Albuterol Sulfate and Budesonide (Oral Inhalation) (Monograph)

Brand name: Airsupra
Drug class: Adrenals

Introduction

Albuterol sulfate and budesonide (albuterol/budesonide) is a fixed-combination preparation containing a beta₂-adrenergic agonist (albuterol) and a corticosteroid (budesonide).

Uses for Albuterol Sulfate and Budesonide (Oral Inhalation)

Albuterol sulfate and budesonide has the following uses:

Albuterol/budesonide is indicated for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients ≥18 years of age with asthma.

Albuterol Sulfate and Budesonide (Oral Inhalation) Dosage and Administration

General

Albuterol/budesonide is available in the following dosage form(s) and strength(s):

Inhalation aerosol: Pressurized metered dose inhaler that delivers a combination of albuterol 90 mcg and budesonide 80 mcg per actuation.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Recommended dosage: albuterol/budesonide 180 mcg/160 mcg (administered as 2 actuations of albuterol/budesonide 90 mcg/80 mcg) by oral inhalation as needed for asthma symptoms.

• Do not take more than 6 doses (12 inhalations) in a 24-hour period.

• Prime inhaler prior to first use. Re-prime when inhaler has not been used for more than 7 days, is dropped, or after cleaning.

• Discard when the dose counter displays 0.

Related/similar drugs

prednisone, Breo Ellipta, Xopenex, Xolair, Dulera, Atrovent

Cautions for Albuterol Sulfate and Budesonide (Oral Inhalation)

Contraindications

Hypersensitivity to albuterol, budesonide, or to any of the excipients.

Warnings/Precautions

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 albuterol/budesonide or requires more doses of albuterol/budesonide than usual, this may be a marker of destabilization of asthma and requires evaluation of the patient and their treatment regimen.

Paradoxical Bronchospasm

Albuterol/budesonide can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with albuterol/budesonide, 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.

Cardiovascular Effects

Albuterol/budesonide, 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, albuterol/budesonide 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, albuterol/budesonide, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Do Not Exceed Recommended Dosage

As with other inhaled drugs containing beta-adrenergic agents, albuterol/budesonide should not be used more than the maximum daily dose, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, can occur after administration of albuterol sulfate and budesonide, as demonstrated by cases of anaphylaxis, angioedema, bronchospasm, oropharyngeal edema, rash, and urticaria. Discontinue albuterol/budesonide if such reactions occur.

Risk of Sympathomimetic Amines with Certain Coexisting Conditions

Albuterol/budesonide, 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 IV albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

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. The decrease in serum potassium is usually transient, not requiring supplementation.

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.

Oropharyngeal Candidiasis

Albuterol/budesonide 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 albuterol/budesonide continues. In some cases, therapy may need to be interrupted. Advise the patient to rinse his/her mouth with water, if available, without swallowing following administration of albuterol/budesonide to help reduce the risk of oropharyngeal candidiasis.

Hypercorticism and Adrenal Suppression

Budesonide, a component of albuterol/budesonide, 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 albuterol/budesonide 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 albuterol/budesonide.

Because of the possibility of systemic absorption of ICS, patients treated with albuterol/budesonide 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.

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.

Glaucoma and Cataracts

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

Drug Interactions with Strong Cytochrome P-450 (CYP)3A4 Inhibitors

Caution should be exercised when considering the co-administration of albuterol/budesonide 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.

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 albuterol/budesonide have not been established in pediatric patients, and albuterol/budesonide is not indicated for use in this population.

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy. For more information, contact the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists at 1-877-311-8972 or visit [Web].

Available data from published case series, epidemiological studies and reviews with budesonide use in pregnant women have not identified a drug-related risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Available data from epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. The available epidemiological studies have methodologic limitations, including inconsistent comparator groups, definitions of outcomes, and assessment of disease impact. There are risks to the mother and fetus associated with asthma in pregnancy. Animal reproduction studies have not been conducted with albuterol/budesonide, however, animal studies are available with its individual components.

Administration of albuterol to mice and rabbits during the period of organogenesis revealed evidence of adverse developmental outcomes (cleft palate in mice, delayed ossification in rabbits) at less than maximum recommended human daily inhalation dose (MRHDID).

In animal reproduction studies, budesonide, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at less than the MRHDID in adults, but these effects were not seen in rats that received inhaled doses approximately 2.5 times the MRHDID in adults. Experience with oral corticosteroids suggests that rodents are more prone to structural abnormalities from corticosteroid exposure than humans.

