AHFS Class:

• Corticosteroids 52:08.08

Generic Name(s):

• Beclomethasone Dipropionate

• Beclomethasone Dipropionate Monohydrate

Beclomethasone dipropionate, a diester of beclomethasone, is a synthetic corticosteroid.

Rhinitis

Beclomethasone dipropionate nasal aqueous suspensions (as the monohydrate) are used for the symptomatic treatment of seasonal or perennial rhinitis.103

In patients with seasonal or perennial rhinitis of allergic or nonallergic etiology, intranasal administration of beclomethasone dipropionate generally provides symptomatic relief of watery rhinorrhea, nasal congestion, sneezing (including relief of morning sneezing attacks), and nasal and pharyngeal itching. Sense of smell is restored in some patients. Although intranasal beclomethasone dipropionate therapy generally does not relieve signs and symptoms of conjunctivitis or those involving the lower respiratory tract (e.g., coughing), improvement in ophthalmic and respiratory signs and symptoms has occurred in some patients receiving intranasal beclomethasone dipropionate. Relief of pruritus, redness, and tearing of the eyes and edema of the eyelids has been reported. Since intranasal beclomethasone dipropionate is thought to exert a local effect on the nasal mucosa, the mechanism for these ophthalmic effects is not fully understood. Improvement in ophthalmic signs and symptoms may be partly caused by a decrease in the nasolacrimal reflex which occurs as nasal symptoms of rhinitis improve. Alternatively, these improvements may represent difficulty in differentiating between nasal and ophthalmic symptoms. In a placebo-controlled study, coughing decreased during intranasal beclomethasone dipropionate therapy, and this effect on the lower respiratory tract may have resulted from penetration of a portion of an intranasal dose of the drug into the bronchial tree.

In some patients, therapy with ophthalmic preparations may be necessary to relieve signs and symptoms of conjunctivitis not controlled by intranasal corticosteroids. Although ophthalmic products containing vasoconstrictors and antihistamines or corticosteroids may be effective in relieving ophthalmic inflammatory symptoms in patients with rhinitis, concurrent use of ophthalmic and intranasal corticosteroids generally is not recommended since the risk of adverse ophthalmic effects associated with corticosteroid therapy (e.g., glaucoma, cataract formation, exacerbation of ophthalmic infections) may be increased. In patients with seasonal or perennial rhinitis, especially those with concurrent asthmatic conditions, continuous concomitant therapies (e.g., oral or orally inhaled corticosteroids, bronchodilators, antihistamines, decongestants) may be required for optimum symptomatic relief.

Intranasal beclomethasone dipropionate appears to provide greater symptomatic relief in patients with allergic rhinitis (i.e., associated with IgE-mediated reactivity manifested as positive skin tests to common allergens or increased serum or nasal IgE concentrations) than in patients with nonallergic rhinitis. When intranasal beclomethasone dipropionate is added to a therapeutic regimen that includes an oral antihistamine, dosage of the antihistamine can often be decreased in allergic patients with seasonal or perennial rhinitis even during periods of peak exposure to pollen. In a study in patients with perennial rhinitis, allergic patients (based on positive skin- test reactivity) with nasal eosinophilia showed greater symptomatic improvement with intranasal beclomethasone dipropionate therapy than allergic individuals without nasal eosinophilia or nonallergic individuals with or without nasal eosinophilia. Several well-controlled studies have shown similar symptomatic relief following intranasal administration of beclomethasone dipropionate in both allergic and nonallergic individuals with perennial rhinitis. Although the efficacy of intranasal beclomethasone dipropionate in the treatment of perennial nonallergic rhinitis has been questioned, most clinicians agree that a therapeutic trial with the drug is warranted in these patients since greater symptomatic relief occurs during intranasal beclomethasone dipropionate therapy than during intranasal placebo therapy.

In patients with seasonal or perennial rhinitis, symptomatic relief is usually evident within several days of continuous intranasal beclomethasone dipropionate therapy; however, up to 2 weeks may be required for optimum effectiveness in some patients. Onset of response occasionally occurs within hours following initiation of intranasal beclomethasone dipropionate therapy in patients with seasonal allergic rhinitis, but optimum symptomatic relief usually does not occur until one or more weeks of therapy in patients with perennial allergic or nonallergic rhinitis. Supplemental therapy with topical nasal decongestants and/or oral antihistamines may be necessary until an acceptable clinical response is achieved. Duration of symptomatic relief with intranasal beclomethasone dipropionate also may vary depending on the type of rhinitis. Following discontinuance of intranasal beclomethasone dipropionate therapy, symptoms generally recur after 1-2 days in patients with seasonal allergic rhinitis and after one or more weeks in patients with perennial nonallergic rhinitis.

