AHFS Class:

• Adrenals 68:04

Generic Name(s):

• Beclomethasone Dipropionate

Beclomethasone dipropionate is a synthetic corticosteroid. 1,2,149

Asthma

Beclomethasone dipropionate is used by oral inhalation for the long-term prevention of bronchospasm in patients with asthma. 1,2,8,21,24,25,26,103,112,113,116,144,149,152

Beclomethasone dipropionate oral inhalation therapy should not be used in the treatment of nonasthmatic bronchitis.1,28,112,113,144 Oral inhalation of beclomethasone dipropionate is contraindicated in the primary treatment of severe acute asthmatic attacks or status asthmaticus when intensive measures1,2,29,112,113,149 (e.g., oxygen, parenteral bronchodilators, IV corticosteroids)147 are required. Beclomethasone dipropionate oral inhaler is not a bronchodilator, and patients should be warned that the drug should not be used for rapid relief of bronchospasm.1,2,103,112,113,144,149 Beclomethasone dipropionate oral inhalation therapy is not effective for all patients with bronchial asthma1,2,103,112,113,144,149 (e.g., in patients with bronchorrhea or severe pulmonary obstruction when proper penetration of the drug into the lungs is prevented).105 In addition, the drug is not always effective at all stages of the disease in a particular patient.1,2,112,113,144,149

Mild Persistent Asthma

Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma).161,163 In the stepped-care approach to antiasthmatic drug therapy, current asthma management guidelines and most clinicians recommend initiation of a controller drug such as an anti-inflammatory agent, preferably a low-dose orally inhaled corticosteroid (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adolescents and adults, children 5-11 years of age, or children 4 years of age or younger, respectively) as first-line therapy for persistent asthma (i.e., patients with daytime symptoms of asthma more than twice weekly, but less than once daily, and nocturnal symptoms of asthma 3-4 times per month), supplemented by as-needed use of a short-acting, inhaled β₂-agonist.161,163 For equivalent orally inhaled dosages of corticosteroids, see General Dosage under Dosage and Administration: Dosage, in the Corticosteroids General Statement 68:04.

Moderate Persistent Asthma

According to current asthma management guidelines, therapy with a long-acting inhaled β₂-agonist such as salmeterol or formoterol generally is recommended in adults and adolescents who have moderate persistent asthma and daily asthmatic symptoms that are inadequately controlled following addition of low-dose inhaled corticosteroids to as-needed inhaled β₂-agonist treatment.161,163 However, the National Asthma Education and Prevention Program (NAEPP) recommends that the beneficial effects of long-acting inhaled β₂-agonists should be weighed carefully against the increased risk (although uncommon) of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.161 (See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects, in Salmeterol Xinafoate 12:12.08.12.) Current asthma management guidelines also state that an alternative, but equally preferred option for management of moderate persistent asthma that is not adequately controlled with a low dosage of inhaled corticosteroid is to increase the maintenance dosage to a medium dosage (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adults and adolescents).152,161,163

In children 5-11 years of age with moderate persistent asthma that is not controlled with a low dosage of an inhaled corticosteroid, a long-acting inhaled β₂-agonist (e.g., salmeterol, formoterol), a leukotriene modifier (i.e., montelukast, zafirlukast), or extended-release theophylline (with appropriate monitoring) may be added to low-dose inhaled corticosteroid therapy according to current asthma management guidelines; another preferred option is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler).161 In infants and children 4 years of age or younger with moderate persistent asthma that is not controlled by a low dosage of an inhaled corticosteroid, the only preferred option is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler).161

Severe Persistent Asthma

Maintenance therapy with an inhaled corticosteroid at medium or high dosages (e.g., exceeding 440 mcg of fluticasone propionate in adults and adolescents or 352 mcg of the drug in children 5-11 years of age [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with a long-acting inhaled β₂-agonist is the preferred treatment according to current asthma management guidelines for patients 5 years of age or older with severe persistent asthma (i.e., continuous daytime asthma symptoms, nighttime symptoms 7 times per week).152,161,163 In infants and children 4 years of age or younger with severe asthma, maintenance therapy with an inhaled corticosteroid at medium or high dosages (e.g., exceeding 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with either a long-acting inhaled β₂-agonist or montelukast is recommended in current asthma management guidelines as the only preferred treatment.161

Poorly Controlled Asthma

If asthma symptoms in patients with moderate to severe asthma are very poorly controlled (i.e., at least 2-3 exacerbations per year requiring oral corticosteroids), a short course (3-10 days) of an oral corticosteroid may be added to gain prompt control of asthma.161 Regular use of oral corticosteroids as add-on therapy in adults and children 5 years of age or older with severe asthma who are inadequately controlled with high-dose inhaled corticosteroid, intermittent oral corticosteroid therapy, and a long-acting inhaled β₂-agonist bronchodilator is suggested, based on consensus and clinical experience.161,163 A short course (2 weeks) of oral corticosteroids may be considered to confirm clinical response prior to implementing long-term therapy with these agents.161 Once long-term oral corticosteroid therapy is initiated, the lowest possible effective dosage (i.e., alternate-day or once-daily administration) should be used, and the patient should be monitored carefully for adverse effects.161 Once asthma is well controlled, repeated attempts should be made to reduce the oral corticosteroid dosage.161 Use of orally inhaled beclomethasone dipropionate as adjunctive therapy in patients who require chronic administration of systemic corticosteroids to control asthma symptoms may permit a reduction in dosage or discontinuance of systemic corticosteroids.1,24,70,103,116 For additional details on the stepped-care approach to drug therapy in asthma,145,146,148,161,163 see Uses, in Albuterol 12:12.08.12 and see Asthma under Uses: Respiratory Diseases, in the Corticosteroids General Statement 68:04.

