Atazanavir sulfate

(ah - t a h - z a h - N A H - v e e r )
CLASSIFICATION(S): Antiretroviral agent, protease inhibitor PREGNANCY CATEGORY: B Rx: Reyataz.
USES In combination with other antiretroviral drugs for HIV-1 infections in adults and children, 6 to less than 18 years of age. ACTION/KINETICS Action Atazanavir is an azapeptide HIV-1 protease inhibitor that selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Resistance to the drug has been observed. Pharmacokinetics Readily absorbed; Tmax: 2.5 hr (average). Food enhances bioavailability and reduces pharmacokinetic variability. Steady state is reached between 4 and 8 days. Is extensively metabolized by CYP3A. Metabolites and unchanged drug are excreted in the feces (79%) 1 and urine (13%). t /2, elimination: 7 hr at steady-state after a 400 mg/day dose 1 with a light meal. t /2 increases in clients with impaired hepatic function. Plasma protein binding: 86%. CONTRAINDICATIONS Use in clients with severe hepatic insufficiency (Child-Pugh C). Use with drugs (e.g., dihydroergotamine, ergonovine, ergotamine, indinavir, irinotecan, lovastatin, methylergonovine, midazolam, rifampin, St. Johns wort, simvastatin, triazolam) that are highly dependent on CYP3A for clearance and for which increased plasma levels are associated with serious and/or life-threatening events. Lactation. Use in pediatric clients below 3 months of age due to the possibility of kernicterus. SPECIAL CONCERNS Concentration- and dose-dependent prolongation of the PR interval in ECGs

has been observed. Use with caution when used with drugs (e.g., beta-blockers, digoxin, verapamil) that may prolong the PR interval. Use with caution in clients with moderate hepatic impairment and in the elderly. Cross-resistance among protease inhibitors has been observed. SIDE EFFECTS Most Common Adults: N&V, jaundice/scleral icterus, myalgia, rash (all grades), headache, fever, abdominal pain, diarrhea, hyperbilirubinemia. Children: Cough, fever, rash, jaundice/ scleral icterus, diarrhea, vomiting, headache, rhinorrhea, asymptomatic second-degree AV block, hyperbilirubinemia. Many side effects occur when atazanavir is combined with other antiviral drugs. CNS: Headache, depression, dizziness, insomnia, peripheral neurologic symptoms, abnormal dreams/gait, agitation, amnesia, anxiety, confusion, convulsions, decreased libido, emotional lability, hallucinations, hostility, hyperkinesia, hypesthesia, increased reflexes, nervousness, psychosis, sleep disorder, somnolence, suicide attempt, twitch. GI: N&V, scleral icterus, abdominal pain, diarrhea, acholia, anorexia, aphthous stomatitis, colitis, constipation, dental pain, dyspepsia, enlarged abdomen, esophageal ulcer, esophagitis, flatulence, gastritis, gastroenteritis, GI disorder, increased appetite, mouth ulcer, pancreatitis, peptic ulcer. Hepatic: Hepatitis, jaundice, hepatomegaly, hepatosplenomegaly, liver damage, liver fatty deposit, cholecystitis, cholelithiasis, cholestasis. Metabolic: New-onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia, diabetic ketoacidosis, lactic acidosis syndrome (when used with nucleoside analogs), dehydration, dyslipidemia, gout, lipohypertrophy, obesity, weight decrease/gain. Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral/facial wasting, breast enlargement, cushingoid appearance. CV: Increased bleeding, inIV = Intravenous

