Atazanavir + Cobicistat

Atazanavir + Cobicistat is used for: HIV-1 Infection

HIV-1 Infection Indicated in combination with other antiretroviral (ART) agents for the treatment of human immunodeficiency virus type 1 (HIV-1) in adults 1 tablet (300 mg/150 mg) PO qDay with food When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required Hepatic impairment: Do not use in patients with any degree of hepatic impairment

<18 years: Safety and efficacy not established

Renal impairment CrCl <70 mL/min: Coadministered with tenofovir disoproxil fumarate (DF) is not recommended ESRD managed with hemodialysis: Use not recommended Concomitant or recent use of nephrotoxic drug: atazanavir/cobicistat plus tenofovir DF is not recommended

Oral Administration Take once daily with food (improves absorption)

Previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) Coadministration with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events Coadministration with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of atazanavir/cobicistat Contraindicated drugs Alfuzosin: Potential for increased alfuzosin concentrations, which can result in serious or life-threatening reactions (eg, hypotension) Dronedarone, ranolazine: Potential for increased dronedarone and ranolazine concentrations that may result in prolonged QT interval Colchicine: Contraindicated in patients with renal and/or hepatic impairment due to the potential for serious and/or life-threatening reactions 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 Carbamazepine: Potential for decreased atazanavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance Cisapride, pimozide, lurasidone: Potential for serious and/or life-threatening reactions (eg, cardiac arrhythmias) Elbasvir/grazoprevir: Atazanavir OATP1B1/3 inhibition may cause a significant increase in grazoprevir levels, and therefore increase risk of elevated ALT 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) Indinavir: Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia Irinotecan: UGT1A1 inhibition by atazanavir may interfere with the metabolism of irinotecan, resulting in increased toxicity Nevirapine: Nevirapine substantially decreases atazanavir exposure which may result in loss of therapeutic effect and development of resistance; potential risk for nevirapine-associated adverse reactions due to increased nevirapine exposures PDE5 inhibitors (long-term administration [eg, sildenafil as Revatio for PAH]): Potential for sildenafil-associated adverse reactions (eg, visual disturbances, hypotension, priapism, syncope) Phenobarbital, phenytoin: Potential for decreased atazanavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance Triazolam, midazolam PO: These are extensively metabolized by CYP3A4; potential for prolonged or increased sedation or respiratory depression

Atazanavir prolongs the PR interval of the electrocardiogram in some patients; reports of second-degree AV block and other conduction abnormalities Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported; mild-to-moderate maculopapular skin eruptions have also been reported in atazanavir clinical trials and generally did not result in treatment discontinuation 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 Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir reported; consider alternatives to therapy in patients at high risk for renal disease or with preexisting renal disease; renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy and continued during treatment Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients receiving atazanavir Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases may be at increased risk for developing further transaminase elevations or hepatic decompensation Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyltransferase (UGT) New-onset diabetes mellitus, exacerbation of preexisting 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

Pregnancy Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogues Nucleoside analogues are associated with an increased risk of lactic acidosis syndrome Hyperbilirubinemia occurs frequently in patients who take atazanavir, including pregnant women All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life Animal data Atazanavir In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir coadministered with 100 mg/day ritonavir) In prenatal and postnatal development studies in the rat, atazanavir caused body weight loss or weight gain suppression in the animal offspring with maternal drug exposure (AUC) 1.3 times the human exposure at this clinical dose; however, maternal toxicity also occurred at this exposure level Cobicistat Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function In offspring from rat and rabbit dams treated with cobicistat during pregnancy, there were no toxicologically significant effects on developmental endpoints The exposures at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 1.4 and 3.3 times higher than the exposure in humans at the recommended daily dose of 150 mg Lactation The CDC recommends that HIV infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV to infant Unknown whether atazanavir or cobicistat are secreted in human milk

Drugs that induce CYP3A4 may lead to lower exposure of atazanavir and loss of virologic response Atazanavir inhibits CYP3A4 and is a substrate for CYP3A4 Cobicistat inhibits 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

Side effects of Atazanavir + Cobicistat : >10% Total bilirubin >2.5 xULN (65%) Ocular icterus, all grades (15%) Jaundice, all grades (13%) Nausea, all grades (12%) 1-10% Jaundice, grades 2-4 (5%) Rash, grades 2-4 (5%) Creatinine kinase >10 xULN (5%) Serum amylase >2 xULN (4%) ALT/AST >5 xULN (3%) Ocular icterus, grades 2-4 (3%) Glycosuria ≥1000 mcg/dL (3%) Hematuria >75 RBC/HPF (3%) GGT >5 xULN (2%) Nausea, grades 2-4 (2%) Nephrolithiasis (2%) Gastrointestinal disorders: Diarrhea, vomiting, upper abdominal pain (<2%) General disorders and administration site conditions: Fatigue (<2%) Musculoskeletal and connective tissue disorders: Rhabdomyolysis (<2%) Nervous system disorders: Headache (<2%) Psychiatric disorders: Depression, abnormal dreams, insomnia (<2%) Renal and urinary disorders: Nephropathy, Fanconi syndrome (<2%)

Atazanavir: 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 atazanavir (a CYP3A4 substrate)