Particular care is needed for patients who are transferred from systemically active corticosteroids to the ASMANEX TWISTHALER inhaler 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 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its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.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 infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although the ASMANEX TWISTHALER inhaler may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity necessary for coping with these emergencies.
During periods of stress or severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe asthma attack.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to ASMANEX TWISTHALER. Lung function (FEV1 or PEF), beta agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy to the ASMANEX TWISTHALER inhaler may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, eg, rhinitis, conjunctivitis, and eczema.
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 nonimmune children or adults on corticosteroids. In such children or adults who have not had these diseases or who are not properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If 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.
The ASMANEX TWISTHALER inhaler is not a bronchodilator and is not indicated for rapid relief of bronchospasm or other acute episodes of asthma.
As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with the ASMANEX TWISTHALER inhaler, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with the ASMANEX TWISTHALER inhaler should be discontinued and alternative therapy instituted.
Patients should be instructed to contact their physician immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with the ASMANEX TWISTHALER inhaler. 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, eg, joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.
The ASMANEX TWISTHALER inhaler will often improve control of asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since mometasone furoate is absorbed into the circulation and can be systemically active at higher doses, the full beneficial effects of the ASMANEX TWISTHALER inhaler in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing the ASMANEX TWISTHALER inhaler.
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 effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
It is possible that systemic corticosteroid effects such as hypercorticism, reduced bone mineral density and adrenal suppression may appear in a small number of patients, particularly at higher doses. If such changes occur, the ASMANEX TWISTHALER inhaler dose should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic steroids.
Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled glucocorticoids, including mometasone furoate. The clinical significance of small changes in bone mineral density with regard to long-term outcomes is unknown. In a two-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV1 85–88% predicted), treatment with ASMANEX TWISTHALER 220 mcg twice daily resulted in significant reductions in lumbar spine (LS) BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.015 (-1.43%) for the ASMANEX TWISTHALER group compared to 0.002 (0.25%) for the placebo group. In another two-year double-blind study in 87 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV1 82–83% predicted), treatment with ASMANEX TWISTHALER 440 mcg twice daily demonstrated no statistically significant changes in lumbar spine BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.018 (-1.57%) for the ASMANEX TWISTHALER group compared to -0.006 (-0.43%) for the placebo group.
Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants and corticosteroids) should be monitored and treated with established standards of care.
Orally inhaled corticosteroids, including mometasone furoate inhalation powder, may cause a reduction in growth velocity when administered to pediatric patients. A reduction in growth velocity in children or teenagers may occur as a result of inadequate control of asthma or from use of corticosteroids for treatment. The potential effects of prolonged treatment on growth velocity should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including ASMANEX TWISTHALER, each patient should be titrated to his/her lowest effective dose. (See PRECAUTIONS, Pediatric Use section.)
Although patients in clinical trials have received the ASMANEX TWISTHALER inhaler on a continuous basis for periods of up to 2 years, the long-term local and systemic effects of ASMANEX TWISTHALER in human subjects are not completely known. In particular, the effects resulting from chronic use of the ASMANEX TWISTHALER inhaler on developmental or immunological processes in the mouth, pharynx, trachea, and lung are unknown.
In clinical trials with the ASMANEX TWISTHALER inhaler, localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (ie, oral) antifungal therapy while still continuing with ASMANEX TWISTHALER therapy, but at times therapy with the ASMANEX TWISTHALER inhaler may need to be temporarily interrupted under close medical supervision.
Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.
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 the ASMANEX TWISTHALER inhaler should be given the following information. This information is intended to aid in the safe and effective use of the ASMANEX TWISTHALER inhaler. It is not a disclosure of all intended or possible adverse effects.
- Patients should be advised that ASMANEX TWISTHALER is not a bronchodilator and should not be used to relieve acute asthma symptoms. Acute asthma symptoms should be treated with an inhaled, short-acting beta-2 agonist such as albuterol.
- Patients should be advised to use the ASMANEX TWISTHALER inhaler at regular intervals since its effectiveness depends on regular use. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. If symptoms do not improve in that time frame or if the condition worsens, the patient should be instructed to contact the physician.
- Patients should be warned to avoid exposure to chickenpox or measles, and if they are exposed, to consult their physicians without delay.
- Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk and should be monitored and, where appropriate, be treated for this condition.
