Salmeterol and Fluticasone Propionate Inhalation aerosol is indicated in the regular treatment
of asthma where use of a combination product (long- acting β2-agonist and inhaled
corticosteroid) is appropriate:
 Patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled
short acting β2-agonist
Or
 Patients already adequately controlled on both inhaled corticosteroid and long-acting
β2-agonist

Posology
Route of administration: Inhalation use.
Patients should be made aware that Salmeterol and Fluticasone propionate inhalation aerosol
must be used daily for optimum benefit, even when asymptomatic.
Patients should be regularly reassessed by a doctor, so that the strength of Salmeterol and
Fluticasone propionate inhalation aerosol they are receiving remains optimal and is only
changed on medical advice. The dose should be titrated to the lowest dose at which
effective control of symptoms is maintained. Where the control of symptoms is
maintained with the lowest strength of the combination given twice daily then the next
step could include a test of inhaled corticosteroid alone. As an alternative, patients
requiring a long-acting β2 agonist could be titrated to Salmeterol and Fluticasone propionate
inhalation aerosol, given once daily if, in the opinion of the prescriber, it would be adequate
to maintain disease control. In the event of once daily dosing when the patient has a history of
nocturnal symptoms the dose should be given at night and when the patient has a history of
mainly daytime symptoms the dose should be given in the morning.
Patients should be given the strength of Salmeterol and Fluticasone propionate inhalation
aerosol, containing the appropriate fluticasone propionate dosage for the severity of their
disease.
Note: Salmeterol and Fluticasone propionate inhalation aerosol, 25 microgram /50 microgram
strength is not appropriate for adults and children with severe asthma. If an individual patient
should require dosages outside the recommended regimen, appropriate doses of β2 agonist
and/or corticosteroid should be prescribed.
Recommended Doses:
Adults and adolescents 12 years and older:
- Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone
propionate twice daily.
or
- Two inhalations of 25 micrograms salmeterol and 125 micrograms fluticasone
propionate twice daily.
or
- Two inhalations of 25 micrograms salmeterol and 250 micrograms fluticasone
propionate twice daily.
A short-term trial of Salmeterol and Fluticasone propionate inhalation aerosol, may be
considered as initial maintenance therapy in adults or adolescents with moderate persistent

asthma (defined as patients with daily symptoms, daily rescue use and moderate to severe
airflow limitation) for whom rapid control of asthma is essential. In these cases, the
recommended initial dose is two inhalations of 25 micrograms salmeterol and 50 micrograms
fluticasone propionate twice daily. Once control of asthma is attained treatment should be
reviewed and consideration given as to whether patients should be stepped down to an
inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is
important.
A clear benefit has not been shown as compared to inhaled fluticasone propionate alone used
as initial maintenance therapy when one or two of the criteria of severity are missing. In
general, inhaled corticosteroids remain the first line treatment for most patients. Salmeterol
and Fluticasone propionate inhalation aerosol, is not intended for the initial management of
mild asthma. Salmeterol and Fluticasone propionate inhalation aerosol, 25 micrograms /50
micrograms strength is not appropriate in adults and children with severe asthma; it is
recommended to establish the appropriate dosage of inhaled corticosteroid before any fixedcombination
can be used in patients with severe asthma.

Paediatric population
Children 4 years and older:
- Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate
twice daily.
The maximum licensed dose of fluticasone propionate delivered by Salmeterol and
Fluticasone propionate inhalation aerosol, in children is 100 microgram twice daily.
There are no data available for use of Salmeterol and Fluticasone propionate inhalation
aerosol, in children aged under 4 years.
Patients should be instructed in the proper use and care of their inhaler and their technique
checked to ensure optimum delivery of the inhaled drug to the lungs.
Special patient groups
There is no need to adjust the dose in elderly patients or in those with renal impairment.
There are no data available for use of Salmeterol and Fluticasone propionate inhalation
aerosol, in patients with hepatic impairment.
Instructions for Use
Patients should be instructed in the proper use of their inhaler. During inhalation, the patient
should preferably sit or stand. The inhaler has been designed for use in a vertical position.

