Atazanavir

Pronunciation

(at a za NA veer)

U.S. Brand Names

Reyataz®

Synonyms

Atazanavir Sulfate; BMS-232632

Generic Available

Use

Treatment of HIV-1 infections in combination with at least two other antiretroviral agents

Note: In patients with prior virologic failure, coadministration with ritonavir is recommended.

Pregnancy Risk Factor

Pregnancy Implications

Teratogenic effects not observed in animal studies. It is not known if atazanavir crosses the human placenta. Pregnancy and protease inhibitors are both associated with an increased risk of hyperglycemia. Glucose levels should be closely monitored. It is not known if atazanavir will exacerbate hyperbilirubinemia in neonates. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to atazanavir or any component of the formulation. Concurrent therapy with: Bepridil; cisapride; ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine); indinavir; irinotecan; lovastatin; midazolam; pimozide; proton pump inhibitors (esomeprazole, lansoprazole, omeprazole); rifampin; simvastatin; St John's wort; or triazolam.

Warnings/Precautions

Atazanavir is hepatically metabolized and has multiple drug interactions. A listing of medications that should not be used is available with each bottle and patients should be provided with this information. Use caution with medications metabolized by CYP3A4 and/or UGT1A1 (many are contraindicated). Additional CYP3A4 substrates include calcium channel blockers, immunosuppressants, and sildenafil.

Atazanavir may prolong PR interval, use with caution in patients with pre-existing conduction abnormalities or with medications which prolong AV conduction (dosage adjustment required with some agents); rare cases of AV block have been reported. May exacerbate pre-existing hepatic dysfunction; use caution in patients with hepatitis B or C or in patients with cirrhosis. Asymptomatic elevations in bilirubin (unconjugated) occur commonly during therapy with atazanavir; consider alternative therapy if bilirubin is >5 times ULN. Evaluate alternative etiologies if transaminase elevations also occur.

Use with caution in patients with hemophilia A or B; increased bleeding during protease inhibitor therapy has been reported. Changes in glucose tolerance, hyperglycemia, exacerbation of diabetes, DKA, and new-onset diabetes mellitus have been reported in patients receiving protease inhibitors. May be associated with fat redistribution (buffalo hump, increased abdominal girth, breast engorgement, facial atrophy). Atazanavir has been associated with development of rash (median onset 8 weeks); if mild-moderate, treatment may be continued (rash may resolve); discontinue therapy in cases of severe rash. Optimal dosing in pediatric patients has not been established; do not use in children <3 months of age due to potential for kernicterus.

Adverse Reactions

Protease inhibitors cause dyslipidemia which includes elevated cholesterol and triglycerides and a redistribution of body fat centrally to cause increased abdominal girth, buffalo hump, facial atrophy, and breast enlargement. These agents also cause hyperglycemia.

>10%:

Dermatologic: Rash (21%; median onset 8 weeks)

Gastrointestinal: Nausea (6% to 14%)

Hepatic: Bilirubin increased (>2.6 times ULN: 35% to 47%), amylase increased (14%)

3% to 10%:

Central nervous system: Depression (4% to 8%), dizziness (1% to 2%), fatigue (2% to 5%), fever (4% to 5%), headache (1% to 6%), insomnia (1% to 3%), pain (1% to 3%), peripheral neuropathy (1% to 4%)

Endocrine & metabolic: Lipodystrophy (1% to 8%)

Gastrointestinal: Abdominal pain (4%), vomiting (3% to 4%), diarrhea (1% to 11%)

Hepatic: Jaundice (7% to 8%), transaminases increased (2% to 9%)

Neuromuscular & skeletal: Myalgia (4%)

Respiratory: Cough increased (3% to 5%)

<3%: Abnormal dreams, acholia, agitation, allergic reaction, alopecia, amenorrhea, amnesia, angioedema, anorexia, anxiety, aphthous stomatitis, bone pain, buffalo hump, cardiac arrest, chest pain, colitis, confusion, constipation, crystalluria, dehydration, diabetes mellitus, diaphoresis increased, dyslipidemia, dyspepsia, dyspnea, ecchymosis, eczema, edema, emotional lability, esophageal ulcer, esophagitis, facial atrophy, fertility (male) decreased, gastritis, gout, gynecomastia, hallucination, heart block, hematuria, hepatitis, hepatomegaly, hiccup, hyperkinesias, hypertension, impotence, infection, lactic acidosis, libido decreased, malaise, menstrual disorder, myasthenia, myocarditis, myopathy, nail disorder, nervousness, otitis, palpitation, pancreatitis, peptic ulcer, photosensitivity, polyuria, pruritus, psychosis, purpura, reflexes decreased, renal calculus, renal failure, seborrhea, seizure, sleep disorder, suicide attempt, syncope, taste perversion, tinnitus, urinary frequency, urticaria, vasodilation, vesiculobullous rash, weakness, weight gain/loss

Postmarketing and/or case reports: Erythema multiforme, PR interval prolongation (first-degree AV block; rarely second-degree AV block), Stevens-Johnson syndrome

Overdosage/Toxicology

Limited experience in overdose. Treatment is symptomatic and supportive. Dialysis is not likely to remove significant amounts of drug.

