Class: Other Miscellaneous Therapeutic Agents
Chemical Name: 1,3-thiazol-5-ylmethyl N-[(2R,5R)-5-[[(2S)-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]-4-morpholin-4-ylbutanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate
Molecular Formula: C40H53N7O5S2
CAS Number: 1004316-88-4
Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A).
Uses for Cobicistat
Cobicistat has the following uses:
Cobicistat, a CYP3A inhibitor, is indicated for coadministration with atazanavir or darunavir (once daily dosing regimen) to increase systemic exposure of these antiretrovirals when used with additional antiretroviral agents in the treatment of HIV-1 infection.
Cobicistat has the following limitations of use:
Cobicistat is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data. Coadministration of cobicistat with darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir is not recommended.
Because of complex or unknown mechanisms of drug interactions, ritonavir drug interactions cannot be extrapolated to certain cobicistat interactions. Coadministration of cobicistat or ritonavir with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications.
Cobicistat Dosage and Administration
Cobicistat is available in the following dosage form(s) and strength(s):
Tablets: 150 mg.
It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:
Cobicistat must be coadministered with atazanavir or darunavir at the same time, with food, and with additional HIV-1 antiretroviral agents.
Coadministered Agent Dosage
150 mg orally once daily
Atazanavir: 300 mg orally once daily
Treatment-naive or treatment-experienced
150 mg orally once daily
Darunavir: 800 mg orally once daily
Treatment-naive or treatment-experienced with no darunavir-associated resistance substitutions
Prior to starting cobicistat, assess estimated creatinine clearance.
If used in regimens that contain tenofovir disoproxil fumarate (tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein at baseline. Coadministration with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with cobicistat.
Cautions for Cobicistat
Coadministration with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect.
Effects on Serum Creatinine
Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating cobicistat, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.
Prior to initiating therapy with cobicistat, assess estimated creatinine clearance. Dosage recommendations are not available for drugs that require dosage adjustments in cobicistat-treated patients with renal impairment. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.
New Onset or Worsening Renal Impairment when used with Tenofovir Disoproxil Fumarate
Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used in an antiretroviral regimen that contained tenofovir DF.
Coadministration of cobicistat and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with cobicistat.
Document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when cobicistat is used with tenofovir DF. Measure serum phosphorus in patients with or at risk for renal impairment when used with tenofovir DF.
Coadministration of cobicistat with tenofovir DF and with concomitant or recent use of a nephrotoxic agent is not recommended.
In a clinical trial of cobicistat over 144 weeks (N=692), 10 (2.9%) subjects treated with cobicistat coadministered with atazanavir and the fixed combination of emtricitabine and tenofovir DF (Truvada) and 11 (3.2%) subjects treated with ritonavir coadministered with atazanavir and Truvada discontinued study drug due to a renal adverse event. Seven of the 10 subjects (2% overall) in the cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation compared to 7 of 11 subjects (2% overall) in the ritonavir group. One subject in the cobicistat group had renal impairment at baseline (i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of cobicistat coadministered with atazanavir and Truvada. Renal replacement therapy was not required in any subject.
Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
Initiation of cobicistat, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving cobicistat may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of cobicistat with atazanavir or darunavir.
- Increased concentrations may lead to:
Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from higher exposures of concomitant medications.
Clinically significant adverse reactions from higher exposures of cobicistat and atazanavir or darunavir.
- Decreased antiretroviral concentrations may lead to:
Loss of therapeutic effect of cobicistat coadministered with atazanavir or darunavir and possible development of resistance.
Consider the potential for drug interactions prior to and during therapy with cobicistat coadministered with atazanavir or darunavir; review concomitant medications during cobicistat with atazanavir or darunavir therapy; and monitor for the adverse reactions associated with concomitant medications.
Cobicistat or ritonavir coadministered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain cobicistat interactions.
Antiretrovirals that Are Not Recommended in Combination with Cobicistat
The following antiretrovirals should not be coadministered with cobicistat because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance:
More than one antiretroviral that requires pharmacokinetic enhancement (i.e., two protease inhibitors or a protease inhibitor with elvitegravir).
Darunavir with efavirenz, nevirapine, or etravirine.
Atazanavir with etravirine.
Atazanavir with efavirenz in treatment-experienced patients.
Darunavir 600 mg twice daily.
Other HIV-1 protease inhibitors including fosamprenavir, saquinavir, or tipranavir.
Cobicistat should not be administered with fixed-dose combination tablets that contain cobicistat.
Coadministration of cobicistat with lopinavir/ritonavir or with regimens containing ritonavir is not recommended due to similar effects of cobicistat and ritonavir on CYP3A.
Pregnancy Exposure Registry: There is a pregnancy exposure registry (APR) that monitors fetal outcomes in women exposed to cobicistat during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry 1-800-258-4263.
Risk Summary: Cobicistat coadministered with darunavir or atazanavir is not recommended during pregnancy. In a clinical trial of individuals taking cobicistat coadministered with darunavir, exposures of cobicistat and darunavir were substantially lower during the second and third trimesters of pregnancy.
Cobicistat use during pregnancy has been evaluated in a limited number of individuals as reported by the APR, and available data show no difference in the rate of overall birth defects for cobicistat compared with the background rate for major defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15–20%.
