FLUNISOLIDE
DESCRIPTION:
Flunisolide, is an anti-inflammatory steroid having the chemical name 6alpha-fluoro-11beta, 16alpha, 17,21-tetrahydroxypregna-1, 4-diene-3, 20-dione cyclic-16, 17-acetal with acetone.
Flunisolide is a white to creamy white crystalline powder with a molecular
weight of 434.49. It is soluble in acetone, sparingly soluble in chloroform,
slightly soluble in methanol, and practically insoluble in water. It has a
melting point of about 245 deg C.
ACTIONS/CLINICAL PHARMACOLOGY:
Flunisolide has demonstrated marked anti- inflammatory and anti-allergic
activity in classical test systems. It is a corticosteroid that is several
hundred times more potent in animal anti-inflammatory assays than the cortisol
standard. The molar dose of each activation of flunisolide in this preparation
is approximately 2.5 to 7 times that of comparable inhaled corticosteroid
products marketed for the same indication. The dose of flunisolide delivered per
activation in this preparation is 10 times that per activation of Nasalide(R)
(flunisolide) nasal solution. Clinical studies have shown therapeutic activity
on bronchial mucosa with minimal evidence of systemic activity at recommended
doses.
After oral inhalation of 1 mg flunisolide, total systemic availability was 40%.
The flunisolide that is swallowed is rapidly and extensively converted to the
6beta-OH metabolite and to water-soluble conjugates during the first pass
through the liver. This offers a metabolic explanation for the low systemic
activity of oral flunisolide itself since the metabolite has the low
corticosteroid potency (on the order of the cortisol standard). The inhaled
flunisolide absorbed through the bronchial tree is converted to the same
metabolites. Repeated inhalation of 2.0 mg of flunisolide per day (the maximum
recommended dose) for 14 days did not show accumulation of the drug in plasma.
The plasma half-life of flunisolide is approximately 1.8 hours.
The following observations relevant to systemic absorption were made in clinical
studies. In one uncontrolled study a statistically significant decrease in
responsiveness to metyrapone was noted in 15 adult steroid-independent patients
treated with 2.0 mg of flunisolide per day (the maximum recommended dose) for 3
months. A small but statistically significant drop in eosinophils from 11.5% to
7.4% of total circulating leucocytes was noted in another study in children who
were not taking oral corticosteroids simultaneously. A 5% incidence of menstrual
disturbances was reported during open studies, in which there were no control
groups for comparison.
After administration of flunisolide 2.0 mg twice daily for one week to 6
healthy male subjects revealed neither suppression of adrenal function as
measured by early morning cortisol levels nor impairment of HPA axis function as
determined by insulin hypoglycemia tests.
Controlled clinical studies have included over 500 patients with asthma, among
them 150 children age 6 and over. More than 120 patients have been treated in
open trials for two years or more. No significant adrenal suppression attributed
to flunisolide was seen in these studies.
Significant decreases of systemic steroid dosages have been possible in
flunisolide-treated patients. Recommended doses of flunisolide appear to be the
therapeutic equivalent of an average of 10 mg/day of oral prednisone. Asthma
patients have had further symptomatic improvement with flunisolide treatment
even while reducing concomitant medication.
INDICATIONS AND USAGE:
SYNTARIS (flunisolide) Inhaler is indicated in the maintenance treatment of
asthma as prophylactic therapy. SYNTARIS is also indicated for asthma patients
who require systemic corticosteroid administration, where adding SYNTARIS may
reduce or eliminate the need for the systemic corticosteroids.
is NOT indicated for the relief of acute bronchospasm.
CONTRAINDICATIONS:
SYNTARIS (flunisolide) 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:
*************************************************
* *
* WARNINGS *
* Particular care is needed in patients who *
* are transferred from systemically active *
* corticosteroids to SYNTARIS Inhaler because *
* deaths due to adrenal insufficiency have *
* occurred in asthmatic patients during and *
* after transfer from systemic *
* corticosteroids to SYNTARIS corticosteroids. *
* After withdrawal from systemic *
* corticosteroids, a number of months are *
* required for recovery of hypothalamic- *
* pituitary-adrenal (HPA) function. During *
* this period of HPA suppression, patients *
* may exhibit signs and symptoms of adrenal *
* insufficiency when exposed to trauma, *
* surgery or infections, particularly *
* gastroenteritis. Although SYNTARIS Inhaler *
* may provide control of asthmatic symptoms *
* during these episodes, it does NOT provide *
* the systemic steroid 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 systemic steroids (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. To assess the risk of adrenal *
* insufficiency in emergency situations, *
* routine tests of adrenal cortical function, *
* including measurement of early morning *
* resting cortisol levels, should be *
* performed periodically in all patients. An *
* early morning resting cortisol level may be *
* accepted as normal if it falls at or near *
* the normal mean level. *
* *
*************************************************
Localized infections with Candida Albicans or Aspergillus Niger have occurred in
the mouth and pharynx and occasionally in the larynx. Positive cultures for oral
Candida may be present in up to 34% of patients. Although the frequency of
clinically apparent infection is considerably lower, these infections may
require treatment with appropriate antifungal therapy or discontinuance of
treatment with SYNTARIS Inhaler.
