Darunavir + Cobicistat

Indications

Darunavir + Cobicistat is used for: HIV-1 Infection

Adult Dose

HIV-1 Infection Indicated in combination with other antiretroviral agents in naïve and treatment-experienced patients without darunavir resistance-associated mutations 1 tablet (800 mg/150 mg) PO qDay with food Severe hepatic impairment: Not recommended

Child Dose

Renal Dose

Renal failure CrCl <70 mL/min: Coadministration with tenofovir disoproxil fumarate (DF) is not recommended

Administration

Take once daily with food (improves absorption)

Contra Indications

Alfuzosin, dronedarone, ivabradine, ranolazine, naloxegol, CYP inducers (rifampin, St. John’s wort), cisapride, pimozide, lurasidone, ergot derivatives (dihydroergotamine, ergotamine, methylergonovine), HMG-CoA reductase inhibitors (lomitapide, lovastatin, simvastatin), PDE5 inhibitors (long-term administration [eg, sildenafil as Revatio for PAH]), triazolam, midazolam, anticonvulsants (carbamazepine, phenobarbital, phenytoin), hepatitis C direct-acting antiviral (elbasvir/grazoprevir), colchicine (in patients with renal/and or hepatic impairment)

Precautions

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; Stevens-Johnson syndrome rarely; mild-to-moderate rash reported to occur within first 4 weeks of treatment and resolved with continued dosing Assess eCrCl before initiating therapy; cobicistat decreases estimated creatinine clearance without affecting actual renal glomerular function by inhibiting tubular secretion of creatinine 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 Increased bleeding, including spontaneous skin hematomas and hemarthrosis, reported in patients with hemophilia type A and B treated with HIV protease inhibitors Not recommended for use in pregnant women because of substantially lower exposures of darunavir and cobicistat during pregnancy

Pregnancy-Lactation

Pregnancy Not recommended for use in pregnant women because of substantially lower exposures of darunavir and cobicistat during 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 Contraception Consider additional or alternative (non-hormonal) forms of contraception when estrogen- containing contraceptives are co-administered; for co-administration with drospirenone, clinical monitoring is recommended due to potential for hyperkalemia; no data are available to make recommendations on co-administration with other hormonal contraceptives 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

Interactions

Adverse Effects

Side effects of 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%)

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)