In animal reproduction studies in rats and rabbits, no evidence of fetal harm was observed with oral administration of cobicistat during organogenesis at doses that produced exposures up to 1.4 and 3.3 times, respectively, the maximal recommended human dose (MRHD) of 150 mg. Because cobicistat is coadministered with atazanavir or darunavir and other antiretroviral drugs, also refer to the prescribing information of each drug for information about pregnancy.
Human Data: Cobicistat coadministered with darunavir as a fixed dose combination (darunavir/cobicistat), in combination with a background regimen, was evaluated in a clinical trial of 7 pregnant individuals taking darunavir/cobicistat prior to enrollment and who were willing to remain on darunavir/cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals completed the trial.
Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum.
One out of 6 individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five individuals had sustained virologic response (HIV-1 RNA <50 copies/mL) throughout the study period. There are no clinical data on the virologic response when darunavir/cobicistat is initiated during pregnancy.
There were no new clinically relevant safety findings compared with the known safety profile of darunavir/cobicistat in HIV-1-infected adults.
The APR has received prospective reports of live births following exposure to cobicistat-containing regimens during pregnancy, including 204 exposures in the first trimester and 58 exposures in the second/third trimester. Birth defects occurred in 5 of 204 (2.5%, 95% CI: 0.8% to 5.6%) live births with first trimester exposure of cobicistat-containing regimens. Insufficient numbers of pregnancies with earliest exposure to cobicistat in the second/third trimesters have been reported to the APR to estimate the rate of birth defects in this population. Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between cobicistat and overall birth defects observed in the APR. Prospective reports from the APR of overall major birth defects in pregnancies exposed to cobicistat are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.
Animal Data: Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, and 125 mg/kg/day on gestation day 6 to 17. Maternal toxicity (adverse clinical signs, decreased body weight and food consumption) was noted at 125 mg/kg/day and was associated with increases in postimplantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females was 1.4-fold higher than the exposures at the MRHD.
In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3-fold higher than exposures at the MRHD.
In a pre- and postnatal developmental study, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation day 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were slightly lower than (0.9-fold) the MRHD.
There is no information regarding the 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 recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
Females And Males Of Reproductive Potential
Cobicistat interacts with certain oral contraceptives.
Safety and effectiveness of cobicistat in pediatric patients younger than 18 years of age have not been established.
Clinical trials of cobicistat did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.
No dosage adjustment of cobicistat is required in patients with renal impairment, including those with severe renal impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. Cobicistat is coadministered with atazanavir or darunavir; therefore, refer to the prescribing information for atazanavir or darunavir for information regarding dosing recommendations of these drugs in patients with renal impairment.
Cobicistat has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosing adjustment for renal impairment when used with cobicistat.
No dosing adjustment of cobicistat is necessary for patients with mild-to-moderate hepatic impairment. No data are available in patients with severe hepatic impairment. Cobicistat is coadministered with atazanavir or darunavir and additional antiretroviral drugs; therefore, refer to the prescribing information of these other drugs for information regarding dosing recommendations in patients with hepatic impairment.
Common Adverse Effects
The most common adverse drug reactions observed with cobicistat coadministered with atazanavir (incidence greater than 5%, Grades 2–4) are jaundice and rash.
It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:
Cobicistat, coadministered with atazanavir or darunavir, can alter the concentrations of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of cobicistat, atazanavir, and darunavir. Consult the full prescribing information prior to and during treatment for potential drug interactions.
Actions and Spectrum
Mechanism of Action
Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates such as atazanavir and darunavir.
Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity of selected HIV-1 antiretroviral drugs in cell cultures was not antagonized by cobicistat.
In an analysis of treatment-failure subjects who received cobicistat coadministered with atazanavir and the fixed combination of emtricitabine and tenofovir DF (Truvada) in Study 114 through Week 144, evaluable genotypic data from paired baseline and treatment-failure isolates from subjects who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in the cobicistat group [6%, 21/344]. Among the 21 subjects, 3 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures [5%, 19/348]. Among the 19 patients, 1 developed the emtricitabine-associated resistance substitution M184V with no tenofovir or protease inhibitor associated resistance substitutions.
Advice to Patients
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients that cobicistat coadministered with atazanavir or darunavir may interact with many drugs with potential serious implications and that some drugs are contraindicated with cobicistat coadministered with atazanavir or darunavir. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication, including acid-modifying medications or herbal products, including St. John's wort.
New Onset or Worsening Renal Impairment
Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat is used in combination with tenofovir DF.
Advise patients that cobicistat is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking cobicistat.
Inform patients that there is a pregnancy exposure registry that monitors fetal outcomes in women exposed to cobicistat during pregnancy.
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.
Inform patients that cobicistat must be taken at the same time as atazanavir or darunavir and with food once daily as prescribed. It is important to take cobicistat and atazanavir or darunavir together on a regular dosing schedule and to avoid missing doses. Counsel patients about the risks of developing resistance to their HIV-1 medications.
AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Tablet, Film Coated
Gilead Sciences Inc.
AHFS Drug Information. © Copyright 2021, Selected Revisions February 11, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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