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).
|