Pulmicort Flexhaler

Drug overview for PULMICORT FLEXHALER (budesonide):

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

Budesonide is a synthetic, nonhalogenated corticosteroid that has potent glucocorticoid and weak mineralocorticoid activity.

Budesonide is used orally for the management of mild to moderate Crohn's disease. Budesonide is used by oral inhalation for the management of bronchial asthma. Budesonide in fixed combination with formoterol fumarate is used by oral inhalation for the treatment of asthma and also for maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

DRUG IMAGES

PULMICORT 90 MCG FLEXHALER
PULMICORT 180 MCG FLEXHALER

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

Indications:
Maintenance therapy for asthma

Professional Synonyms:
Therapy to achieve long-term asthma control

Dosing information for PULMICORT FLEXHALER
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
PULMICORT 90 MCG FLEXHALER	Maintenance	Adults inhale 2 puffs (180 mcg) by inhalation route 2 times per day

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

Contraindicated
Severe
Moderate

There are 1 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Desmopressin/Glucocorticoids SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Glucocorticoids increase the risk of hyponatremia.(1-4) CLINICAL EFFECTS: Concurrent use of glucocorticoids may increase the risk of hyponatremia with desmopressin.(1-4) PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (carbamazepine, chlorpromazine, lamotrigine, loop diuretics, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants). PATIENT MANAGEMENT: The concurrent use of systemic or inhaled glucocorticoids with desmopressin is contraindicated.(1-4) Desmopressin may be initiated 3 days or 5 half-lives after glucocorticoid discontinuation, whichever is longer. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1) DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)	DDAVP, DESMOPRESSIN ACETATE, NOCDURNA

Drug Interaction

Drug Names

Desmopressin/Glucocorticoids

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Glucocorticoids increase the risk of hyponatremia.(1-4)

CLINICAL EFFECTS: Concurrent use of glucocorticoids may increase the risk of hyponatremia with desmopressin.(1-4)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (carbamazepine, chlorpromazine, lamotrigine, loop diuretics, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants).

PATIENT MANAGEMENT: The concurrent use of systemic or inhaled glucocorticoids with desmopressin is contraindicated.(1-4) Desmopressin may be initiated 3 days or 5 half-lives after glucocorticoid discontinuation, whichever is longer. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83

mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

DDAVP, DESMOPRESSIN ACETATE, NOCDURNA

There are 6 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
Cosyntropin/Agents Affecting Plasma Cortisol Levels SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1) CLINICAL EFFECTS: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of cosyntropin states accuracy of diagnosis using the cosyntropin diagnostic test may be complicated by concomitant medications affecting plasma cortisol levels.(1) Agents affecting plasma cortisol levels and recommendation to stop prior to cosyntropin diagnostic test include: - Glucocorticoids: May elevate plasma cortisol levels. Stop these drugs on the day of testing. Long-acting glucocorticoids may need to be stopped for a longer period before testing. - Spironolactone: May elevate plasma cortisol levels. Stop spironolactone on the day of testing. - Estrogen: May elevate plasma total cortisol levels. Discontinue estrogen containing drugs 4 to 6 weeks prior to testing to allow cortisol binding globulin levels to return to levels within the reference range. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.(1) DISCUSSION: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)	CORTROSYN, COSYNTROPIN
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 5 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
Quinolones/Corticosteroids SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Quinolone-induced arthropathy is a class effect of the quinolones.(1) Exactly how corticosteroid use increases the risk of tendon rupture is unknown. CLINICAL EFFECTS: Concurrent use of quinolones and corticosteroids may increase the risk of tendonitis and/or tendon rupture. This affect is most common in the Achilles tendon, but has been reported in the rotator cuff (shoulder), hand, biceps, thumb, and other tendons.(2-9) PREDISPOSING FACTORS: Risk factors for tendinitis and tendon rupture include age greater than 60; a history of kidney, heart, or lung transplantation, strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. PATIENT MANAGEMENT: Quinolone use should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should be instructed to rest and refrain from exercise until the diagnosis of tendonitis tendon rupture has been excluded.(2-9) DISCUSSION: Ruptures of the shoulder, hand, Achilles tendon, or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving ciprofloxacin,(2) gatifloxacin,(3) levofloxacin,(4) lomefloxacin,(5) moxifloxacin,(6) nalidixic acid,(7) norfloxacin,(8) and ofloxacin.(9) A retrospective review of the IMS Health database examined quinolone use use from July 1, 1992 to June 30, 1998. The adjusted relative risk of tendon disorder with concurrent quinolone use was 1.9. Relative risk increased to 3.2 in patients aged 60 or older compared to 0.9 in patients aged less than 60. In patients aged 60 or older who used corticosteroids and quinolones concurrently, relative risk increased to 6.2.(10) In contrast, another retrospective review examined patients from a health insurance claims database and found no apparent effect from concurrent quinolone and corticosteroid use.(11) In a review of the follow-up to 42 spontaneously reported case of quinolone-associated tendon disorders in the Netherlands between January, 1988 and January, 1998, risk factors for tendon disorders included age older than 60, oral corticosteroid use, and existing joint problems.(12) In a review of the Swiss Drug Monitoring system, four of seven cases of levofloxacin-associated tendon problems also involved concurrent oral or inhaled corticosteroids.(13) In a review of the Medline database from 1966-2001, 98 case reports of tendinopathy associated with quinolones were located. Thirty-two (32.7%) of the patients had received systemic or inhaled corticosteroids before and during quinolone therapy. Of the 40 patients who suffered a tendon rupture, 21 (52.5%) were receiving corticosteroids.(14) Other authors have reported cases of tendon disorders in patients receiving concurrent corticosteroids and ciprofloxacin,(15) levofloxacin, (16-20) and ofloxacin.(21)	AVELOX IV, BAXDELA, CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W, GATIFLOXACIN SESQUIHYDRATE, LEVOFLOXACIN, LEVOFLOXACIN HEMIHYDRATE, LEVOFLOXACIN-D5W, MOXIFLOXACIN, MOXIFLOXACIN HCL, NALIDIXIC ACID, OFLOXACIN
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 PULMICORT FLEXHALER (budesonide):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

