cobicistat

General

Pronunciation:
koe-bik-i-stat


Trade Name(s)

  • Tybost

Ther. Class.
pharmacoenhancers
antiretrovirals

Pharm. Class.
enzyme inhibitors

Indications

To increase blood levels of atazanavir and darunavir (in combination with other antiretrovirals) in the treatment of HIV-1 infection.

Action

By strongly inhibiting CYP3A enzymes, enhances systemic exposure to atazanavir and darunavir.

Therapeutic Effect(s):

Slowed progression of HIV infection and decreased occurrence of sequelae.

Pharmacokinetics

Absorption: Absorption follows oral administration.

Distribution: Unknown.

Protein Binding: 97–98%.

Metabolism and Excretion: Metabolized by CYP3A and to a small extent by CYP2D6; 86.2 eliminated in feces, 8.2% in urine.

Half-life: 3–4 hr.

TIME/ACTION PROFILE

ROUTEONSETPEAKDURATION
POunknown3 hr24 hr

Contraindication/Precautions

Contraindicated in:

  • Concurrent use of other drugs for which ↑ or ↓ blood levels would be associated with serious/life-threatening toxicity/adverse reactions or loss of effectiveness including alfuzosin, dronedarone, rifampin, irinotecan, dihydroergotamine, drospirenone/ethinyl estradiol (when used with atazanavir only), ergotamine, methylergonovine, St. John's wort, lovastatin, simvastatin, pimozide, nevirapine, sildenafil (when used for pulmonary hypertension), indinavir, ranolazine, colchicine, lurasidone, pimozide, triazolam, midazolam (oral), carbamazepine, phenobarbital, and phenytoin
  • Concurrent use with other antiretrovirals whose blood levels/effectiveness may be ↓ or risk of resistance ↑
  • Lactation: HIV-infected women should not breastfeed due to risk of viral transmission.

Use Cautiously in:

  • Concurrent use of tenofovir (↑ risk of acute renal failure or Fanconi syndrome)
  • OB:  Use during pregnancy only if potential benefits justify fetal risks
  • Pedi:  Safety and effectiveness not established.

Adverse Reactions/Side Effects

Noted for combination use with atazanavir

EENT: ocular icterus

GI: jaundice, nausea

GU: acute renal failure (↑ with tenofovir), Fanconi syndrome (↑ with tenofovir)

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Due to the potential for interactions, regimens should be reviewed during any changes (starting or stopping medications or altering dose). Because cobicistat is used in conjunction with darunavir or atazanavir, those interactions are considered here.

