atazanavir/cobicistat

General

**Off Market Drug**
This medication is no longer available in the United States. Information provided here is for reference purposes only.

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, apalutamide, carbamazepine, colchicine, dihydroergotamine, dronedarone, drospirenone/ethinyl estradiol, elbasvir/grazoprevir, encorafenib, ergotamine, glecaprevir/pibrentasvir, irinotecan, ivosidenib, 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

Apalutamide, carbamazepine, phenobarbital, phenytoin, rifampin and nevirapine may significantly ↓ levels and effectiveness of atazanavir and cobicistat; concurrent use contraindicated.

Concurrent use with ivosidenib may significantly ↓ levels and effectiveness of atazanavir and cobicistat as well as significantly ↑ levels and risk of toxicity of ivosidenib; concurrent use contraindicated.
Concurrent use with encorafenib may significantly ↓ levels and effectiveness of atazanavir and cobicistat as well as significantly ↑ levels and risk of toxicity of encorafenib; concurrent use contraindicated.

May significantly ↑ levels and risk of toxicity of alfuzosin, dihydroergotamine, dronedarone, ergotamine, irinotecan, lomitapide, lovastatin, lurasidone, methylergonovine, pimozide, ranolazine, sildenafil (for pulmonary hypertension), simvastatin, and triazolam ; concurrent use contraindicated.
May significantly ↑ levels and risk of toxicity of 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.
May ↑ levels and risk of toxicity of 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.
May ↑ risk of sedation with sedative/hypnotics, including buspirone, diazepam, midazolam, zolpidem and others metabolized by CYP3A ; careful monitoring with dose ↓ recommended).
Proton-pump inhibitors may ↓ absorption of atazanavir; administer 12 hr after PPI; do not use PPI doses >20 mg omeprazole or equivalent/day. Concurrent use not recommended in treatment-experienced patients.

Antacids (separate dose by 2 hr) and H2-receptor antagonists may ↓ absorption of atazanavir; separate from antacids by 2 hr. Administer at same time or ≥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).

Efavirenz or etravirine may ↓ levels and effectiveness; concurrent use not recommended.
May ↑ levels and risk of toxicity of maraviroc ; ↓ maraviroc dose to 150 mg twice daily).
Concurrent use with clarithromycin orerythromycin may ↑ levels and risk of toxicity of clarithromycin, erythromycin, atazanavir, and cobicistat; consider alternative anti-infective.
May ↑ levels and risk of bleeding with apixaban, dabigatran, edoxaban, and rivaroxaban ; concurrent use of rivaroxaban not recommended. Dose adjustments or alternatives necessary when considering use of apixaban, dabigatran, or edoxaban.
Oxcarbazepine may ↓ levels and effectiveness of atazanavir and cobicistatconsider alternative anticonvulsant.
May alter effects of antidepressants, including SSRIs, tricyclic antidepressants and trazodone ; monitor for drug effect and titrate to lowest effective dose.
Concurrent use may ↑ levels and risk of toxicity of ketoconazole and itraconazole, and voriconazole as well as those of atazanavir and cobicistat; concurrent use with voriconazole not recommended.
May ↑ levels and risk of toxicity of rifabutin ; ↓ rifabutin dose by 75%.
May ↑ levels and risk of toxicity of beta-blockers, including carvedilol, metoprolol and timolol .
May ↑ levels and risk of toxicity of calcium channel blockers, including amlodipine, diltiazem, felodipine, nifedipine and verapamil .
Concurrent use with corticosteroids, including dexamethasone, may ↓ levels and effectiveness of atazanavir and cobicistat and ↑ levels and risk of toxicity of corticosteroid; consider alternative corticosteroid, including beclomethasone, prednisone, or prednisolone.
Concurrent use with bosentan may ↑ levels and risk of toxicity of bosentan and ↓ levels and effectiveness of atazanavir and cobicistat; specific dose alteration of bosentan required.
May ↑ levels and risk of toxicity of 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.
May ↑ levels and risk of toxicity of immunosuppressants, including cyclosporine, everolimus, sirolimus. and tacrolimus ; level monitoring recommended.
May ↑ risk of adverse cardiovascular effects with salmeterol ; concurrent use not recommended.
May ↑ risk of CNS and respiratory depression with opioid analgesics ; ↓ opioid analgesic dose.
May ↑ levels and risk of toxicity of perphenazine, risperidone and thioridazine ; ↓ antipsychotic dose.
May ↑ levels and risk of adverse cardiovascular effects of PDE-5 inhibitors, including avanafil, sildenafil, tadalafil and vardenafil ; concurrent use with avanafil not recommended; ↓ dose of sildenafil (for erectile dysfunction), tadalafil and vardenafil.
May ↑ levels and risk of toxicity of quetiapine ; ↓ quetiapine dose to 1/6 of current dose
Concurrent use with sofosbuvir/velpatasvir/voxilaprevir may ↑ levels and risk of toxicity of voxilaprevir; 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 may ↓ 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 block.
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/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. If DRESS suspected, discontinue atazanavir/cobicistat.

Lab Test Considerations:

Monitor viral load and CD4 cell count regularly during therapy.

Monitor CCr before starting therapy and when atazanavir/cobicistat is co-administered with tenofovir disoproxil fumarate. Cobicistat causes modest ↑ serum creatinine and ↓ in estimated CCr without affecting renal glomerular function. If serum creatinine ↑ by >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 ↑ serum amylase, lipase; may also cause hyperglycemia.
Assess liver function tests before starting therapy and periodically during therapy in patients with hepatitis B or C virus infections. May ↑ liver enzymes.
May ↑ CK.
May ↑ unconjugated bilirubin; reversible on discontinuation.

Implementation

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

Patient/Family Teaching

Explain purpose and side effects of medication. Advise patient to read Patient Information before starting therapy. 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 within 12 hr until next dose, omit dose and take next dose at regular time. Do not double doses.

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.

Advise patient that atazanavir/cobicistat should not be shared with others.
Advise patient that atazanavir/cobicistat does not cure HIV or prevent associated or opportunistic infections. Treatment may ↓ 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.
Advise patient to notify health care professional immediately if signs/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.
Advise 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 unknown.
Rep: May cause fetal harm. Advise women of reproductive potential to avoid pregnancy and breastfeeding during therapy. Instruct women using hormonal contraceptives to use an effective alternative nonhormonal method of contraception. If patient is exposed to atazanavir/cobicistat during pregnancy, 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 1st few days of life.

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.
Advise patient to notify health care professional immediately if signs/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.
Advise 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 unknown.
Rep: May cause fetal harm. Advise women of reproductive potential to avoid pregnancy and breastfeeding during therapy. Instruct women using hormonal contraceptives to use an effective alternative nonhormonal method of contraception. If patient is exposed to atazanavir/cobicistat during pregnancy, 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 1st few days of life.

Evaluation/Desired Outcomes