Important: Follow instructions carefully.
Shake the inhaler well immediately before each use.
Testing your inhaler:
If you are using the inhaler for the first time or if the inhaler has not been used for a minimum
of seven days, “test spray” the inhaler. Remove the cap from the mouthpiece; the mouthpiece
should be inspected for the presence of foreign objects before each use. Spray the inhaler 4
times into the air after shaking the device prior to each actuation. (See pic no. 1)

Make sure the canister is fully and firmly inserted into the actuator. (See pic no. 2)

Hold the inhaler upright with your thumb on the base. Place either one or two fingers on the
top of the canister. Breathe out fully through your mouth expelling as much air from your
lungs as possible. Thereafter, place the mouthpiece of the inhaler in your mouth between your
teeth. (See pic no. 3)

Close your lips around it (do not bite it) tilt your head slightly backwards. Start breathing in
slowly through your mouth. As you breathe in steadily and deeply, press down the canister to
release one puff. (See pic no. 4)

While holding their breath, patients should take off the inhaler from their mouth and should
continue holding their breath for 10 seconds or for as long as it is comfortable. Breathe out
slowly. (See pic no. 5)

Note:
If the second dose is required wait for at least one minute and repeat steps 2 through 5 for
each puff prescribed by your Physician. Rinse your mouth or gargle with water after inhaling
your recommended dose (Single dose means total number of puffs advised by the Physician
at once). This is likely to reduce the soreness that may be caused by the drug. After use,
replace the mouthpiece cover. (See pic no.6)

Practice in front of the mirror for the first few times. If you see 'mist' coming from top of the
inhaler or sides of the mouth, this indicates failure of technique. Start again from Step 2. (See
pic no. 7)

For Children:
Children should use the inhaler under adult supervision, as instructed by the Physician. (See
pic no. 8)

Cleaning:
Clean the inhaler at least once in a week.

1. To clean your inhaler remove the mouthpiece cover.
2. Do not remove the metal canister from the plastic actuator.
3. Wipe the inside and outside of the mouthpiece with dry cloth or tissue.
4. Replace the mouthpiece cover correctly.
5. Do not put the inhaler in water.
Discard the inhaler along with the canister after using the labeled number of inhalation. DO
NOT PUT THE METAL CONTAINER IN WATER

Salmeterol and Fluticasone propionate inhalation aerosol, should not be used to treat acute
asthma symptoms for which a fast- and short-acting bronchodilator is required. Patients
should be advised to have their inhaler to be used for relief in an acute asthma attack
available at all times.
Patients should not be initiated on Salmeterol and Fluticasone propionate inhalation aerosol,
during an exacerbation, or if they have significantly worsening or acutely deteriorating
asthma.
Serious asthma-related adverse events and exacerbations may occur during treatment with
Salmeterol and Fluticasone propionate inhalation aerosol. Patients should be asked to
continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or
worsen after initiation on Salmeterol and Fluticasone propionate inhalation aerosol.
Increased requirements for use of reliever medication (short-acting bronchodilators), or
decreased response to reliever medication indicate deterioration of asthma control and
patients should be reviewed by a physician.
Sudden and progressive deterioration in control of asthma is potentially life-threatening and
the patient should undergo urgent medical assessment. Consideration should be given to
increasing corticosteroid therapy.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the
dose of Salmeterol and Fluticasone propionate inhalation aerosol,. Regular review of patients
as treatment is stepped down is important. The lowest effective dose of Salmeterol and
Fluticasone propionate inhalation aerosol, should be used.
Treatment with Salmeterol and Fluticasone propionate inhalation aerosol, should not be
stopped abruptly due to risk of exacerbation. Therapy should be down-titrated under
physician supervision.

