Airsupra: Package Insert / Prescribing Info

2.1 Recommended Dosage and Administration

The recommended dosage of AIRSUPRA is albuterol 180 mcg and budesonide 160 mcg (administered as 2 actuations of AIRSUPRA [albuterol/budesonide 90 mcg/80 mcg]) as needed for asthma symptoms by oral inhalation. Do not take more than 6 doses (12 inhalations) in a 24-hour period [see Warnings and Precautions (5.4)].

2.2 Priming Before Use

•

Priming AIRSUPRA is essential to ensure appropriate drug content in each actuation. Prime AIRSUPRA before using for the first time. To prime AIRSUPRA, release 4 sprays into the air away from the face, shaking well before each spray.

•

AIRSUPRA must be re-primed when the inhaler has not been used for more than 7 days, is dropped, or after cleaning. To re-prime AIRSUPRA, release 2 sprays into the air away from the face, shaking well before each spray.

2.3 Dose Counter

The canister has an attached dose indicator (also known as puff indicator) which indicates how many inhalations (puffs) remain. The dose indicator pointer will move after every actuation. The pointer will show the number of inhalations remaining in the canister. When nearing the end of the usable inhalations, the color behind the number in the dose indicator display window changes to yellow. AIRSUPRA should be discarded when the pointer reaches zero.

5.1 Deterioration of Asthma

Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient continues to experience symptoms after using AIRSUPRA or requires more doses of AIRSUPRA than usual, this may be a marker of destabilization of asthma and requires evaluation of the patient and their treatment regimen.

5.2 Paradoxical Bronchospasm

AIRSUPRA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with AIRSUPRA, it should be discontinued immediately, and alternative therapy should be instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister.

5.3 Cardiovascular Effects

AIRSUPRA, like other drugs containing beta2-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, blood pressure, and/or other symptoms. If such effects occur, AIRSUPRA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST-segment depression. The clinical significance of these findings is unknown. Therefore, AIRSUPRA, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.4 Do Not Exceed Recommended Dosage

As with other inhaled drugs containing beta-adrenergic agents, AIRSUPRA should not be used more than the maximum daily dose [see Dosage and Administration (2.1)], as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

5.5 Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions can occur after administration of albuterol sulfate and budesonide, components of AIRSUPRA, as demonstrated by cases of anaphylaxis, angioedema, bronchospasm, oropharyngeal edema, rash, and urticaria. Discontinue AIRSUPRA if such reactions occur [see Contraindications (4)].

5.6 Risk of Sympathomimetic Amines with Certain Coexisting Conditions

AIRSUPRA, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.7 Hypokalemia

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Warnings and Precautions (5.3), Clinical Pharmacology (12.1)]. The decrease in serum potassium is usually transient, not requiring supplementation.

5.8 Immunosuppression and Risk of Infections

Patients who are using drugs that suppress the immune system are more susceptible to infection. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients using corticosteroids. In patients who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective Prescribing Information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.9 Oropharyngeal Candidiasis

AIRSUPRA contains budesonide, an inhaled corticosteroid (ICS). Localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with ICS agents. Monitor patients periodically. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with AIRSUPRA continues. In some cases, therapy with AIRSUPRA may need to be interrupted. Advise the patient to rinse his/her mouth with water, if available, without swallowing following administration of AIRSUPRA to help reduce the risk of oropharyngeal candidiasis.

5.10 Hypercorticism and Adrenal Suppression

Budesonide, a component of AIRSUPRA, will often help control asthma symptoms with less suppression of hypothalamic-pituitary-adrenal (HPA) function than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of AIRSUPRA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing AIRSUPRA.

Because of the possibility of systemic absorption of ICS, patients treated with AIRSUPRA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, appropriate therapy should be initiated as needed.

5.11 Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, post-menopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.

5.12 Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported following the long-term administration of ICS, including budesonide, a component of AIRSUPRA. Consider referral to an ophthalmologist in patients who develop ocular symptoms.

5.13 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the co-administration of AIRSUPRA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

5.14 Effects on Growth in Pediatric Patients

Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of AIRSUPRA have not been established in pediatric patients, and AIRSUPRA is not indicated for use in this population [see Use in Specific Populations (8.4)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of AIRSUPRA is based on data from 2 trials: MANDALA and DENALI [see Clinical Studies (14)]. All reported safety data is based on patients who received AIRSUPRA 180 mcg/160 mcg.

In MANDALA, in which patients with moderate to severe asthma were administered AIRSUPRA as needed, a total of 1015 patients 12 to 84 years of age (mean 51 years) received at least one dose of AIRSUPRA and participated in the study for a mean duration of 310 days. Of these, 905 patients were exposed for at least 24 weeks and 323 patients had exposure for at least 1 year. The mean daily use was 2.6 actuations. On the majority of study days, patients used 2 or less actuations; more than 8 actuations were used on less than 2% of study days. AIRSUPRA is not approved for patients 12 to 17 years of age.

