Atazanavir

HIV-1 infection.

Oral Adult: HIV-1 infection Indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection Treatment-naïve (capsules) Recommended dose: 300 mg PO (with ritonavir 100 mg) once daily Unable to tolerate ritonavir: 400 mg PO once daily In combination with efavirenz: 400 mg PO (with ritonavir 100 mg) once daily Treatment-experienced (capsules) Recommended dose: 300 mg PO (with ritonavir 100 mg) once daily In combination with H2-receptor antagonist (H2RA) and tenofovir DF: 400 mg PO (with ritonavir 100 mg) once daily Not recommended for treatment-experienced adults without ritonavir coadministration

Oral HIV-1 Infection Oral capsules 6-18 years (treatment naïve and treatment-experienced) <15 kg: Capsules not recommended 15 to <35 kg: 200 mg PO (with ritonavir 100 mg) once daily >35: 300 mg PO (with ritonavir 100 mg) once daily >13 years (treatment naïve and cannot tolerate ritonavir) >40 kg: 400 mg PO once daily

Renal impairment No dose adjustment is necessary including for those with severe renal impairment who are not managed with hemodialysis Treatment-naïve patients with end-stage renal disease on hemodialysis: 300 mg PO (with ritonavir 100 mg) once daily Antiretroviral-experienced patients: Not recommended

Hepatic impairment For treatment naïve patients Mild (Child-Pugh Class A): 400 mg PO once daily Moderate (Child-Pugh Class B): 300 mg PO once daily Severe (Child-Pugh Class C): Not recommended Coadministration of atazanavir with ritonavir in patients with any degree of hepatic impairment is not recommended

Should be taken with food. When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required

Hypersensitivity. Treatment-experienced patient on haemodialysis. Mild to moderate (w/ ritonavir) and severe (w/ or w/o ritonavir) hepatic impairment. Lactation. Concomitant use w/ statins (e.g. simvastatin, lovastatin), antiarrhythmics (e.g. amiodarone, bepridil, quinidine, systemic lidocaine), antihistamines (e.g. astemizole, terfenadine), antipsychotics (e.g. pimozide, quetiapine), ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine), GI prokinetics (e.g. cisapride), sedative and hypnotics (e.g. triazolam, oral midazolam), alpha1-adrenergic antagonists (e.g. alfuzosin), sildenafil (for treatment of pulmonary arterial HTN), irinotecan, and indinavir.

Patient w/ haemophilia A/B, pre-existing cardiac conduction disorder (e.g. 1st-3rd degree AV or complex bundle branch block), DM, bradycardia, long congenital QT, electrolyte imbalance. Hepatic impairment (including chronic hepatitis B or C). Pregnancy. Monitoring In pregnancy, monitor viral load and plasma atazanavir concentration during the third trimester.

Not Classi Pregnancy Atazanavir has been evaluated in a limited number of women during pregnancy; available human and animal data suggest that atazanavir does not increase risk of major birth defects overall compared to background rate Therapy must be administered with ritonavir in pregnant women Dosage modifications No dosage adjustment is required with the following exceptions Treatment-experienced pregnant women during second or third trimester, when therapy is coadministered with either an H2-receptor antagonist or tenofovir DF, a dose of 400 mg with ritonavir 100 mg once daily recommended There are insufficient data to recommend with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant women No dosage adjustment is required for postpartum patients; however, patients should be closely monitored for adverse events because atazanavir exposures could be higher during first 2 months after delivery Maternal adverse reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women receiving therapy in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome Hyperbilirubinemia occurs frequently in patients who receive therapy; advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to therapy in utero, should be monitored for development of severe hyperbilirubinemia during first few days of life Lactation The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed infants to avoid risking postnatal transmission of HIV-1 Atazanavir has been detected in human milk; no data available regarding atazanavir effects on milk production; atazanavir was present in milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning Because of both the potential for HIV-1 transmission and potential for serious adverse reactions in breastfed infants, advise women not to breastfeed

Decreased concentration w/ PPIs, efavirenz, nevirapine, and rifampicin. May increase serum concentration of inhaled fluticasone and salmeterol. May increase serum concentration of astemizole, terfenadine, pimozide, quetiapine, dihydroergotamine, ergometrine, ergotamine, methylergometrine, triazolam, and oral midazolam. May increase risk for hypotension, visual changes, and priapism w/ sildenafil (when used for pulmonary arterial HTN). May inhibit UGT1A1 causing an increase toxicity of irinotecan. May cause indirect hyperbilirubinaemia w/ indinavir. Initiation of atazanavir with ritonavir, a CYP3A inhibitor: Patients receiving medications metabolized by CYP3A, may increase plasma concentrations of medications metabolized by CYP3A Initiation of CYP3A4 inducers/inhibitors may increase or decrease concentrations of atazanavir with ritonavir, respectively Interactions may lead to clinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications; clinically significant adverse reactions from greater exposures of atazanavir with ritonavir, or loss of therapeutic effect of atazanavir with ritonavir and possible development of resistance Potentially Fatal: Increased risk for myopathy (i.e. rhabdomyolysis) w/ simvastatin and lovastatin. Increased risk for cardiac arrhythmia w/ cisapride. May increase risk of hypotension w/ alfuzosin. May increase potential of serious AR of amiodarone, bepridil, quinidine, and systemic lidocaine. Contraindicated (37) alfuzosin carbamazepine cobimetinib conivaptan dihydroergotamine dihydroergotamine intranasal elbasvir/grazoprevir eliglustat elvitegravir/cobicistat/emtricitabine/tenofovir DF enzalutamide ergoloid mesylates ergonovine finerenone flibanserin gepirone isavuconazonium sulfate ivabradine lomitapide lonafarnib lovastatin mavacamten methylergonovine naloxegol pacritinib phenobarbital phenytoin pimozide pitavastatin regorafenib rifampin saquinavir sildenafil simvastatin St John's Wort ubrogepant venetoclax voclosporin

Incidence based on combination therapy >10% Total bilirubin increased (35-49%) Fever (19%) Rash (3-21%) Cholesterol is increased (6-25%) Nausea (4-14%) CPK increased (6-11%) Cough (21%) Diarrhea (3-11%) 1-10% Neutrophils decrease (6-10%) Jaundice (5-9%) Headache (1-7%) Peripheral neuropathy (1-4%) Insomnia (1-3%) Fever (2%) Vomiting (3-7%) Dizziness (1-2%) Myalgia (4%) Abdominal pain (2-4%) Depression (1-2%) <1% Prolonged PR interval New onset diabetes mellitus, exacerbation of diabetes mellitus & hyperglycemia

Atazanavir, a synthetic azapeptide, is a selective, competitive, and reversible HIV-1 protease inhibitor. It inhibits the cleavage of viral Gag and Gag-Pol polyprotein precursors into individual functional proteins, preventing the processing of the polyproteins into mature and infectious virions.