Beclomethasone (Oral Inhalation)

Name: Beclomethasone (Oral Inhalation)

Pharmacology

Controls the rate of protein synthesis; depresses the migration of polymorphonuclear leukocytes, fibroblasts; reverses capillary permeability and lysosomal stabilization at the cellular level to prevent or control inflammation

Absorption

Readily; quickly hydrolyzed by pulmonary esterases to active metabolite (beclomethasone-17-monoproprionate [17-BMP]) during absorption

Distribution

Vd: Beclomethasone dipropionate (BDP): 20 L; 17-BMP: 424 L

Metabolism

BDP is a pro-drug (inactive); undergoes rapid conversion to 17-BMP during absorption; followed by additional metabolism via CYP3A4 to other, less active metabolites (beclomethasone-21-monopropionate [21-BMP] and beclomethasone [BOH])

Excretion

Primary route of excretion is via feces (~60%); <10% to 12% of oral dose excreted in urine as metabolites

Use Labeled Indications

Asthma: Maintenance and prophylactic treatment of asthma in patients ≥5 years (including those who require corticosteroids and those who may benefit from a dose reduction/elimination of systemically administered corticosteroids).

Limitations of use: Not for relief of acute bronchospasm.

Guideline recommendations: A low-dose inhaled corticosteroid (in addition to an as-needed short acting beta2-agonist) is the initial preferred long-term control medication for children, adolescents, and adult patients with persistent asthma who are candidates for treatment according to a step-wise treatment approach (GINA 2016; NAEPP 2007).

Contraindications

Hypersensitivity to beclomethasone or any component of the formulation; status asthmaticus, or other acute asthma episodes requiring intensive measures

Documentation of allergenic cross-reactivity for corticosteroids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Moderate to severe bronchiectasis requiring intensive measures; untreated fungal, bacterial, or tubercular infections of the respiratory tract

Drug Interactions

Aldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Avoid combination

Amphotericin B: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Amphotericin B. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Ceritinib: Corticosteroids may enhance the hyperglycemic effect of Ceritinib. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Corticorelin: Corticosteroids may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy. Monitor therapy

Deferasirox: Corticosteroids may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Desmopressin: Corticosteroids (Orally Inhaled) may enhance the hyponatremic effect of Desmopressin. Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Hyaluronidase: Corticosteroids may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Loop Diuretics: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal suppression: May cause hypercortisolism or suppression of hypothalamic-pituitary-adrenal (HPA) axis, particularly in younger children or in patients receiving high doses for prolonged periods. HPA axis suppression may lead to adrenal crisis. Withdrawal and discontinuation of a corticosteroid should be done slowly and carefully. Particular care is required when patients are transferred from systemic corticosteroids to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Patients receiving >20 mg per day of prednisone (or equivalent) may be most susceptible. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after transfer from systemic corticosteroids to aerosol steroids; aerosol steroids do not provide the systemic steroid needed to treat patients having trauma, surgery, or infections (particularly gastroenteritis), or other conditions with severe electrolyte loss. Select surgical patients on long-term, high-dose, inhaled corticosteroid (ICS), should be given stress doses of hydrocortisone intravenously during the surgical period and the dose reduced rapidly within 24 hours after surgery (Expert Panel Report 3, 2007).

• Bronchospasm: May occur with wheezing after inhalation (possibly life-threatening); if bronchospasm occurs, discontinue steroid and treat with a fast-acting bronchodilator.

• Hypersensitivity reactions: Immediate hypersensitivity reactions may occur, including angioedema, bronchospasm, rash, and urticaria; discontinue use if reaction occurs.

• Immunosuppression: Prolonged use of corticosteroids may also increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit response to vaccines. Avoid use, if possible, in patients with ocular herpes, active or quiescent respiratory tuberculosis, or untreated viral, fungal, parasitic or bacterial systemic infections (Canadian labeling contraindicates use with untreated respiratory infections). Exposure to chickenpox and measles should be avoided. Close observation is required in patients with latent tuberculosis and/or TB reactivity.