A poor clinical response to beclomethasone dipropionate can result from improper drug administration techniques, poor drug penetration (secondary to marked nasal congestion, presence of nasal polyps, or symptoms originating in the nasal sinuses), or localized infections of the nasal mucosa.

Intranasal administration of beclomethasone dipropionate (400 mcg/day in 4 divided doses) appears to be as effective as intranasal flunisolide (200 mcg/day in 2 divided doses) in the treatment of seasonal or perennial allergic rhinitis. Although the symptomatic relief provided by usual dosages of intranasal beclomethasone dipropionate, flunisolide, or dexamethasone phosphate is similar, beclomethasone dipropionate and flunisolide appear to be associated with fewer adverse systemic effects than dexamethasone phosphate; however, no direct comparison of the adverse effects of these drugs has been performed.

Comparative studies have been performed with beclomethasone dipropionate nasal aerosol (400 mcg/day in 4 divided doses; no longer commercially available in the US) and intranasal cromolyn sodium (40 mg/day in 4 or 6 divided doses). Following nasal inhalation in a study in patients with seasonal or perennial rhinitis, beclomethasone dipropionate and cromolyn sodium provided similar symptomatic relief. In other studies in patients with perennial allergic or nonallergic rhinitis, greater symptomatic relief was provided by intranasal beclomethasone dipropionate than intranasal cromolyn sodium. Further studies comparing the effects of intranasal beclomethasone dipropionate and intranasal cromolyn sodium in the treatment of seasonal and perennial rhinitis are needed.

Nasal Polyposis

Intranasal beclomethasone dipropionate as the aqueous suspension (containing the monohydrate) is used in the management of nasal polyposis, principally to prevent recurrence of nasal polyps following surgical removal. Since most patients with this condition require periodic surgery for removal of polyps, prophylactic therapy with intranasal beclomethasone dipropionate following surgical removal of polyps may delay the need for subsequent surgery; however, intranasal administration of beclomethasone dipropionate should not preclude surgical measures (i.e., polypectomy) when the polyps are of such size that the drug can no longer adequately penetrate the nasal passages. Following long-term intranasal beclomethasone dipropionate therapy (several weeks to months) in patients with existing nasal polyps, reductions in the size of polyps and the degree of nasal obstruction have been observed. Intranasal beclomethasone dipropionate does not appear to alter the underlying disease, since signs and symptoms usually recur when the drug is discontinued. All patients with nasal polyps receiving prolonged therapy with intranasal corticosteroids should be monitored periodically with rhinoscopic examinations, since atrophic rhinitis may be more likely to develop in these patients.

Other Uses

Intranasal beclomethasone dipropionate has been used in the treatment of serous otitis media† (eustachian tube dysfunction, middle ear effusion) in children. In a study comparing intranasal beclomethasone dipropionate and oral prednisone, beclomethasone dipropionate-treated children had otoscopic evidence of resolution of middle ear effusion, but oral prednisone appeared to be more effective. Although systemic corticosteroids are apparently more effective than intranasal corticosteroids in treating this condition, intranasal corticosteroids are associated with fewer adverse systemic effects. Some clinicians recommend an initial trial of intranasal beclomethasone dipropionate therapy in children with serous otitis media, but the specific role of intranasal beclomethasone dipropionate in the treatment of this condition has not been established.

For other uses of beclomethasone dipropionate, see 68:04.

Administration

Beclomethasone dipropionate is administered by nasal inhalation as the monohydrate using a spray pump. Nasal aerosol inhaler formulations of the drug no longer are commercially available in the US. Patients should be carefully instructed in the use of the nasal spray pump. To obtain optimum results, patients should also be given a copy of the patient instructions provided by the manufacturers. An adult should carefully supervise a child in the administration of intranasal beclomethasone dipropionate. The manufacturer states that intranasal beclomethasone dipropionate should be used by nasal inhalation only. 103,104

Prior to administration of intranasal beclomethasone dipropionate, patients should clear their nasal passages; administration of a topical nasal vasoconstrictor may be required in patients with blocked nasal passages during the first 2-3 days of therapy to ensure adequate penetration of the drug.103 The aqueous suspension (pump spray) should be shaken well immediately prior to use.104

To actuate the spray pump for priming and for intranasal use, the bottle is held in one hand, with 2 fingers on the white collar of the pump unit and the thumb on the bottom of the bottle.104 Before initial use of beclomethasone dipropionate nasal spray pump, patients should prime the pump by pressing downward and releasing the pump collar 6 times or until a fine mist is produced.104 If the nasal spray pump has not been used for 7 days, the pump should be reprimed until a fine mist appears.104 Caution should be exercised to avoid spraying beclomethasone dipropionate nasal spray into the eyes.104

