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Active ingredient: Atazanavir - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

  • Anti-HIV Agents
  • Protease Inhibitors

Dosage Forms

  • Capsule (100 mg, 150 mg, or 200 mg)

Brands / Synonyms

ATV; ATZ; Latazanavir; Reyataz; Zrivada

Indications

For use, in combination with other antiretroviral agents, in the treatment of HIV-1 infection.

Pharmacology

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). It is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. 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.

Mechanism of Action

Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.

Absorption

Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability

Toxicity

Not Available

Biotrnasformation / Drug Metabolism

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.

Contraindications

REYATAZ is contraindicated in patients with known hypersensitivity to any of its ingredients, including atazanavir.

Coadministration of REYATAZ is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 1.

Table 1: Drugs That Are Contraindicated with REYATAZ Due to Potential CYP450-Mediated Interactions

Drug class

Drugs within class that are contraindicated with REYATAZ

Benzodiazepines

midazolam, triazolam

Ergot Derivatives

dihydroergotamine, ergotamine, ergonovine, methylergonovine

GI Motility Agent

cisapride

Neuroleptic

pimozide

Drug Interactions

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A (eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE5 inhibitors) 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. Coadministration of REYATAZ and drugs that induce CYP3A, such as rifampin, may decrease atazanavir plasma concentrations and reduce its therapeutic effect. Coadministration of REYATAZ and drugs that inhibit CYP3A may increase atazanavir plasma concentrations.

The potential for drug interactions with REYATAZ changes when REYATAZ is coadministered with the potent CYP3A inhibitor ritonavir. The magnitude of CYP3A mediated drug interactions (effect on atazanavir or effect on coadministered drug) may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for Norvir® (ritonavir) for information on drug interactions with ritonavir.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if antacids, buffered medications, H2-receptor antagonists, and proton-pump inhibitors are administrated with atazanavir.

Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Caution should be used when coadministering REYATAZ with medicinal products known to induce PR interval prolongation (eg, atenolol, diltiazem [see Table 11]).

Drugs that are contraindicated or not recommended for coadministration with REYATAZ are included in Table 10. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table 10: Drugs That Should Not Be Administered with REYATAZ
Drug class: Specific Drugs Clinical Comment
Antimycobacterials: rifampin Decreases plasma concentrations and AUC of most protease inhibitors by about 90%. This may result in loss of therapeutic effect and development of resistance.
Antineoplastics: irinotecan Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.
Benzodiazepines: midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
Ergot Derivatives: dihydrorergotamine, ergotamine, ergonovine, methylergonovine CONTRAINDICATED due to potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent: cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin Potential for serious reactions such as myopathy including rhabdomyolysis.
Neuroleptic: pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Protease Inhibitors: indinavir Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. Combinations of these drugs have not been studied and coadministration of REYATAZ and indinavir is not recommended.
Proton-Pump Inhibitors Concomitant use of REYATAZ and proton-pump inhibitors is not recommended. Coadministration of REYATAZ with proton-pump inhibitors is expected to substantially decrease REYATAZ plasma concentrations and reduce its therapeutic effect.
Herbal Products: St. John's wort (Hypericum perforatum) Patients taking REYATAZ should not use products containing St. John's wort (Hypericum perforatum) because coadministration may be expected to reduce plasma concentrations of atazanavir. This may result in loss of therapeutic effect and development of resistance

Table 11: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

Concomitant Drug Class:
Specific Drugs

Effect on Concentration of Atazanavir or Concomitant Drug

Clinical Comment

HIV Antiviral Agents

Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
Didanosine buffered formulations

↓ atazanavir

Coadminist ration of REYATAZ with didanosine buffered tablets did not alter exposure to didanosine; however, exposure to atazanavir was markedly decreased (presumably due to the increase in gastric pH caused by buffers in the didanosine tablets). In addition, it is recommended that didanosine be administered on an empty stomach; therefore, REYATAZ should be given (with food) 2 h before or 1 h after didanosine buffered formulations. Because didanosine EC capsules are to be given on an empty stomach and REYATAZ is to be given with food, they should be administered at different times.

Nucleotide Reverse
Transcriptase Inhibitors:
tenofovir disoproxil fumarate

↓ atazanavir
↑ tenofovir

Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events.

