Atazanavir + Cobicistat

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 once daily with food When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required

HIV-1 Infection Indicated in combination with other antiretroviral (ART) agents for treatment of human immunodeficiency virus type 1 (HIV-1) in patients who weigh at least 35 kg <35 kg: Safety and efficacy not established >35 kg 1 tablet (300 mg/150 mg) PO once daily with food

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

In general, appropriate caution should be exercised in the administration and monitoring of Atazanavir + Cobicistat in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic impairment: Do not use in patients with any degree of hepatic impairment

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 atazanavi

Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. Consider ECG monitoring in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. Severe skin reactions: Discontinue if severe rash develops. When cobicistat, a component of Atazanavir + 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. Coadministration with tenofovir DF is not recommended in patients with CLcr below 70 mL/min or in patients also receiving a nephrotoxic agent. Chronic kidney disease has been reported during postmarketing surveillance in HIV-infected patients treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. Hepatotoxicity: Patients with hepatitis B or C coinfection are at risk of increased transaminases or hepatic decompensation. Antiretrovirals that are not recommended: Atazanavir + Cobicistat is not recommended for use with ritonavir or products containing ritonavir, or in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other protease inhibitors and elvitegravir). Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. Patients receiving Atazanavir + Cobicistat may develop immune reconstitution syndrome, new onset or exacerbations of diabetes mellitus/hyperglycemia, and redistribution/accumulation of body fat . Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. Monitoring Parameters Consider ECG

Not Classi 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 Atazanavir solubility decreases as pH increases; reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered 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 Not recommended in combination with products containing the individual components (atazanavir and cobicistat) or with ritonavir Contraindicated (60) alfuzosin alprazolam carbamazepine astemizole cobimetinib conivaptan dihydroergotamine dihydroergotamine intranasal dronedarone elbasvir/grazoprevir eletriptan eliglustat elvitegravir elvitegravir/cobicistat/emtricitabine/tenofovir DF elvitegravir/cobicistat/emtricitabine/tenofovir DF enzalutamide eplerenone ergoloid mesylates ergonovine ergotamine finerenone finerenone flibanserin gepirone indinavir isavuconazonium sulfate irinotecan irinotecan liposomal isavuconazonium sulfate ivabradine lomitapide lonafarnib lonafarnib lovastatin lurasidone mavacamten mavacamten methylergonovine midazolam naloxegol naloxegol pacritinib phenobarbital pimozide phenytoin pimozide pitavastatin ranolazine regorafenib rifampin ritonavir saquinavir sildenafil simvastatin St John's Wort tipranavir triazolam ubrogepant venetoclax voclosporin

>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)