Prior to administration of beclomethasone dipropionate using the nasal spray pump, patients should clear their nasal passages by gently blowing their nose.104 Patients should insert the nasal spray tip into 1 nostril and tilt the head slightly forward while holding the bottle upright.104 The pump collar should then be firmly pressed downward to administer the drug into the nostril while holding the other nostril closed and gently inspiring through the nostril at the same time.104 Patients should then breathe out through the mouth.104 This procedure then is repeated for the other nostril.104

To clean the nasal applicator, remove the dust cap and safety clip and press up gently on the white collar to free the nasal applicator.104 The nasal applicator and dust cap should be washed with cold water and dried, then replaced on the nasal applicator.104 If the spray nozzle becomes clogged, remove the dust cap, unscrew the pump mechanism and soak the spray pump unit in warm water for a few minutes.104 The spray pump should be rinsed in cold water, dried, refitted to the bottle, and reprimed.104

Dosage

Dosage of beclomethasone dipropionate monohydrate is expressed in terms of anhydrous drug. A double-strength (84 mcg per metered spray) no longer is commercially available in the US. Each actuation of the spray pump delivers 100 mg of suspension containing 42 mcg of beclomethasone dipropionate.103 Each 25-g bottle of beclomethasone dipropionate aqueous nasal spray provides 180 metered sprays.103 Patients should discard the bottle after 180 sprays have been used.103,104

For the symptomatic treatment of seasonal or perennial allergic or nonallergic (vasomotor) rhinitis and for the management of nasal polyposis, the usual initial dosage of intranasal beclomethasone dipropionate as the aqueous suspension for adults and children 12 years of age or older is 42 or 84 mcg (1 or 2 sprays) in each nostril twice daily (168-336 mcg total daily dosage).103 The usual initial dosage of beclomethasone dipropionate spray pump for children 6-12 years of age is 42 mcg (1 spray) in each nostril twice daily (168 mcg total daily dosage).103 Patients not responding to 168 mcg daily or those with more severe symptoms may increase the dosage to 84 mcg (2 sprays) in each nostril (336 mcg total daily dosage).103 Once adequate control is achieved, the dosage should be decreased to 84 mcg (1 spray in each nostril) twice daily.103

In patients with seasonal or perennial rhinitis, symptomatic relief is usually evident within a few days of continuous therapy; however, up to 2 weeks may be required for optimum effectiveness in some patients.103 Although systemic effects are minimal at recommended dosages, therapy with intranasal beclomethasone dipropionate in patients with seasonal or perennial allergic or nonallergic rhinitis should not be continued beyond 3 weeks in the absence of substantial symptomatic improvement.103 The therapeutic effects of beclomethasone dipropionate on nasal polyps also are delayed, and several weeks or more of therapy may be necessary before effects can be fully assessed. To ensure compliance and avoid patient-initiated escalation in dosage, patients should be advised prior to initiating therapy that onset of the beneficial effects of the drug will be delayed. There is no evidence that higher than recommended dosages or increased frequency of administration of intranasal beclomethasone dipropionate are beneficial; exceeding the usual recommended dosage may only increase the risk of adverse systemic effects (e.g., HPA-axis suppression, Cushing's syndrome) and should be avoided.103 Maximum daily dosage of intranasal beclomethasone dipropionate should not exceed 2 sprays in each nostril twice daily (336 mcg daily).103

Nasopharyngeal Effects

The most frequent adverse effects of intranasal beclomethasone dipropionate involve the nasal mucous membranes. Sensations of nasal burning and irritation occur in about 10% of patients receiving intranasal beclomethasone dipropionate aerosol (no longer commercially available in the US). Mild nasopharyngeal irritation occurs in up to 24% of patients receiving the aqueous suspension intranasally. Sneezing attacks, which immediately follow intranasal administration of the drug, occur in about 10% of adults receiving the aerosol (no longer commercially available in the US) and in about 4% of patients receiving the aqueous suspension; limited data suggest that sneezing may occur more frequently in children than in adults. If such sneezing occurs, the patient should wait until the sneezing has stopped, and then clear the nasal passages and repeat the administration of the dose; some clinicians recommend switching to intranasal flunisolide therapy if sneezing persists. Effects on nasal mucous membranes are usually of short duration and rarely require discontinuance of therapy. Sneezing and sensations of nasal burning and irritation may result from excipients in the formulation of the commercially available preparation, since the frequency and severity of these effects are similar in patients receiving an aqueous suspension placebo. In addition, the similar occurrence of adverse nasal effects in beclomethasone dipropionate- or placebo-treated patients with seasonal or perennial rhinitis may result from physical contact and irritation of the characteristically sensitive nasal passages of these patients. If persistent nasopharyngeal irritation occurs during intranasal beclomethasone dipropionate therapy, the need to discontinue such therapy should be considered.

