Advair® Diskus®
Salmeterol Xinafoate--Fluticasone
Propionate
Bronchodilator--Corticosteroid for Oral
Inhalation
GlaxoSmithKline
http://www.gsk.com/index.htm
Advair Monograph PDF download here.
Advair® Inhalation Aerosol
Salmeterol Xinafoate--Fluticasone
Propionate
Bronchodilator--Corticosteroid for Oral
Inhalation
GlaxoSmithKline
CPS:PIS_m008500
Date of Preparation: June 13, 2001
Date of Revision: March 8, 2004
Pharmacology
Advair contains salmeterol and fluticasone,
which have differing modes of action for the treatment of COPD and reversible
obstructive airways disease, including asthma. Salmeterol is a long-acting
bronchodilator that prevents breakthrough symptoms of wheezing and chest
tightness; fluticasone is an inhaled anti-inflammatory agent that reduces
airways irritability. Advair can offer a more convenient regime for patients
requiring concurrent long-acting beta2-agonist and inhaled
corticosteroid therapy. Advair is designed to produce a greater improvement in
pulmonary function and symptom control than either fluticasone or salmeterol
used alone at their recommended dosages. The respective mechanisms of action of
both drugs are discussed below:
Salmeterol is a
selective, long-acting (12 hours), slow onset (10 to 20 minutes)
beta2-adrenoceptor agonist with a long side-chain which binds to the
exo-site of the receptor.
Salmeterol offers more
effective protection against histamine-induced bronchoconstriction and produces
a longer duration of bronchodilation, lasting for at least 12 hours, than
recommended doses of conventional short-acting beta2-agonists.
In vitro tests on human
lung, have shown that salmeterol is a potent and long-lasting inhibitor of the
release of mast cell mediators, such as histamine, leukotrienes and
prostaglandin D2.
In man, salmeterol
inhibits the early and late phase response to inhaled allergen. The late phase
response is inhibited for over 30 hours after a single dose, when the
bronchodilator effect is no longer evident. The full clinical significance of
these findings is not yet clear. The mechanism is different from the
anti-inflammatory effect of corticosteroids.
Fluticasone is a highly
potent glucocorticoid anti-inflammatory steroid. When administered by
inhalation at therapeutic dosages, it has a direct potent anti-inflammatory
action within the lungs, resulting in reduced symptoms and exacerbations of
asthma, and less adverse effects than systemically administered
corticosteroids.
In comparisons with
beclomethasone dipropionate, fluticasone propionate has demonstrated greater
topical potency.
Pharmacokinetics
There is no evidence in animal or human subjects
that the administration of salmeterol and fluticasone together by the inhaled
route affects the pharmacokinetics of either component. For pharmacokinetic
purposes, therefore, each component can be considered separately.
Salmeterol acts locally
in the lung; therefore, plasma levels are not an indication of therapeutic
effect. Because of the low therapeutic dose, systemic levels of salmeterol are
low or undetectable after inhalation of recommended doses (50 µg twice
daily).
Salmeterol is
predominantly cleared by hepatic metabolism; liver function impairment may lead
to accumulation of salmeterol in plasma. Therefore, patients with hepatic
disease should be closely monitored.
Following i.v.
administration, the pharmacokinetics of fluticasone are proportional to the
dose. Fluticasone is extensively distributed within the body. The volume of
distribution at steady state is approximately 300 L and has a very high
clearance which is estimated to be 1.1 L/m, indicating extensive hepatic
extraction. Peak plasma fluticasone concentrations are reduced by approximately
98% within 3 to 4 hours and only low plasma concentrations are
associated with the terminal half-life, which is approximately 8 hours.
Following oral
administration of fluticasone, 87 to 100% of the dose is excreted in the
feces. Following doses of either 1 or 16 mg, up to 20% and 75%,
respectively, is excreted in the feces as the parent compound. There is a
non-active major metabolite. Absolute oral bioavailability is negligible
(<1%), due to a combination of incomplete absorption from the
gastrointestinal tract and extensive first-pass metabolism.
