Budesonide

Drug overview for BUDESONIDE (budesonide):

Generic name: BUDESONIDE (bue-DES-oh-nide)
Drug class: Nasal Steroids
Therapeutic class: Respiratory Therapy Agents

Budesonide is a synthetic, non-halogenated corticosteroid that has potent glucocorticoid and weak mineralocorticoid activity.

No enhanced Uses information available for this drug.

DRUG IMAGES

BUDESONIDE 32 MCG NASAL SPRAY

The following indications for BUDESONIDE (budesonide) have been approved by the FDA:

Indications:
Allergic rhinitis prevention
Allergic rhinitis
Chronic non-allergic rhinitis
Perennial allergic rhinitis

Professional Synonyms:
Allergic rhinitis prophylaxis
Atopic rhinitis
Chronic nonallergic rhinitis
Non-seasonal allergic rhinitis

The following drug interaction information is available for BUDESONIDE (budesonide):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 5 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Selected Steroids/Antiretroviral CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Antiretroviral CYP3A4 inhibitors may inhibit the metabolism of corticosteroids metabolized by CYP3A4. Dexamethasone may induce metabolism of agents that are substrates of CYP3A4.(1-13,50) CLINICAL EFFECTS: Concurrent use of antiretroviral CYP3A4 inhibitors may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4, including Cushing's syndrome and adrenal suppression. Concurrent dexamethasone may result in decreased levels and effectiveness of CYP3A4 substrates. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If possible, avoid concurrent therapy of betamethasone, budesonide, ciclesonide, fluticasone, dexamethasone, methylprednisolone, or triamcinolone with antiretroviral CYP3A4 inhibitors. Alternative corticosteroids that are less affected by CYP3A4 inhibitors should be considered, like beclomethasone, prednisone, and prednisolone. If concurrent therapy is warranted, patients should be closely monitored for systemic effects. The corticosteroid may need to be discontinued. Patients receiving concurrent therapy with dexamethasone and substrates of CYP3A4 should also be monitored for decreased effectiveness of the CYP3A4 substrate. The manufacturers of nasal fluticasone(14-16) and fluticasone for inhalation(17) state that concurrent use of fluticasone and atazanavir, indinavir, nelfinavir, ritonavir or saquinavir is not recommended. The US manufacturers of atazanavir,(1) fosamprenavir,(5) indinavir(6) and nelfinavir(8) recommend caution with concurrent use of inhaled or nasal fluticasone. Consider alternatives to fluticasone if long-term use is required. DISCUSSION: In a study, boceprevir (800 mg TID for 7 days) increased the area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%. The maximum concentration (Cmax) and AUC of prednisolone increased by 16% and 37%, respectively.(2) A study of 14 healthy adults found that concurrent use of ketoconazole with ciclesonide increased the AUC of ciclesonide's active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. However, the study concluded that no dosage adjustments were required because ciclesonide has a very low potential to cause side effects.(18) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(7,11,14) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(3) The cortisol AUC decreased by 86%.(6,14-16) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(19) There have been several case reports of Cushing's syndrome in patients treated concurrently with ritonavir and inhaled budesonide,(19-20) dexamethasone,(22) injectable triamcinolone,(23-26) nasal fluticasone.(28-46) Hepatitis has also been reported with concurrent budesonide and ritonavir.(47) In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3 days) increased the AUC, Cmax, and elimination half-life of methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(48) In a study in 8 healthy subjects, following nefazodone administration the following changes were seen with methylprednisolone: mean (+/-SD) area under the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966 +/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs. 14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(49) Selected steroids linked to this monograph include: betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, and triamcinolone.(50) Selected CYP3A4 inhibitors and substrates linked to this monograph include: atazanavir, cobicistat, darunavir, fosamprenavir, indinavir, lenacapavir, lopinavir, nelfinavir, saquinavir, and tipranavir.(50)	APTIVUS, ATAZANAVIR SULFATE, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, GENVOYA, KALETRA, LOPINAVIR-RITONAVIR, PREZCOBIX, PREZISTA, REYATAZ, STRIBILD, SUNLENCA, SYMTUZA, TYBOST, VIRACEPT
Radioactive Iodide/Agents that Affect Iodide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1) CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1) PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less. PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(2) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(3) DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1)	ADREVIEW, JEANATOPE, MEGATOPE, SODIUM IODIDE I-123
Selected Sensitive CYP3A4 Substrates/Oral Lefamulin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,4) CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1) PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(5) PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(3) DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alfentanil, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, sirolimus, ticagrelor, triazolam, and ulipristal.(1,4,6)	XENLETA
Selected Steroids/Selected Strong CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of corticosteroids metabolized by CYP3A4. CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4, including Cushing's syndrome and adrenal suppression. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If possible, avoid concurrent therapy between betamethasone, budesonide, ciclesonide, fluticasone, dexamethasone, methylprednisolone, or triamcinolone and strong CYP3A4 inhibitors. Alternative corticosteroids that are less affected by CYP3A4 inhibitors should be considered, like beclomethasone, prednisone, and prednisolone. If concurrent therapy is warranted, patients should be closely monitored for systemic effects. The corticosteroid may need to be discontinued. DISCUSSION: In a study, boceprevir (800 mg TID for 7 days) increased the area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%. The maximum concentration (Cmax) and AUC of prednisolone increased by 16% and 37%, respectively.(3) A study of 14 healthy adults found that concurrent use of ketoconazole with ciclesonide increased the AUC of ciclesonide's active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. However, the study concluded that no dosage adjustments were required because ciclesonide has a very low potential to cause side effects.(4) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(6-8) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(6) The cortisol AUC decreased by 86%.(10-13) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(14) There have been several case reports of Cushing's syndrome in patients treated concurrently with ritonavir and inhaled budesonide,(15-16) dexamethasone,(17) injectable triamcinolone,(18-21) nasal fluticasone.(23-41) Hepatitis has also been reported with concurrent budesonide and ritonavir.(42) In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3 days) increased the AUC, Cmax, and elimination half-life of methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(43) In a study in 8 healthy subjects, following nefazodone administration the following changes were seen with methylprednisolone: mean (+/-SD) area under the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966 +/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs. 14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(44) Selected steroids linked to this monograph include: betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, and triamcinolone.(45) Selected CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, lonafarnib, mibefradil, nefazodone, ribociclib, paritaprevir, telaprevir, and tucatinib.(1-2,45)	KISQALI, KRAZATI, NEFAZODONE HCL, TUKYSA, ZOKINVY, ZYKADIA
Sodium Iodide I 131/Agents that Affect Iodide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1,2) CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2) PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less. PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(3) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(4) DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2)	HICON, SODIUM IODIDE I-131