Nasal secretions containing blood have been observed in patients treated with intranasal beclomethasone dipropionate. The manufacturer states that mild nasal bleeding occurs in less than 3% of patients during intranasal beclomethasone dipropionate therapy.103 Since nasal bleeding usually occurs within a few days after initiating therapy, it has been suggested that this effect results from dryness of the nasal mucous membranes and is apparently not related to the topical vasoconstriction induced by intranasal corticosteroids. Since episodes of nasal bleeding are usually transient, this effect rarely requires discontinuance of therapy but may require dosage reduction in some patients.

Other adverse nasopharyngeal effects of intranasal beclomethasone dipropionate include rhinorrhea, nasal stuffiness, nasal dryness or , pharyngeal dryness or irritation, and development of nasal mucosal ulcerations.103 Rarely, perforation of the nasal septum has occurred in patients receiving aerosolized intranasal corticosteroids and with intranasal administration of beclomethasone dipropionate aqueous suspension.

Although resistance to localized infections may be expected to decrease during treatment with intranasal corticosteroids, most clinicians have not observed an increased incidence of infection during intranasal beclomethasone dipropionate therapy. Localized candidal infections of the nose and/or pharynx have occurred rarely during intranasal beclomethasone dipropionate therapy. In a long-term study, nasal candidiasis did not develop in patients during 12 months of intranasal beclomethasone dipropionate therapy, but pharyngeal candidiasis did occur in one patient. Overgrowth of Candida has occurred in the nasopharynx of patients receiving intranasal beclomethasone dipropionate, but signs and symptoms of candidal infection have usually not developed. The incidence of candidiasis is less during nasal inhalation than during oral inhalation of beclomethasone dipropionate; this difference may result from more effective drug clearance by the mucociliary action of the nasal mucosa. If a candidal infection is suspected, appropriate local anti-infective therapy and/or discontinuance of beclomethasone dipropionate therapy should be considered. Nasopharyngeal overgrowth of bacterial pathogens has generally not occurred in patients treated with intranasal beclomethasone dipropionate; however, Staphylococcus aureus has been cultured from specimens taken from the nose and pharynx of patients receiving intranasal beclomethasone dipropionate, and a staphylococcal nasal furuncle has developed in at least one patient.

Although not reported to date in patients receiving beclomethasone dipropionate or other intranasal corticosteroids, some clinicians caution that atrophic rhinitis may develop during chronic therapy with an intranasal corticosteroid, since atrophic dermatitis has occurred in patients treated with topical corticosteroids applied to the skin for prolonged periods. Nasal biopsies in patients who were treated continuously with intranasal beclomethasone dipropionate for 3 months to 6 years have shown no evidence of serious mucosal damage. Although rhinoscopic and microscopic examinations have shown no evidence of atrophic rhinitis following long-term intranasal beclomethasone dipropionate therapy, some patients may develop dryness and crusting of the nasal mucosa (symptoms characteristic of atropic rhinitis) during therapy. Some clinicians recommend that rhinoscopic examinations be performed every 6 months in patients receiving prolonged therapy with intranasal corticosteroids.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

Adrenal suppression, based on plasma cortisol determinations, has not been observed to date when intranasal beclomethasone dipropionate inhalation aerosol was administered in clinical trials.103 The effect of beclomethasone dipropionate administered via the nasal spray pump has not been evaluated, but would not be expected to differ from intranasal beclomethasone dipropionate inhalation aerosol.103 Adrenal suppression is less likely to occur following administration of beclomethasone dipropionate by nasal than by oral inhalation. In a long-term study, slight reductions in plasma cortisol concentrations occurred in patients treated with usual dosages of intranasal beclomethasone dipropionate for at least 6 months each year over a 6-year period. Reductions in plasma cortisol concentrations did not occur in adults when beclomethasone dipropionate was administered by oral inhalation at dosages of 1000 mcg/day for 1 month or by IM injection at the same dosage for 3 days. Partial suppression of adrenal function has been observed when beclomethasone dipropionate was administered in 4 divided doses at dosages of 2000 mcg/day by oral inhalation or IM injection. Following IM administration of single 4000-mcg doses of beclomethasone dipropionate, marked adrenal suppression has been observed. HPA-axis suppression has also been reported in adults following oral inhalation of beclomethasone dipropionate 1600 mcg daily for 1 month. Some data suggest that the risk of developing appreciable adrenal suppression in adults receiving orally inhaled dosages of up to 1500 mcg daily long term is relatively minimal.