Non-nucleoside Reverse
Transcriptase Inhibitors

(NNRTIs): efavirenz

↓ atazanavir

In treatment-naive patients who receive efavirenz and REYATAZ, the recommended dose is REYATAZ 300 mg with ritonavir 100 mg and efavirenz 600 mg (all once daily), as this combination results in atazanavir exposure that approximates the mean exposure to atazanavir produced by 400 mg of REYATAZ alone. Dosing recommendations for efavirenz and REYATAZ in treatment-experienced patients have not been established.

Non-nucleoside Reverse
Transcriptase Inhibitors

: nevirapine

↓ atazanavir

REYATAZ/ritonavir: The effects of coadministration have not been studied. Nevirapine, an inducer of CYP3A, is expected to decrease atazanavir exposure. In the absence of data, coadministration is not recommended.

Protease Inhibitors:
Saquinavir (soft gelatin capsules)

↑ saquinavir

Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy.

Protease Inhibitors:
ritonavir

↑ atazanavir

If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for Norvir® (ritonavir) for information on drug interactions with ritonavir.

Protease Inhibitors:
other

↑ other protease inhibitor

REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.

Other Agents

Antacids and buffered medications

↓ atazanavir

Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 h before or 1 h after these medications.

Antiarrhythmics:
amiodarone, bepridil, lidocaine (systemic), quinidine

↑ amiodarone, bepridil, lidocaine (systemic), quinidine

Coadministration with REYATAZ has the potential to produce serious and/or lifethreatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.

Anticoagulants:
warfarin

↑ warfarin

Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.

Antidepressants:
Tricyclic antidepressants

↑ tricyclic
antidepressants

Coadministration with REYATAZ has the potential to produce serious and/or life- threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.

Antifungals: ketoconazole itraconazole

REYATAZ/ ritonavir:
↑ ketoconazole
↑ itraconazole

Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.

Antifungals: voriconazole

Effect is unknown

Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied. However, administration of voriconazole with ritonavir 400 mg every 12 hours decreased voriconazole steady-state AUC by an average of 82%. The effect of lower ritonavir doses on voriconazole is not known at this time. Until data are available, voriconazole should not be administered to patients receiving REYATAZ/ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may increase atazanavir concentrations; however, no data are available.

Antimycobacterials:
rifabutin

↑ rifabutin

A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended.

Calcium channel
blockers:
diltiazem

↑ diltiazem and
desacetyl-diltiazem

Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.

eg, felodipine, nifedipine, nicardipine, and verapamil

↑ calcium channel blocker

Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.

HMG-CoA reductase inhibitors: atorvastatin

↑ atorvastatin

The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including REYATAZ, are used in combination with atorvastatin. Caution should be exercised.

H2-Receptor antagonists

↓ atazanavir

Reduced plasma concentrations of atazanavir are expected if H2-receptor antagonists are administered with REYATAZ. This may result in loss of therapeutic effect and development of resistance. To lessen the effect of H2-receptor antagonists on atazanavir exposure, it is recommended that an H2-receptor antagonist and REYATAZ be administered as far apart as possible, preferably 12 hours apart.

Immunosuppressants: cyclosporin, sirolimus, tacrolimus

↑immunosuppressants

Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ.

Macrolide antibiotics: clarithromycin

↑ clarithromycin
↓ 14-OH
clarithromycin
↑ atazanavir

Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.

Hormonal contraceptives:
ethinyl estradiol and norethindrone

↑ ethinyl estradiol
↑ norethindrone

Coadministration of REYATAZ/ritonavir with hormonal contraceptives has not been studied. However, higher doses of ritonavir, without REYATAZ, decrease contraceptive steroid concentrations. Because contraceptive steroid concentrations may be altered when REYATAZ or REYATAZ/ritonavir is coadministered with oral contraceptives or with the contraceptive patch, alternate methods of nonhormonal contraception are recommended.

PDE5 inhibitors: Sildenafil Tadalafil Vardenafil

↑ sildenafil
↑ tadalafil
↑ vardenafil

Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism.

Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.

Use tadalafil with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.

Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.

a For magnitude of interactions see CLINICAL PHARMACOLOGY: Tables 4 and 5.


Based on known metabolic profiles, clinically significant drug interactions are e not expected between REYATAZ and fluvastatin, pravastatin, dapsone, trimethoprim/sulfa methoxazole, azithromycin, erythromycin, or fluconazole. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).

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