Clinical Experience with Beclomethasone Dipropionate

Well-controlled clinical studies have shown that oral inhalation of beclomethasone dipropionate relieves symptoms of bronchial asthma (cough, dyspnea, wheezing) and improves lung function (e.g., forced expiratory volume in 1 second [FEV₁]) in most adults and children.6,7,8,9,10,11,12,13,14,15,16,17,103,116,149,155,156 Although some improvement may occur shortly after therapy is initiated,101,149 optimum symptomatic relief may require 1-4 weeks of continuous beclomethasone dipropionate oral inhalation therapy in patients who have not previously received systemic corticosteroid therapy.1,2,61,77,100,112,113,144,149 In corticosteroid-dependent asthmatic patients being switched to beclomethasone dipropionate oral inhalation therapy, withdrawal of systemic corticosteroid therapy and management of asthma with orally inhaled beclomethasone dipropionate may be delayed, since recovery from hypothalamic-pituitary-adrenal (HPA) axis suppression occurs slowly.1,2,100,103,112,113,149 Clinical studies have shown that therapy with orally inhaled beclomethasone dipropionate may allow eventual dosage reduction or total replacement of systemic corticosteroid therapy.1,2,6,8,9,10,11,12,18,21,22,23,24,25,26,27,100,103,112,113,116,144,149

When beclomethasone dipropionate is administered by oral inhalation, the principal sites of action are the bronchi and bronchioles.149 Limited data suggest that substantially more drug is deposited into the airways of the lung and less reaches the oropharynx with beclomethasone dipropionate inhalation aerosols containing tetrafluoroethane (HFA-134a, a non-chlorofluorocarbon [CFC] propellant) (QVAR^®) than with inhalation aerosols containing CFC propellant (e.g., Beclovent^®, Vanceril^®, Vanceril^® Double Strength; all no longer commercially available in the US).153,154,155,159 In clinical studies of 6 weeks' to 12 months' duration, treatment with beclomethasone dipropionate with non-CFC propellant, administered at approximately half the daily dosage of beclomethasone dipropionate with CFC propellant,149 was associated with similar efficacy (i.e., control of moderate or moderately severe asthma) and safety; however, a definitive comparative therapeutic ratio has not been demonstrated to date.149,153,154,155,157 Unlike dexamethasone sodium phosphate, beclomethasone dipropionate appears to have higher topical anti-inflammatory activity with fewer adverse systemic effects following oral inhalation;14,29,30 however, no direct comparison of the adverse effects of these drugs has been performed.

Concomitant Therapy

In corticosteroid-dependent patients, use of beclomethasone dipropionate oral inhalation therapy usually permits a substantial reduction in the daily maintenance dosage of the systemic corticosteroid,1,2,6,8,9,10,11,12,18,21,22,23,24,25,26,27,100,103,112,113,116,144,149 conversion from daily to alternate-day corticosteroid therapy,24,25,26,149 or gradual discontinuance of corticosteroid maintenance dosages.6,8,9,18,21,22,23,24,25,26,27,103,116,149 (See Cautions: Hypothalamic-Pituitary-Adrenal Axis Suppression.)

In the management of asthma, the need for single- vs multiple-drug therapy must be determined on an individual basis.56,103 Beclomethasone dipropionate oral inhalation therapy has been administered to patients receiving bronchodilator and/or cromolyn sodium therapy.6,7,12,13,32,87,88,109,124 In a well-controlled study in corticosteroid-dependent asthmatic patients receiving either orally inhaled beclomethasone dipropionate or alternate-day prednisone, the addition of theophylline to either regimen at dosages that maintained therapeutic serum theophylline concentrations resulted in greater symptomatic relief and improved pulmonary function compared with therapy that did not include theophylline.87 In several controlled studies in asthmatic patients, concurrent therapy with orally inhaled beclomethasone dipropionate and cromolyn sodium did not provide a clinical advantage over beclomethasone dipropionate therapy alone;88,109 however, in an uncontrolled study, symptomatic relief of bronchial asthma was greater during concurrent therapy with orally inhaled beclomethasone dipropionate and cromolyn sodium than with either drug alone.32