• Kaposi sarcoma: Prolonged treatment with corticosteroids has been associated with the development of Kaposi sarcoma (case reports); if noted, discontinuation of therapy should be considered.

• Oral candidiasis: Candida albicans infections may occur in the mouth and pharynx; rinsing (and spitting) with water after inhaler use may decrease risk.

• Psychiatric disturbances: Corticosteroid use may cause psychiatric disturbances, including depression, euphoria, insomnia, mood swings, and personality changes. Preexisting psychiatric conditions may be exacerbated by corticosteroid use.

• Vasculitis: Rare cases of vasculitis (eosinophilic granulomatosis with polyangiitis [formerly known as Churg-Strauss]) or other systemic eosinophilic conditions can occur; often associated with decrease and/or withdrawal of oral corticosteroid therapy following initiation of inhaled corticosteroid.

Disease-related concerns:

• Asthma: Supplemental steroids (oral or parenteral) may be needed during stress or severe asthma attacks. Not to be used in status asthmaticus or for the relief of acute bronchospasm.

• Bone mineral density: Use with caution in patients with major risk factors for decreased bone mineral count such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants, oral corticosteroids); long-term use of inhaled corticosteroids have been associated with decreases in bone mineral density.

• Cardiovascular disease: Use with caution in patients with HF; long-term corticosteroid use has been associated with fluid retention and hypertension.

• Diabetes: Use with caution in patients with diabetes mellitus; corticosteroids may alter glucose production/regulation leading to hyperglycemia.

• Gastrointestinal disease: Use corticosteroids with caution in patients with GI diseases (diverticulitis, peptic ulcer, ulcerative colitis) due to perforation risk.

• Hepatic impairment: Use with caution in patients with hepatic impairment, including cirrhosis; long-term corticosteroid use has been associated with fluid retention.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation of symptoms has occurred especially during initial treatment with corticosteroids.

• Myocardial infarct (MI): Use with caution following acute MI; corticosteroids have been associated with myocardial rupture.

• Ocular disease: Use with caution in patients with cataracts and/or glaucoma; increased intraocular pressure, glaucoma, and cataracts have occurred (rarely) with oral inhalation of corticosteroids.

• Renal impairment: Use with caution in patients with renal impairment; fluid retention may occur with long-term corticosteroid use.

• Seizure disorders: Use with caution in patients with a history of seizure disorder; seizures have been reported with adrenal crisis.

• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases in hypothyroid ones.

Special populations:

• Pediatric: Orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients (~1 centimeter per year [range: 0.3 to 1.8 cm per year] and related to dose and duration of exposure). To minimize the systemic effects of orally inhaled corticosteroids, each patient should be titrated to the lowest effective dose. Growth should be routinely monitored in pediatric patients.

Other warnings/precautions:

• Discontinuation of therapy: A gradual tapering of dose may be required prior to discontinuing therapy; there have been reports of systemic corticosteroid withdrawal symptoms (eg, joint/muscle pain, lassitude, depression) when withdrawing oral inhalation therapy.

• Transfer to oral inhaler: When transferring to oral inhalation therapy from systemic corticosteroid therapy; previously suppressed allergic conditions (rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions) may be unmasked. Withdraw systemic therapy with gradual tapering of dose; during transition monitor pulmonary function tests (FEV1 or PEF), beta-agonist use, and asthma symptoms and observe for signs and symptoms of adrenal insufficiency (eg, fatigue, lassitude, weakness, nausea/vomiting, hypotension).

Pregnancy Risk Factor C Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Hypoadrenalism may occur in newborns following maternal use of corticosteroids in pregnancy. Based on available data, an overall increased risk of congenital malformations or a decrease in fetal growth has not been associated with maternal use of inhaled corticosteroids during pregnancy (Bakhireva, 2005; NAEPP, 2005; Namazy, 2004). Uncontrolled asthma is associated with adverse events in pregnancy (increased risk of perinatal mortality, pre-eclampsia, preterm birth, low birth weight infants). Inhaled corticosteroids are recommended for the treatment of asthma during pregnancy (most information available using budesonide) (ACOG, 2008; NAEPP, 2005).

(web3)