Atazanavir (Page 5 of 12)

6.2 Postmarketing Experience

The following events have been identified during postmarketing use of atazanavir. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: edema

Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions (5.1)]

Gastrointestinal System: pancreatitis

Hepatic System: hepatic function abnormalities

Hepatobiliary Disorders: cholelithiasis [see Warnings and Precautions (5.6)] , cholecystitis, cholestasis

Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.9)]

Musculoskeletal System: arthralgia

Renal System: nephrolithiasis [see Warnings and Precautions (5.6)] , interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease [see Warnings and Precautions (5.5)]

Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.2)], pruritus, angioedema

7 DRUG INTERACTIONS

7.1 Potential for Atazanavir to Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Co-administration of atazanavir and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.

Atazanavir is a weak inhibitor of CYP2C8. Use of atazanavir without ritonavir is not recommended when co-administered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g., paclitaxel, repaglinide). When atazanavir with ritonavir is co-administered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3)].

The magnitude of CYP3A-mediated drug interactions on co-administered drug may change when atazanavir is co-administered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.

7.2 Potential for Other Drugs to Affect Atazanavir

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce atazanavir’s therapeutic effect.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2 -receptor antagonists are administered with atazanavir [see Dosage and Administration (2.3, 2.4 and 2.6)].

7.3 Established and Other Potentially Significant Drug Interactions

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 Studies a or Predicted Interactions (Information in the table applies to atazanavir with or without ritonavir, unless otherwise indicated)

Concomitant Drug Class: Specific Drugs

Effect on Concentration of Atazanavir or Concomitant Drug

Clinical Comment

HIV Antiviral Agents

Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric-coated (EC) capsules

↓ atazanavir

↓ didanosine

Co-administration of atazanavir with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that atazanavir be given (with food) 2 hours before or 1 hour 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 co-administered 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 patients 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: Co-administration of atazanavir with efavirenz in treatment-experienced patients is not recommended due to decreased atazanavir exposure.

nevirapine

↓ atazanavir

↑ nevirapine

Co-administration of atazanavir with nevirapine is contraindicated. This is due to substantial decreases in atazanavir exposure, which may result in loss of therapeutic effect and development of resistance. Potential risk for nevirapine-associated adverse reactions due to increased nevirapine exposures [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 1,200 mg co-administered with atazanavir 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

Co-administration of atazanavir with indinavir is contraindicated. Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4)].

ritonavir

↑ atazanavir

If atazanavir is co-administered 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 co-administration of atazanavir with ritonavir and an additional protease inhibitor would be expected to increase exposure to the other protease inhibitor. Such co-administration is not recommended.

Hepatitis C Antiviral Agents

elbasvir/grazoprevir

↑ grazoprevir

Co-administration of atazanavir with grazoprevir is contraindicated. The resulting increase in grazoprevir plasma concentrations can lead to an increased risk of ALT elevations [see Contraindications (4)].

glecaprevir/pibrentasvir

↑ glecaprevir

↑ pibrentasvir

Co-administration of atazanavir with glecaprevir/pibrentasvir is contraindicated. It may increase the risk of ALT elevations due to an increase in glecaprevir and pibrentasvir concentrations [see Contraindications (4)].

voxilaprevir/sofosbuvir/ velpatasvir

↑ voxilaprevir

Co-administration with atazanavir is not recommended.

Other Agents

Alpha 1-Adrenoreceptor Antagonist: alfuzosin

↑ alfuzosin

Co-administration of atazanavir with alfuzosin is contraindicated. The resulting increase in alfuzosin plasma concentrations can lead to hypotension [see Contraindications (4)].

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, quinidine

↑ amiodarone, bepridil, lidocaine (systemic), quinidine

Concomitant use of atazanavir with ritonavir and either quinidine or amiodarone is contraindicated. This is due to the potential for substantial increase in systemic exposure of either quinidine or amiodarone, which may result in serious or life-threatening reactions such as cardiac arrhythmias [(see Contraindications (4)].

amiodarone, bepridil, lidocaine (systemic), quinidine

Co-administration with atazanavir 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 atazanavir.

Anticoagulants: warfarin

↑ warfarin

Co-administration 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.

Direct-Acting Oral

Anticoagulants: betrixaban,

dabigatran, edoxaban

↑ betrixaban

↑ dabigatran

↑ edoxaban

Concomitant use of atazanavir with ritonavir, a strong CYP3A4/P-gp inhibitor, with either betrixaban, dabigatran, or edoxaban may result in increased exposure of the respective DOAC that could lead to an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for co-administration with P-gp inhibitors.

rivaroxaban

Atazanavir with ritonavir

↑ rivaroxaban

Co-administration of atazanavir with ritonavir and rivaroxaban is not recommended. Concomitant treatment with agents that are combined P-glycoprotein (P-gp) strong CYP3A4 inhibitors, such as ritonavir, increase exposure to rivaroxaban and may increase risk of bleeding.

Atazanavir

↑ rivaroxaban

Co-administration of atazanavir, a CYP3A4 inhibitor, and rivaroxaban may result in increased increase exposure to rivaroxaban and may increase risk of bleeding. Close monitoring is recommended when atazanavir is co-administered with rivaroxaban.

apixaban

Atazanavir with ritonavir

↑ apixaban

Concomitant use of atazanavir with ritonavir, a strong CYP3A4/P-gp inhibitor, with apixaban may result in increased exposure of apixaban, which could lead to an increased risk of bleeding. Refer to apixaban dosing instructions for co-administration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information.

