REYATAZ (atazanavir sulfate 200 mg) Dailymed

Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults) .

Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults) [see Use in Specific Populations (8.1)]. Table 4:  Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patientsa a  See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b  REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with BOTH tenofovir DF and H2RA. REYATAZ Once Daily Dosage Ritonavir Once Daily Dosage Treatment-Naive and Treatment-Experienced Recommended Regimen 300 mg 100 mg Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DFb In combination with EITHER H2RA OR tenofovir DF 400 mg 100 mg

Table 16 provides dosing recommendations in adults as a result of drug interactions with REYATAZ. 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 16:  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 a  For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3) . b  See Contraindications (4), Table 6 for orally administered midazolam. c  In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d  In combination with atazanavir 400 mg once daily. HIV Antiviral Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulationsenteric coated (EC) capsules ↓ atazanavir↓ didanosine 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 (DF) ↓ atazanavir↑ tenofovir When coadministered with tenofovir DF in adults, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, [see Dosage and Administration (2.6) ] . Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir In HIV-treatment-naive adult patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended. nevirapine ↓ atazanavir ↑ nevirapine Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4)]. 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 DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2)]. indinavir Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4)]. 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 in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. Others ↑ other protease inhibitor Coadministration with other protease inhibitors is not recommended. Hepatitis C Antiviral Agents elbasvir/grazoprevir ↑ grazoprevir Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4)]. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4)]. voxilaprevir/sofosbuvir/velpatasvir ↑ voxilaprevir Coadministration with REYATAZ is not recommended. Other Agents Alpha 1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4)]. Antacids and buffered medications: ↓ atazanavir REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications. Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir. 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 International Normalized Ratio (INR) be monitored. Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban ↑ betrixaban ↑ dabigatran ↑ edoxaban Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. rivaroxaban REYATAZ with ritonavir ↑ rivaroxaban Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding. REYATAZ ↑ rivaroxaban Coadministration of REYATAZ, a CYP3A4 inhibitor, and rivaroxaban may result in an increased risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban. apixaban REYATAZ with ritonavir ↑ apixaban Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information. REYATAZ ↑ apixaban Concomitant use of REYATAZ, a CYP3A4 inhibitor, and apixaban may result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with REYATAZ. 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 Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with 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. Antiepileptics: carbamazepine ↓ atazanavir↑ carbamazepine Coadministration of REYATAZ (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)]. phenytoin, phenobarbital ↓ atazanavir↓ phenytoin↓ phenobarbital Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)]. lamotrigine ↓ lamotrigine Coadministration of lamotrigine and REYATAZ with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir. Antifungals: ketoconazole, itraconazole REYATAZ with 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 when administering REYATAZ with ritonavir. voriconazole REYATAZ with ritonavir in subjects with a functional CYP2C19 allele: ↓ voriconazole↓ atazanavir REYATAZ with ritonavir in subjects without a functional CYP2C19 allele: ↑ voriconazole↓ atazanavir The use of voriconazole in patients receiving REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout: colchicine ↑ colchicine The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with REYATAZ: Treatment of gout flares:      0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. Prophylaxis of gout flares:      If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.      If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF):      Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterials: rifampin ↓ atazanavir Coadministration of REYATAZ with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)]. rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. Antineoplastics: irinotecan ↑ irinotecan Coadministration of REYATAZ with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4)]. apalutamide ↓ atazanavir Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4)]. ivosidenib ↓ atazanavir ↑ ivosidenib Coadministration of ivosidenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation. encorafenib ↓ atazanavir ↑ encorafenib Coadministration of encorafenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation. Antiplatelets: ticagrelor ↑ ticagrelor Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor. clopidogrel ↓ clopidogrel active metabolite Coadministration of REYATAZ (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel. Antipsychotics: pimozide ↑ pimozide Coadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. lurasidone REYATAZ with ritonavir ↑ lurasidone REYATAZ with ritonavir Coadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4)]. REYATAZ ↑ lurasidone REYATAZ without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. quetiapine ↑ quetiapine Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration of REYATAZ with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4)]. parenterally administered midazolamb ↑ midazolam Coadministration with parenteral midazolam 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. 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 diltiazem and REYATAZ with ritonavir has not been studied. 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. Corticosteroids: dexamethasone and other corticosteroids (all routes of administration) ↓ atazanavir ↑ corticosteroids Coadministration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of REYATAZ and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information. Endothelin receptor antagonists: bosentan REYATAZ ↓ atazanavir REYATAZ with ritonavir ↑ bosentan Coadministration of bosentan and REYATAZ without ritonavir is not recommended. For adult patients who have been receiving REYATAZ with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. For adult patients who have been receiving bosentan, discontinue bosentan at least 36 hours before starting REYATAZ with ritonavir. At least 10 days after starting REYATAZ with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine ↑ ergot derivatives Coadministration of REYATAZ with ergot derivatives is contraindicated. This is due to the 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 [see Contraindications (4)]. GI Motility Agents: cisapride ↑ cisapride Coadministration of REYATAZ with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: elagolix ↓ atazanavir ↑ elagolix Coadministration of elagolix and REYATAZ with or without ritonavir is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200mg twice daily with REYATAZ with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with REYATAZ (with or without ritonavir) for up to 6 months and monitor virologic response. Herbal Products: St. John’s wort (Hypericum perforatum) ↓ atazanavir Coadministration of products containing St. John’s wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4)]. Kinase inhibitors: fostamatinib ↑ R406 (active metabolite of fostamatinib) When coadministering fostamatinib with REYATAZ (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)]. atorvastatin, rosuvastatin ↑ atorvastatin↑ rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. Other Lipid Modifying Agents: lomitapide ↑ lomitapide Coadministration of REYATAZ with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4)]. H2 -Receptor antagonists ↓ atazanavir Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult 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 (H2RA). An H2RA 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.                                                               OR 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 H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. •REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA. •REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA. •REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA. Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol↑ norgestimatec ↑ ethinyl estradiol↑ norethindroned Use caution if considering coadministration of oral contraceptives with REYATAZ or REYATAZ with ritonavir. If REYATAZ with ritonavir is coadministered with an oral contraceptive, 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 with ritonavir and other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. Immunosuppressants: cyclosporine, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ. Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: fluticasone REYATAZ ↑ fluticasone Concomitant use of fluticasone propionate and REYATAZ without ritonavir should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. REYATAZ with ritonavir ↑ fluticasone With concomitant use of fluticasone propionate and REYATAZ with ritonavir, 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 with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1)]. 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 with ritonavir and clarithromycin has not been studied. Opioids: buprenorphine REYATAZ or REYATAZ with ritonavir ↑ buprenorphine↑ norbuprenorphine Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. REYATAZ ↓ atazanavir The coadministration of REYATAZ and buprenorphine without ritonavir is not 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 reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4)].  The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ:  Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir):   •For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®:   •Avoid the use of ADCIRCA® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Use of PDE5 inhibitors for erectile dysfunction:  Use VIAGRA® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.  Use CIALIS® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.   REYATAZ with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.   REYATAZ : Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions. Proton-pump inhibitors: omeprazole ↓ atazanavir Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) 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 HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended.

