indication

Used in combination with other antiretroviral agents for the treatment of HIV-1 infection, as well as postexposure prophylaxis of HIV infection in individuals who have had occupational or nonoccupational exposure to potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.

pharmacology

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Atazanavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals.

mechanism of action

Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2.

biotransformation

Atazanavir is extensively metabolized in humans, primarily by the liver. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.

absorption

Atazanavir is rapidly absorbed with a T_max of approximately 2.5 hours. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Oral bioavailability is 60-68%.

half life

Elimination half-life in adults (healthy and HIV infected) is approximately 7 hours (following a 400 mg daily dose with a light meal). Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg dose).

drug interactions

Abacavir: The serum concentration of Abacavir may be decreased by protease inhibitors such as Atazanavir. The antiviral response should be closely monitored.

Acenocoumarol: The protease inhibitor, atazanavir, may increase the anticoagulant effect of acenocoumarol.

Aluminium: This gastric pH modifier decreases the levels/effects of atazanavir

Amiodarone: Increased risk of cardiotoxicity and arrhythmias.

Amitriptyline: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if atazanavir if initiated, discontinued or dose changed.

Amoxapine: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, amoxapine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amoxapine if atazanavir if initiated, discontinued or dose changed.

Anisindione: The protease inhibitor, atazanavir, may increase the anticoagulant effect of anisindione.

Atorvastatin: Atazanavir may increase the serum concentration of atorvastatin by decreasing its metabolism. Concomitant therapy is contraindicated.

Bepridil: Atazanavir may increase the effect and toxicity of bepridil.

Bismuth Subsalicylate: This gastric pH modifier decreases the levels/effects of atazanavir

Bromazepam: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum concentration of bromazepam by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of bromazepam if atazanavir is initiated, discontinued or dose changed. Dosage adjustments may be required.

Buprenorphine: Atazanavir may increase the serum concentration of Buprenorphine. Buprenorphine may decrease the serum concentration of Atazanavir. Avoid use of buprenorphine in patients receiving atazanavir without ritonavir boosting due to possible decreases in atazanavir exposure. In patients receiving buprenorphine with atazanavir/ritonavir, monitor for increased buprenorphine effects and consider dose reductions if patients experience adverse effects.

Calcium: This gastric pH modifier decreases the levels/effects of atazanavir

Cimetidine: This gastric pH modifier decreases the levels/effects of atazanavir

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clarithromycin: Atazanavir may increase serum level of clarithromycin.

Clomipramine: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, clomipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of clomipramine if atazanavir is initiated, discontinued or dose changed.

Cyclosporine: Atazanavir may increase the therapeutic and adverse effects of cyclosporine.

Dantrolene: Atazanavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if atazanavir is initiated, discontinued or dose changed.

Desipramine: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if atazanavir is initiated, discontinued or dose changed.

Dicumarol: The protease inhibitor, atazanavir, may increase the anticoagulant effect of dicumarol.

Dihydroergotamine: Atazanavir may increase the therapeutic and adverse effects of dihydroergotamine.

Dihydroquinidine barbiturate: Increased risk of cardiotoxicity and arrhythmias

Dihydroxyaluminium: This gastric pH modifier decreases the levels/effects of atazanavir

Diltiazem: Atazanavir may increase the therapeutic and adverse effects of diltiazem resulting in increased risk of AV block. Consider alternate therapy, a 50% dose reduction of diltiazem and monitor for changes in the therapeutic and adverse effects of diltiazem if atazanavir is initiated, discontinued or dose changed.

Doxepin: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, doxepin, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of doxepin if atazanavir if initiated, discontinued or dose changed.

Efavirenz: Efavirenz decreases the levels/effects of atazanavir

Ergotamine: Atazanavir may increase the effect and toxicity of ergotamine.

Erlotinib: This CYP3A4 inhibitor increases levels/toxicity of erlotinib

Esomeprazole: This gastric pH modifier decreases the levels/effects of atazanavir

Famotidine: This gastric pH modifier decreases the levels/effects of atazanavir

Imipramine: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if atazanavir if initiated, discontinued or dose changed.

Indinavir: Increased risk of hyperbilirubinemia with this association

Irinotecan: Increases levels/effect of irinotecan

Lansoprazole: This gastric pH modifier decreases the levels/effects of atazanavir

Lidocaine: Increased risk of cardiotoxicity and arrhythmias

Lovastatin: Atazanavir may increase the effect and toxicity of lovastatin. Concomitant therapy is contraindicated.

Magnesium: This gastric pH modifier decreases the levels/effects of atazanavir

Magnesium oxide: This gastric pH modifier decreases the levels/effects of atazanavir

Magnesium Sulfate: This gastric pH modifier decreases the levels/effects of atazanavir

Methylergonovine: Increases the effect and toxicity of ergot derivative

Midazolam: Atazanavir may increase the effect and toxicity of the benzodiazepine, midazolam.