Following inhaled
dosing in healthy volunteers, absolute systemic bioavailability of fluticasone
varies between approximately 10-30% of the nominal dose depending on the
inhalation device used. Systemic absorption of fluticasone occurs mainly
through the lungs, and is initially rapid, then prolonged.
The plasma protein
binding of fluticasone is 91%. Fluticasone is extensively metabolized by CYP3A4
enzyme to an inactive carboxylic acid derivative.
Indications
Asthma: Advair is indicated for the maintenance
treatment of asthma in patients with reversible obstructive airways disease
where the use of a combination product is considered to be appropriate.
Advair should not be
used in patients whose asthma can be managed by occasional use of short-acting,
inhaled beta2-agonists. Advair contains a long-acting beta2-agonist
and should not be used as a rescue medication. To relieve acute asthmatic
symptoms, a short-acting inhaled bronchodilator (e.g., salbutamol) should be
used.
Chronic Obstructive Pulmonary Disease (COPD): Advair 250 Diskus and
Advair 500 Diskus are indicated for the maintenance treatment of COPD,
including emphysema and chronic bronchitis, in patients where the use of a
combination product is considered appropriate.
Advair Diskus should
not be used as a rescue medication.
Physicians should
reassess patients several months after the initiation of Advair Diskus and if
symptomatic improvement has not occurred, Advair Diskus should be discontinued.
Contraindications
Advair is contraindicated in patients with
cardiac tachyarrhythmias, in patients with untreated fungal, bacterial or
tuberculous infections of the respiratory tract, and in patients with a known
or suspected hypersensitivity to any ingredient of the preparation.
Advair is not to be
used in the primary treatment of status asthmaticus or other acute episodes of
asthma, or in patients with moderate to severe bronchiectasis.
Advair Diskus contains
lactose (which contains milk protein) (see Supplied) and is contraindicated in
patients with IgE-mediated allergic reactions to lactose or milk.
Warnings
Use in Asthma (see also General Warnings for
Asthma and COPD): Advair should not be used to treat acute symptoms of asthma: It is crucial to inform
patients of this and prescribe a fast- and short-acting, inhaled bronchodilator
(e.g., salbutamol) to relieve acute symptoms of asthma.
Use with Short-acting beta2-agonists:
Patients should be clearly instructed to use short-acting, inhaled beta2-agonists
only for symptomatic relief if they develop asthma symptoms while taking Advair
(see Precautions, Drug Interactions).
Monitoring Asthma Control: Increasing use of
short-acting inhaled bronchodilators to control symptoms indicates
deterioration of asthma control. Sudden and progressive deterioration in asthma
control is potentially life-threatening and the treatment plan should be
re-evaluated. Also, where current dosage of Advair has failed to give adequate
control of reversible obstructive airways disease, the patient should be reviewed
by a physician. Consideration should be given to additional corticosteroid
therapy, and to antibiotics if an infection is present.
Before introducing
Advair, adequate education should be provided to the patient on how to use the
drug and what to do if asthma flares up.
Systemic Steroid Replacement by Inhaled Steroid:
Particular care is needed in patients who are transferred from systemically
active corticosteroids to inhaled corticosteroids because deaths due to adrenal
insufficiency have occurred in patients with asthma during and after transfer.
For the transfer of patients being treated with oral corticosteroids, inhaled
corticosteroids should first be added to the existing oral steroid therapy,
which is then gradually withdrawn.
Patients with
adrenocortical suppression should be monitored regularly and the oral steroid
reduced cautiously. Some patients transferred from other inhaled steroids or
oral steroids remain at risk of impaired adrenal reserve for a considerable
time after transferring to inhaled fluticasone.
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 inhaled fluticasone may provide control of asthmatic symptoms during
these episodes, it does not provide the systemic steroid which is necessary for
coping with these emergencies. The physician may consider supplying oral
steroids for use in times of stress (e.g., worsening asthma attacks, chest
infections, surgery).
During periods of
stress or a severe asthmatic attack, patients who have been withdrawn from
systemic corticosteroids should be instructed to resume systemic steroids
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 and evening cortisol levels, should be performed periodically
in all patients. An early morning resting cortisol level may be accepted as
normal only if it falls at or near the normal mean level.
