atazanavir/cobicistat

General

Pronunciation:
a-ta-zan-a-veer/koe-bik-i-stat

Trade Name(s)

Evotaz

Ther. Class.

antiretrovirals

Pharm. Class.

protease inhibitors

pharmacoenhancers

Indications

HIV infection in treatment-experienced and treatment-naïve patients (in combination with other antiretrovirals).

Action

Atazanavir: Inhibits the action of HIV protease, preventing maturation of virions.
Cobicistat: ↑ blood levels of atazanavir.

Therapeutic Effect(s):

↑ CD4 cell counts and ↓ viral load with subsequent slowed progression of HIV and its sequelae.

Pharmacokinetics

Atazanavir

Absorption: Rapidly absorbed (↑ by food).

Distribution: Enters cerebrospinal fluid and semen.

Metabolism and Excretion: Primarily metabolized in the liver via the CYP3A isoenzyme; 80% excreted in feces, 13% excreted unchanged in urine.

Half-life: 7 hr.

Cobicistat

Absorption: Absorption follows oral administration.

Distribution: Unknown.

Protein Binding: 97–98%.

Metabolism and Excretion: Primarily metabolized in this liver via the CYP3A isoenzyme, and to a lesser extent by the CYP2D6 isoenzyme; 86.2% excreted in feces, 8.2% excreted in urine.

Half-life: 3–4 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
atazanavir (PO)	rapid	2.5 hr	24 hr
cobicistat (PO)	unknown	3 hr	24 hr

Contraindication/Precautions

Contraindicated in:

Previous hypersensitivity, including Stevens-Johnson syndrome, erythema multiforme or other serious skin reactions;
Concurrent use of alfuzosin, carbamazepine, colchicine, dihydroergotamine, dronedarone, drospirenone/ethinyl estradiol, elbasvir/grazoprevir, ergotamine, glecaprevir/pibrentasvir, irinotecan, lomitapide, lovastatin, lurasidone, methylergonovine, nevirapine, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, sildenafil (for pulmonary hypertension), simvastatin, St. John's wort and triazolam;
Renal impairment (CCr <70 mL/min) (when used concomitantly with tenofovir disoproxil fumarate);
End-stage renal disease managed by dialysis (treatment-experienced patients);
Hepatic impairment;
OB: Not recommended for use during pregnancy (↓ concentrations of atazanavir and cobicistat);
Lactation: Avoid breastfeeding in women with HIV.

Use Cautiously in:

History of pre-existing cardiac conduction disease (marked first-degree AV block, second-or third-degree AV block; ECG monitoring recommended);
Renal impairment (consider alterative medications);
Hepatitis B or C co-infection (↑ risk of further hepatic impairment);
Diabetes mellitus (↑ risk of new onset/ exacerbation);
Hemophilia (risk of spontaneous bleeding and need for additional factor VIII);
Pedi: Children <35 kg (safety and effectiveness not established); use of atazanavir in infants <3 mo may ↑ risk of kernicterus).

Adverse Reactions/Side Effects

CV: cardiac conduction abnormalities

Derm: DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), ERYTHEMA MULTIFORME, rash, STEVENS-JOHNSON SYNDROME

EENT: ocular icterus

Endo: Graves' disease, hyperglycemia

GI: autoimmune hepatitis, cholelithiasis, hepatotoxicity, hyperbilirubinemia, jaundice, nausea