Reductions in plasma cortisol concentrations have occurred when intranasal and orally inhaled beclomethasone dipropionate were used concomitantly. Slight reductions in plasma cortisol concentrations occurred when the combined dosage reached 3000 mcg daily (2000 mcg of intranasal and 1000 mcg of orally inhaled beclomethasone dipropionate). Marked adrenal suppression occurred when the combined dosage reached 5000 mcg daily (4000 mcg of intranasal and 1000 mcg of orally inhaled beclomethasone dipropionate). The effect of intranasal beclomethasone dipropionate on the HPA-axis response to stress (e.g., surgery) is not known. Intranasal administration of usual dosages of beclomethasone dipropionate apparently produces less HPA-axis suppression than intranasal administration of usual dosages of dexamethasone phosphate; however, comparative studies have not been conducted to date.

Other Adverse Effects

Other adverse effects associated with intranasal beclomethasone dipropionate therapy include headache, tearing, unpleasant taste and smell, loss of taste and smell, and nausea.103 Increased intraocular pressure (IOP), cataracts, and glaucoma have been reported rarely following intranasal application of beclomethasone dipropionate.103

Immediate or delayed hypersensitivity reactions, including anaphylactoid/anaphylactic reactions, urticaria, angioedema, rash, wheezing, and bronchospasm, have occurred rarely following oral or intranasal inhalation of beclomethasone dipropionate.103 Wheezing has developed rarely in patients receiving intranasal beclomethasone dipropionate and has required discontinuance of the drug in some patients.

Precautions and Contraindications

Higher than recommended dosages of intranasal beclomethasone dipropionate should be avoided, since suppression of HPA function may occur. Intranasal 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.

Patients who have received systemic corticosteroids for prolonged periods and are being switched to treatment with intranasal beclomethasone dipropionate should be carefully monitored, since corticosteroid withdrawal symptoms (e.g., joint pain, muscular pain, lassitude, depression), acute adrenal insufficiency, or severe symptomatic exacerbation of asthma or other clinical conditions may occur. Systemic corticosteroid dosage should be tapered, and patients should be carefully monitored during dosage reduction. 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 intranasal corticosteroids.

The possibility that manifestations of hypercortisolism (e.g., menstrual irregularities, acneiform lesions, cataracts, cushingoid features) could occur during intranasal beclomethasone dipropionate therapy should be considered in patients who are particularly sensitive to corticosteroid effects or when usual dosages of the drug are exceeded.103 If such manifestations occur, therapy with the drug should gradually be withdrawn (tapered).

Patients should be advised that intranasal beclomethasone dipropionate must be used at regular intervals to be therapeutically effective. In addition, patients should be advised that the drug will not provide immediate symptomatic relief and use of topical nasal decongestants or oral antihistamines may be necessary until the effects of intranasal beclomethasone dipropionate are fully manifested. Patients should also be advised not to exceed the prescribed dosage. (See Dosage and Administration: Dosage.) Patients with severe allergies should be instructed to avoid exposure to allergens during intranasal beclomethasone dipropionate therapy to prevent the occurrence of severe allergic symptoms in the eyes and/or lower respiratory tract. Patients should be instructed to contact their clinician during intranasal beclomethasone dipropionate therapy if signs or symptoms of the condition do not improve, if the condition worsens, or if sneezing or nasal irritation occurs. While 2 weeks of continuous intranasal beclomethasone therapy may be necessary for optimum effectiveness, therapy should not be continued for longer than 3 weeks in the absence of substantial symptomatic improvement.

Because adequate penetration of beclomethasone dipropionate to the nasal mucosa is necessary for the drug to be effective in the management of nasal polyposis, intranasal beclomethasone therapy is not a substitute for but an adjunct to surgery and/or other drugs that will permit effective intranasal penetration of the drug. It should be remembered, however, that nasal polyps may recur following any form of therapy.

Increased intraocular pressure has occurred rarely in patients receiving intranasal beclomethasone dipropionate therapy.103

During long-term intranasal therapy with beclomethasone dipropionate (several months or longer), the nasal passages should be examined periodically for mucosal changes. Intranasal beclomethasone dipropionate should not be used until healing occurs in patients with recent nasal septal ulcers, nasal surgery, or nasal trauma, since the drug may inhibit wound healing.103 Intranasal beclomethasone dipropionate should be used with caution, if at all, in patients with clinical tuberculosis or asymptomatic Mycobacterium tuberculosis infections of the respiratory tract; untreated fungal or bacterial infections; ocular herpes simplex, or untreated, systemic or parasitic viral infections.103 In addition, use of intranasal beclomethasone dipropionate may result in localized candidal infections of the nose or pharynx. When infection occurs, appropriate local treatment of the infection may be necessary and discontinuance of intranasal beclomethasone dipropionate therapy may be required. Intranasal beclomethasone dipropionate should not be used in the presence of untreated localized infections involving the nasal mucosa.