The incidence of common adverse reactions in MANDALA is described in Table 1.

The safety profile of AIRSUPRA in MANDALA was similar across the 2 treatment groups irrespective of background ICS dose.

In DENALI, AIRSUPRA 180 mcg/160 mcg was administered 4 times a day for 12 weeks. A total of 197 patients 13 to 81 years of age (mean 50 years) with mild to moderate asthma received at least 1 dose of AIRSUPRA. The adverse reactions profile was similar to MANDALA except for the following adverse reactions for AIRSUPRA with an incidence ≥ 1.0% that exceeded the incidence in MANDALA: headache (5.1%), dysphonia (2.0%), and oral/oropharyngeal candidiasis (1.5%), compared to headache (7.1%), dysphonia (0%), and oral/oropharyngeal candidiasis (0%) in the placebo arm.

6.2 Postmarketing Experience

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

Cardiovascular disorders: myocardial ischemia, tremor, tachycardia, palpitations, extrasystoles, arrhythmias (including atrial fibrillation, supraventricular tachycardia), syncope, hypertension, peripheral vasodilatation

Endocrine disorders: signs or symptoms of systemic glucocorticosteroid effect (including hypofunction of the adrenal gland and reduction of growth rate)

Eye disorders: cataracts, glaucoma, increased intraocular pressure

Immune system disorders: immediate and delayed hypersensitivity reactions (including anaphylactic reaction, angioedema, bronchospasm, rash, contact dermatitis and urticaria)

General disorders: fever, weight gain, taste perversion, flu syndrome

Gastrointestinal disorders: nausea, vomiting, dyspepsia, diarrhea

Infections: sinusitis, pharyngitis, respiratory tract infection, nasopharyngitis, gastroenteritis, otitis media, laryngitis

Metabolic disorders: hypokalemia, metabolic acidosis

Musculoskeletal disorders: hypertonia, musculoskeletal pain, myalgia, asthenia, arthralgia, muscle cramps, fracture

Neurological or psychiatric system disorders: migraine, dizziness, central nervous system stimulation, insomnia, hyperactivity, psychiatric symptoms (including psychosis, depression, aggressive reactions, irritability, nervousness, restlessness, behavioral disturbances and anxiety)

Respiratory, thoracic, and mediastinal disorders: rhinitis, nasal congestion, throat irritation, oropharyngeal edema, upper respiratory inflammation, drying or irritation of the oropharynx

Skin and subcutaneous tissue disorders: skin bruising, ecchymosis

7.1 Inhibitors of Cytochrome P450 3A4

The main route of metabolism of corticosteroids, including budesonide, a component of AIRSUPRA, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of a CYP3A4 inhibitor may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the co-administration of AIRSUPRA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.11)].

7.2 Use with Other Short-Acting Bronchodilators

AIRSUPRA contains the short-acting beta-agonist, albuterol. Therefore, concomitant use of additional beta-agonists with AIRSUPRA should be used judiciously to prevent beta-agonist overdose.

7.3 Beta-Blockers

Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as albuterol, a component of AIRSUPRA, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic-blocking agents in these patients. In this setting, consider cardioselective beta-blockers, although they should be administered with caution.

7.4 Diuretics

The ECG changes and/or hypokalemia which may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of AIRSUPRA with non-potassium-sparing diuretics. Consider monitoring potassium levels.

7.5 Digoxin

Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and AIRSUPRA.

7.6 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

AIRSUPRA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on the cardiovascular system may be potentiated.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of AIRSUPRA have not been established in pediatric patients. A limited number of pediatric patients (4 to 17 years of age) were enrolled in the efficacy trial (MANDALA) to evaluate AIRSUPRA to reduce the risk of severe asthma exacerbations. The primary efficacy endpoint was time to first severe asthma exacerbation. Results showed there were 9 patients with severe exacerbation events in 34 patients 12 to 17 years of age treated with AIRSUPRA 180 mcg/160 mcg and 7 patients with severe exacerbation events in 34 patients treated with albuterol (AS MDI) [HR 1.44 (0.54, 3.87)]. There were 11 patients with severe exacerbation events in 41 patients 4 to 11 years of age treated with albuterol/budesonide (AS-BD MDI) 180 mcg/80 mcg and 10 in the 42 patients 4 to 11 years of age treated with AS MDI [HR: 1.09 (0.46, 2.56)]. These data are inadequate to make a determination regarding the safety or effectiveness of AIRSUPRA or AS-BD 180 mcg/80 mcg in pediatric patients 4 to 17 years of age [see Clinical Studies (14)].