Other Uses

The efficacy of orally inhaled beclomethasone dipropionate in the management of patients with chronic obstructive pulmonary disease (e.g., bronchitis)† who are stabilized with oral corticosteroids33,34,37,117 or whose disease is corticosteroid responsive117,118 remains to be fully evaluated. Limited data suggest that orally inhaled beclomethasone dipropionate may be useful in some patients with chronic obstructive pulmonary disease,117,118 but is probably not an adequate substitute for oral corticosteroid therapy in patients with steroid-responsive disease.117 Whether orally inhaled beclomethasone can maintain improvement in pulmonary function initially produced by oral corticosteroid therapy has not been established.117,118

Beclomethasone dipropionate has been used as an oral solution35 or rectal suspension36 in the management of inflammatory diseases of the GI tract†.35,36 In a group of patients with inflammatory bowel disease†, treatment with enemas containing beclomethasone dipropionate resulted in symptomatic improvement without producing adverse systemic effects.36 In a patient with eosinophilic gastroenteritis†, administration of an oral solution of beclomethasone dipropionate improved intestinal absorptive function.35 The role of beclomethasone dipropionate in the management of inflammatory conditions of the GI tract remains to be established.35,36

For other uses of beclomethasone dipropionate, see 52:08.08.

Administration

Beclomethasone dipropionate is administered by oral inhalation using an oral aerosol inhaler.149 Patients should be carefully instructed in the use of the oral inhaler.149 To obtain optimum results, patients should also be given a copy of the patient instructions provided by the manufacturer.149 An adult should carefully supervise a child in the administration of beclomethasone dipropionate for oral inhalation.71,74 The manufacturer states that beclomethasone dipropionate oral inhaler should be used by oral inhalation only. 149 The manufacturer states that the regular- (40 mcg/metered dose) and double-strength inhalation aerosols with tetrafluoroethane (non-CFC) propellant (QVAR^®)149 should be tested by spraying twice into the air before using the device for the first time or whenever the aerosol has not been used for more than 10 days.149

Because the commercially available beclomethasone dipropionate oral inhalation aerosol with tetrafluoroethane (non-CFC) propellant (QVAR^®) is formulated as a solution, it is not necessary to shake the inhaler prior to use.149 After exhaling as fully as is comfortable, the mouthpiece of the inhaler should be placed well into the mouth and the lips closed firmly around it, keeping the tongue below the mouthpiece.162 The patient should then inhale slowly and deeply through the mouth while pressing the metal canister down with the forefinger.162 After holding the breath for as long as possible (about 5-10 seconds), the mouthpiece should be removed and the patient should exhale gently.162 If additional inhalations are required, the patient should repeat the procedure.162 Following each treatment, the patient should rinse the mouth thoroughly with water to remove drug deposited in the oropharyngeal area.33,48,49,52,59,149,162 The patient instructions provided by the manufacturer should be referred to for further information regarding use of beclomethasone dipropionate for oral inhalation.149

Weekly cleansing of the mouthpiece of the beclomethasone dipropionate oral inhaler is recommended.162 The mouthpiece should be cleaned using a clean, dry tissue or cloth.162 The patient should be instructed not to wash or place any part of the inhaler canister in water. 162

According to the manufacturer of beclomethasone dipropionate inhalation aerosol with tetrafluoroethane (non-CFC) propellant (QVAR^®), lung deposition does not differ when the drug is administered with or without a spacer device, and administration with a spacer device is not necessary.160 However, the manufacturer states that the QVAR^® inhaler is compatible with the AeroChamber^® spacer device, which may be used if preferred by the clinician or patient.153,160

Dosage

The commercially available 7.3-g regular- or double-strength oral inhalation aerosol with tetrafluoroethane (non-CFC) propellant (QVAR^®) delivers about 40 or 80 mcg of beclomethasone dipropionate per metered spray and provides 100 metered sprays.149 Dosage of orally inhaled beclomethasone dipropionate must be carefully adjusted according to individual requirements and response.1,2,61,83,112,113,144,149

The recommended dosage of orally inhaled beclomethasone dipropionate administered via metered-dose aerosol with tetrafluoroethane (non-CFC) propellant (QVAR^® is lower than that with inhalation aerosols containing CFC propellant (e.g., Beclovent^®, Vanceril^®, Vanceril^® Double Strength; all no longer commercially available in the US), although a definitive comparative therapeutic ratio between non-CFC and CFC-containing beclomethasone preparations has not been demonstrated.149 The usual initial dosage of beclomethasone dipropionate oral inhalation aerosol with tetrafluoroethane (non-CFC) propellant (QVAR^®) for adults and children 12 years of age or older in whom previous asthma therapy consisted of bronchodilators alone is 40 or 80 mcg twice daily.149 The usual initial dosage of the drug for adults and children 12 years of age or older in whom previous asthma therapy consisted of inhaled corticosteroids is 40-160 mcg twice daily.149 In children 5-11 years of age in whom previous asthma therapy consisted of bronchodilators alone or inhaled corticosteroids, the usual initial dosage of the drug is 40 mcg twice daily.149 After a satisfactory response is obtained, dosage should be decreased gradually to the lowest dosage that maintains an adequate clinical response, particularly in children, since inhaled corticosteroids have the potential to affect growth.149,150 (See Cautions: Pediatric Precautions.) The manufacturer of QVAR^® states that the safety and efficacy of dosages exceeding 320 mcg twice daily in adults and children 12 years of age or older or 80 mcg twice daily in children 5-11 years of age have not been established.149