Patients who are taking immunosuppressant drugs 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.100,101,102,103 In patients who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.100,101,103 The relationship of dose, route of administration, and duration of corticosteroid therapy to the risk of developing a disseminated infection is not known, nor is the contribution of the underlying disease and/or prior corticosteroid therapy.100,101,103 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.100,102,103 If exposure to varicella or measles occurs in such individuals, administration of varicella zoster immune globulin (VZIG) or immune globulin, respectively, may be indicated.100,101,103 If varicella develops, treatment with an antiviral agent may be considered.100,101,103 For additional information, see Cautions: Increased Susceptibility to Infection and also see Precautions and Contraindications, in the Corticosteroids General Statement 68:04.

Beclomethasone dipropionate nasal suspensions are intended for nasal use only and should not be applied to the eye.101

Intranasal beclomethasone dipropionate is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.103

Pediatric Precautions

Safety and efficacy of beclomethasone dipropionate nasal inhalation aqueous suspension (as the monohydrate) in children younger than 6 years of age have not been established. Intranasal beclomethasone dipropionate may be a useful therapeutic alternative to oral corticosteroids in children 6 years of age or older with seasonal or perennial rhinitis, since intranasal beclomethasone dipropionate is associated with a decreased risk of adverse systemic effects.

In a double-blind, placebo-controlled, 1-year study in children 6-9.5 years of age with allergic rhinitis, growth velocity (as assessed by stadiometry) was less in children receiving intranasal beclomethasone dipropionate 168 mcg twice daily compared with placebo.103 A difference in mean change in height was observed within 1 month of initiation of treatment with intranasal beclomethasone dipropionate.103 At the end of the study, growth velocity averaged 4.75 cm/year with beclomethasone and 6.20 cm/year with placebo.103 Approximately 50% of beclomethasone-treated children were below the 10th percentile for height.103 No differences in HPA axis function (as assessed by mean basal plasma cortisol or adrenocorticotropic hormone (ACTH)-stimulated plasma cortisol concentrations) were observed between the 2 treatment groups.103 The growth of pediatric patients receiving intranasal corticosteroids, including intranasal beclomethasone, should be monitored routinely.103

Mutagenicity and Carcinogenicity

Beclomethasone dipropionate did not exhibit mutagenic potential in vitro in bacterial or mammalian (Chinese hamster ovary cells) test systems.103 In addition, the drug was not shown to be clastogenic in vitro in Chinese hamster ovary cells or in the in vivo micronucleus test in mice.103 No evidence of carcinogenicity was observed when rats were given the drug for 95 weeks (13 weeks by oral inhalation [up to 0.4 mg/kg daily] and 82 weeks by combined oral and inhalation routes [up to 2.4 mg/kg daily, about 60 or 35 times the maximum recommended daily intranasal dosage in adults or children, respectively on a mg/m² basis]).103

Pregnancy, Fertility, and Lactation

Pregnancy

Intranasal beclomethasone dipropionate should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Since adrenal insufficiency may occur in neonates born to women who received corticosteroids during pregnancy, these neonates should be carefully monitored for signs and symptoms of this condition. Although there are no adequate and controlled studies to date in humans, subcutaneous beclomethasone dipropionate has been shown to be teratogenic and embryocidal in mice and rabbits receiving 0.1 mg/kg and 0.025 mg/kg daily, respectively, dosages that are about equal to the maximum recommended intranasal dosage in adults (on a mg/m² basis).103 Teratogenic effects in these animals included fetal resorption, cleft palate, agnathia, microstomia, aglossia, delayed ossification, and agenesis of the thymus gland. Teratogenic or embryocidal effects were not observed in rats following a combination of oral administration and inhalation of beclomethasone dipropionate at dosages of 10 and 0.1 mg/kg daily, respectively (about 240 times the maximum recommended adult intranasal dosage [on a mg/m² basis]).103

Fertility

It is not known whether beclomethasone dipropionate affects fertility in humans. Reproduction studies in female dogs using oral beclomethasone dipropionate dosages of 500 mcg/kg daily (about 40 times the maximum recommended adult intranasal dosage [on a mg/m²] basis) have shown evidence of impaired fertility (inhibition of the estrus cycle); however, inhibition of the estrus cycle has not been observed in dogs following treatment with orally inhaled beclomethasone dipropionate.103 Reproduction studies in rats receiving an oral beclomethasone dipropionate dosage of 16 mg/kg (approximately 390 times the maximum recommended daily intranasal dosage in adults on mg/m² basis) have shown evidence of decreased conception rates.103 No appreciable effects on fertility was observed in rats receiving oral beclomethasone dipropionate dosages of 1.6 mg/kg (approximately 40 times the maximum recommended daily intranasal dosage in adults on a mg/m² basis).103

Lactation

Beclomethasone dipropionate should be used with caution in nursing women, since it is not known whether the drug is distributed into milk. Other corticosteroids are distributed into milk and may cause adverse effects such as growth suppression in nursing infants.