Use in COPD (see also General Warnings for
Asthma and COPD): Advair should not be used to treat acute symptoms of COPD.
Monitoring COPD Control: It is important that
even mild chest infections be treated immediately since COPD patients may be
more susceptible to damaging lung infections than healthy individuals. Patients
should be instructed to contact their physician as soon as possible if they
suspect an infection. Consideration should be given to additional
corticosteroid therapy, and to antibiotics if an exacerbation is associated
with an infection.
Physicians should
recommend that COPD patients receive an annual influenza vaccination.
General Warnings for Asthma and COPD: Cardiovascular Effects:
Although clinically not significant, a small increase in QTc interval has been
reported with therapeutic doses of salmeterol. It is not known if this becomes
clinically significant when concomitant medications causing similar effects are
prescribed and/or in the presence of heart diseases, hypokalemia, or hypoxia.
Fatalities have been
reported following excessive use of aerosol preparations containing
sympathomimetic amines, the exact cause of which is unknown. Cardiac arrest was
reported in several instances.
In individual patients,
any beta2-adrenergic agonist may have a clinically significant
cardiac effect.
Immediate Hypersensitivity Reactions: Immediate
hypersensitivity reactions may occur after administration of salmeterol, as
demonstrated by rare cases of urticaria, angioedema, rash and bronchospasm.
Upper Airway Symptoms: Symptoms of laryngeal
spasm, irritation, or swelling, such as stridor and choking, have been reported
rarely in patients receiving salmeterol.
Metabolic Changes: In common with other
beta-adrenergic agents, salmeterol can induce reversible metabolic changes
(hyperglycemia, hypokalemia) (see Precautions).
Candidiasis: Therapeutic dosages of fluticasone
propionate frequently cause the appearance of C. albicans (thrush)
in the mouth and throat. The development of pharyngeal and laryngeal
candidiasis is a cause for concern because the extent of its penetration into
the respiratory tract is unknown. Patients may find it helpful to rinse the
mouth and gargle with water after using Advair. Symptomatic candidiasis can be
treated with topical antifungal therapy while continuing to use Advair (see
Precautions, Drug Interactions).
Effect on Infection: Patients who are on drugs
that 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 susceptible 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 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 i.m. immunoglobulin (IG) may be indicated. If
chickenpox develops, treatment with antiviral agents may be considered.
Paradoxical Bronchospasm: As with other
inhalation therapy, paradoxical bronchospasm may occur, characterized by an
immediate increase in wheezing after dosing. This should be treated immediately
with a fast-acting inhaled bronchodilator (e.g., salbutamol) to relieve acute
asthmatic symptoms. Advair should be discontinued immediately, the patient
assessed, and if necessary, alternative therapy instituted.
Drug Interactions
A drug interaction study of intranasal
fluticasone in healthy subjects has shown that ritonavir (a highly potent
cytochrome P450 3A4 inhibitor) can greatly increase fluticasone plasma
concentrations, resulting in markedly reduced serum cortisol concentrations.
During post-marketing use, there have been reports of clinically significant
drug interactions in patients receiving intranasal or inhaled fluticasone and
ritonavir, resulting in systemic corticosteroid effects including Cushing’s
syndrome and adrenal suppression. Therefore, concomitant use of fluticasone and
ritonavir should be avoided, unless the potential benefit to the patient
outweighs the risk of systemic corticosteroid side-effects.
Precautions
General Precautions for Asthma
Do not use Advair to treat acute symptoms of
asthma:
A short-acting, inhaled beta2-agonist, not Advair, should be used to
relieve acute symptoms of asthma. When prescribing Advair, the physician should
also provide the patient with a short-acting, inhaled beta2-agonist
(e.g., salbutamol) to treat symptoms that occur acutely, despite regular twice
daily (morning and evening) use of Advair.
When beginning
treatment with Advair, patients who have been taking short-acting, inhaled beta2-agonists
on a regular basis (e.g., q.i.d.) should be instructed to discontinue the
regular use of these drugs and use them only for symptomatic relief if they
develop acute symptoms of asthma while taking Advair.
