ATAZANAVIR (atazanavir 300 mg capsule) Dailymed

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

Table 4 includes the recommended dosage of atazanavir capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, atazanavir capsules must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended atazanavir capsules dosage in adults) [see Use in Specific Populations (8.1)]. Table 4 Recommended Dosage of Atazanavir Capsules and Ritonavir in Pregnant Patientsa aSee Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (e.g., H2RA or PPIs), and other antiretroviral drugs (e.g., efavirenz, tenofovir DF, and didanosine). bAtazanavir is not recommended for treatment-experienced pregnant patients during the second and third trimester taking atazanavir capsules with both tenofovir DF and H2RA. Atazanavir 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 atazanavir. 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 Atazanavir with or without ritonavir, unless otherwise indicated) aFor magnitude of interactions see Clinical Pharmacology, Tables 21 and 2 2 (12.3) . bSee Contraindications (4), Table 6 for orally administered midazolam. cIn combination with atazanavir 300 mg and ritonavir 100 mg once daily. dIn combination with atazanavir 400 mg once daily. 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 enteric-coated (EC) capsules ↓ atazanavir ↓ didanosine Coadministration of atazanavir with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that atazanavir be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, atazanavir and didanosine EC should be administered at different times. Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate (DF) ↓ atazanavir ↑ tenofovir Tenofovir DF may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir DF in adults, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). Atazanavir increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving atazanavir and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant women taking atazanavir with ritonavir and tenofovir DF, see Dosage and Administration (2.6) . Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir Efavirenz decreases atazanavir exposure. In treatment-naive adult patients: If atazanavir is combined with efavirenz, atazanavir 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 treatment-experienced adult patients: Coadministration of atazanavir with efavirenz in treatment-experienced patients is not recommended due to decreased atazanavir exposure. 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 1,200 mg coadministered with atazanavir 400 mg and tenofovir DF 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2)] . ritonavir ↑ atazanavir If atazanavir is coadministered with ritonavir, it is recommended that atazanavir 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 Although not studied, the coadministration of atazanavir/ritonavir and an additional protease inhibitor would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended. HCV Antiviral Agents Protease Inhibitors: boceprevir ↓ atazanavir ↓ ritonavir Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended. sofosbuvir, velpatasvir, voxilaprevir ↑ voxilaprevir Coadministration with atazanavir 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 atazanavir. Atazanavir 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 atazanavir 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 atazanavir. Anticoagulants: warfarin ↑ warfarin Coadministration with atazanavir 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. Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with atazanavir 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 atazanavir. Trazodone ↑ trazodone Concomitant use of trazodone and atazanavir with or without ritonavir may increase plasma concentrations of trazodone. Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as atazanavir, the combination should be used with caution and a lower dose of trazodone should be considered. Antiepileptics: carbamazepine ↓ atazanavir ↑ carbamazepine Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with atazanavir without ritonavir. Coadministration of carbamazepine and atazanavir without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with atazanavir/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary. phenytoin, phenobarbital ↓ atazanavir ↓ phenytoin ↓ phenobarbital Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with atazanavir without ritonavir. Coadministration of phenytoin or phenobarbital and atazanavir without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When atazanavir with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required. lamotrigine ↓ lamotrigine Coadministration of lamotrigine and atazanavir with ritonavir may decrease lamotrigine plasma concentrations. Dose adjustment of lamotrigine may be required when coadministered with atazanavir and ritonavir. Coadministration of lamotrigine and atazanavir without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with atazanavir without ritonavir. Antifungals: ketoconazole, itraconazole Atazanavir/ ritonavir: ↑ ketoconazole ↑ itraconazole Coadministration of ketoconazole has only been studied with atazanavir 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 atazanavir/ritonavir. voriconazole Atazanavir/ ritonavir in subjects with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir Atazanavir/ ritonavir in subjects without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir The use of voriconazole in patients receiving atazanavir/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 atazanavir /ritonavir. Coadministration of voriconazole with atazanavir (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout: colchicine ↑ colchicine The coadministration of atazanavir with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with Atazanavir: 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: rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (e.g., 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. Antipsychotics: quetiapine and lurasidone ↑ quetiapine Initiation of Atazanavir 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 Atazanavir with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Atazanavir ↑ lurasidone Atazanavir without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors Atazanavir/ ritonavir ↑ lurasidone Atazanavir/ritonavir Use of lurasidone is contraindicated. Benzodiazepines: parenterally administered midazolamb ↑ midazolam Concomitant use of parenteral midazolam with atazanavir 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 atazanavir 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 atazanavir/ritonavir with diltiazem 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. Endothelin