Nevirapine: Nevirapine, a strong CYP3A4 inducer, may decrease the serum concentration of atazanavir by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of atazanavir if nevirapine is initiated, discontinued or dose changed.

Nizatidine: This gastric pH modifier decreases the levels/effects of atazanavir

Nortriptyline: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if atazanavir if initiated, discontinued or dose changed.

Omeprazole: This gastric pH modifier decreases the levels/effects of atazanavir

Pantoprazole: This gastric pH modifier decreases the levels/effects of atazanavir

Pimozide: The protease inhibitor, atazanavir, may increase the effect and toxicity of pimozide.

Protriptyline: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, protriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of protriptyline if atazanavir if initiated, discontinued or dose changed.

Quinidine: Increased risk of cardiotoxicity and arrhythmias.

Quinidine barbiturate: Increased risk of cardiotoxicity and arrhythmias

Rabeprazole: Rabeprazole may decrease the serum levels and therapeutic effects of atazanavir.

Ramelteon: Atazanavir increases levels/toxicity of ramelteon

Ranitidine: Ranitidine may decrease the levels/effects of atazanavir.

Ranolazine: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum level of ranolazine. Concomitant therapy is contraindicated.

Rifabutin: Atazanavir may increase levels/toxicity of rifabutin.

Rifampin: Rifampin reduces levels and efficacy of atazanavir

Ritonavir: Association with dose adjustment

Sildenafil: Increases the effect and toxicity of sildenafil

Simvastatin: Increased risk of myopathy/rhabdomyolysis

Sirolimus: Increases the effect and toxicity of immunosuppressant

Sodium bicarbonate: This gastric pH modifier decreases the levels/effect of atazanavir

St. John's Wort: St. John's Wort decreases the levels/effects of atazanavir

Sunitinib: Possible increase in sunitinib levels

Tacrolimus: The protease inhibitor, Atazanavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Atazanavir therapy is initiated, discontinued or altered.

Tadalafil: Atazanavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Tamoxifen: Atazanavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Tamsulosin: Atazanvir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Atazanavir is initiated, discontinued, or dose changed.

Telithromycin: Co-administration may result in altered plasma concentrations of Atazanavir and/or Telithromycin. Consider alternate therapy or monitor the therapeutic/adverse effects of both agents.

Temsirolimus: Atazanavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Teniposide: The strong CYP3A4 inhibitor, Atazanavir, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Atazanavir is initiated, discontinued or dose changed.

Tenofovir: Concomitant therapy may result in decreased serum levels of Atazanavir and increased levels of Tenofovir. Concomitant therapy should only be used with the inclusion of Ritonavir.

Tiagabine: The strong CYP3A4 inhibitor, Atazanavir, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Atazanavir is initiated, discontinued or dose changed.

Tipranavir: Tipranavir, co-administered with Ritonavir, may decrease the plasma concentration of Atazanavir. Consider alternate therapy.

Tolterodine: Atazanavir may decrease the metabolism and clearance of Tolterodine. Adjust the Tolterodine dose and monitor for efficacy and toxicity.

Tramadol: Atazanavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Trazodone: The protease inhibitor, Atazanavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Atazanavir is initiated, discontinued or dose changed.

Tretinoin: The strong CYP2C8 inhibitor, Atazanavir, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Atazanavir is initiated, discontinued to dose changed.

Triazolam: Atazanavir may increase the effect and toxicity of the benzodiazepine, triazolam.

Trimipramine: The strong CYP3A4 inhibitor, Atazanavir, may decrease the metabolism and clearance of Trimipramine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Atazanavir is initiated, discontinued or dose changed.

Vardenafil: Atazanavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Venlafaxine: Atazanavir, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Atazanavir is initiated, discontinued, or dose changed.

Verapamil: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Atazanavir is initiated, discontinued or dose changed.

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. imit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors.

Vinblastine: Atazanavir, a strong CYP3A4 inhibitor, may decrease the metabolism of Vinblastine. Consider alternate therapy to avoid Vinblastine toxicity. Monitor for changes in the therapeutic/adverse effects of Vinblastine if Atazanavir is initiated, discontinued or dose changed.

Vincristine: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Atazanavir is initiated, discontinued or dose changed.

Vinorelbine: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Atazanavir is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of atazanavir by decreasing its metabolism. The serum concentration of voriconazole may be increased by atazanavir. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.

Warfarin: The protease inhibitor, atazanavir, may increase the anticoagulant effect of warfarin.

Zolpidem: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zolpidem by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zolpidem if atazanavir is initiated, discontinued or dose changed.

Zonisamide: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if atazanavir is initiated, discontinued or dose changed.

Zopiclone: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if atazanavir is initiated, discontinued or dose changed.