Acute Toxicity

It is unlikely that acute overdosage of intranasal beclomethasone dipropionate could occur, since the commercially available preparation contains a total of 10.5 mg of beclomethasone dipropionate.103 No deaths occurred when beclomethasone dipropionate was given as single oral doses of 3 g/kg in mice (approximately 36,000 or 21,000 times the maximum daily recommended intranasal dosage in adults or children, respectively on a mg/m² basis) or in rats given 2 g/kg (approximately 48,000 or 29,000 times the maximum recommended daily dosage in adults or children, respectively, on a mg/m² basis).103

Chronic Toxicity

Overdosage of beclomethasone dipropionate may produce signs and symptoms that are mainly extensions of common adverse reactions to corticosteroids (e.g., HPA-axis suppression, Cushing's syndrome). (See Cautions: Hypothalamic-Pituitary-Adrenal [HPA]Axis Suppression.) When chronic intoxication occurs, a reduction in dosage is usually sufficient.

Pharmacology

In mice, beclomethasone dipropionate has potent glucocorticoid and weak mineralocorticoid activity; as a glucocorticoid, the drug is 6-7 times more potent than hydrocortisone when administered orally or subcutaneously.

Following topical application to the nasal mucosa, beclomethasone dipropionate produces anti-inflammatory and vasoconstrictor effects. The anti-inflammatory potency of topically applied beclomethasone dipropionate is about 5000 times greater than hydrocortisone; 500 times greater than beclomethasone, betamethasone, or dexamethasone; and about 5 times greater than fluocinolone or the acetonides of fluocinolone or triamcinolone, as measured by vasoconstrictor assay. The exact mechanism(s) of these actions of corticosteroids remains unknown, but may involve reductions in the following: number of mediator cells (basophil leukocytes and mast cells) at the epithelial level, number of eosinophils, sensitivity of sensory nerves to mechanical stimuli, secretory response to cholinergic receptor stimulation, and fibroblast activity. Other mechanisms may involve inhibition of capillary dilation and permeability, and stabilization of lysosomal membranes and subsequent prevention of release of proteolytic enzymes.

Adrenal suppression, based on plasma cortisol determinations, has not been observed to date when intranasal beclomethasone dipropionate inhalation aerosol was administered in clinical trials.103 In addition, no substantial difference in adrenal suppression has been reported in patients receiving beclomethasone dipropionate double strength formulation (no longer commercially available in the US) at 168 mcg twice daily, 336 mcg once daily, or placebo via the aqueous suspension spray pump for 36 consecutive days.101 (See Cautions: Hypothalamic-Pituitary-Adrenal [HPA] Axis Suppression.) Plasma cortisol response to 6-hour cosyntropin stimulation was attenuated in patients who received an oral prednisone dosage of 10 mg daily.101

Pharmacokinetics

Absorption

Beclomethasone dipropionate is readily absorbed from the respiratory and GI tracts following nasal inhalation of a suspension of the drug as an aerosol (no longer commercially available in the US) or aqueous spray (containing the monohydrate). The majority of an intranasal dose of the drug is swallowed.103,105 Following intranasal administration, the absolute bioavailability (as measured by the plasma concentrations of the active metabolite beclomethasone 17-monopropionate) is 44%, of which 43 or 1% is derived from absorption of the swallowed portion or from the nose, respectively.103,105 Orally administered beclomethasone dipropionate is readily absorbed and apparently undergoes extensive first-pass metabolism in the liver and/or GI tract. In addition, a portion of the drug that enters the bronchial tree may undergo enzymatic hydrolysis in the respiratory tract. (See Pharmacokinetics: Elimination.)

Following intranasal and oral administration of beclomethasone dipropionate, plasma concentrations of unchanged drug are undetectable.103,105 A correlation between plasma beclomethasone dipropionate concentrations and therapeutic effects has not been described; however, it is thought that systemically absorbed drug contributes little to the effect of the drug on the nasal mucosa.

Distribution

Beclomethasone dipropionate is not widely distributed into tissues following IM or subcutaneous administration. The major metabolite of beclomethasone dipropionate appears to be more extensively distributed (424 L) at steady state than the parent compound (20 L).103,105 Beclomethasone dipropionate and its metabolites do not undergo storage in the tissues.103 Distribution of beclomethasone dipropionate following intranasal administration has not been described. At a plasma concentration of 100 ng/mL, about 87% of beclomethasone dipropionate is bound to plasma proteins.