Watch for increasing use of short-acting,
inhaled beta2-agonists, which is a marker of deteriorating asthma: The patient’s condition
may deteriorate acutely over a period of hours or chronically over several days
or longer. If the patient's short-acting inhaled beta2-agonist
becomes less effective or the patient needs more inhalations than usual, this
may be a marker of destabilization of their disease. In this setting, the
patient requires immediate re-evaluation with reassessment of the treatment
regimen.
Use in Adolescents/Children and Asthma Severity
Reassessment: In adolescents and children, the severity of asthma may vary with
age and periodic reassessment should be considered to determine if continued
maintenance therapy with Advair is still indicated.
General Precautions for Asthma and COPD: Do not
introduce Advair as a treatment for acutely deteriorating asthma or COPD. Advair is intended for
the maintenance treatment of asthma and COPD (see Indications) and should not
be introduced in acutely deteriorating asthma or COPD, which is a potentially
life threatening condition.
Do not exceed recommended dosage: Advair should not be
used more frequently than twice daily (morning and evening) at the recommended
dose. Fatalities have been reported in association with excessive use of
inhaled sympathomimetic drugs. Large doses of inhaled or oral salmeterol
(12 to 20 times the recommended dose) have been associated with
clinically significant prolongation of the QTc interval, which has the
potential for producing ventricular arrhythmias.
Cardiovascular and Other Effects: No clinically
significant effect on the cardiovascular system is usually seen after the
administration of inhaled salmeterol in recommended doses, but the
cardiovascular and CNS effects seen with all sympathomimetic drugs (e.g.,
increased blood pressure, heart rate, excitement) can occur after use of
salmeterol and may require discontinuation of the drug. Salmeterol, like all
sympathomimetic amines, should be used with caution in patients with
cardiovascular disorders, especially coronary insufficiency, cardiac
arrhythmias, and hypertension; in patients with convulsive disorders or
thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic
amines (see also Precautions, Do not exceed recommended dosage).
As has been described
with other beta-adrenergic agonist bronchodilators, clinically significant
changes in systolic and/or diastolic blood pressure, pulse rate, and ECGs have
been seen infrequently in individual patients in controlled clinical studies
with salmeterol.
Metabolic Effects: Doses of the related beta2-adrenoceptor
agonist salbutamol, when administered i.v., have been reported to aggravate
pre-existing diabetes mellitus and ketoacidosis. Administration of beta2-adrenoceptor
agonists may cause a decrease in serum potassium, possibly through
intracellular shunting, which has the potential to increase the likelihood of
arrythmias. The decrease is usually transient, not requiring supplementation.
Clinically significant
changes in blood glucose and/or serum potassium were seen rarely during
clinical studies with long-term administration of salmeterol at recommended
doses.
Systemic Effects: Systemic effects may occur
with any inhaled corticosteroid, particularly at high doses prescribed for long
periods; these effects are much less likely to occur than with oral
corticosteroids (see Overdose). Possible systemic effects include adrenal
suppression, growth retardation in children and adolescents, decrease in bone
mineral density, cataract and glaucoma. It is important therefore, that the
dose of inhaled corticosteroid is titrated to the lowest dose at which
effective control is maintained (see Adverse Effects).
The possibility of
impaired adrenal response should always be borne in mind in emergency and
elective situations likely to produce stress and appropriate corticosteroid
treatment must be considered (see Overdose).
Certain individuals can
show greater susceptibility to the effects of inhaled corticosteroid than do
most patients.
Long-Term Effects: The long-term effects of
fluticasone in human subjects are still unknown. In particular, the local
effects of the drug on developmental or immunologic processes in the mouth,
pharynx, trachea, and lungs are unknown. There is also no information about the
possible long-term systemic effects of the agent. During long-term therapy, HPA
axis function and hematological status should be assessed periodically.
Long-term use of orally
inhaled corticosteroids may affect normal bone metabolism resulting in a loss
of bone mineral density. A 2-year study of patients with asthma receiving
CFC-propelled fluticasone propionate inhalation aerosol (100 and 500 µg twice
daily) demonstrated no statistically significant changes in bone mineral density
at any time point (24, 52, 76 and 104 weeks of double blind treatment) as
assessed by dual-energy x-ray absorptiometry at lumbar region L1 and L4.
