Oral Inhaler
(triamcinolone acetonide)
For Oral Inhalation Only
Shake Well Before Using
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
DESCRIPTION: Triamcinolone acetonide, USP, the active ingredient in Azmacort® Oral Inhaler, is a glucocorticosteroid with a molecular weight of 434.5 and with the chemical designation 9-Fluoro-11beta
, 16α, 17, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione cyclic 16, 17-acetal with acetone. (C24H31FO6).
Azmacort Oral Inhaler is a metered-dose aerosol unit containing a microcrystalline suspension of triamcinolone acetonide in the propellant dichlorodifluoromethane and dehydrated alcohol USP 1% w/w. Each canister contains 60 mg triamcinolone acetonide. Eac
h actuation releases approximately 200 mcg triamcinolone acetonide, of which approximately 100 mcg are delivered from the unit (in-vitro testing). There are at least 240 actuations, in one Azmacort aerosol canister. After 240 actuations the amount
delivered per actuation may not be consistent and the unit should be discarded.
CLINICAL PHARMACOLOGY: The precise mechanism of the action of the inhaled drug is unknown. However, use of the inhaler makes it possible to provide effective local steroid activity with minimal systemic effect.
Triamcinolone acetonide is a more potent derivative of triamcinolone. Although triamcinolone itself is approximately one to two times as potent as prednisone in animal models of inflammation, triamcinolone acetonide is approximately 8 times more potent th
an prednisone.
Pharmacokinetic studies with radiolabeled triamcinolone acetonide have been carried out by the oral route and intravenous route in several species. The pharmacokinetic behavior of the triamcinolone acetonide was similar in all species within each route of
administration. The major portion of the dose was eliminated in the feces irrespective of route of administration with only one species (rabbit) showing significant urinary excretion of radioactivity.
The results of studies in which triamcinolone acetonide was administered as an aerosol showed rapid disappearance of radioactivity from the lungs comparable to that observed following oral administration with peak blood levels occurring in one to two hour
s. Virtually no radioactivity was present in the lung and trachea 24 hours after dosing.
Based upon intravenous dosing of triamcinolone acetonide phosphate ester, the half-life of triamcinolone acetonide was reported to be 88 minutes. The volume of distribution (Vd) reported was 99.5 L (SD ± 27.5) and clearance was 45.2 L /hour (SD ± 91) for
triamcinolone acetonide. The plasma half-life of corticoids does not correlate well with the biologic half-life.
Three metabolites of triamcinolone acetonide have been identified.
They are 6beta-hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy- 6beta-hydroxytriamcinolone acetonide. All three metabolites are expected to be substantially less active than the parent compound due to (a
) the dependence of anti-inflammatory activity on the presence of a 21-hydroxyl group, (b) the decreased activity observed upon 6-hydroxylation, and (c) the markedly increased water solubility favoring rapid elimination. There appeared to be some quantita
tive differences in the metabolites among species. No differences were detected in metabolic pattern as a function of route of administration.
INDICATIONS: Azmacort Oral Inhaler is indicated only for patients who require chronic treatment with corticosteroids for the control of the symptoms of bronchial asthma. Such patients would include those already receivin
g systemic corticosteroids and selected patients who are inadequately controlled on a non-steroid regimen and in whom steroid therapy has been withheld because of concern over potential adverse effects.
Azmacort Oral Inhaler is NOT indicated:
1. For relief of asthma which can be controlled by bronchodilators and other non-steroid
medications.
2. In patients who require systemic corticosteroid treatment infrequently.
3. In the treatment of non-asthmatic bronchitis
CONTRAINDICATIONS: Azmacort Oral Inhaler is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
Hypersensitivity to any of the ingredients of this preparation contraindicates its use.