There are 4 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Corticosteroids/Selected Macrolide Antibiotics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Some macrolide antibiotics may inhibit the metabolism of corticosteroids. CLINICAL EFFECTS: Concurrent use of some macrolide antibiotics may result in elevated levels and clinical effects of corticosteroids. Immunosuppression and Cushing's syndrome have been reported during concurrent therapy, including therapy with inhaled corticosteroids. PREDISPOSING FACTORS: Concurrent administration of enzyme inducing drugs. PATIENT MANAGEMENT: Patients receiving concurrent therapy with corticosteroids and macrolide antibiotics should be monitored for increased corticosteroid affects. The dosage of the corticosteroid may need to be adjusted or the macrolide antibiotic may need to be discontinued. One US manufacturer of inhaled fluticasone states that the concurrent use of macrolide antibiotics is not recommended.(1) DISCUSSION: In a study in 10 steroid-dependent asthmatics, concurrent troleandomycin (1 gram/day) decreased methylprednisolone clearance by 60%. All subjects developed adverse effects typical of excessive corticosteroid use such as weight gain, fluid retention, and cushingoid features.(2) Other studies and reports have shown increased methylprednisolone levels with concurrent troleandomycin,(3-10) in some of these reports, the interaction was used to lower steroid dosages.(6-10) There is one report of fatal varicella infection in a patient receiving concurrent therapy with methylprednisolone and troleandomycin.(11) Cushing's syndrome has been reported with concurrent inhaled budesonide and clarithromycin.(12) Psychosis(13) and mania(14) have been reported with concurrent prednisone and clarithromycin. Erythromycin(3-9) and troleandomycin(9) have also been reported to interact with methylprednisolone.	CLARITHROMYCIN, CLARITHROMYCIN ER, E.E.S. 200, E.E.S. 400, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, LANSOPRAZOL-AMOXICIL-CLARITHRO, OMECLAMOX-PAK, VOQUEZNA TRIPLE PAK
Selected Corticosteroids/Selected Azole Antifungal Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Itraconazole, ketoconazole, posaconazole, and voriconazole may inhibit the CYP3A4 mediated metabolism of some corticosteroids, resulting in increased systemic exposure. Itraconazole and ketoconazole may also suppress endogenous cortisol output. CLINICAL EFFECTS: Concurrent use of itraconazole, ketoconazole, posaconazole, or voriconazole may result in elevated levels of and effects from the corticosteroid, including Cushing syndrome. These effects have been seen with systemic as well as inhaled corticosteroids. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients should be carefully monitored with concurrent administration of these agents, or when itraconazole, ketoconazole, posaconazole, or voriconazole is added to corticosteroid therapy. The dose of the corticosteroid may need to be adjusted or alternative therapy considered. DISCUSSION: In a randomized, double-blind, cross-over study in 10 healthy subjects, pretreatment with itraconazole (200 mg daily for 5 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single inhaled dose of budesonide (1000 mcg) by 4.2-fold and 1.6-fold, respectively. Suppression of cortisol production was increased 43%.(1) A study examined adrenal insufficiency in 25 cystic fibrosis patients treated with itraconazole and inhaled budesonide and in 12 patients receiving itraconazole alone. Eleven of the 25 patients receiving concurrent itraconazole and budesonide and none of the patients receiving only itraconazole had adrenal insufficiency.(2) There are case reports of Cushing syndrome in patients receiving concurrent itraconazole (range 200 mg to 800 mg daily) and inhaled budesonide (range 400 mcg to 1400 mcg daily).(3-5) The concurrent use of ketoconazole has been shown to increase budesonide area-under-curve (AUC) by eight-fold.(6) In a study in eight healthy subjects, the simultaneous administration of ketoconazole increased budesonide AUC by 6.5-fold. Administering the two agents 12 hours apart increased budesonide AUC by 3.8-fold.(7) There are case reports of Cushing syndrome in patients receiving concurrent itraconazole (range 100 mg to 400 mg daily) and inhaled fluticasone (range 250 mcg to 1.5 mg daily).