WARNINGS
Particular care is needed for patients who are transferred from systemically active corticosteroids to PULMICORT FLEXHALER 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its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.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 infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although PULMICORT FLEXHALER may provide 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 that is necessary for coping with these emergencies.
During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further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 a severe asthma attack.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to PULMICORT FLEXHALER. Lung function (FEV1 or AM 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 PULMICORT FLEXHALER may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, eg, rhinitis, conjunctivitis, arthritis, eosinophilic conditions, and eczema.
Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible pediatric patients or adults on immunosuppressant doses of corticosteroids. In pediatric or adult patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects 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, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, 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 chicken pox develops, treatment with antiviral agents may be considered.
PULMICORT FLEXHALER 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, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with PULMICORT FLEXHALER, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with PULMICORT FLEXHALER should be discontinued and alternate therapy instituted.
Patients should be instructed to contact their physician immediately when episodes of asthma not responsive to their usual doses of bronchodilators occur during treatment with PULMICORT FLEXHALER. During such episodes, patients may require therapy with oral corticosteroids.
PRECAUTIONS
General
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 (see DOSAGE AND ADMINISTRATION).
In responsive patients, PULMICORT FLEXHALER may permit control of asthma symptoms with less suppression of HPA-axis function than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active, the beneficial effects of PULMICORT FLEXHALER 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 PULMICORT FLEXHALER.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT FLEXHALER 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, PULMICORT FLEXHALER should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic steroids.
Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. A reduction in growth velocity 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 the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including PULMICORT FLEXHALER, each patient should be titrated to his/her lowest effective dose (see PRECAUTIONS, Pediatric Use).
Although patients in clinical trials have received inhaled budesonide on a continuous basis for periods of 1 to 2 years, the long-term local and systemic effects of PULMICORT FLEXHALER in human subjects are not completely known. In particular, the effects resulting from chronic use of PULMICORT FLEXHALER on developmental or immunological processes in the mouth, pharynx, trachea, and lung are unknown.
In clinical trials with PULMICORT FLEXHALER, localized infections with Candida albicans occurred in the mouth and pharynx in some patients. These infections may require treatment with appropriate antifungal therapy and/or discontinuance of treatment with PULMICORT FLEXHALER.
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 PULMICORT FLEXHALER should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects. For proper use of PULMICORT FLEXHALER and to attain maximum improvement, the patient should read and follow the accompanying Patient Information and Instructions for Use.
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Patients should use PULMICORT FLEXHALER at regular intervals as directed since its effectiveness depends on regular use. The patient should not alter the prescribed dosage unless advised to do so by the physician.
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Patients should be advised that PULMICORT FLEXHALER is not a bronchodilator and is not intended to treat acute or life-threatening episodes of asthma.
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Patients should be advised that the effectiveness of PULMICORT FLEXHALER depends on proper use of the device and inhalation-administering technique:
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PULMICORT FLEXHALER must be in the upright position (mouthpiece on top) during loading in order to provide the correct dose.
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PULMICORT FLEXHALER must be primed before the unit is used for the very first time. To prime your PULMICORT FLEXHALER, follow the steps below:
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Hold PULMICORT FLEXHALER by the brown grip, in the upright position (with mouthpiece up) in one hand. Using the thumb and index finger of your other hand, grasp the inhaler in the middle. DO NOT HOLD THE INHALER AT THE TOP OF THE MOUTHPIECE.
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Twist the brown grip as far as it will go in one direction and then fully back again in the other direction until it stops (it does not matter which way you turn it first). You will hear a click during one of the twisting movements.
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Repeat Step 3. Your PULMICORT FLEXHALER is now primed.
YOU DO NOT HAVE TO PRIME IT ANY OTHER TIME AFTER THIS, EVEN IF YOU PUT IT ASIDE FOR A PROLONGED PERIOD OF TIME.
To load the first dose, twist the brown grip fully in one direction as far as it will go and then fully back again in the other direction as far as it will go until it clicks. It does not matter which way you turn it first.
PULMICORT FLEXHALER is designed to deliver only one dose at a time, no matter how often you click the brown grip, although the dose indicator will continue to advance. If you accidentally blow into your inhaler after loading a dose, simply follow the instructions for loading a new dose.
Patients should be advised not to shake the inhaler.
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Patients should place the mouthpiece between the lips and inhale forcefully and deeply. The powder is then delivered to the lungs.
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Patients should not exhale through PULMICORT FLEXHALER.
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Due to the small volume of powder, patients may not sense the presence of any medication entering the lungs when inhaling from PULMICORT FLEXHALER. This lack of sensation does not indicate that the patient is not receiving benefit from PULMICORT FLEXHALER.
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Patients should be advised that rinsing the mouth with water without swallowing after each dosing may decrease the risk of the development of oral candidiasis.
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Patients should be instructed that they will receive a new PULMICORT FLEXHALER unit each time they refill their prescription. Patients should be advised to discard the whole device after the labeled number of inhalations has been used even though it may not feel completely empty and may continue to operate. The number in the middle of the dose indicator window tells how many doses are left in the inhaler. The inhaler is empty when the number zero (“0”) on the red background reaches the middle of the window. You may still hear a sound if you shake it — this sound is not the medicine. This sound is produced by the drying agent inside.
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The dose indicator is connected to the turning grip and moves (counts down) every time a dose is loaded. It is unlikely that you will see the dose indicator move with each individual dose. Advancement of the indicator can be seen after intervals of 5 or so doses.
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The dose indicator starts with either the number 60 or 120 when full, depending upon the strength of the product. The indicator is marked in intervals of 10 doses, alternating numbers and dashes, down to “0”.
