Darunavir + Cobicistat

Indications

Darunavir + Cobicistat is used for: HIV-1 Infection

Adult Dose

Oral 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) once daily with food

Child Dose

HIV-1 Infection Indicated in combination with other antiretroviral agents for HIV in treatment-naïve and treatment-experienced patients weighing at least 25 kg with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) <25 kg: Safety and efficacy not established Weight-based dosing Administer with food in conjunction with other antiretroviral agents 25 to <40 kg: One 675 mg/150 mg tablet PO daily >40 kg: One 800 mg/150 mg tablet PO Daily

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

Coadministration iwth 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) CYP3A4 substrates with narrow therapeutic index

Precautions

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis), liver injury, including some fatalities can occur with Darunavir + Cobicistat. Skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms and acute generalized exanthematous pustulosis, can occur with Darunavir + Cobicistat. Discontinue treatment if severe reaction develops. When Darunavir + Cobicistat is used in combination with a tenofovir disoproxil fumarate (tenofovir DF) containing regimen, cases of acute renal failure and Fanconi syndrome have been reported. Darunavir + Cobicistat is not recommended in combination with other antiretroviral drugs that require pharmacokinetic boosting. Patients receiving Darunavir + Cobicistat may develop new onset or exacerbations of diabetes mellitus/hyperglycemia, redistribution/accumulation of body fat, and immune reconstitution syndrome. Patients with hemophilia may develop increased bleeding events. Monitoring Parameters Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases. Monitor in patients with a known sulfonamide allergy.

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 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

Co-administration of Darunavir + Cobicistat with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of darunavir or cobicistat. Consult the full prescribing information prior to and during treatment for potential drug interactions. Contraindicated (40) alfuzosin aprepitant carbamazepine cobimetinib conivaptan dihydroergotamine intranasal dronedarone elbasvir/grazoprevir eliglustat elvitegravir/cobicistat/emtricitabine/tenofovir DF ergoloid mesylates ergonovine finerenone flibanserin fosaprepitant gepirone irinotecan irinotecan liposomal isavuconazonium sulfate ivabradine lomitapide lonafarnib lovastatin lurasidone methylergonovine naloxegol pacritinib phenobarbital phenytoin pimozide ranolazine regorafenib rifampin salmeterol simvastatin St John's Wort suzetrigine triazolam venetoclax voclosporin

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)