(8,9) In a randomized, placebo-controlled, crossover, four phase study in 8 healthy subjects, itraconazole decreased the systemic clearance of intravenous dexamethasone by 68%, increased the area-under-curve (AUC) of dexamethasone by 3.3-fold, and prolonged its half-life by 3.2-fold. The AUC of oral dexamethasone was increased 3.7-fold, maximum concentration (Cmax) was increased by 1.7-fold, and the elimination half-life was prolonged 2.8-fold by itraconazole.(10) In a randomized, cross-over study in 14 healthy subjects, pretreatment with itraconazole (400 mg Day 1, 200 mg Days 2-4) increased the AUC of a single oral dose of methylprednisolone by 1.5-fold. Cortisol levels were significantly lower after concurrent therapy than with methylprednisolone alone.(11) There is a case report of Cushing syndrome following the addition of itraconazole (400 mg daily) to methylprednisolone (12 mg/day).(12) In a study in 6 healthy subjects, pretreatment with ketoconazole (200 mg daily) increased the AUC of a single intravenous dose of methylprednisolone (20 mg) by 135% and decreased its clearance by 60%. Concurrent ketoconazole also increased the reduction in 24-hour cortisol AUC and suppressed morning cortisol concentrations.(13) In a study in 8 healthy subjects, ketoconazole decreased the clearance of methylprednisolone by 46% and increased mean residence time by 37%.(14) In a randomized, cross-over study in 14 healthy subjects, pretreatment with itraconazole (400 mg Day 1, 200 mg Days 2-4) had no effect on the pharmacokinetics of a single oral dose of prednisone (60 mg).(11) In a randomized, cross-over study in 6 healthy subjects, pretreatment with ketoconazole (200 mg daily for 6 days) had no effect on the pharmacokinetics of a single intravenous dose of prednisolone (14.8 mg).(15) In a randomized, double-blind, cross-over study in 10 healthy subjects, pretreatment with itraconazole (200 mg daily for 4 days) increased the AUC and half-life of a single oral dose of prednisolone (20 mg) by 24% and 29%, respectively.(16) In a study, concurrent oral ketoconazole increased the AUC of des-ciclesonide from orally inhaled ciclesonide by 3.6-fold. There were no changes in ciclesonide levels.(17) In a study in 24 healthy subjects, subjects were randomized to receive either ketoconazole (200 mg BID) or placebo on Days 4-9 of a a 9 day course of mometasone (400 mcg BID). No subject had mometasone levels greater than 150 pcg/ml on Day 3. Four of 12 subjects who received ketoconazole had mometasone Cmax levels greater than 200 mcg/ml on Day 9. Plasma cortisol levels appeared to decrease as well.(18) In a cross-over study in 15 healthy subjects, subjects were randomized to receive fluticasone furoate and vilanterol on days 5-11 with either ketoconazole (200mg once daily) or placebo for days 1-11 with a washout period of 7-14 days. Fluticasone furoate AUC was increased by 36%, Cmax was increased by 33%, and decreased systemic cortisol levels by 27%. There were no effects on heart rate and blood potassium levels. There was a small increase in QTc which was 7.6ms greater when compared to placebo; however, ketoconazole has been reported to increase QTc by 5-6ms. Vilanterol AUC was increased by 65% and Cmax was increased by 22%. There were no effects on heart rate and blood potassium levels. No serious adverse events occurred and no subjects withdrew from the study due to adverse events. The most common adverse event reported was headache. (19) Coadministration of orally inhaled fluticasone (1000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol AUC.(20) There is a case report of Cushing syndrome following the addition of voriconazole (200 mg twice daily for 21 days for 2 courses) to budesonide,(21) as well as voriconazole added to intranasal mometasone(22) and inhaled fluticasone.(22) There is a case report of Cushing syndrome following the addition of posaconazole (200 mg three times daily) to inhaled fluticasone.(23)	ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, NOXAFIL, POSACONAZOLE, SPORANOX, TOLSURA, VFEND, VFEND IV, VORICONAZOLE