receptor antagonists: Bosentan ↓ atazanavir ↑ bosentan Plasma concentrations of atazanavir may be decreased when bosentan is administered with atazanavir without ritonavir. Coadministration of bosentan and atazanavir without ritonavir is not recommended. Coadministration of bosentan in adult patients on Atazanavir/ritonavir: For patients who have been receiving atazanavir /ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Coadministration of Atazanavir/ritonavir in adult patients on bosentan: Discontinue bosentan at least 36 hours before starting atazanavir/ritonavir. At least 10 days after starting atazanavir/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. HMG-CoA reductase inhibitors: 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 atazanavir, are used in combination with these drugs. H2‑Receptor antagonists ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when atazanavir 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily in adults, which may result in loss of therapeutic effect and development of resistance. In treatment-naive adult patients: Atazanavir 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 atazanavir 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, atazanavir 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 atazanavir without ritonavir in pregnant women is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving atazanavir with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the atazanavir and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. Atazanavir 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA. Atazanavir 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA. Atazanavir 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 women during the second and third trimester. Atazanavir is not recommended for pregnant women during the second and third trimester taking atazanavir with both tenofovir DF and an H2RA. Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol ↑ norgestimatec ↑ ethinyl estradiol ↑ norethindroned Use with caution if coadministration of atazanavir or atazanavir/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with atazanavir plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If atazanavir 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 atazanavir or atazanavir /ritonavir with other hormonal contraceptives (e.g., 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 atazanavir. Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with atazanavir is not recommended. Concomitant use of salmeterol and atazanavir may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: fluticasone Atazanavir ↑ fluticasone Concomitant use of fluticasone propionate and atazanavir (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Atazanavir/ ritonavir ↑ fluticasone Concomitant use of fluticasone propionate and atazanavir/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 atazanavir/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 atazanavir. 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 atazanavir/ritonavir with clarithromycin has not been studied. Opioids: Buprenorphine ↑ buprenorphine ↑ norbuprenorphine Coadministration of buprenorphine and atazanavir with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of atazanavir plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and atazanavir with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and atazanavir without ritonavir may decrease atazanavir plasma concentrations. The coadministration of atazanavir and buprenorphine without ritonavir is not recommended. PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Coadministration with atazanavir 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):   Use of REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with atazanavir [see Contraindications (4)] .   The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with atazanavir:   Coadministration of ADCIRCA® in patients on atazanavir (with or without ritonavir): For patients receiving atazanavir (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 atazanavir (with or without ritonavir) in patients on ADCIRCA®: Avoid the use of ADCIRCA® when starting atazanavir (with or without ritonavir). Stop ADCIRCA® at least 24 hours before starting atazanavir (with or without ritonavir). At least one week after starting atazanavir (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.   Atazanavir/ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.   Atazanavir: 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 Plasma concentrations of atazanavir were substantially decreased when atazanavir 400 mg or atazanavir 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily in adults, which may result in loss of therapeutic effect and development of resistance. In 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 atazanavir 300 mg with ritonavir 100 mg dose. In treatment-experienced adult patients: The use of PPIs in treatment-experienced patients receiving atazanavir is not recommended.



Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atazanavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary 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% to 4% and 15% to 20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7 times to 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]. Clinical Considerations Dose Adjustments during Pregnancy and the Postpartum Period Atazanavir must be administered with ritonavir in pregnant women. For pregnant patients, no dosage adjustment is required for atazanavir with the following exceptions: For treatment-experienced pregnant women during the second or third trimester, when atazanavir is coadministered with either an H2-receptor antagonist or tenofovir DF, atazanavir 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a atazanavir dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant women. 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)] . Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take atazanavir [see Warnings and Precautions (5.8)], including pregnant women [see Data]. Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data]. Data Human Data In clinical trial AI424-182, atazanavir/ritonavir (300 mg /100 mg or 400 mg /100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on atazanavir/ritonavir 300 mg /100 mg and 13 of 21 (62%) women on atazanavir/ritonavir 400 mg/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 HIV-infected pregnant women, 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 1,600 live births following exposure to atazanavir-containing regimens (including 1,037 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% to 4%. Animal Data In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level.