Drug-Drug

  • Concurrent use with  alfuzosin  ↑ risk of potentially life threatening reactions and is contraindicated.
  • ↑ blood levels/risk of potentially dangerous adverse reactions with  dronedarone ; concurrent use contraindicated.
  • Rifampin, carbamazepine, phenobarbital, or  phenytoin may ↓ blood levels/antiretroviral effectiveness of atazanavir or darunavir; concurrent use in a regimen with cobicistat is contraindicated.
  • ↑ blood levels and risk of serious toxicity from  irinotecan  when used in a regimen containing atazanavir and cobicistat; concurrent use contraindicated (due to atazanavir ↓ metabolism of irinotecan).
  • ↑ risk of serious toxicity including peripheral vasospasm/ischemia from dihydroergotamine, ergotamine, and  methylergonovine ; concurrent use contraindicated.
  • ↑ risk of serious arrhythmias with  pimozide ; concurrent use contraindicated.
  • ↑ risk of myopathy/rhabdomyolysis with  lovastatin  and  simvastatin ; concurrent use contraindicated.
  • Concurrent use with  nevirapine  may ↓ levels/effectiveness of atazanavir and ↑ levels/risk of adverse reactions from nevirapine; concurrent use contraindicated.
  • ↑ risk of adverse reactions including visual disturbances, hypotension, priapism and syncope with  sildenafil ; contraindicated when used for pulmonary hypertension.
  • ↑ blood levels and risk of potentially life threatening reactions from  ranolazine ; concurrent use contraindicated.
  • ↑ blood levels and risk of potentially life threatening reactions from  colchicine ; concurrent use contraindicated in patients with renal and/or hepatic impairment.
  • ↑ blood levels and risk of potentially life threatening reactions from  lurasidone ; concurrent use contraindicated.
  • ↑ blood levels and risk of potentially life threatening reactions, including arrhythmias, from  pimozide ; concurrent use contraindicated in patients with renal and/or hepatic impairment.
  • Concurrent use with  indinavir  in a regimen containing atazanavir ↑ risk of hyperbilirubinemia and is contraindicated.
  • ↑ risk of prolonged sedation/respiratory depression with oral  midazolam  and  triazolam ; concurrent use contraindicated.
  • ↑ risk of hyperkalemia from  drosperinone/ethinyl estradiol  when used in a regimen containing atazanavir and cobicistat; concurrent use contraindicated.
  • Concurrent use of more than one antiretroviral that requires another agent to ↑ blood levels, such as  two protease inhibitors  or a  protease inhibitor in conjunction with elvitegravir  may ↓ antiretroviral effectiveness; concurrent use is not recommended.
  • Concurrent use of darunavir concurrently with efavirenz, nevirapine, or  etravirine  may ↓ antiretroviral effectiveness and ↑ risk of resistance; concurrent use is not recommended.
  • Concurrent use of atazanavir with  etravirine  or  efavirenz  (in treatment-experienced patients) may ↓ antiretroviral effectiveness and ↑ risk of resistance; concurrent use is not recommended.
  • Concurrent use of  darunavir  at a dose of 600 mg twice daily may ↓ antiretroviral effectiveness and ↑ risk of resistance; concurrent use at that dose is not recommended.
  • Concurrent use of other protease inhibitors, including fosamprenavir, saquinavir,  tipranavir  may ↓ antiretroviral effectiveness and ↑ risk of resistance; concurrent use is not recommended.
  • Should not be used concurrently with other  cobicistat-containing fixed-dose combinations  or  ritonavir-containing regimens or fixed-dose combinations due to cumulative effects on CYP3A.
  • ↑ levels of  maraviroc ; (↓ maraviroc dose to 150 mg twice daily.
  •  Antacids  ↓ absorption of atazanavir; separate doses by 2 hr.
  • ↑ level/risk of toxicity/adverse reactions with  antiarrhythmics  including amiodarone, digoxin, disopyramide, flecainide, mexiletine, propafenone, and  quindine ; careful monitoring and titration is recommended.
  • Clarithromycin, and  erythromycin  may ↑ levels of atazanavir, darunavir and cobicistat; consider alternative anti-infectives.
  • ↑ blood levels/risk of toxicity with dasatinib, nilotinib, vinblastine, and  vincristine ; careful monitoring for toxicity and dose adjustments recommended.
  • May ↑ bleeding risk with  rivaroxaban ; avoid concurrent use.
  • Effect on  warfarin  is not know; monitor INR.
  •  Oxcarbazepine  ↓ levels of cobicistat and atazanavir; consider alternative anticonvulsants or antiretroviral.
  • May ↑ levels of  clonazepam ; careful anticonvulsant monitoring recommended.
  • May ↑ levels/effects of  tricyclic antidepressants  and  trazodone ; careful dosing of antidepressants recommended (effect on  SSRIs  in unknown).
  • Concurrent use with itraconazole, ketoconazole, and  voriconazole  may result in ↑ levels of itraconazole and ketoconazole (effect on voriconazole is unknown) and ↑ levels of atazanavir, cobicistat and darunavir; voriconazole use not recommended.
  • ↑ levels/risk of adverse reactions with  colchicine ; concurrent use in patients with renal/hepatic impairment not recommended; for others, ↓ dose ( for gout flare– 0.6 mg followed by 0.3 mg one hr later, may repeat no sooner than 3 days for prophylaxis of gout flare– if dose was originally 0.6 mg twice daily, ↓ to 0.3 mg once daily, if original regimen was 0.6 mg once daily, ↓ to 0.3 mg every other day for treatment of familial Mediterranean fever– daily dose should not exceed 0.6 mg or 0.3 mg twice daily).
