides (3-10%)

Diarrhea (9%)

Headache (7%)

Rash (6%)

Abdominal pain (6%)

Nausea (4%)

Vomiting (2%)

Anorexia (2%)

1-10% (cobicistat)

Creatine kinase, >10 x ULN (5%)

Jaundice, grades 2-4 (5%)

Rash, grades 2-4 (5%)

Serum amylase, >2 x ULN (4%) ALT or AST, >5 x ULN (3%)

Glycosuria, >1000 mg/dL (3%)

Urine RBC, >75 RBC/HPF (3%)

Ocular icterus, grades 2-4 (3%)

GGT, >5 x ULN (2%)

Nausea, grades 2-4 (2%)

Contraindications

Alfuzosin: Potential for increased alfuzosin concentrations, which can result in serious or life-threatening reactions (eg, hypotension)

Dronedarone: Potential for increased dronedarone or ranolazine concentrations that may result in QT prolongation

CYP inducers (rifampin, St. John’s wort): Rifampin is a potent inducer of CYP metabolism, and coadministration may cause a significant decrease in the plasma concentrations of darunavir and result in loss of therapeutic effect and development of resistance

Cisapride, pimozide, lurasidone: Potential for serious and/or life-threatening reactions (eg, cardiac arrhythmias)

Ergot derivatives (dihydroergotamine, ergotamine, methylergonovine): Potential for serious and/or life-threatening reactions (eg, acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues)

HMG-CoA reductase inhibitors (lovastatin, simvastatin): Potential for serious reactions (eg, myopathy, including rhabdomyolysis)

PDE5 inhibitors (long-term administration [eg, sildenafil as Revatio for PAH]): Potential for sildenafil-associated adverse reactions (eg, visual disturbances, hypotension, priapism, syncope)

Triazolam, midazolam PO: These are extensively metabolized by CYP3A4; potential for prolonged or increased sedation or respiratory depression

Anticonvulsants (carbamazepine, phenobarbital, phenytoin): Potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effects and development of resistance

Hepatitis C direct-acting antiviral (elbasvir/grazoprevir): Pontential for the increased risk of alanine transaminase (ALT) elevations

Cautions

Hepatotoxicity reported; monitor liver enzymes at baseline and during treatment; consider interrupting or discontinuing treatment with evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms [eg, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly])

Severe skin reactions accompanied by fever and/or elevations of transaminases in some cases was reported in 0.4% of subjects; rare reports of Stevens-Johnson syndrome (<0.1%); mild-to-moderate rash was also reported and often occurred within the first 4 weeks of treatment and resolved with continued dosing

Effects on serum creatinine: Assess eCrCl before initiating; cobicistat decreases estimated creatinine clearance, owing to inhibition of tubular secretion of creatinine, without affecting actual renal glomerular function

Sulfa allergy: Darunavir contains a sulfa moiety; monitor patients with a known sulfonamide allergy

New-onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitors

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 ARTs

Immune reconstitution syndrome reported in patients treated with combination ART therapy; during the initial phase of combination ART treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium infection, CMV, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment; autoimmune disorders (eg, Graves disease, polymyositis, Guillan-Barre syndrome) have also been reported

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, reported in patients with hemophilia type A and B treated with HIV protease inhibitors

Renal impairment

• Renal impairment, including cases of acute renal failure and Fanconi syndrome, reported when cobicistat was used in an ART regimen that contained tenofovir DF
• Document urine glucose and urine protein at baseline and perform routine monitoring of eCrCl, urine glucose, and urine protein during treatment
• Coadministration of darunavir/cobicistat plus tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended

Drug interaction overview

• Also see Contraindications and Drug Interaction Checker
• When evaluated separately, darunavir and cobicistat both inhibited CYP3A and CYP2D6
• Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3
• Drugs that are metabolized by CYP3A and CYP2D6, or are substrates of the transporters P-gp, BCRP, OATP1B1, or OATP1B3, may show increased systemic exposure if coadministered with darunavir/cobicistat

ART agents that are not recommended

• Not recommended in combination with other ART drugs that require pharmacokinetic boosting (ie, another protease inhibitor or elvitegravir) because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the ART agents, leading to loss of therapeutic effect and development of resistance
• Darunavir/cobicistat is not recommended in combination with products containing the individual components (darunavir and cobicistat) or with ritonavir

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to therapy during pregnancy; healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263

There are insufficient data from the APR to inform a drug-associated risk of pregnancy outcomes; rate of miscarriage is not reported in the APR; the background risk of major birth defects and miscarriage for the indicated population is unknown

Lactation

There are no data on presence of darunavir or cobicistat in human milk, effects on breastfed infant, or on milk production; darunavir and cobicistat are secreted into milk of lactating rats; because of 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 receiving therapy

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Darunavir: Protease inhibitor; selectively inhibits cleavage of Gag-Pol polyprotein precursors, thereby preventing the formation of mature virus particles

Cobicistat: CYP3A4 inhibitor; mechanism-based pharmacokinetic enhancer, increases the systemic exposure of darunavir (a CYP3A4 substrate)

Absorption

Peak plasma time: 4-4.5 hr (darunavir); 4-5 hr (cobicistat)

Trough concentration (darunavir): 1875 ng/mL

AUC (darunavir): 100,152 ng∙hr/mL High-fat meal increases absorption; darunavir/cobicistat should be taken with food

Distribution

Protein bound: 95% (darunavir); 97-98% (cobicistat)

Metabolism

Darunavir: Primarily undergoes oxidative metabolism; extensively metabolized by CYP enzymes, primarily by CYP3A

Cobicistat: Metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation

Elimination

Half-life: 7 hr (darunavir); 4 hr (cobicistat)

Excretion

• Darunavir: 79.5% feces (41.2% unchanged); 13.9% urine (7.7% unchanged)
• Cobicistat: 86.2% feces; 8.2% urine

Pharmacogenomics

HIV genotypic testing is recommended for ART treatment-experienced patients

However, when HIV genotypic testing is not feasible, darunavir/cobicistat can be used in protease inhibitor-naïve patients, but is not recommended in protease inhibitor-experienced patients