C = see color insert

H = Herbal

E = sound alike drug

ATAZANAVIR SULFATE
interval; use together with caution Antiarrhythmics (e.g., amiodarone, systemic lidocaine, quinidine) / Possible serious/life-threatening side effects; monitor carefully if given together Antidepressants, tricyclic / Possible tricyclic levels Benzodiazepines (e.g., midazolam, triazolam) / Potential for serious/life-threatening prolonged or increased sedation or respiratory depression; do not use together Bepridil / Possible prolongaton of PR interval; do not use together Buffered drugs / Atazanavir plasma levels Calcium channel blockers (e.g., amlodipine, diltiazem, felodipine, nicardipine, nifedipene, verapamil) / Possible prolongation of PR interval; dose reduction may be needed Carbamazepine / Carbamazepine levels risk of toxicity; atazanavir levels treatment failure Clarithromycin / Clarithromycin levels QTc prolongation; consider a 50% dose reduction; also, significant in the active 14-OH clarithromycin; consider alternative therapy except for Mycobacterium avium complex Corticosteroids (e.g., fluticasone, prednisone) / Corticosteroid plasma levels; monitor for signs of adrenal insufficiency Didanosine, buffered formulation / Atazanavir levels; take atazanavir 2 hr before or 1 hr after buffered didanosine Didanosine, enteric-coated / Didanosine levels when taken with food; give atazanavir and didanosine at different times Diltiazem / Diltiazem plasma levels two-fold additive effect on PR interval; consider a dose reduction by 50% and ECG monitoring Efavirenz / Atazanavir plasma levels and clinical efficacy Ergot derivatives (e.g., dihydroergotamine, ergonovine, ergotamine, methylergonovine) / Potential for serious/lifethreatening acute ergot toxicity (e.g., peripheral vasospasm, ischemia of the extremities); do not use together
W = Available in Canada

cluding spontaneous skin hematomas and hemarthrosis in hemophilia type A and B; prolongation of PR interval, asymptomatic second-degree AV block in children, left bundle branch block, second-degree or third-degree AV block, QTc prolongation. Heart arrest, heart block, hypertension, myocarditis, palpitation, syncope, vasodilation. GU: Abnormal urine, amenorrhea, crystalluria, decreased male fertility, gynecomastia, hematuria, impotence, kidney calculus/failure/pain, menstrual disorder, oliguria, pelvic pain, polyuria, proteinuria, urinary frequency, UTI, nephrolithiasis. Musculoskeletal: Bone/ extremity pain, muscle atrophy, myalgia, myasthenia, myopathy, arthralgia. Respiratory: Dyspnea, hiccough, hypoxia, increased cough. Dermatologic: Rash (all grades), alopecia, cellulitis, dermatophytosis, dry skin, eczema, nail disorder, pruritus, seborrhea, urticaria, vesiculobullous rash, ecchymosis, purpura, sweating, maculopapular rash. Otic: Otitis, tinnitus. Body as a whole: Fatigue, fever, lipodystrophy, pain, allergic reaction, angioedema, asthenia, burning sensation, edema, heat sensitivity, infection, malaise, pallor, peripheral edema. Miscellaneous: Photosensitivity, taste perversion, back/chest pain, dysplasia, substernal chest pain, immune reconstitution syndrome (inflammatory response to indolent or residual opportunistic infections), hyperbilirubinemia. LABORATORY TEST CONSIDERATIONS ALT, AST, total bilirubin, amylase, lipase, creatine kinase, total cholesterol, HDL-C, LDL-C, triglycerides. Hemoglobin, neutrophils, platelets. OD OVERDOSE MANAGEMENT Symptoms: Jaundice, PR interval prolongation. Treatment: General supportive measures, including monitoring of VS and ECG. Emesis or gastric lavage. Activated charcoal. Dialysis is unlikely to be beneficial. DRUG INTERACTIONS Antacids and buffered drugs / Atazanavir plasma levels; give atazanavir 2 hr before or 1 hr after these medications Atenolol / Possible prolongation of PR
Bold Italic = life threatening side effect