SYNTARIS 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 that are not responsive to bronchodilators occur during the
course of treatment. During such episodes, patients may require therapy with
systemic corticosteroids. Theoretically, the use of inhaled corticosteroids with
alternate day prednisone systemic treatment should be accompanied by more HPA
suppression than a therapeutically equivalent regimen of either alone.
Transfer of patients from systemic steroid therapy to SYNTARIS Inhaler may unmask
allergic conditions previously suppressed by the systemic steroid therapy, e.g.
rhinitis, conjunctivitis, and eczema.
Persons who are on drugs which suppress the immune system are more susceptible
to infections than healthy individuals. Chicken pox 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,
particular care should be taken to avoid exposure. How the dose, route and
duration of corticosteriod 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
to chicken pox, 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 chicken pox develops,
treatment with antiviral agents may be considered.
PRECAUTIONS:
GENERAL: Because of the relatively high molar dose of flunisolide per
activation in this preparation, and because of the evidence suggesting higher
levels of systemic absorption with flunisolide than with other comparable
inhaled corticosteroids (see ACTIONS/CLINICAL PHARMACOLOGY section), patients
treated with SYNTARIS (flunisolide) should be observed carefully for any evidence
of systemic corticosteroid effect, including suppression of bone growth in
children. Particular care should be taken in observing patients post-operatively
or during periods of stress for evidence of a decrease in adrenal function.
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 or even improvement of respiratory
function. (See DOSAGE AND ADMINISTRATION for details.)
In responsive patients, flunisolide may permit control of asthmatic symptoms
without suppression of HPA function. Since flunisolide is absorbed into the
circulation and can be systemically active, the beneficial effects of SYNTARIS
Inhaler in minimizing or preventing HPA dysfunction may be expected only when
recommended dosages are not exceeded.
The long-term local and systemic effects of SYNTARIS (flunisolide) in human
subjects are still not fully known. In particular, the effects resulting from
chronic use of SYNTARIS 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.
Pulmonary infiltrates with eosinophilia may occur in patients on SYNTARIS Inhaler
therapy. Although it is possible that in some patients this state may become
manifest because of systemic steroid withdrawal when inhalational steroids are
administered, a causative role for the drug and/or its vehicle cannot be ruled
out.
INFORMATION FOR PATIENTS:
Since the relief from SYNTARIS Inhaler depends on its regular use and on proper
inhalation technique, patients must be instructed to take inhalations at regular
intervals. They should also be instructed in the correct method of use (See
Patient Instruction Leaflet.)
Patients whose systemic corticosteroids have been reduced or withdrawn should be
instructed to carry a warning card indicating that they may need supplemental
systemic steroids during periods of stress or a severe asthmatic attack that is
not responsive to bronchodilators.
Persons who are on immunosuppressant doses of corticosteroids should be warned
to avoid exposure to chicken pox or measles. Patients should also be advised
that if they are exposed, medical advice should be sought without delay.
An illustrated leaflet of patient instructions for proper use accompanies each
SYNTARIS Inhaler System.
CONTENTS UNDER PRESSURE
Do not puncture. Do not use or store near heat or open flame. Exposure to
temperatures above 120 deg F (49 deg C) may cause container to explode. Never
throw container into fire or incinerator. Keep out of reach of children.
CARCINOGENESIS: Long-term studies were conducted in mice and rats using oral
administration to evaluate the carcinogenic potential of the drug. There was an
increase in the incidence of pulmonary adenomas in mice, but not in rats.
Female rats receiving the highest oral dose had an increased incidence of
mammary adenocarcinoma compared to control rats. An increased incidence of this
tumor type has been reported for other corticosteroids.
IMPAIRMENT OF FERTILITY: Female rats receiving high doses of flunisolide (200
mcg/kg/day) showed some evidence of impaired fertility. Reproductive performance
in the low-(8 mcg/kg/day) and mid- dose (40 mcg/kg/day) groups was comparable to
controls.
PREGNANCY: Pregnancy Category C. As with other corticosteroids, flunisolide has
been shown to be teratogenic in rabbits and rats at doses of 40 and 200
mcg/kg/day respectively. It was also fetotoxic in these animal reproductive
studies. There are no adequate and well-controlled studies in pregnant women.
Flunisolide should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
NURSING MOTHERS: It is not known whether this drug is excreted in human milk.
Because other corticosteroids are excreted in human milk, caution should be
exercised when flunisolide 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 adolescents, particularly with higher doses over extended
periods. If a child or adolescent 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:
Adverse events reported in controlled clinical trials and long-term open studies
in 514 patients treated with SYNTARIS (flunisolide) are described below. Of those
patients, 463 were treated for 3 months or longer, 407 for 6 months or longer,
287 for 1 year or longer, and 122 for 2 years or longer.
Musculoskeletal reactions were reported in 35% of steroid-dependent patients in
whom the dose of oral steroid was being tapered. This is a well- known effect of
steroid withdrawal.