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV- infected patients after administration of atazanavir 400 mg once daily and after administration of atazanavir 300 mg with ritonavir 100 mg once daily (see Table 17). Table 17 Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or HIV-Infected Patients in the Fed State an=26. bn=12. 400 mg once daily 300 mg with ritonavir 100 mg once daily Parameter Healthy Subjects (n=14) HIV-Infected Patients (n=13) Healthy Subjects (n=28) HIV-Infected Patients (n=10) Cmax (ng/mL)    Geometric mean (CV%) 5,199 (26) 2,298 (71) 6,129 (31) 4,422 (58)    Mean (SD) 5,358 (1,371) 3,152 (2,231) 6,450 (2,031) 5,233 (3,033) Tmax (h)    Median 2.5 2 2.7 3 AUC (ng•h/mL)    Geometric mean (CV%) 28,132 (28) 14874 (91) 57039 (37) 46073 (66)    Mean (SD) 29,303 (8,263) 22,262 (20,159) 61,435 (22,911) 53,761 (35,294) T-half (h)    Mean (SD) 7.9 (2.9) 6.5 (2.6) 18.1 (6.2)a 8.6 (2.3) Cmin (ng/mL)    Geometric mean (CV%) 159 (88) 120 (109) 1,227 (53) 636 (97)    Mean (SD) 218 (191) 273 (298)b 1,441 (757) 862 (838) Figure 1 displays the mean plasma concentrations of atazanavir at steady state after atazanavir 400 mg once daily (as two 200-mg capsules) with a light meal and after atazanavir  300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients. Figure 1 Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult Patients Absorption Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3 fold. Food Effect Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of atazanavir with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state. Coadministration of a single 300-mg dose of atazanavir and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24 hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24 hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2 hours to 5 hours. Coadministration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state. Distribution Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients dosed with atazanavir 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42. Metabolism Atazanavir is extensively metabolized in humans. 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. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. Elimination Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal. Specific Populations Renal Impairment In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Atazanavir is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7)]. Hepatic Impairment Atazanavir has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC(0 to ∞) was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. Atazanavir is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of atazanavir with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.8)]. Pediatrics The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2.4)]. Table 19 Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in HIV-Infected Pediatric Patients Body Weight (range in kg) atazanavir/ritonavir Dose (mg) C max ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) C min ng/mL Geometric Mean (CV%) 15 to <35 200/100 3,303 (86%) 37,235 (84%) 538 (99%) ≥35 300/100 2,980 (82%) 37,643 (83%) 653 (89%) Pregnancy The pharmacokinetic data from HIV-infected pregnant women receiving atazanavir Capsules with ritonavir are presented in Table 20. Table 20 Steady-State Pharmacokinetics of Atazanavir with Ritonavir in HIV-Infected Pregnant Women in the Fed State aAvailable data during the 2nd trimester are limited. bAtazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4 weeks to 12 weeks) than those observed historically in HIV-infected, non-pregnant patients. Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in HIV-infected, non-pregnant patients. 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%) 3,078.85 (50) 3,291.46 (48) 5,721.21 (31) AUC ng•h/mL    Geometric mean (CV%) 27,657.1 (43) 34,251.5 (43) 61,990.4 (32) Cmin ng/mLc    Geometric mean (CV%) 538.70 (46) 668.48 (50) 1,462.59 (45) Drug Interaction Data Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min−1 and Ki value of 0.84 to 1 µM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 µM) and CYP2C8 (Ki=2.1 µM). Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, atazanavir decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir. Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. Atazanavir does not interact with substrates of CYP2D6 (e.g., nortriptyline, desipramine, metoprolol). Drug interaction studies were performed with atazanavir and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of atazanavir on the AUC, Cmax, and Cmin are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). Atazanavir did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7). Table 21Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa aData provided are under fed conditions unless otherwise noted. bAll drugs were given under fasted conditions. cAtazanavir 300 mg plus ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean Cmax that was similar and AUC and Cmin values that were 1.79- and 4.46-fold higher relative to atazanavir 400 mg once daily alone. dSimilar results were noted when famotidine 20 mg BID was administered 2 hours after and 10 hours before atazanavir 300 mg and ritonavir 100 mg plus tenofovir DF 300 mg. eAtazanavir/ritonavir/tenofovir DF was administered after a light meal. fStudy was conducted in HIV-infected individuals. gCompared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 1.42 (0.98, 2.05), 1.64 (1.11, 2.42), and 1.25 (0.66, 2.36), respectively, for atazanavir/ritonavir 300/100 mg; and 2.02 (1.42, 2.87), 2.28 (1.54, 3.38), and 1.80 (0.94, 3.45), respectively, for atazanavir/ritonavir 400/100 mg. hParallel group design; n=23 for atazanavir/ritonavir plus nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without nevirapine. Subjects were treated with nevirapine prior to study entry. iOmeprazole 40 mg was administered on an empty stomach 2 hours before atazanavir. jOmeprazole 20 mg was administered 30 minutes prior to a light meal in the morning and atazanavir 300 mg plus ritonavir 100 mg in the evening after a light meal, separated by 12 hours from omeprazole. k Atazanavir 300 mg plus ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases in atazanavir geometric mean AUC (10%) and Cmin (2.4-fold), with a decrease in Cmax (29%) relative to atazanavir 400 mg once daily in the absence of omeprazole (study days 1 to 6). lOmeprazole 20 mg was given 30 minutes prior to a light meal in the morning and atazanavir 400 mg plus ritonavir 100 mg once daily after a light meal, 1 hour after omeprazole. Effects on atazanavir concentrations were similar when atazanavir 400 mg plus ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours. mAtazanavir 400 mg plus ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in atazanavir geometric mean AUC (32%) and Cmin (3.3-fold), with a decrease in Cmax (26%) relative to atazanavir 400 mg once daily in the absence of omeprazole (study days 1 to 6). nCompared with atazanavir 400 mg QD historical data, administration of atazanavir/ritonavir 300/100 mg QD increased the atazanavir geometric mean values of Cmax, AUC, and Cmin by 18%, 103%, and 671%, respectively. oNote that similar results were observed in studies where administration of tenofovir DF and atazanavir was separated by 12 hours. pRatio of atazanavir plus ritonavir plus tenofovir DF to atazanavir plus ritonavir. Atazanavir 300 mg plus ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnoteo). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: Cmax = 3,190 ng/mL, AUC = 34,459 ng•h/mL, and Cmin = 491 ng/mL. Study was conducted in HIV-infected individuals. NA = not available. Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1 Cmax AUC Cmin atenolol 50 mg QD, d 7 to 11 (n=19) and d 19 to 23 400 mg QD, d 1 to 11 (n=19) 1 (0.89, 1.12) 0.93 (0.85, 1.01) 0.74 (0.65, 0.86) boceprevir 800 mg TID, d 1 to 6, 25 to 31 300 mg QD/ritonavir 100 mg QD, d 10 to 31 atazanavir: 0.75 (0.64 to 0.88) ritonavir: 0.73 (0.64 to 0.83) atazanavir: 0.65 (0.55 to 0.78) ritonavir: 0.64 (0.58 to 0.72) atazanavir: 0.51 (0.44 to 0.61) ritonavir: 0.55 (0.45 to 0.67) clarithromycin 500 mg BID, d 7 to 10 (n=29) and d 18 to 21 400 mg QD, d 1 to 10 (n=29) 1.06 (0.93, 1.20) 1.28 (1.16, 1.43) 1.91 (1.66, 2.21) didanosine (ddI) (buffered tablets) plus stavudine (d4T)b ddI: 200 mg × 1 dose, d4T: 40 mg × 1 dose (n=31) 400 mg × 1 dose simultaneously with ddI and d4T (n=31) 0.11 (0.06, 0.18) 0.13 (0.08, 0.21) 0.16 (0.10, 0.27) ddI: 200 mg × 1 dose, d4T: 40 mg × 1 dose (n=32) 400 mg × 1 dose 1 h after ddI + d4T (n=32) 1.12 (0.67, 1.18) 1.03 (0.64, 1.67) 1.03 (0.61, 1.73) efavirenz 600 mg QD, d 7 to 20 (n=27) 400 mg QD, d 1 to 20 (n=27) 0.41 (0.33, 0.51) 0.26 (0.22, 0.32) 0.07 (0.05, 0.10) 600 mg QD, d 7 to 20 (n=13) 400 mg QD, d 1 to 6 (n=23) then 300 mg/ritonavir 100 mg QD, 2 h before efavirenz, d 7 to 20 (n=13) 1.14 (0.83, 1.58) 1.39 (1.02, 1.88) 1.48 (1.24, 1.76) 600 mg QD, d 11 to 24 (pm) (n=14) 300 mg QD/ritonavir 100 mg QD, d 1 to 10 (pm) (n=22), then 400 mg QD/ritonavir 100 mg QD, d 11 to 24 (pm), (simultaneously with efavirenz) (n=14) 1.17 (1.08, 1.27) 1 (0.91, 1.10) 0.58 (0.49, 0.69) famotidine 40 mg BID, d 7 to 12 (n=15) 400 mg QD, d 1 to 6 (n=45), d 7 to 12 (simultaneous administration) (n=15) 0.53 (0.34, 0.82) 0.59 (0.40, 0.87) 0.58 (0.37, 0.89) 40 mg BID, d 7 to 12 (n=14) 400 mg QD (pm), d 1 to 6 (n=14), d 7 to 12 (10 h after, 2 h before famotidine) (n=14) 1.08 (0.82, 1.41) 0.95 (0.74, 1.21) 0.79 (0.60, 1.04) 40 mg BID, d 11 to 20 (n=14)c 300 mg QD/ritonavir 100 mg QD, d 1 to 10 (n=46), d 11 to 20d (simultaneous administration) (n=14) 0.86 (0.79, 0.94) 0.82 (0.75, 0.89) 0.72 (0.64, 0.81) 20 mg BID, d 11 to 17 (n=18) 300 mg QD/ritonavir 100 mg QD/tenofovir DF 300 mg QD, d 1 to 10 (am) (n=39), d 11 to 17 (am) (simultaneous administration with am famotidine) (n=18)d,e 0.91 (0.84, 0.99) 0.90 (0.82, 0.98) 0.81 (0.69, 0.94) 40 mg QD (pm), d 18 to 24 (n=20) 300 mg QD/ritonavir 100 mg QD/tenofovir DF 300 mg QD, d 1 to 10 (am) (n=39), d 18 to 24 (am) (12 h after pm famotidine) (n=20)e 0.89 (0.81, 0.97) 0.88 (0.80, 0.96) 0.77 (0.63, 0.93) 40 mg BID, d 18 to 24 (n=18) 300 mg QD/ritonavir 100 mg QD/tenofovir DF 300 mg QD, d 1 to 10 (am) (n=39), d 18 to 24 (am) (10 h after pm famotidine and 2 h before am famotidine) (n=18)e 0.74 (0.66, 0.84) 0.79 (0.70, 0.88) 0.72 (0.63, 0.83) 40 mg BID, d 11 to 20 (n=15) 300 mg QD/ritonavir 100 mg QD, d 1 to 10 (am) (n=46), then 400 mg QD/ritonavir 100 mg QD, d 11 to 20 (am) (n=15) 1.02 (0.87, 1.18) 1.03 (0.86, 1.22) 0.86 (0.68, 1.08) grazoprevir/ elbasvir grazoprevir 200 mg QD d 1 to 35 (n = 11) 300 mg QD/ritonavir 100 mg QD, d 1 to 35 (n = 