EVOTAZ
Clinical safety rating: caution
Comprehensive clinical and safety monograph for EVOTAZ (EVOTAZ).
EVOTAZ is a fixed-dose combination of atazanavir, an HIV-1 protease inhibitor, and cobicistat, a CYP3A inhibitor. Atazanavir inhibits HIV-1 protease, preventing cleavage of viral polyproteins and resulting in immature, non-infectious virions. Cobicistat increases systemic exposure of atazanavir by inhibiting CYP3A-mediated metabolism.
| Metabolism | Atazanavir is primarily metabolized by CYP3A4; cobicistat is metabolized by CYP3A4 and to a minor extent by CYP2D6. |
| Excretion | Cobicistat: primarily hepatic metabolism (CYP3A4) and biliary/fecal excretion; <7% excreted unchanged renally. Atazanavir: primarily biliary/fecal excretion as unchanged drug and metabolites (79–88%); renal excretion accounts for <7%. |
| Half-life | Cobicistat: terminal half-life approximately 3–4 hours; atazanavir: terminal half-life approximately 7 hours (range 5–12 hours) at steady state when boosted with cobicistat. The short half-life of cobicistat necessitates once-daily dosing with atazanavir to maintain therapeutic concentrations. |
| Protein binding | Atazanavir: 86% bound to albumin and alpha-1 acid glycoprotein. Cobicistat: 97–98% bound to plasma proteins (albumin and alpha-1 acid glycoprotein). |
| Volume of Distribution | Atazanavir: apparent Vd of 180 L (approximately 2.6 L/kg for a 70 kg adult), indicating extensive tissue distribution. Cobicistat: apparent Vd of 230 L (approximately 3.3 L/kg), also indicating extensive distribution. |
| Bioavailability | Atazanavir: absolute bioavailability not determined; absorption is enhanced when taken with food (relative bioavailability increased ~70%). Cobicistat: absolute bioavailability not determined; absorption is reduced by 28% when taken with a high-fat meal relative to fasting. |
| Onset of Action | Oral administration: antiretroviral effect begins within 1–2 hours after dosing, corresponding to time to peak plasma concentration (Tmax) for atazanavir (approximately 2.5 hours) and cobicistat (approximately 3 hours). |
| Duration of Action | Atazanavir boosted with cobicistat maintains plasma concentrations above the protein-adjusted 95% inhibitory concentration (IC95) for HIV-1 over the 24-hour dosing interval with once-daily dosing. The pharmacodynamic effect persists throughout the dosing interval. |
1 tablet (300 mg atazanavir and 150 mg cobicistat) orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended for patients with CrCl <30 mL/min or those on hemodialysis due to insufficient data. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh Class C). Not recommended for moderate hepatic impairment (Child-Pugh Class B). Use with caution in mild hepatic impairment (Child-Pugh Class A) as no dose adjustment is available; monitor closely. |
| Pediatric use | Not recommended for pediatric patients weighing <40 kg. For those ≥40 kg, dose as per adult: 1 tablet (300 mg atazanavir/150 mg cobicistat) orally once daily with food. |
| Geriatric use | No specific dose adjustment recommended; monitor renal function and adverse effects due to potential age-related decreases in renal function and concomitant medications. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for EVOTAZ (EVOTAZ).
| Breastfeeding | Atazanavir: Present in human milk at low levels (M/P ratio 0.13); avoid breastfeeding due to potential infant hyperbilirubinemia and HIV transmission. Cobicistat: No data in human milk; present in animal milk. Insufficient safety data; contraindicated in breastfeeding. |
| Teratogenic Risk | Cobicistat: No adequate human studies; animal studies show no fetal harm at clinically relevant exposures. Atazanavir: Human studies show no increased risk of major birth defects; data from Antiretroviral Pregnancy Registry (APR) shows prevalence of defects 2.3% vs background 2.7%. Placental transfer low; risk of hyperbilirubinemia in neonates. Avoid in first trimester if alternative available due to theoretical risk of kernicterus; monitor bilirubin in third trimester. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Coadministration with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious events (e.g., alfuzosin, amiodarone, quinidine, ergot derivatives, pimozide, triazolam, midazolam, lovastatin, simvastatin, sildenafil for pulmonary arterial hypertension, St. John's wort).","Coadministration with drugs that strongly induce CYP3A (e.g., rifampin, carbamazepine, phenobarbital, phenytoin).","Patients with severe hepatic impairment."]
| Precautions | ["Hepatotoxicity: Elevations in bilirubin (primarily indirect) due to inhibition of UGT1A1; monitor hepatic function.","Nephrotoxicity: Acute renal failure, interstitial nephritis, and renal stones reported; avoid with tenofovir disoproxil fumarate if eGFR < 70 mL/min.","Cardiac effects: PR interval prolongation; ECG monitoring recommended if used with other drugs that prolong PR interval.","Cholelithiasis: Gallbladder disease reported.","New onset or worsening diabetes mellitus/hyperglycemia.","Immune reconstitution syndrome.","Fat redistribution/accumulation."] |
Loading safety data…
| Fetal Monitoring | Maternal: Liver function tests, bilirubin, creatinine, glucose tolerance, LFTs. Fetal: Third trimester ultrasound for growth; neonatal bilirubin monitoring for first 48-72 hours. |
| Fertility Effects | No adverse effects on fertility reported in men or women. Atazanavir: no significant impact on spermatogenesis or ovulation. EVOTAZ may be used during fertility treatments. |