Drug Interactions

Substrate of CYP3A4 (major); Inhibits CYP1A2 (weak), 2C9 (weak), 3A4 (strong)

Amiodarone: Serum levels/toxicity may be increased by atazanavir; serious and/or life-threatening reactions may occur. Monitor serum concentrations of amiodarone.

Antacids: May reduce the serum concentrations of atazanavir. Administer atazanavir 2 hours before or 1 hour after these medications.

Anticonvulsants: Phenobarbital and carbamazepine may decrease serum levels/effectiveness of atazanavir.

Benzodiazepines: An increase in midazolam and triazolam serum levels may occur resulting in significant oversedation when administered with atazanavir. Concurrent use is contraindicated. Use caution with other benzodiazepines metabolized by CYP enzymes.

Bepridil: Atazanavir inhibits the metabolism of bepridil. Concurrent use may lead to severe toxicity and is contraindicated.

Calcium channel blockers: Atazanavir may increase the serum concentrations/effects of calcium channel blockers. Careful titration is required. The dosage of diltiazem should be reduced by 50% during concurrent therapy. ECG monitoring is recommended in patients receiving calcium channel blockers with atazanavir. Also see preceding Bepridil entry.

Cisapride: Atazanavir inhibits the metabolism of cisapride and may lead to life-threatening cardiac arrhythmias; concurrent use is contraindicated.

Clarithromycin: Atazanavir may increase serum concentrations of clarithromycin, potentially increasing the risk of QTc prolongation. A 50% reduction in clarithromycin dose or an alternative agent (except in M. avium complex infections) should be considered.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of atazanavir. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of atazanavir. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

CYP3A4 substrates: Atazanavir may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Didanosine (buffered tablets): May reduce the serum concentrations of atazanavir. Administer atazanavir 2 hours before or 1 hour after didanosine.

Ergot alkaloids: Serum levels/toxicity may be increased by atazanavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated (includes dihydroergotamine, ergotamine, ergonovine, and methylergonovine).

Efavirenz: Serum levels of atazanavir are significantly reduced by efavirenz. If coadministration is desirable, atazanavir 300 mg plus ritonavir 100 mg may be administered with efavirenz 600 mg as a single daily dose (with a meal). Atazanavir should not be administered with efavirenz alone.

H2 antagonists: Serum concentrations of atazanavir may be reduced. Avoid concurrent use or administer at least 12 hours apart.

HMG-CoA reductase inhibitors: Atazanavir may increase levels of HMG-CoA reductase inhibitors, increasing the risk of myopathy. Concurrent use of lovastatin and simvastatin is not recommended. Atorvastatin may be used with careful monitoring, in the lowest dose possible. Fluvastatin and pravastatin may have lowest risk.

Immunosuppressants: Atazanavir may increase the serum levels of cyclosporine, sirolimus, or tacrolimus.

Indinavir: Concurrent use may increase the risk of hyperbilirubinemia; concurrent administration is not recommended.

Irinotecan: Atazanavir inhibits the metabolism of irinotecan via UGT1A1. Concurrent use may lead to severe toxicity; concurrent use is not recommended.

Lidocaine (systemic): Serum levels/toxicity may be increased by atazanavir; serious and/or life-threatening reactions may occur. Monitor serum concentrations of lidocaine.

Oral contraceptives: Hormone levels may be altered; alternate methods of contraception are recommended.

Phosphodiesterase-5 (PDE-5) enzyme inhibitors (sildenafil, tadalafil, vardenafil): Protease inhibitors may decrease the metabolism (via CYP enzymes) of PDE-5 inhibitors. Consider therapy modifications: Sildenafil serum concentration may be substantially increased (do not exceed single sildenafil doses of 25 mg in 48 hours). When used concurrently with tadalafil, do not exceed a maximum tadalafil dose of 10 mg in a 72-hour period. Specific guidelines for vardenafil are not established. Recommendations for other strong CYP3A4 inhibitors include vardenafil dose not to exceed 2.5 mg in 24 hours.

Pimozide: Serum levels/toxicity may be increased by atazanavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

Proton pump inhibitors: Serum concentrations of atazanavir may be reduced; concurrent use is not recommended.

Quinidine: Serum levels/toxicity may be increased by atazanavir; serious and/or life-threatening reactions may occur. Monitor serum concentrations of quinidine.

