cobicistat (Rx)

Note: Adverse effects listed below are for cobicistat coadministered with atazanavir

>10%

Total bilirubin, >2.5 x ULN (65%)

Ocular icterus, all grades (15%)

Jaundice, all grades (13%)

Nausea, all grades (12%)

1-10%

Creatine kinase, >10 x ULN (5%)

Jaundice, grades 2-4 (5%)

Rash, grades 2-4 (5%)

Serum amylase, >2 x ULN (4%)

ALT or AST, >5 x ULN (3%)

Glycosuria, >1000 mg/dL (3%)

Urine RBC, >75 RBC/HPF (3%)

Ocular icterus, grades 2-4 (3%)

GGT, >5 x ULN (2%)

Nausea, grades 2-4 (2%)

<2%

Gastrointestinal disorders: Diarrhea, vomiting, upper abdominal pain

General disorders and administration site conditions: Fatigue

Musculoskeletal and connective-tissue disorders: Rhabdomyolysis

Nervous system disorders: Headache

Psychiatric disorders: Depression, abnormal dreams, insomnia

Renal and urinary disorders: Nephropathy, Fanconi syndrome acquired

Frequency Not Defined

Increased triglycerides, +15 from baseline

Increased LDL-C, +5 from baseline

Increased total cholesterol, +4 from baseline

Increased HDL-C, +3 from baseline

Contraindications

Coadministration of with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events

• Alfuzosin
• Carbamazepine, phenobarbital, phenytoin
• Rifampin
• Lurasidone, pimozide
• Dihydroergotamine, ergotamine, methylergonovine
• Cisapride
• St. John’s wort (Hypericum perforatum)
• Lomitapide, lovastatin, simvastatin
• Sildenafil when administered for pulmonary arterial hypertension
• Triazolam, orally administered midazolam

Cautions

Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; serum creatinine >0.4 mg/dL from baseline should be closely monitored for renal safety; assess CrCl before administering

New-onset or worsening renal impairment reported when used with antiretroviral regimens containing tenofovir; do not use with tenofovir if CrCl <70 mL/min

Assess urine glucose and urine protein at baseline and monitor ClCr, urine glucose, and urine protein when using with tenofovir; monitor serum phosphorus in patients with or at risk for renal impairment

CYP inducers may lower systemic exposure of cobicistat and atazanavir or darunavir, resulting in loss of virologic response

Cobicistat is an inhibitor of CYP3A, CYP2D6, p-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3; plasma concentration of drugs that are substrates of the aforementioned isoenzymes or transporters may be increased if coadministered with cobicistat

Antiretrovirals that are not recommended

• The following are NOT recommended in combination with cobicistat because dosing recommendations for the combinations have not been established
• Coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance
• More than 1 antiretroviral that requires pharmacokinetic enhancement (ie, 2 protease inhibitors or a protease inhibitor in combination with elvitegravir)
• Darunavir in combination with efavirenz, nevirapine, or etravirine
• Atazanavir in combination with etravirine
• Atazanavir in combination with efavirenz in treatment-experienced patients
• Darunavir 600 mg BID
• Other HIV-1 protease inhibitors, including fosamprenavir, saquinavir, or tipranavir
• Stribild fixed-dose combination tablets (elvitegravir, cobicistat, emtricitabine, tenofovir) are not recommended because cobicistat is a component of Stribild
• Cobicistat in combination with lopinavir/ritonavir or regimens containing ritonavir are not recommended, owing to similar effects of cobicistat and ritonavir on CYP3A

Pregnancy

An ART pregnancy registry has been established (1-800-258-4263); prospective pregnancy data from the Antiviral Pregnancy Registry (APR) not sufficient to adequately assess risk of birth defects or miscarriage

Not recommended for use during pregnancy because of substantially lower exposures of cobicistat during second and third trimesters

Avoid use in pregnant individuals; an alternative regimen is recommended for individuals who become pregnant during therapy

Lactation

There is no information regarding presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production

The Centers for Disease Control and Prevention do not recommend HIV-infected mothers breastfeed their infants due to potential risk for postnatal transmission of HIV

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.

Mechanism of Action

CYP3A4 inhibitor; mechanism-based pharmaco-enhancer, first product to be developed and submitted solely as pharmacokinetic booster for elvitegravir; enhances the systemic exposure of ART CYP3A substrates (ie, atazanavir, darunavir), where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism

Absorption

Peak Plasma Time: 3.5 hr

Peak Plasma Concentration: 0.99 mcg/mL

Trough Plasma Concentration: 0.03 mcg/mL

AUC: 7.6 mcg•hr/mL

Distribution

Protein bound: 97-98%

Metabolism

Metabolized by CYP3A4 and CYP2D6 (minor)

Inhibits CYP3A, CYP2D6, p-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3

Elimination

Half-life: 3-4 hr

Excretion: 86.2% feces; 8.2% urine

Oral Administration

Must be coadministered with atazanavir or darunavir at the same time, with food, and in combination with other HIV-1 antiretroviral agents

Coadministration with acid-modifying drugs

• Atazanavir systemic exposure is decreased if administered comcomitantly with acid modifying drugs
• Antacids containing aluminum or magnesium hydroxide: Administer antacids at least 2 hr before or after cobicistat with atazanavir
• H2-receptor antagonists: Administer either at the same time or take cobicistat with atazanavir a minimum of 10 hr after administering H2-receptor antagonists
• Proton pump inhibitors: Take cobicistat with atazanavir a minimum of 12 hr after administering proton pump inhibitors

Storage

Tablets: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F)