  • ↑ levels/effects/risk of adverse reaction including neutropenia and uveitis with  rifabutin ; ↓ rifabutin dose to 150 mg every other day.
  • ↑ levels/effects of metoprolol, carvedilol, timolol, or any other  beta-blockers metabolized by CYP2D6 ; clinical monitoring recommended.
  • ↑ levels/effects of amlodipine, diltiazem, felodipine, nifedipine, verapamil, or any other  calcium channel blocker metabolized by CYP3A ; careful monitoring recommended.
  • Concurrent use of corticosteroids that induce CYP3A, including budesonide, dexamethasone, methylprednisolone, prednisone, or inhaled betamethasone, ciclesonide, fluticasone, mometasone, and triamcinolone , may ↓ levels/effectiveness and ↑risk of resistance to atazanavir or darunavir (consider use of other corticosteroids, such as beclomethasone or prednisolone).
  • Concurrent use of  corticosteroids that are metabolized by CYP3A  including budesonide, dexamethasone, methylprednisolone, prednisone, or inhaled betamethasone, ciclesonide, fluticasone, mometasone, and  triamcinolone  may ↑ risk of Cushing's disease and adrenal suppression (consider use of other corticosteroids, such as beclomethasone or prednisolone).
  • Concurrent use with  bosentan  may result in ↑ levels/toxicity of bosentan and ↓ levels of atazanavir, darunavir and cobicistat; dose alteration is required ( initiating bosentan in patients already receiving cobicistat with atazanavir or darunavir for 10 days or more– bosentan 62.5 mg daily or every other day, depending on tolerance initiating cobicistat with atazanavir or darunavir in patient already receiving bosentan – discontinue bosentan for 10 days, resume bosentan at 62.5 mg daily or every other day, depending on tolerance.
  •  H2 -receptor antagonists  including  famotidine  may decrease levels/effectiveness and ↑ risk of resistance; administer simultaneously or ≥ 10 hr after H2 –receptor antagonist (dose of H2 –receptor antagonist should not exceed famotidine 40 mg [or equivalent] twice daily in treatment-naïve patients or famotidine 20 mg [or equivalent] twice daily in treatment-experienced patients; atazanavir dose should be ↑ to 400 mg daily).
  • ↑ levels/risk of toxicity from  immunosuppressants metabolized by CYP3A  including cyclosporine, everolimus, sirolimus, and  tacrolimus ; therapeutic monitoring recommended.
  • ↑ levels of  salmeterol  and may ↑risk of serious adverse cardiovascular events; concurrent use is not recommended.
  • May ↑ levels/risk of respiratory depression with opioids including buprenorphine, buprenorphine/naloxone, fentanyl, and  tramadol ; carefully monitor  opioid  affects when cobicistat with atazanavir or darunavir is initiated, dose adjustment of opioid may be necessary.
  • May ↑ levels/effects of  neuroleptics that are metabolized by CYP3A or CYP2D6  including perphenazine, risperidone, and  thioridazine ; may need to ↓ dose of neuroleptic.
  • May ↑ levels and risk of adverse cardiovascular, ophthalmic and genitourinary effects of  PDE-5 inhibitors  including avanafil, sildenafil, tadalafil, and  vardenafil  avanafil  use is not recommended,  sildenafil – use for pulmonary hypertension is contraindicated, when used for erectile dysfunction single dose should not exceed 25 mg/48 hr,  tadalafil – for pulmonary hypertension-initiating tadalafil in patients receiving cobicistat with atazanavir and darunavir for at least 7 days– 20 mg once daily initially, may be titrated to 40 mg once daily, initiating cobicistat with atazanavir or darunavir in patients receiving tadalafil– discontinue tadalafil 24 hr prior to initiating cobicistat with atazanavir or darunavir, after 7 days reinstitute tadalafil at 20 mg once daily, may be increased to 40 mg once daily, for erectile dysfunction single dose should not exceed 10 mg/72 hr vardenafil– for erectile dysfunction single dose should not exceed 2.5 mg/72 hr.
  •  Proton-pump inhibitors  including  omeprazole  ↓ levels/effectiveness and ↑ risk of resistance; in treatment–naïve patients, administer cobicistat with atazanavir or darunavir ≥12 hr after proton-pump inhibitors, dose of proton-pump inhibitor should not exceed omeprazole 20 mg daily or equivalent, in treatment-experienced patients concurrent use with proton-pump inhibitors is not recommended.
  • ↑ levels/ effects and risk of excess sedation/respiratory depression from some  sedative/hypnotics metabolized by CYP3A  including buspirone, diazepam, and  parenteral midazolam ; concurrent with  other sedative/hypnotics metabolized by CYP3A  should be undertaken with caution, dose ↓ may be necessary.
  • May ↑  quetiapine  levels; ↓ quetiapine dose to 1/6 of current dose.
  • ↑ risk of hyperkalemia from  drospirenone/ethinyl estradiol  when used in a regimen containing darunavir and cobicistat; closely monitor serum potassium concentrations.
  • ↑ risk of myopathy with  atorvastatin  and  rosuvastatin ; avoid concurrent use of atorvastatin with atazanavir and cobicistat; for atazanavir/cobicistat regimens, do not exceed rosuvastatin dose of 10 mg/day; for darunavir/cobicistat regimens, do not exceed atorvastatin or rosuvastatin dose of 20 mg/day.