INCIDENCE 10% OR GREATER:
Gastrointestinal: diarrhea (10%), nausea and/or vomiting (25%), upset stomach
(10%)
General: flu (10%)
Mouth and Throat: sore throat (20%)
Nervous System: headache (25%)
Respiratory: cold symptoms (15%), nasal congestion (15%), upper respiratory
infection (25%)
Special Senses: unpleasant taste (10%)
INCIDENCE 3-9%
Cardiovascular: palpitations
Gastrointestinal: abdominal pain, heartburn
General: chest pain, decreased appetite, edema, fever
Mouth and Throat: Candida infection
Nervous System: dizziness, irritability, nervousness,
shakiness
Reproductive: menstrual disturbances
Respiratory: chest congestion, cough*, hoarseness, rhinitis, runny nose, sinus
congestion, sinus drainage, sinus infection, sinusitis, sneezing, sputum,
wheezing*
Skin: eczema, itching (pruritus), rash
Special Senses: ear infection, loss of smell or taste
INCIDENCE 1-3%
General: chills, increased appetite and weight gain, malaise, peripheral edema,
sweating, weakness
Cardiovascular: hypertension, tachycardia
Gastrointestinal: constipation, dyspepsia, gas
Hemic/Lymph: capillary fragility, enlarged lymph nodes
Mouth and Throat: dry throat, glossitis, mouth irritation, pharyngitis, phlegm,
throat irritation
Nervous System: anxiety, depression, faintness, fatigue, hyperactivity,
hypoactivity, insomnia, moodiness, numbness, vertigo
Respiratory: bronchitis, chest tightness*, dyspnea, epistaxis, head stuffiness,
laryngitis, nasal irritation, pleurisy, pneumonia, sinus discomfort
Skin: acne, hives or urticaria
Special Senses: blurred vision, earache, eye discomfort, eye infection
INCIDENCE LESS THAN 1%, judged by investigators as possibly or probably drug
related: abdominal fullness, shortness of breath.
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*The incidences as shown of cough, wheezing, and chest tightness were judged by
investigators to be possibly or probably drug-related. In placebo- controlled
trials, the Overall incidences of these adverse events (regardless of
investigators' judgment of drug relationship) were similar for drug and placebo-
treated groups. They may be related to the vehicle or delivery system.
DOSAGE AND ADMINISTRATION:
The SYNTARIS (flunisolide) Inhaler System is for oral inhalation only.
Adults: The recommended starting dose is 2 inhalations twice daily, morning and
evening, for a total daily dose of 1 mg. The maximum daily dose should not
exceed 4 inhalations twice a day for a total daily dose of 2 mg. When the drug
is used chronically at 2 mg/day, patients should be monitored periodically for
effects on the hypothalamic-pituitary-adrenal (HPA) axis.
Pediatric Patients: For children and adolescents 6-15 years of age, two
inhalations may be administered twice daily for a total daily dose of 1 mg.
Higher doses have not been studied. Insufficient information is available to
warrant use in children under age 6. With chronic use, pediatric patients should
be monitored for growth as well as for effects on the HPA axis.
Rinsing the mouth after inhalation is advised.
Different Considerations Must Be Given To The Following Groups Of Patients In
Order To Obtain The Full Therapeutic Benefit Of SYNTARIS (flunisolide) Inhaler.
PATIENTS NOT RECEIVING SYSTEMIC CORTICOSTEROIDS:
Patients who require maintenance therapy of their asthma may benefit from
treatment with SYNTARIS at the doses recommended above. In patients who respond
to SYNTARIS, improvement in pulmonary function is usually apparent within one to
four weeks after the start of therapy. Once the desired effect is achieved,
consideration should be given to tapering to the lowest effective dose.
PATIENTS MAINTAINED ON SYSTEMIC CORTICOSTEROIDS:
Clinical studies have shown that SYNTARIS may be effective in the management of
asthmatics dependent or maintained on systemic corticosteroids and may permit
replacement or significant reduction in the dosage of systemic corticosteroids.
The patient's asthma should be reasonably stable before treatment with SYNTARIS
is started. Initially, SYNTARIS should be used concurrently with the patient's
usual maintenance dose of systemic corticosteroid. After approximately one week,
gradual withdrawal of the systemic corticosteroid is started by reducing the
daily or alternate daily dose. Reductions may be made after an interval of one
or two weeks, depending on the response of the patient. A slow rate of
withdrawal is strongly recommended. Generally, these decrements should not
exceed 2.5 mg of prednisone or its equivalent. During withdrawal, some patients
may experience symptoms of systemic corticosteroid withdrawal; e.g. joint and/or
muscular pain, lassitude and depression, despite maintenance or even improvement
of pulmonary function. Such patients should be encouraged to continue with the
inhaler but should be monitored for objective signs of adrenal insufficiency. If
evidence of adrenal insufficiency occurs, the systemic corticosteroid doses
should be increased temporarily and thereafter withdrawal should continue more
slowly.
asthma attack, transfer patients may require supplementary treatment with
systemic corticosteroids.
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