Patients who respond to beclomethasone dipropionate oral inhalation usually show improvement in pulmonary function within 1-4 weeks of continuous therapy.1,2,61,77,100,112,113,144,149

Conversion to Orally Inhaled Therapy in Patients Receiving Systemic Corticosteroids

When orally inhaled beclomethasone dipropionate is administered to patients receiving systemic corticosteroids, the patient's asthma should be reasonably stable before treatment with the oral inhalation begins.1,2,112,113,144,149 Initially, the aerosol is given concurrently with the maintenance dosage of the systemic corticosteroid.1,2,112,113,144,149 After about 1 week, gradual withdrawal of the systemic corticosteroid is begun.1,2,112,113,144,149 (See Dosage and Administration in the Corticosteroids General Statement 68:04.) Gradual withdrawal of systemic corticosteroids following long-term therapy is strongly recommended, since death has occurred in some individuals in whom systemic corticosteroids were withdrawn too rapidly. 1,2,112,113,144,149 (See Cautions: Hypothalamic-Pituitary-Adrenal Axis Suppression.) After systemic corticosteroids have been withdrawn, if exacerbations of asthma occur during beclomethasone dipropionate oral inhalation therapy, short courses of systemic corticosteroids should be given, then tapered as symptoms subside.1,2,112,113,144,149

Hypothalamic-Pituitary-Adrenal Axis Suppression

Suppression of hypothalamic-pituitary-adrenal (HPA) axis function below the clinical normal range was not observed with beclomethasone dipropionate inhalation aerosol with tetrafluoroethane (non-CFC) propellant (QVAR^®) at dosages up to 640 mcg daily during clinical trials; however, a dose-dependent reduction in adrenal cortisol production was detected.149 In a comparative study, corticosteroid-naïve patients receiving beclomethasone dipropionate inhalation aerosol with tetrafluoroethane (non-CFC) propellant (320 mcg twice daily) or the drug formulated with CFC propellant (336 mcg twice daily; preparation no longer commercially available in the US) experienced a reduction in 24-hour urinary free cortisol concentrations of approximately 37 or 47%, respectively.149 In an open-label study of 354 patients receiving beclomethasone oral inhalation aerosol with tetrafluoroethane (non-CFC) propellant at recommended dosages for 1 year, less than 1% had an abnormal response to rapid corticotropin (ACTH) stimulation tests.149,154 Mean changes from baseline in morning plasma cortisol concentrations were similar in patients receiving beclomethasone dipropionate inhalation aerosol with tetrafluoroethane (non-CFC) propellant (exceeding 320-640 mcg daily) or CFC propellant (exceeding 420-840 mcg daily; preparation no longer commercially available in the US) after 12 months of treatment and were not considered clinically meaningful.154

Reductions in plasma cortisol concentrations did not occur in adults when beclomethasone dipropionate was administered by IM injection at dosages of 1000 mcg daily for 3 days.1,2,112,113,144 Partial suppression of adrenal function has been observed when beclomethasone dipropionate was administered by IM injection at dosages of 2000 mcg daily.1,2,112,113 Following IM administration of single 4000-mcg doses of beclomethasone dipropionate, immediate adrenal suppression has been observed.1,2,112,113,144

Concurrent administration of a systemic and orally inhaled corticosteroid may increase the risk of HPA-axis suppression.45,47 Following concurrent therapy with alternate-day prednisone and orally inhaled beclomethasone dipropionate in a group of asthmatic children, reductions in plasma cortisol concentrations were greater than those produced by therapeutic dosages of either drug alone;45 however, studies have not been performed to date comparing the systemic effects of alternate-day systemic corticosteroid therapy alone with therapeutically equivalent doses of orally inhaled beclomethasone dipropionate.101 Reductions in plasma cortisol concentrations have occurred when intranasal and orally inhaled beclomethasone dipropionate were used concomitantly.111

Because beclomethasone dipropionate is absorbed into circulation and can be systemically active, HPA axis suppression could occur when recommended dosages are exceeded or in particularly sensitive individuals.149 Since recommended dosages of orally inhaled beclomethasone dipropionate provide less than normal physiologic amounts of glucocorticoid systemically and do not provide mineralocorticoid activity, the drug will not compensate for insufficient endogenous cortisol production caused by previous systemic corticosteroid therapy.149

In most patients, a number of months are required for recovery of HPA function following withdrawal of long-term systemic corticosteroid therapy. 1,40,80,112,113,149 Since death resulting from acute adrenal insufficiency or an exacerbation of the underlying asthma has occurred rarely in asthmatic patients during and after transfer from systemic corticosteroid to beclomethasone dipropionate oral inhalation therapy,1,2,13,23,28,40,112,113,144,149 systemic corticosteroid therapy should be withdrawn gradually.1,2,112,113,144,149 Several deaths in asthmatic children have occurred about 6 months after conversion from oral corticosteroid to beclomethasone dipropionate oral inhalation therapy.40 Although adrenal stimulation tests performed in some of these children shortly before death indicated normal HPA function, adrenal atrophy was observed on postmortem examination.40