Selected Corticosteroids/Levoketoconazole SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Levoketoconazole may inhibit the CYP3A4 mediated metabolism of some corticosteroids, resulting in increased systemic exposure. Levoketoconazole may also suppress endogenous cortisol output. Levoketoconazole is the enantiomer of ketoconazole. CLINICAL EFFECTS: Concurrent use of levoketoconazole may result in elevated levels of and effects from the corticosteroid, including Cushing syndrome. These effects have been seen with systemic as well as inhaled corticosteroids. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients should be carefully monitored with concurrent administration of these agents, or when levoketoconazole is added to corticosteroid therapy. The dose of the corticosteroid may need to be adjusted or alternative therapy considered. DISCUSSION: The concurrent use of ketoconazole has been shown to increase budesonide area-under-curve (AUC) by eight-fold. In a study in eight healthy subjects, the simultaneous administration of ketoconazole increased budesonide AUC by 6.5-fold. Administering the two agents 12 hours apart increased budesonide AUC by 3.8-fold. In a study in 6 healthy subjects, pretreatment with ketoconazole (200 mg daily) increased the AUC of a single intravenous dose of methylprednisolone (20 mg) by 135% and decreased its clearance by 60%. Concurrent ketoconazole also increased the reduction in 24-hour cortisol AUC and suppressed morning cortisol concentrations. In a study in 8 healthy subjects, ketoconazole decreased the clearance of methylprednisolone by 46% and increased mean residence time by 37%. In a randomized, cross-over study in 6 healthy subjects, pretreatment with ketoconazole (200 mg daily for 6 days) had no effect on the pharmacokinetics of a single intravenous dose of prednisolone (14.8 mg). In a study, concurrent oral ketoconazole increased the AUC of des-ciclesonide from orally inhaled ciclesonide by 3.6-fold. There were no changes in ciclesonide levels. In a study in 24 healthy subjects, subjects were randomized to receive either ketoconazole (200 mg BID) or placebo on Days 4-9 of a a 9 day course of mometasone (400 mcg BID). No subject had mometasone levels greater than 150 pcg/ml on Day 3. Four of 12 subjects who received ketoconazole had mometasone Cmax levels greater than 200 mcg/ml on Day 9. Plasma cortisol levels appeared to decrease as well. In a cross-over study in 15 healthy subjects, subjects were randomized to receive fluticasone furoate and vilanterol on days 5-11 with either ketoconazole (200mg once daily) or placebo for days 1-11 with a washout period of 7-14 days. Fluticasone furoate AUC was increased by 36%, Cmax was increased by 33%, and decreased systemic cortisol levels by 27%. There were no effects on heart rate and blood potassium levels. There was a small increase in QTc which was 7.6ms greater when compared to placebo; however, ketoconazole has been reported to increase QTc by 5-6ms. Vilanterol AUC was increased by 65% and Cmax was increased by 22%. There were no effects on heart rate and blood potassium levels. No serious adverse events occurred and no subjects withdrew from the study due to adverse events. The most common adverse event reported was headache. Coadministration of orally inhaled fluticasone (1000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol AUC.	RECORLEV
Selected Steroids/Nirmatrelvir-Ritonavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Nirmatrelvir/ritonavir may inhibit the metabolism of corticosteroids metabolized by CYP3A4.(1) CLINICAL EFFECTS: Nirmatrelvir/ritonavir may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Coadministration with corticosteroids of all routes of administration of which exposures are significantly increased by strong CYP3A4 inhibitors can increase the risk of Cushing's syndrome and adrenal suppression. However, the risk of Cushing's syndrome and adrenal suppression associated with short-term use of a strong CYP3A4 inhibitor is low.(1) The manufacturer of nirmatrelvir/ritonavir recommends considering alternative corticosteroids including beclomethasone, prednisone, and prednisolone.(1) DISCUSSION: Concurrent use of a single dose of midazolam 2 mg, a CYP3A4 substrate, with nirmatrelvir-ritonavir (300 mg/100 mg twice daily for nine doses) increased the maximum concentration (Cmax) and area-under-curve (AUC) of midazolam by 37% and 143%, respectively.(1) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(7,11,13) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(3) The cortisol AUC decreased by 86%.(3-6) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(7) Selected steroids linked to this monograph include: budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, and triamcinolone.(8)	PAXLOVID