WARNINGS: Particular care is needed in patients who are transferred from systemically active corticosteroids to Azmacort Oral Inhaler because deaths due to adrenal insufficiency have occurred in asthmatic patients during and
after transfer from systemic corticosteroids to aerosolized steroids in recommended doses. After withdrawal from systemic corticosteroids, a number of months is usually required for recovery of hypothalamic-pituitary-adrenal (HPA) function. For some pati
ents who have received large doses of oral steroids for long periods of time before therapy with Azmacort Oral Inhaler is initiated, recovery may be delayed for one year or longer. During this period of HPA suppression, patients may exhibit signs and sym
ptoms of adrenal insufficiency when exposed to trauma, surgery or infections, particularly gastroenteritis or other conditions with acute electrolyte loss. Although Azmacort Oral Inhaler may provide control of asthmatic symptoms during these episodes, in
recommended doses it supplies only normal physiological amounts of corticosteroid systemically and does NOT provide the increased systemic steroid which is necessary for coping with these emergencies.
During periods of stress or a severe asthmatic attack, patients who have been recently withdrawn from systemic corticosteroids should be instructed to resume systemic steroids (in large doses) immediately and to contact their physician for further instruc
tion. 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.
Localized infections with Candida albicans have occurred infrequently in the mouth and pharynx. These areas should be examined by the treating physician at each patient visit. The percentage of positive mouth and throat cultures for Candida albi
cans did not change during a year of continuous therapy. The incidence of clinically apparent infection is low (2.5%). These infections may disappear spontaneously or may require treatment with appropriate antifungal therapy or discontinuance of trea
tment with Azmacort Oral Inhaler.
Children who are on immunosuppressant drugs are more susceptible to infections than healthy children. Chickenpox and measles, for example, can have a more serious or even fatal course in children on immunosuppressant doses of corticosteroids. In such chil
dren, or in adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If chick
enpox develops, treatment with antiviral agents may be considered.
Azmacort Oral Inhaler is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.
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 Azmacort Oral Inhaler. During such episodes, patients may require therapy wi
th systemic corticosteroids.
There is no evidence that control of asthma can be achieved by the administration of Azmacort Oral Inhaler in amounts greater than the recommended doses, which appear to be the therapeutic equivalent of approximately 10 mg/day of oral prednisone.
The use of Azmacort Oral Inhaler with alternate-day systemic prednisone could increase the likelihood of HPA suppression compared to a therapeutic dose of either one alone. Therefore, Azmacort Oral Inhaler should be used with caution in patients already r
eceiving alternate-day prednisone treatment for any disease.
Transfer of patients from systemic steroid therapy to Azmacort Oral Inhaler may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema.
PRECAUTIONS: During withdrawal from oral steroids, some patients may experience symptoms of systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance o
r even improvement of respiratory function (see DOSAGE AND ADMINISTRATION for details). Although steroid withdrawal effects are usually transient and not severe, severe and even fatal exacerbation of asthma can occur if the previous daily oral corticoste
roid requirement had significantly exceeded 10 mg/day of prednisone or equivalent.
In responsive patients, inhaled corticosteroids will often permit control of asthmatic symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since triamcinolone acetonide is absorbed into the circulation
and can be systemically active, the beneficial effects of Azmacort Oral Inhaler in minimizing or preventing HPA dysfunction may be expected only when recommended dosages are not exceeded.
Suppression of HPA function has been reported in volunteers who received 4000 mcg daily of triamcinolone acetonide. In addition, suppression of HPA function has been reported in some patients who have received recommended doses for as little as 6 to 12 we
eks. Since the response of HPA function to inhaled corticosteroids is highly individualized, the physician should consider this information when treating patients.
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 including suppression of growth in children. Particular care
should be taken in observing patients postoperatively or during periods of stress for evidence of a decrease in adrenal function.
The long-term effects of triamcinolone acetonide inhaler in human subjects are not completely known, although patients have received Azmacort Oral Inhaler on a continuous basis for periods of two years or longer. While there has been no clinical evidence
of adverse experiences, the local effects of the agent on developmental or immunologic processes in the mouth, pharynx, trachea and lung are also unknown.
Azmacort Oral Inhaler should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract or in patients with untreated fungal, bacterial, or systemic viral infections or ocular herpes simplex. The
potential effects of long-term administration of Azmacort Oral Inhaler on lung or other tissues are unknown. However, pulmonary infiltrates with eosinophilia have occurred in patients receiving other inhaled corticosteroids.
When used at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, Azmacort Oral Inhaler should be discontinued slowly, consistent with accepted procedures for discontinuing ora
l steroid therapy.