11) 1.12 (1.01, 1.24) 1.43 (1.30, 1.57) 1.23 (1.13, 1.34) elbasvir 50 mg QD d 1 to 35 (n = 8) 300 mg QD/ritonavir 100 mg QD, d 1 to 35 (n = 8) 1.02 (0.96, 1.08) 1.07 (0.98,1.17) 1.15 (1.02, 1.29) ketoconazole 200 mg QD, d 7 to 13 (n=14) 400 mg QD, d 1 to 13 (n=14) 0.99 (0.77, 1.28) 1.10 (0.89, 1.37) 1.03 (0.53, 2.01) nevirapinef,g 200 mg BID, d 1 to 23 (n=23) 300 mg QD/ritonavir 100 mg QD, d 4 to 13, then 400 mg QD/ritonavir 100 mg QD, d 14 to 23 (n=23)h 0.72 (0.60, 0.86) 1.02 (0.85, 1.24) 0.58 (0.48, 0.71) 0.81 (0.65, 1.02) 0.28 (0.20, 0.40) 0.41 (0.27, 0.60) omeprazole 40 mg QD, d 7 to 12 (n=16)i 400 mg QD, d 1 to 6 (n=48), d 7 to 12 (n=16) 0.04 (0.04, 0.05) 0.06 (0.05, 0.07) 0.05 (0.03, 0.07) 40 mg QD, d 11  to 20 (n=15)i 300 mg QD/ritonavir 100 mg QD, d 1 to 20 (n=15) 0.28 (0.24, 0.32) 0.24 (0.21, 0.27) 0.22 (0.19, 0.26) 20 mg QD, d 17 to 23 (am) (n=13) 300 mg QD/ritonavir 100 mg QD, d 7 to 16 (pm) (n=27), d 17 to 23 (pm) (n=13)j,k 0.61 (0.46, 0.81) 0.58 (0.44, 0.75) 0.54 (0.41, 0.71) 20 mg QD, d 17 to 23 (am) (n=14) 300 mg QD/ritonavir 100 mg QD, d 7 to 16 (am) (n=27), then 400 mg QD/ritonavir 100 mg QD, d 17 to 23 (am) (n=14)l,m 0.69 (0.58, 0.83) 0.70 (0.57, 0.86) 0.69 (0.54, 0.88) pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.13 (0.96, 1.32) 1.06 (0.90, 1.26) NA rifabutin 150 mg QD, d 15 to 28 (n=7) 400 mg QD, d 1 to 28 (n=7) 1.34 (1.14, 1.59) 1.15 (0.98, 1.34) 1.13 (0.68, 1.87) rifampin 600 mg QD, d 17 to 26 (n=16) 300 mg QD/ritonavir 100 mg QD, d 7 to 16 (n=48), d 17 to 26 (n=16) 0.47 (0.41, 0.53) 0.28 (0.25, 0.32) 0.02 (0.02, 0.03) ritonavirn 100 mg QD, d 11 to 20 (n=28) 300 mg QD, d 1 to 20 (n=28) 1.86 (1.69, 2.05) 3.38 (3.13, 3.63) 11.89 (10.23, 13.82) tenofovir DFo 300 mg QD, d 9 to 16 (n=34) 400 mg QD, d 2 to 16 (n=34) 0.79 (0.73, 0.86) 0.75 (0.70, 0.81) 0.60 (0.52, 0.68) 300 mg QD, d 15 to 42 (n=10) 300 mg/ritonavir 100 mg QD, d 1 to 42 (n=10) 0.72p  (0.50, 1.05) 0.75p  (0.58, 0.97) 0.77p  (0.54, 1.10) voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID, d 2 to 3, 22 to 30; 400 mg BID, d 1, 21 (n=20) 300 mg/ritonavir 100 mg QD, d 11 to 30 (n=20) 0.87 (0.80, 0.96) 0.88 (0.82, 0.95) 0.80 (0.72, 0.90) voriconazole (Subjects without a functional CYP2C19 allele) 50 mg BID, d 2 to 3, 22 to 30; 100 mg BID, d 1, 21 (n=8) 300 mg/ritonavir 100 mg QD, d 11 to 30 (n=8) 0.81 (0.66, 1) 0.80 (0.65, 0.97) 0.69 (0.54, 0.87) Table 22 Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Atazanavira aData provided are under fed conditions unless otherwise noted. b400 mg ddI EC and atazanavir were administered together with food on Days 8 and 19. cUpon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without atazanavir, the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively. dUpon further dose normalization of ethinyl estradiol 35 mcg with atazanavir/ritonavir relative to ethinyl estradiol 25 mcg without atazanavir/ritonavir, the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1), respectively. eAll subjects were on a 28-day lead-in period; one full cycle of Ortho Tri-Cyclen®. Ortho Tri-Cyclen® contains 35 mcg of ethinyl estradiol. Ortho Tri-Cyclen® LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 mcg. f17-deacetyl norgestimate is the active component of norgestimate. g Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported. h (R)-methadone is the active isomer of methadone. i Study was conducted in HIV-infected individuals. j Subjects were treated with nevirapine prior to study entry. k Omeprazole was used as a metabolic probe for CYP2C19. Omeprazole was given 2 hours after