Controlled clinical studies have shown that ICS agents, including budesonide, one of the components of AIRSUPRA, may cause a reduction in growth velocity in pediatric patients. The effects of long-term treatment of pediatric patients with ICS on final adult height are not known [see Warnings and Precautions (5.14)].

8.5 Geriatric Use

There were 741 patients 65 years of age and older in the clinical studies for asthma [see Clinical Studies (14)]. Of the total number of AIRSUPRA-treated patients in these studies, 231 (19%) were 65 years of age and older, while 41 (3%) were 75 years of age and older. In general, no differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

As with other products containing beta2-agonists, special caution should be observed when using AIRSUPRA in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug.

All beta2-adrenergic agonists, including albuterol, are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, care should be taken when dosing, and it may be useful to monitor renal function.

8.6 Hepatic Impairment

Formal pharmacokinetic studies using AIRSUPRA have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in the plasma. Therefore, patients with hepatic disease should be closely monitored.

8.7 Renal Impairment

Formal pharmacokinetic studies using AIRSUPRA have not been conducted in patients with renal impairment.

12.1 Mechanism of Action

AIRSUPRA contains both albuterol and budesonide; therefore, the mechanisms of action described below for the individual components apply to AIRSUPRA. These drugs represent two classes of medications (a short-acting selective beta2-adrenergic agonist and a synthetic corticosteroid) that have different effects on clinical, physiological, and inflammatory indices of asthma.

Albuterol

In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta2-agonists may have cardiac effects.

Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes [see Warnings and Precautions (5.3)].

Budesonide

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. The clinical significance of this is unknown.

In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.

The precise mechanism of corticosteroid actions on inflammation in asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and both genomic and non-genomic systemic corticosteroid effects over a wide range of doses of inhaled budesonide. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%), and the low potency of formed metabolites (see below).

12.2 Pharmacodynamics

Albuterol

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract in the form of bronchial smooth muscle relaxation than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes [see Warnings and Precautions (5.3)].

Budesonide

The therapeutic effects of conventional doses of orally inhaled budesonide are largely explained by its direct local action on the respiratory tract.

Inhaled budesonide has been shown to decrease airway reactivity in various challenge models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain.

HPA Axis Effects

AIRSUPRA, like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods [see Warnings and Precautions (5.10)].

The effects of AIRSUPRA on hypothalamic-pituitary-adrenal (HPA) axis were not studied in dedicated clinical trials.

The effects of inhaled AIRSUPRA 180 mcg/160 mcg and AS-BD MDI 180 mcg/80 mcg administered as 2 inhalations of 90 mcg/80 mcg or 90 mcg/40 mcg as needed in response to symptoms were studied on morning serum cortisol in 1254 patients in MANDALA with moderate to severe asthma between the ages of 4 and 84 years. Morning serum cortisol was collected at baseline, Week 24, end of study, or time of discontinuation. Morning cortisol concentration changes over time varied across treatment groups with mean changes from baseline to the Week 24 visit of ‑1.52 nmol/L, +5.43 nmol/L, and +15.42 nmol/L in the AIRSUPRA 180 mcg/160 mcg, AS-BD MDI 180 mcg/80 mcg, and AS MDI 180 mcg treatment groups, respectively.

12.3 Pharmacokinetics

The pharmacokinetics of AIRSUPRA and its individual components were evaluated in 3 studies in subjects 18 years of age and older (2 studies in healthy subjects and 1 study in patients with asthma). The pharmacokinetics of albuterol and budesonide from AIRSUPRA are comparable to the pharmacokinetics of albuterol and budesonide when administered as single dose of the individual components in studies of healthy subjects.

The pharmacokinetics presented below are primarily from studies conducted on AIRSUPRA and on its individual components, albuterol (AS MDI) and budesonide (BD MDI), also administered by the inhaled route.

Absorption

Albuterol
Healthy Subjects: Following inhaled administration of AIRSUPRA 180 mcg/160 mcg (administered as 2 inhalations of 90 mcg/80 mcg), the median tmax of albuterol was 1.00 hour (individual values ranged from 0.08 to 6.05 hours). Geometric mean Cmax was 472.2 pg/mL (individual values ranged from 38.4 to 971 pg/mL).

Asthma Patients: Following increasing cumulative doses (a total dose of 1440 mcg) of albuterol (AS MDI) and an active albuterol aerosol inhaler comparator in patients with mild to moderate asthma, mean albuterol plasma concentrations (at 15 minutes after dose) increased from predose levels (44.2 and 51.4 pg/mL) to 3278.0 pg/mL and 5241.7 pg/mL with AS MDI and the comparator, respectively. Results from this study indicate the total systemic exposure of albuterol was 21% (for AUC) and 27% (for Cmax) lower for AS MDI than for the comparator.

