"The U.S. Food and Drug Administration today approved Nucala (mepolizumab) for use with other asthma medicines for the maintenance treatment of asthma in patients age 12 years and older. Nucala is approved for patients who have a history of "...
Particular care is needed in patients who are transferred from systemically active corticosteroids to QVAR because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.
Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infections (particularly gastroenteritis) or other conditions with severe electrolyte loss. Although QVAR may provide control of asthmatic symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid that is necessary for coping with these emergencies.
During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack.
Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. It is not known how the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection. Nor is the contribution of the underlying disease and/or prior corticosteroid treatment known. If exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
QVAR is not a bronchodilator and is not indicated for rapid relief of bronchospasm.
As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with QVAR, it should be treated immediately with a short-acting inhaled bronchodilator. Treatment with QVAR should be discontinued and alternate therapy instituted. Patients should be instructed to contact their physician immediately when episodes of asthma, which are not responsive to bronchodilators, occur during the course of treatment with QVAR. During such episodes, patients may require therapy with oral corticosteroids.
During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function. Although suppression of HPA function below the clinical normal range did not occur with doses of QVAR up to and including 640 mcg/day, a dose-dependent reduction of adrenal cortisol production was observed. Since inhaled beclomethasone dipropionate is absorbed into the circulation and can be systemically active, HPA-axis suppression by QVAR could occur when recommended doses are exceeded or in particularly sensitive individuals. Since individual sensitivity to effects on cortisol production exist, physicians should consider this information when prescribing QVAR. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with these drugs should be observed carefully for any evidence of systemic corticosteroid effect. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
It is possible that systemic corticosteroid effects, such as hypercorticism and adrenal suppression, may appear in a small number of patients, particularly at higher doses. If such changes occur, QVAR should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic steroids.
A 12-month, randomized, controlled clinical trial evaluated the effects of HFA beclomethasone dipropionate without spacer versus CFC beclomethasone dipropionate with large-volume spacer on growth in children age 5 to 11. A total of 520 patients were enrolled, of whom 394 received HFA-BDP (100 to 400 mcg/day ex-valve) and 126 received CFC-BDP (200 to 800 mcg/day ex-valve). Similar control of asthma was noted in each treatment arm. When comparing results at month 12 to baseline, the mean growth velocity in children treated with HFA-BDP was approximately 0.5 cm/year less than that noted with children treated with CFC-BDP via large-volume spacer.
A reduction in growth velocity in growing children may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of all pediatric patients taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression.
The long-term and systemic effects of QVAR in humans are still not fully known. In particular, the effects resulting from chronic use of the agent on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown.
Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic or viral infections; or ocular herpes simplex.
Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids.
Information for Patients:
Patients being treated with QVAR should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed to these diseases, medical advice should be sought without delay.
Patients should use QVAR at regular intervals as directed. Results of clinical trials indicated significant improvements may occur within the first 24 hours of treatment in some patients; however, the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks, or longer. The patient should not increase the prescribed dosage but should contact their physician if symptoms do not improve or if the condition worsens.
Patients should be advised that QVAR is not intended for use in the treatment of acute asthma. The patient should be instructed to contact their physician immediately if there is any deterioration of their asthma.
Patients should be instructed on the proper use of their inhaler. Patients may wish to rinse their mouth after QVAR use. The patient should also be advised that QVAR may have a different taste and inhalation sensation than that of an inhaler containing CFC propellant.
QVAR use should not be stopped abruptly. The patient should contact their physician immediately if use of QVAR is discontinued.
For the proper use of QVAR, the patient should read and carefully follow the accompanying Patient's Instructions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenicity of beclomethasone dipropionate was evaluated in rats which were exposed for a total of 95 weeks, 13 weeks at inhalation doses up to 0.4 mg/kg/day and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg/day. There was no evidence of carcinogenicity in this study at the highest dose, which is approximately 30 and 55 times the maximum recommended daily inhalation dose in adults and children, respectively, on a mg/m2 basis.
Beclomethasone dipropionate did not induce gene mutation in the bacterial cells or mammalian Chinese Hamster ovary (CHO) cells in vitro. No significant clastogenic effect was seen in cultured CHO cells in vitro or in the mouse micronucleus test in vivo.
In rats, beclomethasone dipropionate caused decreased conception rates at an oral dose of 16 mg/kg/day (approximately 200 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). Impairment of fertility, as evidence by inhibition of the estrous cycle in dogs, was observed following treatment by the oral route at a dose of 0.5 mg/kg/day (approximately 20 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). No inhibition of the estrous cycle in dogs was seen following 12 months of exposure to beclomethasone dipropionate by the inhalation route at an estimated daily dose of 0.33 mg/kg (approximately 15 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
Pregnancy Category C: Like other corticosteroids, parenteral (subcutaneous) beclomethasone dipropionate was teratogenic and embryocidal in the mouse and rabbit when given at a dose of 0.1 mg/kg/day in mice or at a dose of 0.025 mg/kg/day in rabbits. These doses in mice and rabbits were approximately one-half the maximum recommended daily inhalation dose in adults on a mg/m2 basis. No teratogenicity or embryocidal effects were seen in rats when exposed to an inhalation dose of 15 mg/kg/day (approximately 190 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Beclomethasone dipropionate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Findings of drug-related adrenal toxicity in fetuses following administration of beclomethasone dipropionate to rats suggest that infants born of mothers receiving substantial doses of QVAR during pregnancy should be observed for adrenal suppression.
Corticosteroids are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from QVAR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Eight-hundred and thirty-four children between the ages of 5 and 12 were treated with HFA beclomethasone dipropionate (HFA-BDP) in clinical trials. The safety and effectiveness of QVAR in children below 5 years of age have not been established.
Use of QVAR with a spacer device in children less than 5 years of age is not recommended. In vitro dose characterization studies were performed with QVAR 40 mcg/actuation with the Optichamber and AeroChamber Plus® spacer utilizing inspiratory flows representative of children under 5 years old. These studies indicated that the amount of medication delivered through the spacing device decreased rapidly with increasing wait times of 5 to 10 seconds as shown in Table 1 If QVAR is used with a spacer device, it is important to inhale immediately.
Based on the average inspiratory flow rates generated by children 6 months to 5 years old, the projected daily dose derived from QVAR 40 mcg at one puff per day at various wait times is depicted in the table below:
|Wait time, seconds||Mean medication delivery through AeroChamber mcg/actuation i||Body Weight 50th percentile, kg ii||Medication delivered per dose, mcg/kg iii, iv|
|Age 6 months, Flow rate 4.8 L/min||0||11.5||7.6||1.2|
|Age 2 years, Flow rate 8.2 L/min||0||14.1||13.5||0.83|
|Age 2 years, Flow rate 8.2 L/min||5||5.4||13.5||0.32|
|Age 2 years, Flow rate 8.2 L/min||10||3.9||13.5||0.23|
|Age 5 years, Flow rate 11.0 L/min||0||17.5||18||0.78|
|iSummary Report; Pediatric Dose Characterization of QVAR
with Spacer; 3M Pharmaceutical Development, July 21, 2004.
ii CDC Growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000).
iii Includes an estimated 20% loss in the masks
iv QVAR 40mcg in an average adult without using a spacer delivers approximately 0.4 mcg/kg, or bid, 0.8 mcg/kg/day.
Oral inhaled corticosteroids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any corticosteroid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of corticosteroids should be considered (see PRECAUTIONS, General).
Clinical studies of QVAR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 8/9/2012
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