The background risk of major birth defects and miscarriage of the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Because of the potential for beta-agonist interference with uterine contractility, use of albuterol/budesonide during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Albuterol/budesonide has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta₂-agonists, including albuterol.

Lactation

There are no available data on the effects of albuterol/budesonide on the breastfed child or on milk production.

There are no available data on the presence of albuterol in human milk, the effects on the breastfed child, or the effects on milk production. However, plasma levels of albuterol after inhaled therapeutic doses are low in humans, and if present in breast milk, are likely to be correspondingly low.

Budesonide, like other inhaled corticosteroids, is present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for albuterol/budesonide and any potential adverse effects on the breastfed child from albuterol/budesonide or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of albuterol/budesonide 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 albuterol/budesonide 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 albuterol/budesonide 180 mcg/160 mcg and 7 patients with severe exacerbation events in 34 patients treated with albuterol sulfate [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 180 mcg/80 mcg and 10 in the 42 patients 4 to 11 years of age treated with albuterol sulfate [HR: 1.09 (0.46, 2.56)]. These data are inadequate to make a determination regarding the safety or effectiveness of albuterol/budesonide in pediatric patients 4 to 17 years of age.

Controlled clinical studies have shown that ICS agents, including budesonide, one of the components of albuterol/budesonide, 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.

Geriatric Use

There were 741 patients 65 years of age and older in the clinical studies for asthma. Of the total number of albuterol/budesonide-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 albuterol/budesonide 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.

Hepatic Impairment

Formal pharmacokinetic studies using albuterol/budesonide 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 the drug in the plasma. Therefore, patients with hepatic disease should be closely monitored.

Renal Impairment

Formal pharmacokinetic studies using albuterol/budesonide have not been conducted in patients with renal impairment.

Common Adverse Effects

Most common adverse reactions (incidence ≥ 1%) are headache, oral candidiasis, cough, dysphonia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong cytochrome P-450 (CYP) 3A4 inhibitors (e.g. ritonavir): Use with caution. May cause systemic corticosteroid effects.

• Other short-acting bronchodilators: Use judiciously with other short-acting beta agonists.

• Beta blockers: May decrease effectiveness of albuterol/budesonide and produce severe bronchospasm. When there are no acceptable alternatives to the use of beta-adrenergic-blocking agents, consider cardioselective beta-blockers and use with caution.

• Diuretics, or non-potassium-sparing diuretics: May potentiate hypokalemia or ECG changes. Consider monitoring potassium levels with concomitant use.

• Digoxin: May decrease serum digoxin levels. Carefully evaluate digoxin levels with concomitant use.

• Monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants: Use albuterol/budesonide with extreme caution with concomitant use.

Actions

Mechanism of Action

Albuterol/budesonide contains both albuterol and budesonide; therefore, the mechanisms of action described below for the individual components apply to the fixed-combination preparation. 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.

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.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• Inform patients to seek medical attention immediately if treatment with albuterol/budesonide becomes less effective for symptomatic relief, and/or symptoms become worse.

• Instruct patients to discontinue albuterol/budesonide and contact their healthcare provider right away if they develop paradoxical bronchospasm.

• Instruct patients concerning the recommended dosage of albuterol/budesonide and not to exceed 6 doses (12 inhalations) in a 24-hour period.

• Advise patients to contact their healthcare provider and discontinue albuterol/budesonide if hypersensitivity reactions (e.g., anaphylaxis, rash, urticaria, angioedema, bronchospasm) occur with albuterol/budesonide use.

• Instruct patients to prime the inhaler before using for the first time, when the inhaler has not been used for more than 7 days, is dropped, or after cleaning and to shake well before each spray.

• To ensure proper dosing and to prevent actuator mouthpiece blockage, instruct patients how to clean the actuator.

• Advise patients concerning the appropriate use of other short-acting bronchodilators while using albuterol/budesonide.

• Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

• Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. Advise patients to rinse the mouth with water, if available, without swallowing after albuterol/budesonide inhalation to help reduce the risk of thrush.

• Advise patients that albuterol/budesonide may cause systemic corticosteroid effects of hypercorticism and adrenal suppression.

• Advise patients who are at an increased risk for decreased BMD that the use of albuterol/budesonide may pose an additional risk.

• Inform patients that long-term use of albuterol/budesonide may increase the risk of increased intraocular pressure, glaucoma, and cataracts; consider regular eye examinations.

• Advise pregnant women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy and to contact the MotherToBaby Pregnancy Studies at 1-877-311-8972 or visit https://mothertobaby.org/ongoing-study/asthma/.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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