The following contraindication information is available for BUDESONIDE (budesonide):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

Known hypersensitivity to budesonide or any ingredient of the formulation.

There are 0 contraindications.

There are 8 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Nasal septal perforation
Nasal septal ulcers
Nasal trauma
Ocular herpes simplex
Ocular hypertension
Open angle glaucoma
Operation on nose
Severe infection

There are 5 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Adrenocortical insufficiency
Cataracts
Epistaxis
Inactive tuberculosis
Parasitic infection

The following adverse reaction information is available for BUDESONIDE (budesonide):

Overview
Severe
Less Severe

Adverse reaction overview.

Adverse effects of budesonide occurring in 2% or more of patients receiving budesonide nasal spray and with an incidence more frequent than that of placebo include epistaxis, pharyngitis, bronchospasm, cough, and nasal irritation.

There are 12 severe adverse reactions.

More Frequent	Less Frequent
None.	Crusted nasal mucosa Epistaxis Lesion of nasal mucosa Lethargy Sore throat

Rare/Very Rare
Contact dermatitis Nasal candidiasis Nasal septal perforation Ocular hypertension Pharyngeal candidiasis Skin rash Urticaria

There are 3 less severe adverse reactions.

More Frequent	Less Frequent
Dry nose Nasal passage irritation	Sneezing

Rare/Very Rare
None.

The following precautions are available for BUDESONIDE (budesonide):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy of intranasal budesonide have not been established in children younger than 6 years of age. Intranasal corticosteroids may cause growth suppression in children or adolescents, and clinicians should routinely monitor (e.g., via stadiometry) the growth of pediatric patients receiving these drugs. See Cautions: Pediatric Precautions, in the Corticosteroids General Statement 68:04.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Category C. (See Users Guide.) Hypoadrenalism may occur in infants of mothers receiving corticosteroid therapy during pregnancy. These infants should be carefully monitored.

Not known whether budesonide is distributed in milk. Caution is advised if the drug is administered in nursing women.

Although no overall differences in safety and efficacy were observed between geriatric and younger patients, frequency of epistaxis appears to increase with age. In addition, the possibility that some older individuals may exhibit increased sensitivity to the drug cannot be ruled out.

The following icd codes are available for BUDESONIDE (budesonide)'s list of indications:

Allergic rhinitis
J30.1	Allergic rhinitis due to pollen
J30.2	Other seasonal allergic rhinitis
J30.5	Allergic rhinitis due to food
J30.8	Other allergic rhinitis
J30.81	Allergic rhinitis due to animal (cat) (dog) hair and dander
J30.89	Other allergic rhinitis
J30.9	Allergic rhinitis, unspecified
Allergic rhinitis prevention
J30.1	Allergic rhinitis due to pollen
J30.2	Other seasonal allergic rhinitis
J30.5	Allergic rhinitis due to food
J30.8	Other allergic rhinitis
J30.81	Allergic rhinitis due to animal (cat) (dog) hair and dander
J30.89	Other allergic rhinitis
J30.9	Allergic rhinitis, unspecified
Chronic non-allergic rhinitis
J31.0	Chronic rhinitis
Perennial allergic rhinitis
J31.0	Chronic rhinitis