Drug-Natural Products:

 St. John's wort  may ↓ blood levels and antiretroviral effectiveness of atazanavir or darunavir; concurrent use with a regimen including cobicistat is contraindicated.

Route/Dosage

With atazanavir

PO  (Adults)   treatment-naïve or experienced) 150 mg once daily with atazanavir 300 mg once daily.

With darunavir

PO  (Adults)   treatment-naïve, treatment-experienced with no darunavir resistance substitutions) 150 mg once daily with darunavir 800 mg once daily.

Availability

Tablets: 150 mg

In Combination with: atazanavir (Evotaz); darunavir (Prezcobix); emtricitabine, tenofovir, and elvitegravir (Stribild). See combination drugs.

Assessment

  • Assess patient for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.

Lab Test Considerations: Assess estimated creatinine clearance before starting therapy; cobicistat decreases estimated creatinine clearance by inhibiting tubular secretion of creatinine without affecting actual renal function.

  • Assess estimated creatinine clearance, urine glucose, and urine protein if cobicistat administered with tenofovir.
  • May cause ↑ total bilirubin, creatine kinase, serum amylase, ALT, AST, GGT, urine glucose and urine RBC.

Potential Diagnoses

Implementation

  • PO  Administer with atazanavir or darunavir once daily with food.
    • Administer antacids containing aluminum or magnesium at least 2 hr before or after cobicistat and atazanavir.
    • Administer H2  receptor antagonists at same time or take cobicistat with atazanavir 10 hr after taking H2  receptor antagonists.
    • Administer cobicistat and atazanavir at least 12 hr after administering proton pump inhibitors.

Patient/Family Teaching

  • Explain purpose of cobicistat to patient; cobicistat does not treat HIV and must be taken with antiretroviral medications. Instruct patient to take cobicistat as directed with food and with atazanavir or darunavir on a regular dosing schedule. Take missed doses as soon as remembered if within 12 hr; if more than 12 hr, skip dose and take next dose as scheduled; do not double doses. Do not stop taking cobicistat without consulting health care professional. Advise patient to read  Patient Information  prior to starting therapy and with each Rx refill in case of change. Also read  Patient Information  for atazanavir or darunavir.
  • Instruct patient that cobicistat should not be shared with others.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's Wort. Cobicistat interacts with many other drugs. Follow instructions for specific timing of or avoiding other medications.
  • Advise female patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding.
  • Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

Evaluation/Desired Outcomes

Increased blood levels of atazanavir or darunavir leading to slowed progression of HIV infection and decreased occurrence of sequelae.

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