atazanavir
Pharmacologic class: HIV-1 protease azapeptide inhibitor
Therapeutic class: Antiretroviral
Pregnancy risk category B
Action
Selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in human immunodeficiency virus (HIV)-1 infected cells, preventing formation of mature virions
Availability
Capsules: 100 mg, 150 mg, 200 mg, 300 mg
Indications and dosages
➣ Treatment-naïve patients with HIV-1 infection in combination with ritonavir
Adults: 300 mg with ritonavir 100 mg P.O. daily. When administered with tenofovir, H2-receptor antagonists, or proton pump inhibitors, give 300 mg with ritonavir 100 mg P.O. daily. When administered with efavirenz, give 400 mg with ritonavir 100 mg P.O. daily. Give 400 mg P.O. daily if patient is unable to tolerate ritonavir.
Adults and children at least age 13 weighing at least 40 kg ( 88 lb) who are unable to tolerate ritonavir: 400 mg (without ritonavir) P.O. daily (For patients at least age 13 and at least 40 kg receiving concomitant tenofovir, H2-receptor antagonists, or proton pump inhibitors, atazanavir should not be administered without ritonavir.)
➣ Treatment-experienced patients with HIV-1 infection in combination with other antiretrovirals
Adults: 300 mg with ritonavir 100 mg P.O. daily. When administered with an H2-receptor antagonist, give 300 mg with ritonavir 100 mg P.O. daily. When administered with tenofovir and an H2-receptor antagonist, give 400 mg with ritonavir 100 mg P.O. daily.
➣ HIV-1 infection
Children ages 6 to younger than 18 weighing at least 40 kg (88 lb): 300 mg with ritonavir 100 mg P.O. daily
Children ages 6 to younger than 18 weighing at least 20 kg (44 lb) to less than 40 kg: 200 mg with ritonavir 100 mg P.O. daily
Children ages 6 to younger than 18 weighing at least 15 kg (33 lb) to less than 20 kg: 150 mg with ritonavir 100 mg P.O. daily
Dosage adjustment
• Hepatic impairment
• Administration with sildenafil citrate, tadalafil, or vardenafil
• Treatment-experienced pregnant women during second or third trimester, when administered with either an H2-receptor antagonist or tenofovir
Contraindications
• Hypersensitivity to drug or its components
• Administration with alfuzosin, triazolam, oral midazolam, ergot derivatives, rifampin, irinotecan, lovastatin, simvastatin, indinavir, cisapride, pimozide, sildenafil (Revatio), or St. John's wort
Precautions
Use cautiously in:
• hepatic impairment (use not recommended)
• renal impairment (drug shouldn't be administered to HIV treatment-experienced patients with end-stage renal disease managed with hemodialysis)
• conduction abnormalities and coadministration of drugs that may prolong PR interval, especially those metabolized by CYP3A (such as verapamil)
• concomitant use of antiarrhythmics (such as amiodarone, bepridil, systemic lidocaine, quinidine); antidepressants (such as trazodone, tricyclic antidepressants); high doses of ketoconazole and itraconazole (above 200 mg/day); calcium channel blockers; hormonal contraceptives
• concomitant use of endothelin-receptor antagonist (such as bosentan) without ritonavir (use not recommended)
• concomitant use of inhaled nasal steroid (such as fluticasone propionate) and atazanavir without ritonavir
• concomitant use of inhaled nasal steroid (such as fluticasone propionate) and atazanavir with ritonavir (use not recommended unless potential benefit to patient outweighs risk of systemic corticosteroid adverse effects)
• concomitant use of proton pump inhibitors (such as omeprazole) (shouldn't be used in treatment-experienced patients receiving atazanavir)
• concomitant use of opioid (such as buprenorphine) and atazanavir without ritonavir (shouldn't be coadministered)
• administration of drugs highly dependent on CYP2C8 with narrow indices (such as paclitaxel, repaglinide) when atazanavir is administered without ritonavir
• concomitant use of antifungal (such as voriconazole) (shouldn't be administered with atazanavir/ritonavir unless benefit/risk assessment justifies use of voriconazole)
• concomitant use of antigout agent (such as colchicine) (shouldn't be administered with atazanavir to patients with hepatic or renal impairment)
• concomitant use of atazanavir with efavirenz in treatment-experienced patients (don't coadminister)
• concomitant use of inhaled beta agonist (such as salmeterol) (use not recommended)
• pregnant (avoid use without ritonavir) or breastfeeding patients
• patients less than 40 kg (88 lb) receiving concomitant tenofovir, H2-receptor antagonists, or protonpump inhibitors (not recommended)
• children younger than age 13 (avoid use without ritonavir)
• children ages 3 months to 6 years (safety and efficacy not established)
• children younger than age 3 months (avoid use).
Administration
• Perform liver function tests before starting therapy.
• Administer drug with food.
☞ Be aware that drug isn't recommended for treatment-experienced patients with prior virologic failure.
☞ Don't administer to patient with severe hepatic impairment or treatment-experienced patient who is receiving dialysis for end-stage renal disease.