GU: nephrolithiasis, new onset/worsening renal impairment

Metabolic: accumulation/redistribution of body fat

MS: polymyositis

Neuro: Guillain-Barré syndrome

Misc: immune reconstitution syndrome

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

Interactions

Drug-Drug

Carbamazepine, phenobarbital, phenytoin, rifampin and nevirapine ↓ blood levels and effectiveness; concurrent use contraindicated.
↑ levels and risk of serious toxicity with alfuzosin, dihydroergotamine, dronedarone, ergotamine, irinotecan, lomitapide, lovastatin, lurasidone, methylergonovine, pimozide, ranolazine, sildenafil (for pulmonary hypertension), simvastatin, and triazolam ; concurrent use contraindicated.
↑ levels and risk of serious toxicity with colchicine ; concurrent use contraindicated in patients with renal or hepatic impairment.
↑ risk of hepatotoxicity with elbasvir/grazoprevir and glecaprevir/pibrentasvir ; concurrent use contraindicated.
Concurrent use with drospirenone/ethinyl estradiol may ↑ drospirenone levels and risk of hyperkalemia; concurrent use contraindicated.
↑ risk of renal impairment with tenofovir disoproxil fumarate ; avoid concurrent use with nephrotoxic agents.
Concurrent use with other antiretrovirals that require inhibition of CYP3A for adequate exposure especially protease inhibitors (may ↓ antiretroviral effectiveness).
↑ levels and risk of toxicity from some antiarrhythmics (including amiodarone, digoxin, disopyramide, flecainide, mexiletine and propafenone, antineoplastics (including dasatinib, nilotinib, vinblastine and vincristine ), anticonvulsants metabolized by CYP3A (including clonazepam ); monitor drug effects carefully, titrate if necessary and consider alternatives.
↑ risk of sedation with sedative/hypnotics, including buspirone, diazepam, midazolam, zolpidem and others metabolized by CYP3A (careful monitoring with dose reduction recommended).
Absorption of atazanavir may be ↓ by proton-pump inhibitors (administer 12 hr after PPI, dose should not >20 mg omeprazole or equivalent/day, not recommended in treatment-experienced patients), antacids (separate dose by 2 hr), buffered medications, H₂ -receptor antagonists (administer famotidine at same time or at least 10 hr after famotidine [dose should not exceed famotidine 40 mg twice daily or equivalent in treatment-naïve patients or 20 mg twice daily or equivalent in treatment-experienced patients]).
Concurrent use with efavirenz or etravirine may ↓ levels and effectiveness (concurrent use is not recommended).
↑ levels of maraviroc (↓ dose of maraviroc to 150 mg twice daily).
↑ levels and risk of adverse reactions from clarithromycin and erythromycin ; concurrent use may also ↑ levels of atazanavir and cobicistat; consider alternative anti-infectives.
↑ levels and risk of bleeding with apixaban, dabigatran, edoxaban, and rivaroxaban (concurrent use of rivaroxaban not recommended, dose adjustments or alternatives necessary for apixaban, dabigatran, or edoxaban).
Levels and effectiveness may be ↓ by oxcarbazepine ; monitor levels and clinical response carefully, consider alternative anticonvulsants.
May ↑ or alter effects of antidepressants including SSRIs, tricyclic antidepressants and trazodone (monitor for drug effect and titrate to lowest effective dose).
↑ levels of ketoconazole and itraconazole (voriconazole not recommended unless benefits outweigh risks); ketoconazole and itraconazole may also ↑ levels of atazanavir and cobicistat.
↑ levels and risk of toxicity with rifabutin (↓ dose by 75% and monitor for adverse reactions).
↑ levels and risk of adverse reactions with beta-blockers metabolized by CYP2D6 including carvedilol, metoprolol and timolol (clinical monitoring for adverse cardiovascular effects recommended).
↑ levels and risk of adverse reactions with calcium channel blockers metabolized by CYP3A including amlodipine, diltiazem, felodipine, nifedipine and verapamil (clinical monitoring for adverse cardiovascular effects recommended).
Concurrent use with corticosteroids that induce CYP3A, including dexamethasone, ↓ effectiveness and ↑ corticosteroid effects (consider alternative corticosteroid).
Levels and effectiveness may be ↓ by bosentan while effects of bosentan are ↑ (specific dose alteration of bosentan is required).
↑ levels and risk of toxicity from atorvastatin, fluvastatin, pravastatin and rosuvastatin ; concurrent use with atorvastatin not recommended; rosuvastatin dose should not exceed 10 mg/day; for other statins, use lowest effective dose and monitor for adverse effects.
↑ levels and effects of immunosuppressants including cyclosporine, everolimus, sirolimus. tacrolimus (blood level monitoring recommended).
↑ risk of adverse cardiovascular effects with inhaled salmeterol (concurrent use not recommended.
↑ risk of corticosteroid effects with corticosteroids metabolized by CYP3A; consider alternative corticosteroids, including beclomethasone, prednisone, or prednisolone.
May ↑ CNS and respiratory depression with opioid analgesics or tramadol (dose reduction and careful titration recommended).
May ↑ levels and risk of adverse reactions with neuroleptics metabolized by CYP3A or CYP2D6 including perphenazine, risperidone and thioridazine (dose reduction may be necessary).
↑ levels and risk of adverse cardiovascular effects with PDE-5 inhibitors including avanafil, sildenafil, tadalafil and vardenafil (avanafil use not recommended, dose reductions required for sildenafil (for erectile dysfunction), tadalafil and vardenafil).
May ↑ quetiapine levels; ↓ quetiapine dose to 1/6 of current dose
Concurrent use with sofosbuvir/velpatasvir/voxilaprevir may ↑ voxilaprevir levels; concurrent use not recommended.
May ↑ ticagrelor levels and risk of bleeding; concurrent use not recommended.
May ↓ levels of active metabolite of clopidogrel and ↓ its effectiveness; concurrent use not recommended.