= black box warning

ATAZANAVIR SULFATE
Famotidine / Significant atazanavir plasma levels possible loss of therapeutic effect and resistance Fluticasone (with or without ritonavir) / Significant plasma fluticasone levels significantly plasma cortisol levels H2 receptor antagonists / Atazanavir plasma levels therapeutic effect and resistance; give atazanavir as far apart as possible from H2-receptor antagonists HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, rosuvastatin, simvastatin) / HMG-CoA reductase inhibitor serum levels toxicity, including rhabdomyolysis; do not use together Immunosuppressants (e.g., cyclosporine, sirolimus, tacrolimus) / Immunosuppressant plasma levels; monitor carefully Indinavir / Both associated with indirect hyperbilirubinemia; do not use together Irinotecan / Irinotecan toxicity R/T metabolism; do not use together Itraconazole / Use with caution with atazanavir/ritonavir due to possible in atazanavir AUC and Cmax Ketoconazole / Use with caution with atazanavir/ritonavir due to possible in atazanavir AUC and Cmax Lapatinib / Do not use together; if use cannot be avoided, lapatinib dose to 500 mg/day Narcotic analgesics (e.g., buprenorphine, fentanyl) / Possible narcotic plasma 1 levels and t /2; closely monitor respiratory function during and after stopping the narcotic Nevirapine / Atazanavir exposure; do not use together Oral contraceptives (ethinyl estradiol and norethindrone) / Levels of hormones; use with caution and use lowest effective dose of each oral contraceptive component PDE5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) / PDE5 inhibitor side effects, including hypotension, visual changes, and priapism; use with caution at reduced doses (sildenafil 25 mg q 48 hr; tadalafil 10 mg q 72 hr; vardenafil up to 2.5 mg q 72 hr) Pimozide / Pimozide serum levels

and toxicity such as cardiac arrhythmias; do not use together Protease inhibitors (e.g., amprenavir, darunavir, fosamprenavir, indinavir, nelfinavir, saquinavir, tipranavir) / Levels of protease inhibitor; do not use togethjer Proton pump inhibitors / Significant in atazanavir levels and therapeutic effect and possible resistance Ranolazine / Risk of dose-related prolongation of the QTc interval, torsade de pointes-type arrhythmias, and sudden death; do not use together Rifabutin / Rifabutin levels; reduce dose up to 75% (i.e., 150 mg q other day or 3 times a week) Rifampin / Atazanavir plasma levels and AUC by 90% loss of therapeutic effect and resistance; do not use together Risperidone / Risperidone plasma levels risk of toxicity Ritonavir / Decrease the dose of atazanavir to 300 mg once daily H St. Johns wort / Atazanavir plasma levels effect R/T possible metabolism by CYP3A4 enzymes; do not use together Sildenafil / Sildenafil-associated side effects, including hypotension, visual changes, and priapism; use together with caution Tenofovir / Atazanavir AUC and Cmax; do not give atazanavir and tenofovir without ritonavir; also, atazanavir tenofovir levels; monitor for tenofovir side effects Trazodone (with or without ritonavir) / Significant plasma trazodone levels risk of toxicity; use with caution and trazodone dose Tricyclic antidepressants (e.g., amitriptyline) / Risk of serious and/or lifethreatening side effects; monitor tricyclic antidepressant levels Voriconazole / Do not use with atazanavir; data not available on use together Warfarin / Possible serious and/or lifethreatening bleeding; monitor INR HOW SUPPLIED Capsules: 100 mg, 150 mg, 200 mg, 300 mg (all as the sulfate). DOSAGE CAPSULES
IV = Intravenous

C = see color insert

H = Herbal

E = sound alike drug

ATAZANAVIR SULFATE
7. In treatment-naive clients who receive efavirenz and atazanavir, the recommended dose of atazanavir is 300 mg with ritonavir 100 mg, and efavirenz, 600 mg. Dosing recommendations for atazanavir and efavirenz have not been determined in treatment-experienced clients. 8. In treatment-naive clients requiring tenofovir disoproxil fumarate, give atazanavir 300 mg, with ritonavir, 100 mg, and tenofovir, 300 mg (all as a single daily dose with food). Atazanavir should not be given with tenofovir without ritonavir. 9. In clients who require famotidine, give atazanavir 300 mg with ritonavir 100 mg both once daily at the same time with food; do not exceed a dose of 40 mg of famotidine twice daily in therapy-naive clients or 20 mg of famotidine in therapy-experienced clients. Give atazanavir/ritonavir at least 10 hr after the dose of famotidine. 10. In treatment-naive clients who require a proton pump inhibitor, do not exceed a 20 mg dose equivalent to omeprazole. Give about 12 hr prior to atazanavir 200 mg and ritonavir 100 mg. Do not use proton pump inhibitors in treatment-experienced clients receiving atazanavir. 11. Treatment-naive clients with endstage renal disease managed with hemodialysis should receive atazanavir 300 mg with ritonavir 100 mg. Do not give atazanavir to treatment-experienced clients with end-stage renal disease managed with hemodialysis. ASSESSMENT 1. Note disease onset, characteristics of S&S, other agents trialed, outcome. 2. List drugs prescribed; ensure none interact. 3. Monitor ECG at baseline and periodically thereafter; assess for prolonged PR interval. 4. Check glucose, lipids, and LFTs; reduce dose with dysfunction. Monitor CD4+ cell count and HIV RNA load. Assess for S&S of lactic acidosis. Observe for any new onset diabetes.
W = Available in Canada