Long-term treatment effects of fluticasone propionate on bone mineral density
in the COPD population have not been studied.
In patients with major
risk factors for decreased bone mineral content, such as chronic alcohol use,
tobacco use, age, sedentary lifestyle, strong family history of osteoporosis,
or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and
corticosteroids), Advair may pose an additional risk.
For patients at risk,
monitoring of bone and ocular effects should also be considered in patients
receiving maintenance therapy with Advair.
Discontinuance: Treatment with inhaled
corticosteroids should not be stopped abruptly in patients with asthma due to
risk of exacerbation. In this case, therapy should be titrated down gradually,
under physician supervision. For patients with COPD, cessation of therapy may
be associated with symptomatic decompensation and should be supervised by a
physician.
Eosinophilic Conditions: In rare cases, patients
on inhaled fluticasone may present with systemic eosinophilic conditions, with
some patients presenting with clinical features of vasculitis consistent with
Churg-Strauss syndrome, a condition that is often treated with systemic
corticosteroid therapy. These events usually, but not always, have been
associated with the reduction and/or withdrawal of oral corticosteroid therapy
following the introduction of fluticasone. Cases of serious eosinophilic
conditions have also been reported with other inhaled corticosteroids in this
clinical setting. Physicians should be alert to eosinophilia, vasculitic rash,
worsening pulmonary symptoms, cardiac complications, and/or neuropathy
presenting in their patients. A causal relationship between fluticasone and
these underlying conditions has not been established.
Effect on Infection: Corticosteroids may mask
some signs of infection and new infections may appear. A decreased resistance
to localized infection has been observed during corticosteroid therapy. This
may require treatment with appropriate therapy or stopping the administration
of fluticasone until the infection is eradicated (see Warnings, Effect on
Infection).
Hypothyroidism and Cirrhosis: There is an
enhanced effect of corticosteroids on patients with hypothyroidism and in those
with cirrhosis.
Proper Use of the Diskus and Inhalation Aerosol:
To ensure the proper dosage and administration of the drug, the patient must be
instructed by a physician or other health professional in the use of the device
(Diskus or inhalation aerosol) (see Information for the Patient).
Drug Interactions
Short-acting beta-agonists: Aerosol
bronchodilators of the short-acting adrenergic stimulant type may be used for
relief of breakthrough symptoms while using salmeterol for asthma. Increasing
use of such preparations to control symptoms indicates deterioration of disease
control and the patient's therapy plan should be reassessed.
The regular,
concomitant use of salmeterol and other sympathomimetic agents is not
recommended, since such combined use may lead to deleterious cardiovascular
effects.
MAOIs and Tricyclic Antidepressants: Salmeterol
should be administered with extreme caution to patients being treated with
MAOIs or tricyclic antidepressants or within 2 weeks of discontinuation of such
agents, because the action of salmeterol on the vascular system may be
potentiated by these agents.
Methylxanthines: The concurrent use of i.v. or
orally administered methylxanthines (e.g., aminophylline, theophylline) by
patients receiving salmeterol has not been completely evaluated.
Beta-blocking Drugs: Nonselective beta-blocking
drugs should never be prescribed in asthma or COPD since they may antagonize
the bronchodilating action of salmeterol. Cardioselective beta-blocking drugs
should be used with caution in patients with asthma or COPD.
ASA: Use with caution in conjunction with
corticosteroids in hypoprothrombinemia.
Other Drugs: Use Advair with caution in patients
receiving other medications causing hypokalemia and/or increased QTc interval
(diuretics, high dose steroids, antiarrhythmics, astemizole, terfenadine) since
cardiac and vascular effects may be potentiated.
Under normal
circumstances, low plasma concentrations of fluticasone are achieved after
inhaled dosing, due to extensive first pass metabolism and high systemic
clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence,
clinically significant drug interactions involving fluticasone are unlikely.
