Cobicistat

Clinical monitoring is recommended for coadministration with beta-blockers that are metabolized by CYP2D6.

Sildenafil at a single dose not exceeding 25 mg in 48 hours, tadalafil at a single dose not exceeding 10 mg in 72 hours, or vardenafil at a single dose not exceeding 2.5 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated adverse events.

When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.

H₂-receptor antagonists e.g., famotidine.

Cobicistat coadministered with atazanavir: Administer atazanavir/cobicistat either at the same time or a minimum of 10 hours after administering H₂-receptor antagonists. The dose of the H₂-receptor antagonist should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naïve patients or 20 mg twice daily in treatment-experienced patients.

Cobicistat coadministered with atazanavir and TDF: Treatment-experienced patients: The recommended once daily dosage regimen is cobicistat 150 mg coadministered with atazanavir 400 mg with concomitant use of H₂-receptor antagonists and tenofovir.

Proton-pump inhibitors (PPIs) e.g., omeprazole.

In treatment-naïve patients, administer cobicistat with atazanavir a minimum of 12 hours after administering PPIs. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily.

In treatment-experienced patients, coadministration with PPIs, with or without tenofovir, is not recommended.

Clinical monitoring is recommended upon coadministration with antiarrhythmics e.g., amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine.

Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A.

Corticosteroids (all routes, excluding cutaneous): e.g., betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, triamcinolone.

Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir or darunavir. Consider alternative corticosteroids.

Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.

A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed upon coadministration.

Cobicistat coadministered with atazanavir or darunavir: due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with cobicistat depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information.

Cobicistat coadministered with atazanavir

In treatment-naïve patients

Atazanavir 400 mg with cobicistat 150 mg should be coadministered once daily as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.

In treatment-experienced patients

Coadministration of atazanavir and cobicistat with efavirenz in treatment-experienced patients is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir.

Coadministration of atazanavir and cobicistat with atorvastatin is not recommended.

For HMG-CoA reductase inhibitors that are not contraindicated with cobicistat coadministered with atazanavir or darunavir, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with atorvastatin or rosuvastatin are as follows.

Cobicistat coadministered with atazanavir:

• Rosuvastatin dosage should not exceed 10 mg

Cobicistat coadministered with darunavir:

• Atorvastatin dosage should not exceed 20 mg
• Rosuvastatin dosage should not exceed 20 mg

Cobicistat coadministered with atazanavir: due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as cobicistat coadministered with atazanavir depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information.

Initiation of bosentan in patients taking cobicistat coadministered with atazanavir or darunavir: In patients who have been receiving cobicistat coadministered with atazanavir or darunavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Initiation of cobicistat coadministered with atazanavir or darunavir in patients taking bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of cobicistat coadministered with atazanavir or darunavir. After at least 10 days following the initiation of cobicistat combined with atazanavir or darunavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Switching from ritonavir to cobicistat coadministered with atazanavir or darunavir: Maintain bosentan dose.

Initiation of buprenorphine, buprenorphine/naloxone, or methadone in patients taking cobicistat coadministered with atazanavir or darunavir: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone, or methadone to the desired effect; use the lowest feasible initial or maintenance dose.

Initiation of cobicistat coadministered with atazanavir or darunavir in patients taking buprenorphine, buprenorphine/naloxone, or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone, or methadone may be needed. Monitor clinical signs and symptoms.

These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended if coadministered.

Consider alternative antibiotics with concomitant use of cobicistat coadministered with atazanavir or darunavir.

Clinical monitoring of anticonvulsants is recommended.

A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with cobicistat coadministered with atazanavir or darunavir. Consult the dasatinib and nilotinib prescribing information for dosing instructions.

For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects.

When coadministering with digoxin, titrate the digoxin dose and monitor digoxin concentrations.

Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response.

Careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended with coadministration.

Maraviroc is a substrate of CYP3A. When coadministering with maraviroc, patients should receive maraviroc 150 mg twice daily.

Coadministration with parenteral midazolam may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosing reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

With other sedatives/hypnotics that are CYP3A metabolized, dose reduction may be necessary and clinical monitoring is recommended.

Initiation of cobicistat coadministered with atazanavir or darunavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking cobicistat coadministered with atazanavir or darunavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

The recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin associated adverse reactions including neutropenia and uveitis.