Although it is not known if beclomethasone dipropionate crosses the placenta in humans, the drug apparently crosses the placenta in animals since teratogenic and embryocidal effects have occurred following subcutaneous administration of the drug. These effects have not been observed in animals following oral administration or oral inhalation of the drug. It is not known if beclomethasone dipropionate is distributed into milk; however, other corticosteroids are distributed into milk.

Elimination

The plasma half-life of beclomethasone dipropionate following intranasal administration has not been determined. Following IV administration of beclomethasone dipropionate, the plasma clearances of beclomethasone dipropionate and its active metabolite are 150 and 120 L/hour, respectively, and the terminal elimination half-lives of the parent drug and its active metabolite are 0.5 and 2.7 hours, respectively.103,105

Beclomethasone dipropionate is a prodrug that is metabolized principally via esterases found in most tissues.103,105 Drug that is swallowed undergoes rapid metabolism to the active metabolite beclomethasone 17-monopropionate, and minor inactive metabolites beclomethasone and beclomethasone 21-monopropionate.103 Beclomethasone 17-monopropionate appears to have some glucocorticoid and mineralocorticoid activity. The portion of a dose of beclomethasone dipropionate that enters the bronchial tree may be partially metabolized in the respiratory tract before reaching systemic circulation. In vitro studies have shown that esterases in the lung rapidly hydrolyze beclomethasone dipropionate to beclomethasone 17-monopropionate and more slowly to beclomethasone.

The excretory fate of beclomethasone dipropionate and its metabolites following intranasal administration has not been described; however, following IV or oral administration, the drug and its metabolites are excreted mainly in feces via biliary elimination and to a lesser extent in urine. Following oral administration, approximately 12% of a dose of beclomethasone dipropionate is excreted in urine as free and conjugated metabolites.103

Chemistry and Stability

Chemistry

Beclomethasone dipropionate, a diester of beclomethasone, is a synthetic corticosteroid. Beclomethasone and beclomethasone dipropionate are 21-carbon steroids and are structurally related to hydrocortisone. 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. (See Chemistry in the EENT Corticosteroids General Statement 52:08.08.)

Beclomethasone dipropionate occurs as the monohydrate.103 The monohydrate occurs as a white to creamy-white powder and is very slightly soluble in water, very soluble in chloroform, and freely soluble in alcohol in acetone.103

For intranasal use, beclomethasone dipropionate is commercially available as a pump spray containing microcrystalline suspensions of the monohydrate in an aqueous vehicle.103 The pH of beclomethasone dipropionate suspension in the spray pump is 5-6.8 throughout its shelf life.103 Potency of beclomethasone dipropionate monohydrate is expressed in terms of anhydrous drug. When using single-strength nasal suspensions (Beconase AQ^®), each actuation of the spray pump delivers from the nasal adapter a dose of the monohydrate equivalent to 42 mcg of beclomethasone dipropionate after initial priming. A double-strength formulation no longer is commercially available in the US.

Stability

Beclomethasone dipropionate nasal pump spray containing an aqueous suspension of the drug as the monohydrate should be stored at 15-30°C (Beconase AQ^® Nasal Spray).

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, and dosage and administration of beclomethasone dipropionate, see the EENT Corticosteroids General Statement 52:08.08. 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.

Only references cited for selected revisions after 1984 are available electronically.

100. Schering. Vancenase^® (beclomethasone dipropionate) POCKETHALER^® nasal inhaler prescribing information. In: Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999(Suppl A):A292-4.

101. Schering. Vancenase^® (beclomethasone dipropionate) AQ 84 mcg double strength prescribing information. Kenilworth, NJ. 1996 Jun.

102. Schering. Vancenase^® (beclomethasone dipropionate) nasal inhaler prescribing information (dated 1997 Apr). In: Physicians; desk reference. 54th ed. Montvale, NJ: Medical Economics Company Inc; 2000:2844-5.

103. GlaxoSmithKline. BeconaseAQ^® (beclomethasone dipropionate monohydrate) nasal spray prescribing information. Research Triangle Park, NC; 2005 Apr.

104. GlaxoSmithKline. BeconaseAQ^® (beclomethasone dipropionate monohydrate) nasal spray patient instructions for use. Research Triangle Park, NC; 2005 Apr.

105. Daley-Yates PT, Price AC, Sisson JR et al. Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics and metabolsim following intravenous, oral, intranasal and inhaled administration in man. Br J Clin Pharmacol . 2001; 51:400-9. [PubMed 11421996][PubMedCentral]