atazanavir/cobicistat (Rx)

Brand and Other Names:Evotaz
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

atazanavir/cobicistat

tablet

  • 300mg/150mg

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

Dosage Modifications

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

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

Dosage Considerations

Limitations of use: Use in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions

Testing before initiating

  • Renal testing
    • Creatinine clearance (CrCl): Before initiating, assess estimated CrCl because cobicistat decreases eCrCl, owing to inhibition of tubular secretion of creatinine, without affecting actual renal glomerular function
    • Coadministration with tenofovir DF: Assess eCrCl, urine glucose, and urine protein at baseline and routinely monitor during treatment
  • Hepatic testing
    • Conduct hepatic laboratory testing prior to initiating therapy and during treatment in patients with underlying hepatitis B or C viral infections

<18 years: Safety and efficacy not established

Atazanavir, and therefore atazanavir/cobicistat, is not recommended for use in patients aged <3 months due to the risk of kernicterus

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Interactions

Interaction Checker

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            Adverse Effects

            >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%)

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            Warnings

            Contraindications

            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

            Cautions

            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

            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
            • Do not use with tenofovir DF if CrCl <70 mL/min
            • Document urine glucose and urine protein at baseline and perform routine monitoring of eCrCl, urine glucose, and urine protein during treatment
            • Measure serum phosphorus in patients at risk for renal impairment
            • Coadministration of atazanavir/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
            • 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

            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
            • Atazanavir/cobicistat is not recommended in combination with products containing the individual components (atazanavir and cobicistat) or with ritonavir
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            Pregnancy & Lactation

            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

            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.

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            Pharmacology

            Mechanism of Action

            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)

            Absorption

            Peak plasma time: 3.5 hr (atazanavir); 3 hr (cobicistat)

            Peak plasma concentration, atazanavir: 3.91 mcg/mL

            AUC, atazanavir: 46.13 mcg•hr/mL

            Distribution

            Protein bound: 86% (atazanavir); 97-98% (cobicistat)

            Metabolism

            Atazanavir

            • Extensively metabolized by CYP3A
            • Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation

            Cobicistat

            • Metabolized by CYP3A and to a minor extent by CYP2D6 enzymes
            • Does not undergo glucuronidation

            Elimination

            Half-life: 7.5 hr (atazanavir); 3-4 hr (cobicistat)

            Elimination, cobicistat: 86.2% feces; 8.2% urine

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            Administration

            Oral Administration

            Take once daily with food (improves absorption)

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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