Information for Patients: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to obtain medical advice.
Carcinogenesis, Mutagenesis: No evidence of treatment-related carcinogenicity was demonstrated after two years of once daily oral administration of triamcinolone acetonide at a maximum daily dose of 1.0 mcg/kg/day (6.1 mcg/m2/day) in
male or female rats and 3.0 mcg/kg/day (12.9 mcg/m2/day) in male or female mice.
Impairment of Fertility: Male and female rats which were administered oral triamcinolone acetonide at doses as high as 15 mcg/kg/day (110 mcg/m2/day, as calculated on a surface area basis) exhibited no evidence of impaired fertility.
The maximum human dose, for comparison, is 22.9 mcg/kg/day (889 mcg/m2/day). However, a few female rats which received maternally toxic doses of 8 or 15 mcg/kg/day (60 mcg/m2/day or 110 mcg/m2/day, respectively, as calc
ulated on a surface area basis) exhibited dystocia and prolonged delivery. Developmental toxicity, which included increases in fetal resorptions and stillbirths and decreases in pup body weight and survival, also occurred at the maternally toxic doses (2
.5-15.0 mcg/kg/day or 20-110 mcg/m2/day, as calculated on a surface area basis). Reproductive performance of female rats and effects on fetuses and offspring were comparable between groups that received placebo and non-toxic or marginally toxi
c doses (0.5 and 1.0 mcg/kg/day or 3.8 mcg/ m2/day and 7.0 mcg/m2/day).
Pregnancy: Pregnancy Category C. Like other corticoids, triamcinolone acetonide has been shown to be teratogenic in rats and rabbits. Teratogenic effects, which occurred in both species at 0.02, 0.04 and 0.08 mg/kg/day (approximately 135, 270 and
540 mcg/m2/day in the rat and 320, 640 and 1280 mcg/m2/day in the rabbit, as calculated on a surface area basis), included a low incidence of cleft palate and/or internal hydrocephaly and axial skeletal defects. Teratogenic effects,
including CNS and cranial malformations, have also been observed in non-human primates at 0.5 mg/kg/day (approximately 6.7 mg/m2/day). Administration of aerosol by inhalation to pregnant rats and rabbits produced embryotoxic and fetotoxic effe
cts which were comparable to those produced by administration by other routes. There are no adequate and
well-controlled studies in pregnant women. Triamcinolone acetonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Experience with oral corticoids since their introduction in pharmacologic as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticoids than humans. In addition, because there is a natural increase in glucocor
ticoid production during pregnancy, most women will require a lower exogenous steroid dose and many will not need corticoid treatment during pregnancy.
Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.
Nursing Mothers: It is not known whether triamcinolone acetonide is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised when Azmacort Oral Inhaler is administered to nursing women.
Pediatric Use: Safety and effectiveness have not been established in children below the age of 6. Oral corticoids have been shown to cause growth suppression in children and teenagers, particularly with higher doses over extended periods. If a ch
ild or teenager on any corticoid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of steroids should be considered.
ADVERSE REACTIONS: A few cases of oral candidiasis have been reported (see WARNINGS). In addition, some patients receiving Azmacort Oral Inhaler have experienced hoarseness, dry throat, irritated throat and dry mou
th. Increased wheezing and cough have been reported infrequently as has facial edema. These adverse effects have generally been mild and transient.
DOSAGE AND ADMINISTRATION: All patients should be instructed that the Azmacort Oral Inhaler must be used on a regular daily basis rather than prn. Reliable dosage delivery cannot be assured after 2
40 actuations and patients should be cautioned against longer use of individual canisters. Good oral hygiene including rinsing of the mouth after inhalation is recommended.
Adults: The usual dosage is two inhalations (approximately 200 mcg) given three to four times a day. The maximal daily intake should not exceed 16 inhalations (1600 mcg) in adults. Higher initial doses (12 to 16 inhalations per day) may be advisa
ble in patients with more severe asthma, the dosage then being adjusted downward according to the response of the patient. In some patients maintenance can be accomplished when the total daily dose is given on a twice a day schedule.