A drug interaction
study of intranasal fluticasone in healthy subjects has shown that ritonavir (a
highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone
plasma concentrations, resulting in markedly reduced serum cortisol
concentrations. During post-marketing use, there have been reports of
clinically significant drug interactions in patients receiving intranasal or
inhaled fluticasone and ritonavir, resulting in systemic corticosteroid effects
including Cushing’s syndrome and adrenal suppression. Therefore, concomitant
use of fluticasone and ritonavir should be avoided, unless the potential
benefit to the patient outweighs the risk of systemic corticosteroid
side-effects.
This study has shown
that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin)
and minor (ketoconazole) increases in systemic exposure to fluticasone
propionate without notable reductions in serum cortisol concentrations.
However, there have been a few case reports during world-wide post-market use
of adrenal cortisol suppression associated with concomitant use of azole
anti-fungals and inhaled fluticasone. Therefore, care is advised when
co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as
there is potential for increased systemic exposure to fluticasone.
Pregnancy
There are no adequate and well-controlled
studies with Advair in pregnant women. Advair should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
In animal studies, some
effects on the fetus, typical for a beta-agonist, occurred at exposure levels
substantially higher than those that occur with therapeutic use. Extensive use
of other beta-agonists has provided no evidence that effects in animals are
relevant to human use.
Like other
glucocorticoids, fluticasone is teratogenic to rodent species. Adverse effects
typical of potent corticosteroids are only seen at high systemic exposure
levels; administration by inhalation ensures minimal systemic exposure. The
relevance of these findings to humans has not yet been established, since
well-controlled trials relating to fetal risk in humans are not available.
Infants born of mothers who have received substantial doses of glucocorticoids
during pregnancy should be carefully observed for hypoadrenalism.
Labor and Delivery: There are no well-controlled
human studies that have investigated effects of salmeterol on preterm labor or
labor at term. Because of the potential for beta-agonist interference with
uterine contractility, use of Advair during labor should be restricted to those
patients in whom the benefits clearly outweigh the risks.
Lactation
Plasma levels of salmeterol after inhaled
therapeutic doses are very low (85 to 200 pg/mL) in humans and
therefore levels in milk should be correspondingly low. Studies in lactating
animals indicate that salmeterol is likely to be secreted in only very small
amounts in breast milk.
Glucocorticoids are excreted
in human milk. The excretion of fluticasone into human breast milk has not been
investigated. When measurable plasma levels were obtained in lactating
laboratory rats following s.c. administration, there was evidence of
fluticasone in the breast milk. However, plasma levels in patients following
inhaled fluticasone at recommended doses are likely to be low.
Since there is no
experience with use of Advair by nursing mothers, 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.
Children
The safety and effectiveness of Advair Diskus in
children younger than 4 years of age have not been established.
The safety and efficacy
of Advair inhalation aerosol in children younger than 12 years of age have
not been established.
It is recommended that
the height of children and adolescents receiving prolonged treatment with
inhaled corticosteroids is regularly monitored (see Adverse Effects).
Geriatrics
As with other beta2-agonists, special
caution should be observed when using salmeterol in elderly patients who have
concomitant cardiovascular disease that could be adversely affected by this
class of drug. Based on available data, no adjustment of salmeterol dosage in
geriatric patients is warranted.
Adverse Effects
As with other inhalation therapy, paradoxical
bronchospasm may occur with an immediate increase in wheezing after dosing.
This should be treated immediately with a fast- and short-acting inhaled bronchodilator.
Advair should be discontinued immediately, the patient assessed and alternative
therapy instituted if necessary.
The type and severity
of adverse reactions associated with salmeterol and fluticasone may be expected
with Advair. There is no incidence of additional adverse events following
combined administration of the two compounds.
Salmeterol: The pharmacological side effects of
beta2-agonist treatment, such as tremor, subjective palpitations and
headache, have been reported, but tend to be transient and reduce with regular
therapy.
Cardiac arrhythmias
(including atrial fibrillation, supraventricular tachycardia and extrasystoles)
may occur in some patients.
There have been reports
of arthralgia and hypersensitivity reactions, including rash, edema and
angioedema.