atazanavir on Day 7; and was given alone 2 hours after a light meal on Day 20. l Not the recommended therapeutic dose of atazanavir. m When compared to rifabutin 150 mg QD alone d1 to 10 (n=14). Total of rifabutin + 25-O-desacetyl-rifabutin: AUC 2.19 (1.78, 2.69). n Rosiglitazone used as a probe substrate for CYP2C8. o Mean ratio (with/without coadministered drug). ↑ indicates an increase in rosuvastatin exposure. p The combination of atazanavir and saquinavir 1,200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the Cmax is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID. q Note that similar results were observed in a study where administration of tenofovir DF and atazanavir was separated by 12 hours. r Administration of tenofovir DF and atazanavir was temporally separated by 12 hours. NA = not available. Coadministered Drug Coadministered Drug Dose/Schedule Atazanavir Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without Atazanavir; No Effect = 1 C max AUC C min acetaminophen 1 gm BID, d 1 to 20 (n=10) 300 mg QD/ritonavir 100 mg QD, d 11 to 20 (n=10) 0.87 (0.77, 0.99) 0.97 (0.91, 1.03) 1.26 (1.08, 1.46) atenolol 50 mg QD, d 7 to 11 (n=19) and d 19 to 23 400 mg QD, d 1 to 11 (n=19) 1.34 (1.26, 1.42) 1.25 (1.16, 1.34) 1.02 (0.88, 1.19) boceprevir 800 mg TID, d 1 to 6, 25 to 31 300 mg QD/ritonavir 100 mg QD, d 10 to 31 0.93 (0.80, 1.08) 0.95 (0.87, 1.05) 0.82 (0.68, 0.98) clarithromycin 500 mg BID, d 7 to 10 (n=21) and d 18 to 21 400 mg QD, d 1 to 10 (n=21) 1.50 (1.32, 1.71) OH-clarithromycin: 0.28 (0.24, 0.33) 1.94 (1.75, 2.16) OH-clarithromycin: 0.30 (0.26, 0.34) 2.60 (2.35, 2.88) OH-clarithromycin: 0.38 (0.34, 0.42) ddI (enteric-coated [EC] capsules)b 400 mg d 1 (fasted), d 8 (fed) (n=34) 400 mg QD, d 2 to 8 (n=34) 0.64 (0.55, 0.74) 0.66 (0.60, 0.74) 1.13 (0.91, 1.41) 400 mg d 1 (fasted), d 19 (fed) (n=31) 300 mg QD/ritonavir 100 mg QD, d 9 to 19 (n=31) 0.62 (0.52, 0.74) 0.66 (0.59, 0.73) 1.25 (0.92, 1.69) diltiazem 180 mg QD, d 7 to 11 (n=28) and d 19 to 23 400 mg QD, d 1 to 11 (n=28) 1.98 (1.78, 2.19) desacetyl-diltiazem: 2.72 (2.44, 3.03) 2.25 (2.09, 2.16) desacetyl-diltiazem: 2.65 (2.45, 2.87) 2.42 (2.14, 2.73) desacetyl-diltiazem: 2.21 (2.02, 2.42) ethinyl estradiol & norethindronec Ortho-Novum® 7/7/7 QD, d 1 to 29 (n=19) 400 mg QD, d 16 to 29 (n=19) ethinyl estradiol: 1.15 (0.99, 1.32) norethindrone: 1.67 (1.42, 1.96) ethinyl estradiol: 1.48 (1.31, 1.68) norethindrone: 2.10 (1.68, 2.62) ethinyl estradiol: 1.91 (1.57, 2.33) norethindrone: 3.62 (2.57, 5.09) ethinyl estradiol & norgestimated Ortho Tri-Cyclen® QD, d 1 to 28 (n=18), then Ortho Tri-Cyclen® LO QD, d 29 to 42e  (n=14) 300 mg QD/ritonavir 100 mg QD, d 29 to 42 (n=14) ethinyl estradiol: 0.84 (0.74, 0.95) 17-deacetyl norgestimate:f  1.68 (1.51, 1.88) ethinyl estradiol: 0.81 (0.75, 0.87) 17-deacetyl norgestimate:f  1.85 (1.67, 2.05) ethinyl estradiol: 0.63 (0.55, 0.71) 17-deacetyl norgestimate:f  2.02 (1.77, 2.31) glecaprevir/ pibrentasvir 300 mg glecaprevir (n=12) 300 mg QD/ritonavir 100 mg QD (n=12) ≥4.06g(3.15, 5.23) ≥6.53g(5.24, 8.14) ≥14.3g(9.85, 20.7) 120 mg pibrentasvir (n=12) 300 mg QD/ritonavir 100 mg QD (n=12) ≥1.29g (1.15, 1.45) ≥1.64g(1.48, 1.82) ≥2.29g(1.95, 2.68) grazoprevir/ elbasvir grazoprevir 200 mg QD d 1 to 35 (n=12) 300 mg QD/ritonavir 100 mg QD d 1 to 35 (n=12) 6.24 (4.42, 8.81) 10.58 (7.78, 14.39) 11.64 (7.96, 17.02) elbasvir 50 mg QD d 1 to 35 (n=10) 300 mg QD/ritonavir 100 mg QD d 1 to 35 (n=10) 4.15 (3.46, 4.97) 4.76 (4.07, 5.56) 6.45 (5.51, 7.54) methadone Stable maintenance dose, d 1 to 15 (n=16) 400 mg QD, d 