Known hypersensitivity to budesonide or any ingredient in the formulation. Orally inhaled budesonide is contraindicated as primary treatment of acute asthmatic attacks or status asthmaticus when intensive measures (e.g., an orally inhaled beta2adrenergic agonist, an orally inhaled anticholinergic agent, subcutaneous epinephrine, IV aminophylline, and/or an oral/IV glucocorticoid) are required. Orally inhaled budesonide powder (Pulmicort(R) Flexhaler(R)) is contraindicated in patients with severe hypersensitivity to milk proteins.

Budesonide in fixed combination with formoterol fumarate (Symbicort(R)) is contraindicated as primary treatment of status asthmaticus or other acute episodes of asthma or chronic obstructive pulmonary disease (COPD) when intensive measures are required. When budesonide is used in fixed combination with formoterol fumarate, contraindications associated with formoterol fumarate should be considered.

There are 0 contraindications.

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

Severe List
Herpes simplex infection
Inactive tuberculosis
Ocular herpes simplex
Ocular hypertension
Parasitic infection
Pulmonary tuberculosis
Varicella contact
Varicella zoster virus infection

There are 6 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Cataracts
Glaucoma
Hypercortisolism
Oropharyngeal candidiasis
Osteopenia
Osteoporosis

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

Overview
Severe
Less Severe

Adverse reaction overview.

Adverse effects occurring in at least 5% of patients receiving budesonide oral capsules include headache, dizziness, nausea, vomiting, dyspepsia, diarrhea, abdominal pain, flatulence, sinusitis, respiratory infection, viral infection, pain (including back pain), arthralgia, and fatigue. Adverse effect profile in long-term treatment was similar to that of short-term treatment. Adverse effects occurring in 1% or more of patients receiving budesonide by oral inhalation (as a powder using a Flexhaler(R) or a Turbuhaler(R) (no longer commercially available in the US) or as an inhalation suspension, administered via nebulization) include infections (e.g., respiratory infection, ocular infection), nasopharyngitis, pharyngitis, nasal congestion, allergic rhinitis, sinusitis, viral infection (e.g., herpes simplex), cough, voice alteration, stridor, earache, otitis (media or externa), viral infection, flu-like syndrome, moniliasis, oral candidiasis, flu syndrome, fever, headache, migraine, insomnia, dysphonia, hyperkinesia, asthenia, fatigue, emotional lability, pain (e.g., back pain), arthralgia, myalgia, hypertonia, fractures, dyspepsia, gastroenteritis, nausea, vomiting, diarrhea, abdominal pain, dry mouth, taste perversion, weight gain, anorexia, epistaxis, ecchymosis, purpura, cervical lymphadenopathy, conjunctivitis, rash (may be pustular), pruritus, allergic reaction, contact dermatitis, syncope, and chest pain.

