| HIV Antiviral Agents |
| Nucleoside Reverse Transcriptase Inhibitors (NRTIs): |
didanosine buffered formulations enteric-coated (EC) capsules
|Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.|
| Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate||↓ atazanavir|
|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||Efavirenz decreases atazanavir exposure.|
In treatment-naive patients:
If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In treatment-experienced patients:
Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
| Non-nucleoside Reverse Transcriptase Inhibitors: nevirapine||↓ atazanavir|
|Do not coadminister REYATAZ with nevirapine because:|
- Nevirapine substantially decreases atazanavir exposure.
- Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
| 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 [see Clinical Studies ].|
| 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: others||↑ 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 hours before or 1 hour 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 life-threatening 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 (atazanavir sulfate). |
| 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.|
|trazodone||↑ trazodone||Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.|
| Antifungals: ketoconazole, itraconazole|| REYATAZ/ritonavir: |
|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. Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. 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.|
| Benzodiazepines: parenterally administered midazolamb||↑ midazolam||Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED. |
| 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, rosuvastatin||↑ atorvastatin |
|Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with or without ritonavir). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.|
| H2-Receptor antagonists ||↓ atazanavir||Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance. |
| || || In treatment-naive patients: |
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients.
For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg.
| || || In treatment-experienced patients: |
Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
- REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist.
- REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist.
| Immunosuppressants: cyclosporin, sirolimus, tacrolimus||↑ immunosuppressants||Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).|
| Inhaled/nasal steroid: fluticasone|| REYATAZ |
|Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.|
| || REYATAZ/ritonavir |
|Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions ].|
| Macrolide antibiotics: clarithromycin||↑ clarithromycin |
↓ 14-OH clarithromycin
|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 infectionsdue to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.|
| Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone||↓ ethinyl estradiol |
↑ ethinyl estradiol
|Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.|
Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.
Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestagens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil||↑ sildenafil|
|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.
| Proton-pump inhibitors: omeprazole||↓ atazanavir||Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.|
| || || In treatment-naive patients: |
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
| || || In treatment-experienced patients: |
Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.