Respiratory Effects

Infectious Complications

Increased colonization and/or localized infections with Candida albicans have occurred frequently in the mouth or pharynx and occasionally in the larynx, bronchus, or esophagus of patients receiving orally inhaled beclomethasone dipropionate;1,2,14,27,29,30,44,48,49,50,51,52,59,60,70,89,100,112,113,116,144 Aspergillus niger infections or overgrowth also have occurred.1,2,7,105,112,113,144 The frequency of positive oral Candida cultures in patients receiving orally inhaled beclomethasone dipropionate is variable.33,48,49,103

The manufacturer of orally inhaled beclomethasone dipropionate aerosol with tetrafluoroethane (non-CFC) propellant states that no patient developed symptomatic oropharyngeal candidiasis during clinical development with this preparation.149 In an open-label study in 354 patients receiving beclomethasone dipropionate oral inhalation aerosol with tetrafluoroethane (non-CFC) propellant (160-640 mcg daily) or CFC propellant (336-1344 mcg daily; no longer commercially available in the US) for 1 year, oropharyngeal candidiasis was not reported in either treatment group.154 Approximately 4 or 8% of patients receiving the drug containing non-CFC (HFA) or CFC propellant, respectively, were instructed to use a spacer device either positive oral Candida cultures or dysphonia; however, the difference between the treatment groups was not statistically significant.154

Most clinicians recommend that patients rinse their mouth and throat with water after each dose of beclomethasone dipropionate to remove residual medication in the oropharyngeal area and to minimize the development of fungal overgrowth and/or infection.33,48,49,52,59 If a fungal infection is suspected, appropriate local anti-infective therapy and/or discontinuance of beclomethasone dipropionate therapy should be considered,149 but usually oropharyngeal Candida or Aspergillus infections are of little clinical importance.33,89

Monilial esophagitis has occurred in several asthmatic patients receiving concomitant therapy with oral prednisone and orally inhaled beclomethasone dipropionate; however, predisposing factors, other than therapy with orally inhaled beclomethasone dipropionate, were present in these patients.51 The development of esophagitis resulting from concurrent infection with Candida and herpes simplex has been reported in at least one corticosteroid-dependent patient receiving orally inhaled beclomethasone dipropionate.97

Although not directly attributable to the drug, clinical tuberculosis developed in one patient during a 6-month period of beclomethasone dipropionate oral inhalation therapy.38 However, concurrent administration of beclomethasone dipropionate oral inhalation did not appear to have an adverse effect on resolution of tuberculosis in this patient.38 In a previous 10-month period, the patient received an oral corticosteroid without any clinical evidence of tuberculosis.38

Eosinophilic pneumonia has occurred in several patients receiving orally inhaled beclomethasone dipropionate.2,53,54,55,98,112,113 A possible relationship of this adverse effect to systemic corticosteroid withdrawal has been suggested.2,53,54,55,98,112,113 A causal relationship to beclomethasone dipropionate and/or the contents of the vehicle (e.g., fluorocarbons, oleic acid) in the preparation has been suggested but remains to be established.2,53,54,55,112,113

Dysphonia

Dysphonia (sometimes persistent and severe) has occurred in patients receiving orally inhaled beclomethasone dipropionate;1,2,27,44,48,56,60,84,103,112,113,116,149 a direct causal relationship to therapy with orally inhaled beclomethasone dipropionate and to chronic voice stress has been shown in at least one study.48 A causal relationship has not been ruled out, but in one controlled study, dysphonia did not appear to be related to the contents of the vehicle (e.g., fluorocarbons, oleic acid) in the preparation of beclomethasone dipropionate oral inhalation that was used.48 Dysphonia may result from dysfunction of the bilateral adductor muscles that control phonation.102 It has been suggested that this adverse effect may result from a local steroid myopathy.102 Dysphonia has occurred concomitantly with candidiasis in some patients.44,116 Although dysphonia and candidiasis were related to beclomethasone dipropionate oral inhalation therapy in some patients, they apparently were not related to each other and required different treatment (voice rest or nystatin).48

Other Adverse Respiratory Effects

Bronchospasm,1,2,57,112,113,133,149 cough,20,25,58,131,132,149 and/or wheezing57,58,131,132,133,149 may occur in some patients following oral inhalation of beclomethasone dipropionate, especially in asthmatic patients with hyperactive airways.20,25,57,58,101,131,132,133 Administration of an orally inhaled β₂-agonist a few minutes before oral inhalation of beclomethasone dipropionate has prevented or minimized these adverse respiratory effects in some patients;20,101,131,132 other patients may require a course of oral corticosteroid therapy to tolerate oral inhalation of the steroid.131,132