Adverse reactions
CNS: headache, insomnia, dizziness, peripheral neurologic symptoms, depression
CV: cardiac conduction abnormalities
EENT: scleral icterus
GI: nausea, vomiting, diarrhea, abdominal pain
GU: nephrolithiasis
Hematologic: neutropenia, thrombocytopenia, leukopenia, increased bleeding (in patients with hemophilia A and B)
Hepatic: jaundice, hepatotoxicity
Metabolic: hyperbilirubinemia, hyperglycemia, possible exacerbation of or new-onset diabetes mellitus
Musculoskeletal: myalgia
Respiratory: cough
Skin: rash, erythema multiforme, toxic skin eruptions, Stevens-Johnson syndrome
Other: fever, body fat redistribution or accumulation, immune reconstitution syndrome
Interactions
Drug-drug. Antacids, buffered drugs, H2-receptor antagonists, proton pump inhibitors: decreased atazanavir plasma concentration
Antiarrhythmics (such as amiodarone, bepridil, systemic lidocaine, quinidine), tricyclic antidepressants): increased risk of serious or life-threatening adverse reactions
Atorvastatin, rosuvastatin: increased risk of myopathy including rhabdomyolysis
Bosentan: decreased atazanavir level, increased bosentan level
Buprenorphine: increased buprenorphine and its active metabolite norbuprenorphine plasma concentrations, decreased atazanavir level
Calcium channel blockers (such as diltiazem, felodipine, nifedipine, nicardipine, verapamil): increased calcium channel blocker effect
Clarithromycin: increased atazanavir and clarithromycin levels resulting in prolonged QTc interval; significantly reduced active clarithromycin metabolite level
Colchicine: increased colchicine effect
Cyclosporine, sirolimus, tacrolimus: increased immunosuppressant levels
Didanosine (buffered tablets): marked decrease in atazanavir exposure
Drugs primarily metabolized by CYP3A, UGT1A1, other drugs (such as alfuzosin, cisapride, ergot derivatives, indinavir, irinotecan, lovastatin, oral midazolam, pimozide, rifampin, sildenafil [Revatio], simvastatin, triazolam): increased plasma concentration of these drugs resulting in serious or life-threatening adverse reactions
Drugs that prolong PR interval (beta blockers other than atenolol, digoxin, verapamil): expected additive effect of atazanavir
Efavirenz: decreased atazanavir exposure
Ethinyl estradiol with norgestimate: decreased ethinyl estradiol level, increased norgestimate level
Ethinyl estradiol with norethindrone: increased ethinyl estradiol and norethindrone levels
Fluticasone: increased fluticasone plasma concentration
Fluticasone and atazanavir/ritonavir: increased fluticasone plasma concentration resulting in significantly reduced cortisol levels
H2-receptor antagonists: decreased atazanavir plasma concentration resulting in loss of therapeutic effect and development of resistance
Itraconazole, ketoconazole: increased atazanavir area under the curve (AUC) and Cmax, increased itraconazole and ketoconazole effects
Midazolam (parenteral): increased midazolam plasma concentrations, risk of respiratory depression and prolonged sedation
Nevirapine: markedly decreased atazanavir effect; increased nevirapine effect with risk of nevirapine-associated toxicity
Other protease inhibitors: expected increased effect of these drugs
Rifabutin: increased risk of rifabutin-associated adverse reactions
Ritonavir: increased atazanavir effect
Salmeterol: increased risk of cardiovascular adverse reactions including prolonged QT interval, palpitations, and sinus tachycardia
Sildenafil, tadalafil, vardenafil: possible increased phosphodiesterase inhibitor-associated adverse reactions (hypotension, syncope, visual disturbances, priapism)
Tenofovir: decreased atazanavir AUC and Cmin, increased tenofovir level
Trazodone: increased trazodone plasma level
Warfarin: increased risk of serious or life-threatening bleeding
Drug-diagnostic tests. Alanine aminotransferase, aspartate aminotransferase, amylase, blood glucose, creatine kinase, high-density lipoproteins, lipase, low-density lipoproteins, total bilirubin, total cholesterol, triglycerides: increased levels
Hemoglobin, neutrophils, platelets: decreased levels
Drug-food. Any food: enhanced bioavailability and reduced pharmacokinetic variability
Drug-herbs. St. John's wort: decreased atazanavir plasma concentrations
Patient monitoring
☞ Monitor patient closely and discontinue drug if severe rash occurs (possible sign of Stevens-Johnson syndrome).
☞ Be aware that immune reconstitution syndrome may occur in patients receiving combination antiretroviral therapy. During initial phase of therapy, patient whose immune system responds may develop inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis), which may necessitate further evaluation and treatment.
☞ Temporarily interrupt or discontinue drug if signs or symptoms of nephrolithiasis occur.
• Monitor blood glucose level during therapy; watch for signs or symptoms of new-onset or exacerbation of diabetes mellitus and redistribution or accumulation of body fat.
• Monitor CBC with differential and liver and kidney function tests closely.
Patient teaching
• Instruct patient to take drug by mouth with food, to swallow capsules whole, and not to crush or chew them.
• Instruct patient to take drug 2 hours before or 1 hour after taking antacids or a buffered form of drugs.
☞ Instruct patient to immediately report severe rash, changes in pulse or heart beat, signs or symptoms of kidney stones (pain in the side, blood in urine, or pain when urinating), yellowing of eyes, or signs and symptoms of immune reconstitution syndrome (such as new signs or symptoms of a previously subclinical infection, worsening or progression of a known infection despite treatment, a new infection or illness, or failure of antiretroviral therapy).
• Inform patient that drug may cause increase in blood glucose level and redistribution or accumulation of body fat.
• Advise patient to consult prescriber before using other prescription or over-the-counter drugs or herbs.
• Advise male patient taking sildenafil, tadalafil, or vardenafil to promptly report hypotension, visual changes, or prolonged penile erection to prescriber.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, and herbs mentioned above.