Indication:
For the treatment of HIV-1 infection (in combination with other antiretroviral agents).

Dosage and Administration:
Atazanavir must be taken with food. When coadministered with didanosine buffered or enteric-coated formulations, Atazanavir should be given (with food) 2 hours before or 1 hour after didanosine. Atazanavir without ritonavir is not recommended for treatment-experienced patients with prior virologic failure. Recommendations for Therapy-Naive Patients: Atazanavir 400 mg (two 200-mg capsules) once daily taken with food. Concomitant Therapy: Atazanavir 300 mg (one 300 mg capsule or two 150-mg capsules) with ritonavir 100 mg once daily (all as a single dose with food) if combined with any of the following: Tenofovir or Efavirenz or H2-receptor antagonist (the H2-receptor antagonist dose should not exceed a 40 mg dose equivalent of famotidine twice daily. Atazanavir 300 mg and ritonavir 100 mg should be administered simultaneously with, and/or at least 10 hours after the dose of the H2-receptor antagonist) or Proton-pump inhibitors (the proton-pump inhibitor dose should not exceed a 20 mg dose equivalent of omeprazole and must be taken approximately 12 hours prior to the Atazanavir 300 mg and ritonavir 100 mg dose). Recommendations for Therapy-Experienced Patients: Atazanavir 300 mg with ritonavir 100 mg once daily (all as a single dose with food). Concomitant Therapy: Atazanavir 300 mg (one 300-mg capsule or two 150-mg capsules) with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist (whenever an H2-receptor antagonist is given to a patient receiving Atazanavir with ritonavir, the H2-receptor antagonist dose should not exceed a dose equivalent to famotidine 20 mg twice daily, and the Atazanavir and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after the dose of the H2-receptor antagonist). Proton-pump inhibitors should not be used in treatment-experienced patients receiving Atazanavir. Dosing recommendations for efavirenz and Atazanavir in treatment experienced patients have not been established. Efficacy and safety of Atazanavir with ritonavir in doses greater than 100 mg once daily have not been established. Patients with renal impairment: Treatment-naïve patients with end stage renal disease managed with hemodialysis should receive Atazanavir 300 mg with ritonavir 100 mg. Atazanavir should not be administered to HIV-treatment experienced patients with end stage renal disease managed with hemodialysis. Patients with hepatic impairment: For patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure, a dose reduction to 300 mg once daily should be considered. Atazanavir should not be used in patients with severe hepatic impairment (Child-Pugh Class C). Atazanavir/ritonavir has not been studied in subjects with hepatic impairment and is not recommended.

Contraindications:
Hypersensitivity to atazanavir or its components; concomitant use with midazolam, triazolam, dihydroergotamine, ergotamine, ergonovine, methylergonovine, cisapride, and pimozide.

Adverse Reactions:
Rash, abdominal pain, diarrhea, nausea, unconjugated hyperbilirubinemia, headache, prolonged PR interval, first-degree AV block, lactic acidosis, urolithiasis (rare).

Warnings & Precautions:
The combination of atazanavir plus indinavir in an antiretroviral regimen is not recommended due to the occurrence of grade 3 to 4 hyperbilirubinemia and jaundice associated with both agents; additive or worsening effects are possible with concomitant use. Caution should be exercised in patients with concurrent administration of drugs that prolong PR interval including beta-blockers (other than atenolol), digoxin, diltiazem, and verapamil; in patients with diabetes mellitus and/or liver disease. Redistribution of body fat with peripheral wasting and central obesity may be seen, though the incidence is less with Atazanavir. Immune Reconstitution syndrome has been seen in patients receiving combination antiretroviral therapy including Atazanavir. Liver functions need to be monitored in patients co-infected with Hepatitis B and Hepatitis C. In patients with pre-existing elevations in transaminase prior to ATV treatment, increased risk for further transaminase elevation or hepatic decompensation can occur. Few cases of increased bleeding have been reported when Atazanavir was administered in patients with haemophilia.

Drug Interactions:
Atazanavir is an inhibitor of CYP3A, CYP2C8, and UGT1A1. Co-administration of Atazanavir and drugs primarily metabolized by CYP3A (eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE5 inhibitors), CYP2C8, or UGT1A1 (eg, irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects. Atazanavir is metabolized in the liver by the cytochrome P450 enzyme system. Co-administration of Atazanavir and drugs that induce CYP3A, such as rifampin, may decrease Atazanavir plasma concentrations and reduce its therapeutic effect. Co administration of Atazanavir and drugs that inhibit CYP3A may increase Atazanavir plasma concentrations. The potential for drug interactions with Atazanavir changes when Atazanavir is co administered with the potent CYP3A inhibitor ritonavir. The magnitude of CYP3A-mediated drug interactions (effect on Atazanavir or effect on co administered drug) may change when Atazanavir is co administered with ritonavir. Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of Atazanavir are expected if proton-pump inhibitors antacids, buffered medications, or H2-receptor antagonists are administered with Atazanavir. Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Caution should be used when co administering Atazanavir with medicinal products known to induce PR interval prolongation (eg, atenolol, diltiazem) especially those that are metabolized by CYP3A (eg, verapamil). Based on known metabolic profiles, clinically significant drug interactions are not expected between Atazanavir and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole. Atazanavir does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Additionally, no clinically significant drug interaction was observed when Atazanavir was co-administered with methadone. Co-administration of Atazanavir with hormonal contraceptives has not been studied. Because levels of contraceptive steroids from pills or contraceptive patches may be altered while patient is on Atazanavir or Atazanavir/ritonavir, a non hormonal method of contraception is recommended.

Pregnancy: Category B.

Lactation:
It is recommended that HIV-infected women do not breast feed their infants to avoid risking postnatal transmission of HIV.

Overdosage:
At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed. Treatment of overdosage with atazanavir should consist of general supportive measures. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. There is no specific antidote for overdose with atazanavir. Dialysis is unlikely to be beneficial in significant removal of atazanavir.