The following dose adjustments are recommended for tadalafil concomitant use:

Initiation of tadalafil in patients taking cobicistat coadministered with atazanavir or darunavir:

In patients taking cobicistat coadministered with atazanavir or darunavir for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.

Initiation of cobicistat coadministered with atazanavir or darunavir in patients taking tadalafil:

Avoid use of tadalafil during the initiation of cobicistat coadministered with atazanavir or darunavir.

Stop tadalafil at least 24 hours prior to starting cobicistat coadministered with atazanavir or darunavir. After at least one week following initiation of cobicistat coadministered with atazanavir or darunavir, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.

Patients switching from ritonavir to cobicistat coadministered with atazanavir or darunavir:

Maintain tadalafil dose.

A dose decrease may be needed for tramadol with concomitant use.

Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole.

Monitor the international normalized ratio (INR) upon coadministration of cobicistat with warfarin.

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 significant 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) (see Data). 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 (see Data). 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.

Data

Human Data

Cobicistat coadministered with darunavir as a fixed dose combination, 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 over 400 exposures in the first trimester and over 80 exposures in the second/third trimester. The prevalence of birth defects in live births was 3.9% (95% CI: 2.2% to 6.3%) and 1.2% (95% CI: 0.0% to 6.5%) following first trimester and second/third trimester exposure, respectively, to cobicistat-containing regimens. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.

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 were 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.

Carcinogenesis

In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.

Mutagenesis

Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma, or rat micronucleus assays.

Impairment of Fertility

Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose.

Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose.

• New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions from Clinical Trials Experience in Adults

The safety of cobicistat is based on Week 144 data from a Phase 3 trial, Trial 114, in which 692 HIV-1 infected, antiretroviral treatment-naïve subjects received:

• Cobicistat coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=344) or
• ritonavir coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=348).

The most common adverse reactions (Grades 2−4) and reported in >5% of subjects in the cobicistat group were jaundice (6%) and rash (5%). The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the cobicistat and ritonavir groups. Table 1 displays the frequency of adverse reactions (Grades 2−4) occurring in at least 2% of subjects in the cobicistat group in Trial 114.

Table 1. Selected Adverse Reactions* (Grades 2–4) Reported in ≥2% of HIV-1 Infected Treatment-Naïve Adults in the Cobicistat Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis):

^* Frequencies of adverse reactions are based on Grades 2–4 adverse events attributed to study drugs.
^† Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria.

Less Common Adverse Reactions

Selected adverse reactions of at least moderate severity (≥Grade 2) occurring in less than 2% of subjects receiving cobicistat coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with cobicistat and with greater frequency compared with ritonavir.

Gastrointestinal Disorders: vomiting, upper abdominal pain

General Disorders and Administration Site Conditions: fatigue

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Psychiatric Disorders: depression, abnormal dreams, insomnia

Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis

Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs.

Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3−4) occurring in at least 2% of subjects in the cobicistat group in Trial 114 is presented in Table 2.

Table 2. Laboratory Abnormalities (Grades 3–4) in ≥2% of HIV-1 Infected Treatment-Naïve Adults in the Cobicistat Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis):

^* For subjects with serum amylase >1.5 × upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3–4) occurring in the cobicistat (N=46) and ritonavir (N=35) groups was 7% and 3%, respectively.

Increase in Serum Creatinine

Cobicistat causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. In Trial 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with cobicistat, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –15.1 ± 16.5 mL/min in the cobicistat group and –8.0 ± 16.8 mL/min in the ritonavir group.

Serum Lipids

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 3. In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown.

Table 3. Lipid Values, Mean Change from Baseline, Reported in HIV-1 Infected Treatment-Naïve Adults Receiving Cobicistat Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Trial 114 (Week 144 Analysis):

^* The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. Analysis excludes subjects receiving an HMG-CoA reductase inhibitor drug.

Adverse Reactions from Clinical Trials Experience in Pediatric Subjects

The safety of cobicistat was evaluated in HIV-1 infected virologically suppressed pediatric subjects between the ages of 12 to less than 18 years through Week 48 in an open-label clinical trial (Trial 128) of cobicistat coadministered with atazanavir (N=14) or darunavir (N=7) plus two nucleoside reverse transcriptase inhibitors. In this trial, the safety profile of cobicistat was similar to that in adults.