There have been reports
of oropharyngeal irritations as well as rare reports of muscle cramps.
Fluticasone: In general, inhaled corticosteroid
therapy may be associated with dose-dependent increases in the incidence of
ocular complications, reduced bone density, suppression of HPA axis
responsiveness to stress, and inhibition of growth velocity in children. Such
events have been reported rarely in clinical trials with fluticasone.
Glaucoma may be
exacerbated by inhaled corticosteroid treatment. In patients with established
glaucoma who require long-term inhaled corticosteroid treatment, it is prudent
to measure intraocular pressure before commencing the inhaled corticosteroid
and to monitor it subsequently. In patients without established glaucoma, but
with a potential for developing intraocular hypertension (e.g., the elderly),
intraocular pressure should be monitored at appropriate intervals.
In elderly patients
treated with inhaled corticosteroids, the prevalence of posterior subcapsular
and nuclear cataracts is probably low but increases in relation to the daily
and cumulative lifetime dose. Cofactors such as smoking, ultraviolet B
exposure, or diabetes may increase the risk. Children may be less susceptible.
A reduction of growth
velocity in children or teenagers 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 children and adolescents
taking corticosteroids by any route and weigh the benefits of corticosteroid
therapy and asthma control against the possibility of growth suppression if any
child's or adolescent's growth appears slowed.
Osteoporosis and
fracture are the major complications of long-term treatment with parenteral or
oral steroids. Inhaled corticosteroid therapy is also associated with
dose-dependent bone loss, although the degree of risk is very much less than
with oral steroid. This risk may be offset by estrogen replacement in
post-menopausal women, and by titrating the daily dose of inhaled steroid to
the minimum required to maintain optimal control of respiratory symptoms. It is
not yet known whether the peak bone density achieved during youth is adversely
affected if substantial amounts of inhaled corticosteroid are administered
prior to 30 years of age. Failure to achieve maximal bone density during
youth could increase the risk of osteoporotic fracture when those individuals
reach 60 years of age and older.
Hoarseness and
candidiasis (thrush) of the mouth and throat can occur in some patients
receiving inhaled fluticasone. These may be relieved by rinsing the mouth and
gargling with water after use of Advair. Symptomatic candidiasis can be treated
with topical antifungal therapy while still continuing with Advair (see
Precautions, Drug Interactions).
There have been
uncommon reports of cutaneous hypersensitivity reactions. There have also been
rare reports of hypersensitivity reactions manifesting as angioedema (mainly
facial and oropharyngeal edema), respiratory symptoms (dyspnea and/or
bronchospasm) and very rarely, anaphylactic reactions.
Eosinophilic Conditions: In rare cases, patients
on inhaled fluticasone may present with systemic eosinophilic conditions, with
some patients presenting with clinical features of vasculitis consistent with
Churg-Strauss syndrome, a condition that is often treated with systemic
corticosteroid therapy. These events usually, but not always, have been
associated with the reduction and/or withdrawal of oral corticosteroid therapy
following the introduction of fluticasone. Cases of serious eosinophilic
conditions have also been reported with other inhaled corticosteroids in this
clinical setting. Physicians should be alert to eosinophilia, vasculitic rash,
worsening pulmonary symptoms, cardiac complications, and/or neuropathy
presenting in their patients. A causal relationship between fluticasone and
these underlying conditions has not been established.
Clinical Trials in Asthma: Advair Diskus:
Adolescents and Adults: In clinical trials involving 1824 adult and
adolescent patients, the most commonly reported adverse events with the
combination salmeterol/fluticasone Diskus were: hoarseness/dysphonia, throat
irritation, headache, candidiasis of mouth and throat, and palpitations as
detailed in Table 1.