Atazanavir

↑ apixaban

Concomitant use of atazanavir, a CYP3A4 inhibitor, and apixaban may result in increased exposure of apixaban, which could lead to an increased risk of bleeding. Close monitoring is recommended when apixaban is co-administered with atazanavir.

Antidepressants: tricyclic antidepressants

↑ tricyclic antidepressants

Co-administration 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 co-administration of trazodone with 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. Co-administration of carbamazepine and atazanavir without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning atazanavir with 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. Co-administration 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 co-administered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.

lamotrigine

↓ lamotrigine

Co-administration of lamotrigine and atazanavir with ritonavir may decrease lamotrigine plasma concentrations, and may require dosage adjustment of lamotrigine. Co-administration of lamotrigine and atazanavir without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when co-administered with atazanavir without ritonavir.

Antifungals: ketoconazole, itraconazole

Atazanavir with ritonavir:

↑ ketoconazole

↑ itraconazole

Co-administration 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 when administering atazanavir with ritonavir.

voriconazole

Atazanavir with ritonavir in subjects with a functional CYP2C19 allele:

↓ voriconazole

↓ atazanavir

Atazanavir with ritonavir in subjects without a functional CYP2C19 allele:

↑ voriconazole

↓ atazanavir

The use of voriconazole in patients receiving atazanavir 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 co-administration of voriconazole and atazanavir with ritonavir. Co-administration of voriconazole with atazanavir (without ritonavir) may affect atazanavir concentrations; however, no data are available.

Antigout: colchicine

↑ colchicine

The co-administration 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: rifampin

↓ atazanavir

Co-administration of atazanavir with rifampin is contraindicated. Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance [see Contraindications (4)].

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.

Antineoplastics:

irinotecan

↑ irinotecan

Co-administration of atazanavir with irinotecan is contraindicated.

Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4)].

Antipsychotics: pimozide

↑ pimozide

Co-administration of atazanavir 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

Atazanavir with ritonavir

↑ lurasidone

Atazanavir

↑ lurasidone

Atazanavir with ritonavir

Co-administration of lurasidone with atazanavir with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4)].

Atazanavir without ritonavir

If co-administration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors.

quetiapine

↑ quetiapine

Initiation of atazanavir with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If co-administration 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.

Benzodiazepines:

midazolam (oral)

triazolam

↑ midazolam

↑ triazolam

Co-administration of atazanavir with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Atazanavir may cause large increases in the concentration of these benzodiazepines that 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

Concomitant use of parenteral midazolam with atazanavir may increase plasma concentrations of midazolam. Co-administration 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. Co-administration of diltiazem and atazanavir 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.

Endothelin receptor antagonists:

bosentan

↓ atazanavir

↑ bosentan

Plasma concentrations of atazanavir may be decreased when bosentan is administered with atazanavir without ritonavir. Co-administration of bosentan and atazanavir without ritonavir is not recommended.

Co-administration of bosentan in adult patients on atazanavir with ritonavir:

For patients who have been receiving atazanavir with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.

Co-administration of atazanavir with ritonavir in adult patients on bosentan:

Discontinue bosentan at least 36 hours before starting atazanavir with ritonavir. At least 10 days after starting atazanavir 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

Co-administration of atazanavir 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

Co-administration of atazanavir with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].

Herbal Products: St. John’s wort (Hypericum perforatum)

↓ atazanavir

Co-administration of products containing St. John’s wort with atazanavir is contraindicated. This may result in loss of therapeutic effect of atazanavir and the development of resistance [see Contraindications (4)].

Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin

↑ lovastatin

↑ simvastatin

Co-administration of atazanavir 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 atazanavir, are used in combination with these drugs.

Other Lipid Modifying Agents: lomitapide

↑ lomitapide

Co-administration of atazanavir 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

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 patients 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 with 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 patients during the second and third trimester. Atazanavir is not recommended for pregnant patients 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 caution if considering co-administration of oral contraceptives with atazanavir or atazanavir with ritonavir.

If atazanavir with ritonavir is co-administered with an oral contraceptive, 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.

Co-administration of atazanavir or atazanavir with ritonavir and 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 co-administered with atazanavir.

Inhaled beta agonist:

salmeterol

↑ salmeterol

Co-administration 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 with ritonavir

↑ fluticasone

Concomitant use of fluticasone propionate and atazanavir with 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. Co-administration of fluticasone propionate and atazanavir 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 co-administered 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. Co-administration of atazanavir with ritonavir and clarithromycin has not been studied.

Opioids: buprenorphine

↑ buprenorphine

↑ norbuprenorphine

Co-administration of buprenorphine and atazanavir with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine.

Co-administration of atazanavir with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Co-administration of buprenorphine and atazanavir with ritonavir is not expected to decrease atazanavir plasma concentrations. Co-administration of buprenorphine and atazanavir without ritonavir may decrease atazanavir plasma concentrations. The co-administration of atazanavir and buprenorphine without ritonavir is not recommended.

PDE5 inhibitors: sildenafil, tadalafil, vardenafil

↑ sildenafil

↑ tadalafil

↑ vardenafil

Co-administration 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):

Co-administration of atazanavir 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 atazanavir:

Co-administration 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.

    Co-administration 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 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.

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 with 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.

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.

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