2 to 15 (n=16) (R)-methadoneh  0.91 (0.84, 1) total: 0.85 (0.78, 0.93) (R)-methadoneh1.03 (0.95, 1.10) total: 0.94 (0.87, 1.02) (R)-methadoneh1.11 (1.02, 1.20) total: 1.02 (0.93, 1.12) nevirapinei,j 200 mg BID, d 1 to 23 (n=23) 300 mg QD/ritonavir 100 mg QD, d 4 to 13, then 400 mg QD/ritonavir 100 mg QD, d 14 to 23 (n=23) 1.17 (1.09, 1.25) 1.21 (1.11, 1.32) 1.25 (1.17, 1.34) 1.26 (1.17, 1.36) 1.32 (1.22, 1.43) 1.35 (1.25, 1.47) omeprazolek 40 mg single dose, d 7 and d 20 (n=16) 400 mg QD, d 1 to 12 (n=16) 1.24 (1.04, 1.47) 1.45 (1.20, 1.76) NA rifabutin 300 mg QD, d 1 to 10 then 150 mg QD, d 11 to 20 (n=3) 600 mg QD,l  d 11 to 20 (n=3) 1.18 (0.94, 1.48) 25-O-desacetyl-rifabutin: 8.20 (5.90, 11.40) 2.10 (1.57, 2.79) 25-O-desacetyl-rifabutin: 22.01 (15.97, 30.34) 3.43 (1.98, 5.96) 25-O-desacetyl-rifabutin: 75.6 (30.1, 190) 150 mg twice weekly, d 1 to 15 (n=7) 300 mg QD/ritonavir 100 mg QD, d 1 to 17 (n=7) 2.49m  (2.03, 3.06) 25-O-desacetyl-rifabutin: 7.77 (6.13, 9.83) 1.48m  (1.19, 1.84) 25-O-desacetyl-rifabutin: 10.90 (8.14, 14.61) 1.40m  (1.05, 1.87) 25-O-desacetyl-rifabutin: 11.45 (8.15, 16.10) pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.60 (1.39, 1.85) 1.31 (1.23, 1.39) NA rosiglitazonen 4 mg single dose, d 1, 7, 17 (n=14) 400 mg QD, d 2 to 7, then 300 mg QD/ritonavir 100 mg QD, d 8 to 17 (n=14) 1.08 (1.03, 1.13) 0.97 (0.91, 1.04) 1.35 (1.26, 1.44) 0.83 (0.77, 0.89) NA NA rosuvastatin 10 mg single dose 300 mg QD/ritonavir 100 mg QD for 7 days ↑ 7-foldo ↑ 3-foldo NA saquinavirp  (soft gelatin capsules) 1200 mg QD, d 1 to 13 (n=7) 400 mg QD, d 7 to 13 (n=7) 4.39 (3.24, 5.95) 5.49 (4.04, 7.47) 6.86 (5.29, 8.91) sofosbuvir/ velpatasvir/ voxilaprevir 400 mg sofosbuvir single dose (n=15) 300 mg/100 mg ritonavir single dose (n=15) 1.29 (1.09, 1.52) sofosbuvir metabolite GS-331007 1.05 (0.99, 1.12) 1.40 (1.25, 1.57) sofosbuvir metabolite GS-331007 1.25 (1.16, 1.36) NA 100 mg velpatasvir single dose (n=15) 300 mg/100 mg ritonavir single dose (n=15) 1.29 (1.07, 1.56) 1.93 (1.58, 2.36) NA 100 mg voxilaprevir single dose (n=15) 300 mg/100 mg ritonavir single dose (n=15) 4.42 (3.65, 5.35) 4.31 (3.76, 4.93) NA tenofovir DFq 300 mg QD, d 9 to 16 (n=33) and d 24 to 30 (n=33) 400 mg QD, d 2 to 16 (n=33) 1.14 (1.08, 1.20) 1.24 (1.21, 1.28) 1.22 (1.15, 1.30) 300 mg QD, d 1 to 7 (pm) (n=14) d 25 to 34 (pm) (n=12) 300 mg QD/ritonavir 100 mg QD, d 25 to 34 (am) (n=12)r 1.34 (1.20, 1.51) 1.37 (1.30, 1.45) 1.29 (1.21, 1.36) voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID, d 2 to 3, 22 to 30; 400 mg BID, d 1, 21 (n=20) 300 mg/ritonavir 100 mg QD, d 11 to 30 (n=20) 0.90 (0.78, 1.04) 0.67 (0.58, 0.78) 0.61 (0.51, 0.72) voriconazole (Subjects without a functional CYP2C19 allele) 50 mg BID, d 2 to 3, 22 to 30; 100 mg BID, d 1, 21 (n=8) 300 mg/ritonavir 100 mg QD, d 11 to 30 (n=8) 4.38 (3.55, 5.39) 5.61 (4.51, 6.99) 7.65 (5.71, 10.2) lamivudine + zidovudine 150 mg lamivudine + 300 mg zidovudine BID, d 1 to 12 (n=19) 400 mg QD, d 7 to 12 (n=19) lamivudine: 1.04 (0.92, 1.16) zidovudine: 1.05 (0.88, 1.24) zidovudine glucuronide: 0.95 (0.88, 1.02) lamivudine: 1.03 (0.98, 1.08) zidovudine: 1.05 (0.96, 1.14) zidovudine glucuronide: 1 (0.97, 1.03) lamivudine: 1.12 (1.04, 1.21) zidovudine: 0.69 (0.57, 0.84) zidovudine glucuronide: 0.82 (0.62, 1.08)

Carcinogenesis 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 1,200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose. Mutagenesis Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay). Impairment of Fertility At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.