Children 6 to 12 years of age: The usual dosage is one or two inhalations (100 to 200 mcg) given three to four times a day according to the response of the patient. The maximal daily intake should not exceed 12 inhalations (1200 mcg) in children 6
to 12 years of age. Insufficient clinical data exist with respect to the administration of Azmacort Oral Inhaler in children below the age of 6. The long-term effects of inhaled steroids on growth are still under evaluation.
Patients receiving bronchodilators by inhalation should be advised to use the bronchodilator before Azmacort Oral Inhaler in order to enhance penetration of triamcinolone acetonide into the bronchial tree. After use of an aerosol bronchodilator, several m
inutes should elapse before use of the Azmacort Oral Inhaler to reduce the potential toxicity from the inhaled fluorocarbon propellants in the two aerosols.
Different considerations must be given to the following groups of patients in order to obtain the full therapeutic benefit of Azmacort Oral Inhaler:
Patients not receiving systemic steroids: The use of Azmacort Oral Inhaler is straightforward in patients who are inadequately controlled with non-steroid medications but in whom systemic steroid therapy has been withheld because of concern over p
otential adverse reactions. In patients who respond to Azmacort, an improvement in pulmonary function is usually apparent within one to two weeks after the start of Azmacort Oral Inhaler.
Patients receiving systemic steroids: In those patients dependent on systemic steroids, transfer to Azmacort Oral Inhaler and subsequent management may be more difficult because recovery from impaired adrenal function is usually slow. Such suppre
ssion has been known to last for up to 12 months or longer. Clinical studies, however, have demonstrated that Azmacort Oral Inhaler may be effective in the management of these asthmatic patients and may permit replacement or significant reduction in the d
osage of systemic corticosteroids.
The patient’s asthma should be reasonably stable before treatment with Azmacort Oral Inhaler is started. Initially, the inhaler should be used concurrently with the patient’s usual maintenance dose of systemic steroid. After approximately one week, gradu
al withdrawal of the systemic steroid is started by reducing the dose. The next reducton is made after an interval of one or two weeks, depending on the response of the patient. Generally, these decrements should not exceed 2.5 mg of prednisone or its equ
ivalent. A slow rate of withdrawal cannot be overemphasized. During withdrawal, some patients may experience symptoms of systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or ev
en improvement of respiratory function. Such patients should be encouraged to continue with the inhaler but should be watched carefully for objective signs of adrenal insufficiency, such as hypotension and weight loss. If evidence of adrenal insufficien
cy occurs, the systemic steroid dose should be boosted temporarily and thereafter further withdrawal should continue more slowly. No clinical studies have been conducted evaluating Azmacort with alternate day prednisone regimens. However, based on the r
esults of such a study with another inhaled corticosteroid, inhaled corticosteroids generally are not recommended for chronic use with alternate day prednisone regimens (see WARNINGS).
During periods of stress or a severe asthma attack, transfer patients will require supplementary treatment with systemic steroids. Exacerbations of asthma which occur during the course of treatment with Azmacort Oral Inhaler shoul
d be treated with a short course of systemic steroid which is gradually tapered as these symptoms subside. There is no evidence that control of asthma can be achieved by administration of Azmacort Oral Inhaler in amounts greater than the recommended doses
.
Directions for Use: An illustrated leaflet of patient instructions for proper use accompanies each package of Azmacort Oral Inhaler.
HOW SUPPLIED: Azmacort Oral Inhaler contains 60 mg triamcinolone acetonide in a 20 gram package which delivers at least 240 actuations. It is supplied with an oral adapter and patient’s leaflet of instructions: box of
one. NDC 0075-0060-37
CONTENTS UNDER PRESSURE: Do not puncture. Do not use or store near heat or open flame Exposure to temporatures above 120°F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children.
STORE AT ROOM TEMPERATURE
Note: The indented statement below is required by the Federal government’s Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs):
WARNING: Contains CFC-12, a substance which harms public health and environment by destroying ozone in the upper atmosphere.
A notice similar to the above WARNING has been placed in the “Information For The Patient” portion of this package insert pursuant to EPA regulations.
Caution: Federal (U.S.A.) law prohibits dispensing without prescription.