Drug-Natural Products:

St. John's wort ↓ blood levels and effectiveness; concurrent use contraindicated.

Route/Dosage

PO (Adults and Children ≥35 kg): One tablet (atazanavir 300 mg/cobicistat 150 mg) once daily.

Availability

Tablets: atazanavir 300 mg/cobicistat 150 mg

Assessment

Assess for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
Monitor ECG periodically in patients with first, second, or third-degree AV blocks.
Assess for rash which can occur within initial 8 wk of therapy. Usually resolves within 2 wk without altering therapy. Discontinue therapy if rash becomes severe.
Monitor for signs and symptoms of DRESS (fever, rash, lymphadenopathy, and/or facial swelling, associated with involvement of other organ systems (hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis) during therapy. May resemble an acute viral infection. Eosinophilia is often present. Discontinue therapy if signs occur.

Lab Test Considerations:

Monitor viral load and CD4 cell count regularly during therapy.

Monitor CCr prior to starting therapy and when atazanavir/cobicistat is co-administered with tenofovir disoproxil fumarate. Cobicistat causes modest ↑ serum creatinine and declines in estimated creatinine clearance without affecting renal glomerular function. If serum creatinine ↑ >0.4 mg/dL from baseline, monitor renal frequently.

Monitor urine glucose and urine protein when administering with tenofovir disoproxil fumarate at baseline and periodically during therapy. May cause ↑ serum amylase, lipase and hyperglycemia.
Assess liver function tests prior to starting therapy and periodically during therapy in patients with hepatitis B or C virus infections. May ↑ liver enzymes.
May ↑ CK.
May cause ↑ in unconjugated bilirubin; reversible on discontinuation.

Implementation

PO Administer once daily with food.
Take with other antiretroviral agents as prescribed.

Patient/Family Teaching

Emphasize the importance of taking atazanavir/cobicistat with food as directed. Advise patient to read the Patient Information before taking and with each Rx refill; in case of changes. Atazanavir/cobicistat must always be used in combination with other antiretroviral drugs. Do not take more than prescribed amount and do not stop taking without consulting health care professional. Take missed doses as soon as remembered if less than 12 hrs of dose, then return to regular dose schedule. If within 12 hr of next dose, omit dose and take next dose at regular time. Do not double doses.
Instruct patient that atazanavir/cobicistat should not be shared with others.
Inform patient that atazanavir/cobicistat does not cure HIV or prevent associated or opportunistic infections. Atazanavir/cobicistat may reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom and to avoid sharing needles or donating blood to prevent spreading the HIV virus to others.
Instruct 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; interactions may be fatal.
May cause dizziness. Caution patient to notify health care professional if this occurs and to avoid driving and other activities requiring alertness until response to medication is known.
Instruct patient to notify health care professional immediately if signs and symptoms of hepatitis (flu-like symptoms, tiredness, nausea, lack of appetite, yellow skin or eyes, dark urine, pale stools, pain or sensitivity to touch on right side below ribs), skin reactions with symptoms (fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema), gallbladder disorder (right or middle upper stomach pain, fever, nausea, vomiting, or yellowing of skin and whites of eyes), kidney stones (side pain, blood in urine, pain upon urination), change in heart rhythm, high blood sugar, or signs of immune reconstitution syndrome (signs and symptoms of an infection) occur.
Inform patient that redistribution and accumulation of body fat may occur, causing central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and cushingoid appearance. The cause and long-term effects are not known.
Rep: May cause fetal harm. Advise females of reproductive potential to avoid pregnancy and breastfeeding during therapy. Instruct females using hormonal contraceptives to use an effective alternative nonhormonal method of contraception. Advise patient to notify health care professional immediately if pregnancy is planned or suspected or if breastfeeding. If pregnant patient is exposed to atazanavir/cobicistat, register patient in Antiretroviral Pregnancy Registry by calling 1-800-258-4263. Monitor neonates exposed to atazanavir in utero for development of severe hyperbilirubinemia during first few days of life.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

Evaluation/Desired Outcomes

Delayed progression of HIV and decreased opportunistic infections in patients with HIV.
Decrease in viral load and increase in CD4 cell counts.