HIV-1 infections, treatment-naive adults and children. Adults, antiretroviral-naive clients: 400 mg (2 x 200 mg capsules) once daily with food. Consider a dose reduction to 300 mg of atazanavir for those with moderate hepatic insufficiency (ChildPugh score from 79). Children, 6 to younger than 18 years of age, 15 to <25 kg: Atazanavir, 150 mg and ritonavir, 80 mg; 25 to <32 kg: Atazanavir, 200 mg and ritonavir, 100 mg; 32 to <39 kg: Atazanavir, 250 mg and ritonavir, 100 mg; 30 kg or greater: Atazanavir, 300 mg and ritonavira, 100 mg. HIV-1 infections, treatment-experienced adults and children. Adults, antiretroviral-experienced clients: 300 mg atazanavir plus 100 mg ritonavir both once daily with food. Children, 6 to younger than 18 years of age, 25 to <32 kg: Atazanavir, 200 mg and ritonavir, 100 mg; 32 to <39 kg: Atazanavir, 250 mg and ritonavir, 100 mg; 39 kg or greater: Atazanavir, 300 mg and ritonavir, 100 mg.

NURSING CONSIDERATIONS
ADMINISTRATION/STORAGE 1. Dosage for children, 6 to younger than 18 years is based on body weight and should not exceed the recommended adult dose. 2. Data are insufficient to recommend doses of atazanavir for the following: Clients less than 6 years of age; without ritonavir in those younger than 13 years of age; and, treatment-experienced children with body weight less than 25 kg. 3. Do not coadminister atazanavir and efavirenz without ritonavir. 4. If given with didanosine buffered products, give with food 2 hr before or 1 hr after didanosine. 5. Atazanavir without ritonavir is not recommended for treatment-experienced clients with prior virologic failure. 6. Safety and efficacy of atazanavir with ritonavir in doses greater than 100 mg once daily have not been determined. Use of higher ritonavir doses is not recommended as they may alter the safety profile of atazanavir (e.g., cardiac effects, hyperbilirubinemia).
Bold Italic = life threatening side effect

= black box warning

ATAZANAVIR SULFATE
CLIENT/FAMILY TEACHING 1. Take with food or snack to increase absorption and effectiveness and with other antiretroviral therapy (always used in combination therapy). Take as directed, do not skip or double doses. Take once daily, at about the same time each day; swallow capsules whole. Do not crush, chew, or open capsules. 2. Do not take any unprescribed or OTC meds/herbals without provider consent. Avoid St. Johns Wort and Viagra type drugsmay cause adverse SE. 3. Report dizziness/lightheadedness, palpitations (pounding in the chest), as EKG may be needed (may prolong PR interval). Also report persistent nausea

or vomiting, profound weakness or tiredness, unexpected stomach discomfort, trouble breathing, or yellowing of the skin or eyes (may cause bilirubin elevations). 4. Drug may cause changes in body fat distribution/accumulation. 5. Does not prevent disease transmission or STDs; use protection. 6. May cause photosensitivity reaction; wear protective clothes/sunscreenavoid prolonged exposure. 7. Keep all F/U to evaluate response to therapy and adverse SE. OUTCOMES/EVALUATE Management of HIV infection HIVRNA

C = see color insert

H = Herbal

IV = Intravenous

E = sound alike drug