The long-term and systemic effects of beclomethasone dipropionate in humans, particularly local effects on developmental or immunologic processes in the mouth, pharynx, trachea, and lung, are unknown.149 Although not reported to date in patients receiving orally inhaled beclomethasone dipropionate, the possibility of atrophic changes in the respiratory epithelium during prolonged therapy with orally inhaled corticosteroids should be considered, since atrophic dermatitis has occurred in patients treated with topical corticosteroids to the skin for prolonged periods.86 In a limited number of patients receiving beclomethasone dipropionate oral inhalation for 12-18 months, light and electron microscopic studies of bronchial and pharyngeal biopsy material did not reveal any changes attributable to the drug.39 Long-term studies using high doses of orally inhaled beclomethasone dipropionate in cushingoid animals also did not reveal any evidence of pulmonary changes as determined by light or electron microscopy.114 Following therapy with orally inhaled beclomethasone dipropionate, bronchial biopsies did not show any evidence of atrophic changes in asthmatic patients receiving the drug for up to 32 months; however, an increased number of mastocytes was observed when biopsies from these patients were compared with those from asthmatic patients not receiving therapy with the drug.96

Other Adverse Effects

In addition to bronchospasm, other immediate or delayed hypersensitivity reactions, including anaphylactic/anaphylactoid reactions,2 urticaria, angioedema, and rash, have occurred rarely following oral or intranasal inhalation of beclomethasone dipropionate.1,2,112,113,149 Other adverse effects reported with oral inhalation of beclomethasone dipropionate include flushing,15 dry mouth1,112,113 or throat,2,58 irritation of the tongue58 or throat,25,27 and dysgeusia;15,25 however, a causal relationship to the drug has not been established. Headache, pharyngitis, rhinitis, sinusitis, pain/back pain, and dysmenorrhea were also reported during clinical trials with beclomethasone dipropionate oral inhalation therapy.149

Glaucoma, increased intraocular pressure, and cataracts have been reported rarely with administration of inhaled corticosteroids.149 Prolonged therapy with orally inhaled beclomethasone dipropionate has been associated with the development of bilateral posterior subcapsular cataracts in at least one patient.99 Several months following discontinuance of corticosteroid therapy in this patient, normal lenses were observed.99 In a group of asthmatic children who developed cataracts during systemic corticosteroid therapy, cataracts resolved within 6 months in 2 patients when prednisone dosage was reduced or discontinued and beclomethasone dipropionate oral inhalation therapy was initiated.104

A bullous eruption of the lips and oral mucosa has been reported in at least one patient receiving oral inhalation of beclomethasone dipropionate.92 Since rechallenge with the drug produced the same adverse reaction in this patient, a causal relationship to beclomethasone dipropionate or an ingredient in the vehicle of the preparation has been suggested.92

Precautions and Contraindications

In patients being switched from systemic corticosteroids to orally inhaled beclomethasone dipropionate, systemic corticosteroid therapy should be withdrawn gradually since a life-threatening exacerbation of asthma or adrenal insufficiency could occur.1,2,112,113,144,149 Patients who have been maintained on at least 20 mg of prednisone (or its equivalent) daily may be most susceptible to such adverse events, particularly when their systemic corticosteroid therapy has been almost completely withdrawn.149 In most patients, up to 12 months may be required for total recovery of HPA function following withdrawal of systemic corticosteroid therapy. 1,2,40,80,112,113 These patients should be carefully monitored during and for a number of months after withdrawal of systemic corticosteroids because of the risk of corticosteroid withdrawal symptoms (e.g., joint pain, muscular pain, lassitude, depression);1,2,112,113,144,149 acute adrenal insufficiency during exposure to trauma, surgery, or infection (particularly gastroenteritis or other conditions associated with acute electrolyte loss);1,2,112,113,144 pulmonary infiltrates with eosinophilia;1,112,113 or symptomatic exacerbation of allergic conditions previously controlled by systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema).1,2,27,44,52,58,70,112,113,144 In asthmatic patients, death, possibly resulting from acute adrenal insufficiency or an exacerbation of the underlying asthma, has occurred rarely during and after transfer from systemic corticosteroid to beclomethasone dipropionate oral inhalation therapy.1,2,13,23,28,40,112,113,144 Systemic corticosteroid dosage should be carefully tapered and patients should be monitored during dosage reduction for objective signs of adrenal insufficiency (e.g., hypotension, weight loss).1,2,112,113,144,149 In general, the greater the dosage and duration of systemic corticosteroid therapy, the greater the time required for withdrawal of systemic corticosteroids and replacement by orally inhaled corticosteroids.73

The manufacturer of beclomethasone dipropionate oral inhalation containing tetrafluoroethane (non-CFC) propellant (QVAR^®) states that higher than recommended dosages of the drug should be avoided, since suppression of HPA function may occur.149 If higher than recommended dosages are used, the relative risks of adrenal suppression and potential therapeutic benefits must be carefully considered; systemic corticosteroids will likely be necessary during prolonged periods of stress (e.g., infection, trauma, surgery),149 particularly in patients who received continuous oral corticosteroid therapy within the previous 12 months.1,2,119,130 Orally inhaled beclomethasone dipropionate should be used with caution in patients receiving systemic prednisone or another systemic corticosteroid in an alternate-day or daily dosing regimen for any disease, since concomitant use of the drugs could increase the likelihood of HPA-axis suppression compared with therapeutic dosages of either drug alone.45,47