                        

There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed .

Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [see Data].

Dose Adjustments during Pregnancy and the Postpartum Period •REYATAZ must be administered with ritonavir in pregnant patients. •For pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions: •For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients. •No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome.

Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take REYATAZ [see Warnings and Precautions (5.8) ], including those who are pregnant [see Data]. Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.

In Study AI424-182, REYATAZ with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1 infection, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182.

In Study AI424-182, REYATAZ with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1 infection, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182. Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1 infection, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life. Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy). Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir, and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%.

The pharmacokinetic data from pregnant women with HIV-1 infection receiving REYATAZ Capsules with ritonavir are presented in Table 20.

The pharmacokinetic data from pregnant women with HIV-1 infection receiving REYATAZ Capsules with ritonavir are presented in Table 20. Table 20:  Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Pregnant Women with HIV-1 Infection in the Fed State a  Available data during the 2nd trimester are limited. b  Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4-12 weeks) than those observed historically in, non-pregnant patients with HIV-1 Infection. Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in non-pregnant patients with HIV-1 infection. c  Cmin is concentration 24 hours post-dose. Atazanavir 300 mg with ritonavir 100 mg Pharmacokinetic Parameter 2nd Trimester (n=5a) 3rd Trimester (n=20) Postpartumb (n=34) Cmax ng/mL    Geometric mean (CV%) 3078.85 (50) 3291.46 (48) 5721.21 (31) AUC ng•h/mL    Geometric mean (CV%) 27657.1 (43) 34251.5 (43) 61990.4 (32) Cmin ng/mLc    Geometric mean (CV%) 538.70 (46) 668.48 (50) 1462.59 (45)

Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.

Inform pregnant patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in pregnant patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry .

Inform pregnant patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in pregnant patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry [see Use in Specific Populations (8.1)]. Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk. REYATAZ can also be passed to the baby in breast milk, and it is not known whether it could harm the baby [see Use in Specific Populations (8.2)].