Dosing and uses of Evotaz (atazanavir/cobicistat)
Adult dosage forms and 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: Use not recommended
Renal impairment
- CrCl <70 mL/min: Coadministered with tenofovir disoproxil fumarate (DF) is not recommended
- ESRD managed with hemodialysis: Use 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
- 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
Pediatric dosage forms and strengths
<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
Evotaz (atazanavir/cobicistat) adverse (side) 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%)
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)
- 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
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
Pregnancy and lactation
Human Data
Pregnancy category: B
Do not give atazanavir/cobicistat to treatment-experienced pregnant patients taking an H2-receptor antagonist and/or tenofovir DF during the second or third trimester
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.
Pharmacology of Evotaz (atazanavir/cobicistat)
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
Administration
Instructions
Take once daily with food (improves absorption)