There are 13 severe adverse reactions.

More Frequent	Less Frequent
None.	None.

Rare/Very Rare
Adrenocortical insufficiency Anaphylaxis Angioedema Cataracts Drug-induced psychosis Eosinophilic granulomatosis with polyangiitis Glaucoma Hypercortisolism Immunosuppression Ocular hypertension Osteopenia Paradoxical bronchospasm Urticaria

There are 36 less severe adverse reactions.

More Frequent	Less Frequent
Allergic rhinitis Cough Dyspepsia Gastroenteritis Nasal congestion Oral candidiasis Pharyngitis Sinusitis Sore throat Upper respiratory infection Voice change	Abdominal pain with cramps Acute bacterial otitis media Bronchitis Bruising Dysgeusia Ecchymosis Fever General weakness Headache disorder Insomnia Nausea Pain Skin rash Syncope Vomiting Xerostomia

Rare/Very Rare
Aggressive behavior Arthralgia Contact dermatitis Depression Esophageal candidiasis Flu-like symptoms Irritability Nervousness Symptoms of anxiety

The following precautions are available for PULMICORT FLEXHALER (budesonide):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy of oral budesonide delayed-release capsules have not been established in pediatric patients younger than 18 years of age with Crohn's disease. Oral budesonide (using preparations other than Entecort(R) EC) has been used for the management of mild to moderately active Crohn's disease in a limited number of pediatric patients without unusual adverse effects. Benign intracranial hypertension has been reported in at least one pediatric patient with Crohn's disease receiving the drug.

Safety and efficacy of budesonide inhalation powder have not been established in children younger than 6 years of age. Efficacy of budesonide inhalation suspension has not been established in children younger than 1 year of age, while safety of the suspension has not been established in children younger than 6 months of age. Safety and efficacy of budesonide in fixed combination with formoterol fumarate (Symbicort(R)) inhalation aerosol in patients 12 years of age or older with asthma have been established in studies of up to 12 months' duration; in addition, safety and efficacy of the fixed-combination preparation in children 6 to less than 12 years of age with asthma have been established in studies of up to 12 weeks' duration.

The manufacturer states that safety and efficacy of the fixed-combination preparation in children younger than 6 years of age with asthma have not been established. Use of corticosteroids may lead to suppression of growth in children and adolescents. Therefore, children receiving prolonged therapy with orally inhaled budesonide should be monitored periodically for possible adverse effects on growth and development. (See Cautions: Pediatric Precautions, in the Corticosteroids General Statement 68:04.)

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Category B (orally inhaled powder and inhalation suspension); category C (oral capsules and the fixed combination of budesonide and formoterol fumarate oral inhalation aerosol). (See Users Guide.) Hypoadrenalism may occur in infants of women receiving corticosteroid therapy during pregnancy. These infants should be carefully monitored.

Like other corticosteroids, budesonide is distributed into milk; however, data are not available on the effects of the drug on the breast-fed child or on milk production. The benefits of breast-feeding and the importance of budesonide to the woman should be considered along with any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition. The manufacturer of budesonide oral inhalation powder (Pulmicort(R) Flexhaler(R)) states that the drug should be used in nursing women only if clinically appropriate and that therapy should be titrated to the lowest effective dosage. In addition, budesonide powder inhaler should be used immediately after nursing to minimize infant exposure to the drug.

Clinical studies of oral budesonide delayed-release capsules or budesonide oral inhalation powder did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients. While other clinical experience with budesonide inhalation powder or inhalation suspension or with the inhalation aerosol containing budesonide in fixed combination with formoterol fumarate has not revealed age-related differences in response, oral drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. Safety of budesonide inhalation powder in patients 65 years of age or older was similar to that observed in younger adults.

No substantial differences in safety and efficacy of budesonide in fixed combination with formoterol fumarate were observed in geriatric patients relative to younger adults. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered. (See Dosage and Administration: Special Populations.)

Maintenance therapy for asthma
J45	Asthma
J45.2	Mild intermittent asthma
J45.20	Mild intermittent asthma, uncomplicated
J45.3	Mild persistent asthma
J45.30	Mild persistent asthma, uncomplicated
J45.4	Moderate persistent asthma
J45.40	Moderate persistent asthma, uncomplicated
J45.5	Severe persistent asthma
J45.50	Severe persistent asthma, uncomplicated
J45.9	Other and unspecified asthma
J45.90	Unspecified asthma
J45.909	Unspecified asthma, uncomplicated