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If the instructions for loading the dose are completed more than once prior to inhaling the dose, only one dose will be received. However, the dose indicator will advance slightly but it is unlikely that you will see the dose indicator move with each individual dose.
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The grip will still twist and “click” even when your inhaler is empty.
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PULMICORT FLEXHALER should not be used with a spacer.
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The mouthpiece should not be bitten or chewed.
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Replace the cover securely after each opening.
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Patients should keep PULMICORT FLEXHALER clean and dry at all times.
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Patients should be advised that improvement in asthma control following inhalation of budesonide can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1 to 2 weeks, or longer. If symptoms do not improve in that time frame, or if the condition worsens, the patient should be instructed not to increase the dosage, but to contact the physician.
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Patients whose systemic corticosteroids have been reduced or withdrawn should be instructed to carry a warning card indicating that they may need supplemental systemic corticosteroids during periods of stress or an asthma attack that does not respond to bronchodilators.
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Patients should be advised not to stop the use of PULMICORT FLEXHALER abruptly.
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Patients should be warned to avoid exposure to chicken pox or measles and if they are exposed, to consult their physicians without delay.
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Long-term use of inhaled corticosteroids, including budesonide, may increase the risk of some eye problems (cataracts or glaucoma). Regular eye examinations should be considered.
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Women considering the use of PULMICORT FLEXHALER should consult with their physician if they are pregnant or intend to become pregnant, or if they are breast-feeding a baby.
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Patients considering use of PULMICORT FLEXHALER should consult with their physician if they are allergic to budesonide or any other orally inhaled corticosteroid.
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Patients should inform their physician of other medications they are taking as PULMICORT FLEXHALER may not be suitable in some circumstances and the physician may wish to use a different medicine.
Drug Interactions
In clinical studies, concurrent administration of budesonide and other drugs commonly used in the treatment of asthma has not resulted in an increased frequency of adverse events. The main route of metabolism of budesonide, as well as other corticosteroids, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a potent inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of other known inhibitors of CYP3A4 (eg, itraconazole, clarithromycin, erythromycin, etc.) may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Care should be exercised when budesonide is coadministered with long-term ketoconazole and other known CYP3A4 inhibitors.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies were conducted in rats and mice using oral administration to evaluate the carcinogenic potential of budesonide.
In a 104-week oral study in Sprague-Dawley rats, a statistically significant increase in the incidence of gliomas was observed in male rats receiving an oral dose of 50 mcg/kg/day (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). The concurrent reference corticosteroids (prednisone and triamcinolone acetonide) in these two studies showed similar findings.
There was no evidence of a carcinogenic effect when budesonide was administered orally for 91 weeks to mice at doses up to 200 mcg/kg/day (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis).
Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella /microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat hepatocyte culture.
In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis).
At 20 mcg/kg/day (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 mcg/kg (less than the maximum recommended human daily inhalation dose in adults on a mcg/m2 basis).
Pregnancy
Teratogenic Effects: Pregnancy category B
As with other glucocorticoids, budesonide produced fetal loss, decreased pup weight, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg/day in rabbits (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis) and 500 mcg/kg/day in rats (approximately 3 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to 250 mcg/kg/day (equivalent to the maximum recommended human daily inhalation dose on a mcg/m2 basis).
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.
Studies of pregnant women, however, have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2,014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared with the general population rate (3.8 % vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs. 3.3, respectively).
These same data were utilized in a second study bringing the total to 2,534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).
Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, PULMICORT FLEXHALER should be used during pregnancy only if clearly needed.
Nonteratogenic Effects
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.
Nursing Mothers
Budesonide, like other corticosteroids, is secreted in human milk. Data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations, Nursing Mothers). No studies have been conducted in breastfeeding women specifically with PULMICORT FLEXHALER; however, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar. PULMICORT FLEXHALER should be used in nursing women only if clinically appropriate. Prescribers should weigh the known benefits of breastfeeding for the mother and the infant against the potential risks of minimal budesonide exposure in the infant. Dosing considerations include prescription or titration to the lowest clinically effective dose and use of PULMICORT FLEXHALER immediately after breastfeeding to maximize the time interval between dosing and breastfeeding to minimize infant exposure. However, in general, PULMICORT FLEXHALER use should not delay or interfere with infant feeding.
Pediatric Use
Safety and effectiveness of PULMICORT FLEXHALER in pediatric patients below 6 years of age have not been established.
Clinical studies with inhaled budesonide included 704 patients 6 to 17 years of age (n=204 treated with PULMICORT FLEXHALER). The frequency of adverse events observed with PULMICORT FLEXHALER in pediatric patients 6 to 17 years of age was similar to that of patients 18 to 80 years of age.
Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been 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.
In a study of asthmatic children 5-12 years of age, those treated with PULMICORT TURBUHALER 200 mcg twice daily (n=311) had a 1.1-centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with PULMICORT TURBUHALER and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.
The growth of pediatric patients receiving orally inhaled corticosteroids, including PULMICORT FLEXHALER, should be monitored routinely (eg, via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks and benefits associated with alternative therapies. To minimize the systemic effects of inhaled corticosteroids, including PULMICORT FLEXHALER, each patient should be titrated to his/her lowest effective dose.
Geriatric Use
Of the total number of patients in controlled clinical studies receiving inhaled budesonide, 153 (n=11 treated with PULMICORT FLEXHALER) were 65 years of age or older and one was age 75 years or older. No overall differences in safety were observed between these patients and younger patients. Clinical studies did not include sufficient numbers of patients aged 65 years and over to determine differences in efficacy between elderly and younger patients. Other reported clinical or medical surveillance 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.
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