Rifabutin: An increase in rifabutin plasma AUC (>200%) has been observed when coadministered with atazanavir (decrease rifabutin's dose by up to 75%).

Rifampin: Rifampin decreases plasma AUC of protease inhibitors by ~90%; loss of virologic response and resistance may occur; concurrent use is contraindicated.

Ritonavir: Serum concentrations of atazanavir are increased by ritonavir. Specific dosing adjustment of atazanavir in combination with ritonavir and efavirenz has been established.

Saquinavir: Serum concentrations of saquinavir may be increased by atazanavir. Dosing recommendations for the combination have not been established.

St John's wort (Hypericum perforatum): May reduce trough serum concentrations of atazanavir, which may lead to treatment failures. Concurrent use is contraindicated.

Tenofovir: May decrease serum concentrations of atazanavir, resulting in a loss of virologic response and/or resistance to atazanavir. Atazanavir increases tenofovir concentrations. Atazanavir-specific dosing recommendations are provided by the manufacturer. Atazanavir should not be coadministered with tenofovir without ritonavir.

Tricyclic antidepressants: Serum concentrations/toxicity may be increased by atazanavir.

Warfarin: Atazanavir may increase warfarin's hypoprothrombinemic effect; monitor INR.

Ethanol/Nutrition/Herb Interactions

Food: Atazanavir taken with food increases bioavailability.

Herb/Nutraceutical: St John's wort (Hypericum perforatum) decreases serum concentrations of protease inhibitors and may lead to treatment failures; concurrent use is contraindicated.

Stability

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Mechanism of Action

Inhibits the HIV-1 protease; inhibition of the viral protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, noninfectious virus

Pharmacodynamics/Kinetics

Protein binding: 86%

Metabolism: Hepatic, via multiple pathways including CYP3A4

Half-life elimination: ~7 hours

Time to peak, plasma: 2.5 hours

Excretion: Feces (79% as metabolites, 20% as unchanged drug); urine (13% as metabolites, 7% as unchanged drug)

Dosage

Oral: Adults:

Antiretroviral-naive patients: 400 mg once daily; administer with food

Antiretroviral-experienced patients: 300 mg once daily plus ritonavir 100 mg once daily; administer with food

Coadministration with efavirenz:

Antiretroviral-naive patients: It is recommended that atazanavir 300 mg plus ritonavir 100 mg be given with efavirenz 600 mg (all as a single daily dose); administer with food

Antiretroviral-experienced patients: Recommendations have not been established.

Coadministration with didanosine buffered formulations: Administer atazanavir 2 hours before or 1 hour after didanosine buffered formulations

Coadministration with tenofovir: The manufacturer recommends that atazanavir 300 mg plus ritonavir 100 mg be given with tenofovir 300 mg (all as a single daily dose); administer with food

Dosage adjustment in renal impairment: No recommendation

Dosage adjustment in hepatic impairment:

Moderate hepatic insufficiency (Child-Pugh Class B): Reduce dose to 300 mg once daily

Severe hepatic insufficiency (Child-Pugh Class C): Avoid use

Note: Data unavailable for patients with underlying hepatitis B or C.

Administration

Administer with food.

Monitoring Parameters

Viral load, CD4, serum glucose; liver function tests, bilirubin

Dietary Considerations

Should be taken with food to enhance absorption.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are using and any allergies you have. Do not take any new medication during therapy without consulting prescriber (you will be provided with a list of specific medications that should not be used). This is not a cure for HIV, nor has it been found to reduce transmission of HIV. Take as directed with meals. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Atazanavir may be prescribed with a combination of other medications; time these medications as directed by prescriber. You may be advised to check your glucose levels (this class of drugs can cause exacerbation or new-onset diabetes). May cause body changes due to redistribution of body fat, facial atrophy, or breast enlargement (normal effects of drug); headache, dizziness, or fatigue (use caution when driving or engaging in hazardous tasks until response to drug is known); nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); back pain, or arthralgia (consult prescriber for approved analgesic). Report any rash, persistent nausea or vomiting, dark urine, pasty stools, yellowing of eyes, or other persistent adverse effects. Pregnancy/breast-feeding precautions: Notify prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Additional Information

A listing of medications that should not be used is available with each bottle and patients should be provided with this information.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause depression, insomnia, dizziness, and fatigue

Mental Health: Effects on Psychiatric Treatment

Contraindicated with midazolam, pimozide, St John's wort, triazolam, and ergot derivatives. Carbamazepine may decrease serum levels of atazanavir. TCA and sildenafil serum concentrations may be increased by atazanavir; monitor.

Dosage Forms

Capsules, as sulfate: 100 mg, 150 mg, 200 mg

References

"Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States," June 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed July 1, 2004.

International Brand Names

Reyataz® (CH, DE)