- Patients should be advised that long-term use of inhaled corticosteroids, including ASMANEX TWISTHALER may increase the risk of some eye problems (cataracts or glaucoma).
- For the proper use of the ASMANEX TWISTHALER inhaler, and to attain maximum improvement, the patient should read and follow the accompanying Patient's Instructions for Use.
Patients should be instructed to record the date of pouch opening on the cap label, and discard the inhaler 45 days after opening the foil pouch or when the dose counter reads "00," whichever comes first. The inhaler should be held upright while removing the cap. The medication should be taken as directed, breathing rapidly and deeply, and patients should not breathe out through the inhaler. The mouthpiece should be wiped dry and the cap replaced immediately following each inhalation, rotated fully until the click is heard. Rinsing of mouth after inhalation is advised. Patients should store the unit as instructed. The digital dose counter displays the doses remaining. When the counter indicates zero, the cap will lock and the unit must be discarded. Patients should be advised that if the dose counter is not working correctly, the unit should not be used and it should be brought to their physician or pharmacist.
In clinical studies, the concurrent administration of the ASMANEX TWISTHALER inhaler and other drugs commonly used in the treatment of asthma was not associated with any unusual adverse events. However, ketoconazole, a potent inhibitor of cytochrome P450 3A4, may increase plasma levels of mometasone furoate during concomitant dosing.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year carcinogenicity study in Sprague Dawley rats, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 67 mcg/kg (approximately 8 times the maximum recommended daily inhalation dose in adults on an AUC basis). In a 19-month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 160 mcg/kg (approximately 10 times the maximum recommended daily inhalation dose in adults on an AUC basis).
Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not have this effect in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.
In reproductive studies in rats, impairment of fertility was not produced by subcutaneous doses up to 15 mcg/kg (approximately 6 times the maximum recommended daily inhalation dose in adults on an AUC basis).
Pregnancy Category C
When administered to pregnant mice, rats, and rabbits, mometasone furoate increased fetal malformations. The doses that produced malformations also decreased fetal growth, as measured by lower fetal weights and/or delayed ossification. Mometasone furoate also caused dystocia and related complications when administered to rats during the end of pregnancy.
In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). Fetal survival was reduced at 180 mcg/kg (approximately equal to the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). No toxicity was observed at 20 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).
In rats, mometasone furoate produced umbilical hernia at topical dermal doses of 600 mcg/kg and above (approximately 6 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). A dose of 300 mcg/kg (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis) produced delays in ossification, but no malformations.
In rabbits, mometasone furoate caused multiple malformations (eg, flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses of 150 mcg/kg and above (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg (less than the maximum recommended daily inhalation dose in adults on an AUC basis). At 2800 mcg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults on an AUC basis) most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg (less than the maximum recommended daily inhalation dose in adults on an AUC basis).
When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 mcg/kg (approximately 6 times the maximum recommended daily inhalation dose in adults on an AUC basis) caused prolonged and difficult labor and reduced the number of live births, birth weight, and early pup survival. Similar effects were not observed at 7.5 mcg/kg (approximately 3 times the maximum recommended daily inhalation dose in adults on an AUC basis).
There are no adequate and well-controlled studies in pregnant women. The ASMANEX TWISTHALER, like other corticosteroids, should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.
Hypoadrenalism may occur in infants born to women receiving corticosteroids during pregnancy. Such infants should be carefully monitored.
It is not known if mometasone furoate is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be used when ASMANEX TWISTHALER is administered to nursing women.
The safety and effectiveness of ASMANEX TWISTHALER treatment have been established in the age group 12 to 16 years. Clinical trials in adults and adolescents included 146 patients in this age group who received ASMANEX TWISTHALER treatment. No age-related differential responses to therapy were apparent. Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one cm per year (range 0.3 to 1.8 per year) and appears to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of children and adolescents (12 years of age and older) receiving orally inhaled corticosteroids, including ASMANEX TWISTHALER, should be monitored routinely (eg, via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including ASMANEX TWISTHALER, each patient should be titrated to his/her lowest effective dose.
A total of 175 patients 65 years of age and over (23 of whom were 75 years of age and over) have been treated with ASMANEX TWISTHALER in controlled clinical trials. No overall differences in safety or effectiveness were observed between these and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.