Budesonide
Healthy Subjects: Following inhaled administration in healthy subjects of AIRSUPRA 180 mcg/160 mcg (administered as 2 inhalations of 90 mcg/80 mcg), the median tmax of budesonide was 0.33 hours (individual values ranged from 0.08 to 4.00 hours). Geometric mean Cmax was 272.8 pg/mL (individual values ranged from 51.7 to 819 pg/mL). Systemic exposure to budesonide with AIRSUPRA did not exceed that from inhaled budesonide via a dry powder inhaler comparator in healthy subjects.

Distribution

Albuterol
Healthy Subjects: Following inhaled administration of AIRSUPRA 180 mcg/160 mcg (administered as 2 inhalations of 90 mcg/80 mcg), the mean apparent volume of distribution (Vz/F) of albuterol was 565.7 L.

Budesonide
Healthy Subjects: Following inhaled administration of AIRSUPRA 180 mcg/160 mcg (administered as 2 inhalations of 90 mcg/80 mcg), the mean apparent volume of distribution (Vz/F) of budesonide administered in AIRSUPRA was 1002 L.

Budesonide was 85-90% bound to plasma proteins. Protein binding was constant over the concentration range of 1‑100 nmol/L. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.

Elimination

Following inhaled single-dose administration with AIRSUPRA in healthy subjects, the mean terminal half-life of albuterol was estimated to be 7.1 hours (individual values ranged from 4.62 to 10.0 hours) and the mean terminal half-life of budesonide was estimated to be 4.1 hours (individual values ranges from 2.46 to 6.15 hours).

Metabolism

Albuterol
Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase).

Budesonide
In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations.

Excretion

Albuterol
The primary route of elimination of albuterol is through renal excretion of either the parent compound or the primary metabolite.

Budesonide
Budesonide is excreted in urine and feces in the form of metabolites. Approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine.

Specific Populations

Specific studies to examine the effects of age, sex, gender/ethnicity, or body weight on the pharmacokinetics of AIRSUPRA have not been conducted.

Patients with Renal or Hepatic Impairment
There are no data regarding the specific use of AIRSUPRA in patients with hepatic or renal impairment.

The effect of renal impairment on the pharmacokinetics of albuterol was evaluated in 5 patients with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used when administering high doses of AIRSUPRA to patients with renal impairment.

Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy subjects.

Drug Interaction Studies

Inhibitors of cytochrome P450 enzymes
Ketoconazole: As a strong inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, ketoconazole increased plasma levels of orally ingested budesonide [see Warnings and Precautions (5.11), Drug Interactions (7.1)].

Cimetidine: At recommended doses, cimetidine, a nonspecific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with AIRSUPRA; however, available studies for the individual components, albuterol and budesonide, are described below. Findings are reported based on the MRHDID for albuterol and budesonide contained in AIRSUPRA.

Albuterol
In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg/day (approximately 15 times the MRHDID for adults on a mg/m2 basis). In another study this effect was blocked by the coadministration of propranolol, a nonselective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg/day (approximately 1,900 times the MRHDID for adults on a mg/m2 basis). In a 22-month study in Golden Hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg/day (approximately 250 times the MRHDID for adults on a mg/m2 basis).

Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg/day (approximately 380 times the MRHDID for adults on a mg/m2 basis).

Budesonide
In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats receiving an oral dose of 50 mcg/kg/day (approximately 0.5 times the MRHDID in adults on a mcg/m2 basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg/day (approximately 0.5 times the MRHDID in adults on a mcg/m2 basis) and in female rats at oral doses up to 50 mcg/kg/day (approximately 0.5 times the MRHDID doses in adults on a mcg/m2 basis). In two additional 2-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg/day (approximately 0.5 times the MRHDID in adults on a mcg/m2 basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg/day (approximately 0.5 times the MRHDID in adults on a mcg/m2 basis). The concurrent reference corticosteroids (prednisone and triamcinolone acetonide) in these two studies showed similar findings.

There was no evidence of a carcinogenic effect when budesonide was administered orally for 91 weeks to mice at doses up to 200 mcg/kg/day (equal to the MRHDID in adults on a mcg/m2 basis). Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat hepatocyte culture.

Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg/day (approximately 0.8 times the MRHDID in adults on a mcg/m2 basis). At a subcutaneous dose of 20 mcg/kg/day (approximately 0.2 times the MRHDID in adults on a mcg/m2 basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 mcg/kg/day (approximately 0.05 times the MRHDID in adults on a mcg/m2 basis).