CPS:Advair_t1Click here for Table 1
Table 1: Advair Diskus
Number (and percentage) of Patients with
Drug-related Adverse Events (incidence ≥ 1%a )—(Safety
Population)
|
Adverse Events
|
Salmeterol Xinafoate/
Fluticasone Propionate
Combination Product
|
Salmeterol Xinafoate
and
Fluticasone
PropionateConcurrent Therapy
|
Fluticasone Propionate
Alone
|
Salmeterol Xinafoate
Alone
|
Placebo
|
|
Number of Patients
|
644
|
486
|
339
|
180
|
175
|
|
Any Event
|
110 (17%)
|
81 (17%)
|
50 (15%)
|
9 (5%)
|
5 (3%)
|
|
Hoarseness/
Dysphonia
|
15 (2%)
|
11 (2%)
|
8 (2%)
|
1 (<1%)
|
0
|
|
Throat Irritation
|
14 (2%)
|
10 (2%)
|
8 (2%)
|
1 (<1%)
|
1 (<1%)
|
|
Candidiasis of Mouth and Throat
|
15 (2%)
|
9 (2%)
|
5 (1%)
|
0
|
0
|
|
Headaches
|
16 (2%)
|
11 (2%)
|
3 (<1%)
|
0
|
0
|
|
Asthmab
|
9 (1%)
|
11 (2%)
|
3 (<1%)
|
0
|
0
|
|
Palpitations
|
7 (1%)
|
4 (<1%)
|
2 (<1%)
|
1 (<1%)
|
0
|
|
Cough
|
6 (<1%)
|
2 (<1%)
|
5 (1%)
|
1 (<1%)
|
0
|
|
Breathing Disorders
|
6 (<1%)
|
2 (<1%)
|
4 (1%)
|
0
|
0
|
|
Candidiasis-
Unspecified Site
|
6 (<1%)
|
3 (<1%)
|
4 (1%)
|
0
|
2 (1%)
|
|
Upper Respiratory Tract Infection
|
5 (<1%)
|
5 (1%)
|
2 (<1%)
|
0
|
0
|
a In any integrated treatment group.
b Asthma was not recorded as an
adverse event in those studies which included treatment with salmeterol alone
or placebo (unless it was a serious adverse event).
In the Advair Diskus
group, there was no apparent relationship to fluticasone dose for drug-related
adverse events (15% with 50/100 µg, 19% with 50/250 µg and 17% with
50/500 µg).
Children
A total of 257 pediatric patients participated
in the clinical development programme and received either the combination
50 µg salmeterol xinafoate/100 µg fluticasone propionate Diskus or
concurrent therapy (with salmeterol and fluticasone propionate administered via
separate inhalers). Only one drug-related adverse event, candidiasis, was
reported with an incidence of 2% or more in the Advair group. The combination
product was generally well tolerated and the safety profile was comparable to
that observed in the concurrent therapy group.
Advair Inhalation Aerosol
Adolescents and Adults: In clinical trials, the
most commonly reported adverse events with the combination salmeterol
xinafoate/fluticasone propionate inhalation aerosol were: hoarseness/dysphonia,
throat irritation and headache. All other adverse events with a reasonable
possibility of being related to study drug were reported in ≤ 1% of
subjects. See Table 2.
CPS:Advair_t2Click here for Table 2
Table 2: Advair Inhalation Aerosol
Number (and percentage) of Patients with
Drug-related Adverse Events (Incidence ≥ 1%a )—(Safety
Population)
|
Adverse Events
|
Salmeterol Xinafoate/
Fluticasone Propionate
MDI Combination Product
|
Fluticasone Propionate
Alone
|
Salmeterol Xinafoate
Alone
|
Placebo
|
|
Number of Patients
|
622
|
614
|
274
|
176
|
|
Any Event
|
67 (11%)
|
71 (11%)
|
29 (11%)
|
9 (5%)
|
|
Hoarseness/Dysphonia
|
13 (2%)
|
7 (1%)
|
3 (2%)
|
0 (0%)
|
|
Throat Irritation
|
13 (2%)
|
14 (2%)
|
10 (4%)
|
3 (2%)
|
|
Candidiasis of Mouth and Throat
|
8 (1%)
|
8 (1%)
|
0 (0%)
|
1 (<1%)
|
|
Headaches
|
11 (2%)
|
11 (2%)
|
5 (2%)
|
3 (2%)
|
|
Cough
|
3 (<1%)
|
3 (<1%)
|
6 (2%)
|
|