Although signs and symptoms of Cushing's syndrome (e.g., hypertension, glucose intolerance, cushingoid features) have not been associated with beclomethasone dipropionate oral inhalation therapy to date, the possibility of their occurrence should be considered in patients who are particularly sensitive to corticosteroid effects or when usual dosages of the drug are exceeded.100,149

Patients should be advised that oral inhalation of beclomethasone dipropionate must be used at regular intervals to be therapeutically effective.100,103,144,149 In addition, patients should be advised that the drug usually will not provide immediate symptomatic relief, but 1-4 weeks of continuous therapy may be required for optimum effects to be achieved.1,2,61,77,100,112,113,144,149 Patients should be advised that orally inhaled beclomethasone dipropionate should not be used as a bronchodilator and is not indicated for emergency use (e.g., relief of acute bronchospasm).1,2,103,112,113,144,149 Patients should be instructed not to exceed the prescribed dosage,71 and to rinse their mouth after the inhalation procedure.1,2,112,113,144,149 (See Dosage and Administration: Administration.) Patients receiving beclomethasone dipropionate oral inhalation therapy should also be advised to contact their physician immediately when asthmatic attacks that are not controlled by bronchodilator therapy occur.1,2,112,113,149 The manufacturer of beclomethasone dipropionate containing tetrafluoroethane (non-CFC) propellant (QVAR^®) states that if bronchospasm occurs following dosing with the drug, it should be treated immediately with a short-acting bronchodilator, treatment with beclomethasone dipropionate should be discontinued, and alternative therapy should be instituted.149 Patients being transferred from systemic corticosteroid to beclomethasone dipropionate oral inhalation therapy should carry special identification (e.g., card, bracelet) indicating the need for supplementary systemic corticosteroids during periods of stress.1,2,112,113,144 Patients receiving orally inhaled beclomethasone dipropionate who are currently being withdrawn or who have been withdrawn recently from systemic corticosteroids should be advised to immediately resume full therapeutic dosages of systemic corticosteroids and to contact their physician for further instructions during stressful periods (e.g., severe infection, severe asthmatic attack).1,2,112,113,144,149

Patients receiving beclomethasone dipropionate oral inhalation with tetrafluoroethane (non-CFC) propellant (QVAR^®) should be advised that this preparation may have a different taste and inhalation sensation than that of an inhaler containing CFC propellants (no longer commercially available in the US).149

Patients who become immunosuppressed while receiving corticosteroids have increased susceptibility to infections compared with healthy individuals, and certain infections (e.g., varicella [chickenpox], measles) can have a more serious or even fatal outcome in such patients, particularly in children.113,134,135,136,137,138,139,140,141,142,143,144 Patients receiving corticosteroids who are potentially immunosuppressed should be warned of the risk of exposure to certain infections (e.g., chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs.113,134,135,136,142,143,144,149 For additional information, see Cautions: Increased Susceptibility to Infection and also see Cautions: Precautions and Contraindications, in the Corticosteroids General Statement 68:04.

The effect of beclomethasone dipropionate oral inhalation therapy on acute, recurrent, or chronic pulmonary infections, including active or latent Mycobacterium tuberculosis infections, is not known.1,112,113 Orally inhaled beclomethasone dipropionate should be used with caution, if at all, in patients with clinical tuberculosis or latent M. tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, or parasitic infections; or ocular herpes simplex or untreated, systemic viral infections.1,2,100,144

Oral inhalation of beclomethasone dipropionate is contraindicated in the primary treatment of severe acute asthmatic attacks or status asthmaticus when intensive measures (e.g., oxygen, parenteral bronchodilators, IV corticosteroids) are required.1,2,61,112,113,144,149 Oral inhalation of beclomethasone dipropionate is also contraindicated in patients who are hypersensitive to the drug or any ingredient in the formulation.1,2,112,113,144,149

Pediatric Precautions

The safety and efficacy of beclomethasone dipropionate oral inhaler with non-CFC (tetrafluoroethane) propellant (QVAR^®) have not been established in children younger than 5 years of age.149 In several studies in children 5-12 years of age not previously treated with corticosteroids, no overall differences in the pattern, severity, or frequency of adverse events were observed compared with those in adults, with the exception of conditions that are more prevalent in the pediatric population generally.149 In a 12-month comparative study in children 5-11 years of age receiving 8-320 mcg daily of orally inhaled non-CFC tetrafluoroethane propellant beclomethasone dipropionate (without a spacer) or 160-640 mcg daily of the drug with CFC propellant with a spacer (no longer commercially available in the US), a small reduction in growth velocity (0.5 cm/year) was observed with the non-CFC inhalation aerosol and no spacer compared with the CFC-containing inhalation aerosol and a spacer.149,150 Children receiving prolonged therapy with orally inhaled beclomethasone dipropionate should be monitored periodically for possible adverse effects on growth and development.62,149 (See Cautions: Pediatric Precautions, in the Corticosteroids General Statement 68:04.)

Geriatric Precautions

Clinical studies of beclomethasone dipropionate did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.149 While clinical experience generally has not revealed age-related differences in response to the drug, care should be taken in dosage selection of beclomethasone dipropionate.149 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturer suggests that patients in this age group receive initial dosages of the drug at the lower end of the usual range.149

Mutagenicity and Carcinogenicity

Beclomethasone dipropionate did not exhibit mutagenic potential in vitro in bacterial or mammalian (Chinese hamster ovary) test systems.149 No evidence of clastogenic potential was found in in vitro tests using cultured CHO cells or in vivo in the mouse micronucleus test.149

No evidence of carcinogenicity was observed when rats were given beclomethasone dipropionate for 95 weeks (13 weeks by oral inhalation and 82 weeks by the oral route).68,69,149

Pregnancy, Fertility, and Lactation

Pregnancy

Orally inhaled beclomethasone dipropionate should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,2,112,113,144,149

Although there are no adequate and controlled studies to date in humans, 20 asthmatic patients who became pregnant and were receiving oral inhalation of beclomethasone dipropionate at usual dosages delivered healthy children.70 Other women with severe asthma who received orally inhaled beclomethasone dipropionate during pregnancy to reduce systemic corticosteroid dosage requirements also delivered healthy children;90,122 however, a cardiac malformation was reported in an infant whose mother had complications and was receiving other drugs.90 Several of these pregnancies resulted in premature deliveries and low birthweight infants,90,122 but evidence of neonatal adrenal insufficiency was not observed.90 Infants born to women who received substantial doses of corticosteroids during pregnancy should be carefully monitored for manifestations of hypoadrenalism.2,61,112,144,149 Subcutaneous beclomethasone dipropionate has been shown to be teratogenic and embryocidal in mice and rabbits at dosages about one-half the maximum recommended daily inhalation dose in adults on a mg/m² basis.149 Teratogenic effects in these animals included fetal resorption, cleft palate, agnathia, microstomia, aglossia, delayed ossification, and agenesis of the thymus gland.1,112,113 Teratogenic or embryocidal effects were not observed following oral inhalation of beclomethasone dipropionate at 190 times the maximum recommended daily human dosage on a mg/m² basis 149 or following oral administration at 1000 times the usual human dosage in rats.68,69

Fertility

It is not known whether beclomethasone dipropionate affects fertility in humans.68,69 Reproduction studies in female dogs given oral beclomethasone dipropionate dosages of 500 mcg/kg daily have shown evidence of impaired fertility (inhibition of the estrus cycle); however, no inhibition of the estrus cycle was observed in dogs following administration of orally inhaled beclomethasone dipropionate for 12 months as an estimated daily dosage of 0.33 mg/kg (about 15 times the maximum recommended daily dosage in humans on a mg/m² basis).149

Lactation

Since corticosteroids are distributed into milk and potentially may cause serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.144,149

Pharmacology

For a discussion of the pharmacology of beclomethasone dipropionate, see Pharmacology in the Corticosteroids General Statement 68:04 and in Beclomethasone Dipropionate 52:08.08.

Pharmacokinetics

For a discussion of the absorption, distribution, and elimination of beclomethasone dipropionate, see Pharmacokinetics in the Corticosteroids General Statement 68:04 and in Beclomethasone Dipropionate 52:08.08.

Chemistry and Stability

Chemistry

Beclomethasone dipropionate, a diester of beclomethasone, is a synthetic corticosteroid.1,2 Beclomethasone and beclomethasone dipropionate are 21-carbon steroids and are structurally related to dexamethasone.1,2,149 Esterification of the hydroxyl group at positions 17 and 21 of the beclomethasone molecule enhances the topical anti-inflammatory activity of beclomethasone dipropionate compared with beclomethasone.4 (See Chemistry in the Corticosteroids General Statement 68:04.)

Beclomethasone dipropionate occurs as a white to creamy white powder3,5,144 and is slightly soluble in water and freely soluble in alcohol.149

Beclomethasone dipropionate is commercially available for oral inhalation in a vehicle containing a fluorocarbon propellant (tetrafluoroethane [HFA-134a], which is not a CFC) and alcohol (QVAR^®).149 Beclomethasone dipropionate oral inhaler containing non-CFC (tetrafluoroethane) propellant (QVAR^®) produces a metered spray containing 50 or 100 mcg of beclomethasone dipropionate per spray at the valve and delivers a beclomethasone dipropionate dose of 40 or 80 mcg, respectively, from the actuator.149

Stability

The manufacturer of beclomethasone dipropionate oral inhaler with non-CFC (tetrafluoroethane) propellant (QVAR^®) states that the aerosol should be stored at 25°C but may be exposed to temperatures ranging from 15-30°C.149 Because the contents of beclomethasone dipropionate oral inhalers are under pressure, the aerosol containers should not be punctured, used or stored near heat or an open flame, exposed to temperatures exceeding 49°C, or placed into a fire or incinerator for disposal.1,112,113,144,149

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, cautions, and dosage and administration of beclomethasone dipropionate, see the Corticosteroids General Statement 68:04. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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