As with all inhaled medication containing corticosteroids, Salmeterol and Fluticasone
propionate inhalation aerosol should be administered with caution in patients with active or
quiescent pulmonary tuberculosis and fungal, viral or other infections of the airway.
Appropriate treatment should be promptly instituted, if indicated.
Rarely, Salmeterol and Fluticasone propionate inhalation aerosol, may cause cardiac
arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild
transient reduction in serum potassium at high therapeutic doses. Salmeterol and Fluticasone
propionate inhalation aerosol, should be used with caution in patients with severe
cardiovascular disorders or heart rhythm abnormalities and in patients with diabetes mellitus,
thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum
potassium.
There have been very rare reports of increases in blood glucose levels and this should be
considered when prescribing to patients with a history of diabetes mellitus.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate
increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm
responds to a rapid-acting bronchodilator and should be treated straightaway. Salmeterol and
Fluticasone propionate inhalation aerosol, should be discontinued immediately, the patient
assessed and alternative therapy instituted if necessary.
The pharmacological side effects of β2 agonist treatment, such as tremor, palpitations and
headache, have been reported, but tend to be transient and reduce with regular therapy.
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. Possible systemic effects include Cushing's syndrome, Cushingoid features,
adrenal suppression, decrease in bone mineral density, cataract and glaucoma and more
rarely, a range of psychological or behavioural effects including psychomotor hyperactivity,
sleep disorders, anxiety, depression or aggression (particularly in children). It is important,
therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is
reduced to the lowest dose at which effective control of asthma is maintained.
Prolonged treatment of patients with high doses of inhaled corticosteroids may result in
adrenal suppression and acute adrenal crisis. Very rare cases of adrenal suppression and acute
adrenal crisis have also been described with doses of fluticasone propionate between 500 and
less than 1000 micrograms. Situations, which could potentially trigger acute adrenal crisis,
include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are
typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache,
nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and
seizures. Additional systemic corticosteroid cover should be considered during periods of
stress or elective surgery.

Systemic absorption of salmeterol and fluticasone propionate is largely through the lungs.
The benefits of inhaled fluticasone propionate therapy should minimise the need for oral
steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal
reserve for a considerable time. Therefore these patients should be treated with special care
and adrenocortical function regularly monitored. Patients who have required high dose
emergency corticosteroid therapy in the past may also be at risk. This possibility of residual
impairment should always be borne in mind in emergency and elective situations likely to
produce stress, and appropriate corticosteroid treatment must be considered. The extent of the
adrenal impairment may require specialist advice before elective procedures.
Ritonavir can greatly increase the concentration of fluticasone propionate in plasma.
Therefore, concomitant use should be avoided, unless the potential benefit to the patient
outweighs the risk of systemic corticosteroid side effects. There is also an increased risk of
systemic side effects when combining fluticasone propionate with other potent CYP3A
inhibitors.
There was an increased reporting of lower respiratory tract infections (particularly pneumonia
and bronchitis) in a 3-year study in patients with Chronic Obstructive Pulmonary Disease
(COPD) receiving salmeterol and fluticasone propionate as a fixed-dose combination
administered via the Diskus/Accuhaler compared with placebo. In a 3-year COPD study,
older patients, patients with a lower body mass index (<25 kg/m2) and patients with very
severe disease (FEV1<30% predicted) were at greatest risk of developing pneumonia
regardless of treatment. Physicians should remain vigilant for the possible development of
pneumonia and other lower respiratory tract infections in patients with COPD as the clinical
features of such infections and exacerbation frequently overlap. If a patient with severe
COPD has experienced pneumonia the treatment with Salmeterol and Fluticasone propionate
inhalation aerosol should be re-evaluated. The safety and efficacy of Salmeterol and
Fluticasone propionate inhalation aerosol, has not been established in patients with COPD
and therefore Salmeterol and Fluticasone propionate inhalation aerosol, is not indicated for
use in the treatment of patients with COPD.
Concomitant use of systemic ketoconazole significantly increases systemic exposure to
salmeterol. This may lead to an increase in the incidence of systemic effects (e.g.
prolongation in the QTc interval and palpitations). Concomitant treatment with ketoconazole
or other potent CYP3A4 inhibitors should therefore be avoided unless the benefits outweigh
the potentially increased risk of systemic side effects of salmeterol treatment.
Visual disturbance
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient
presents with symptoms such as blurred vision or other visual disturbances, the patient should
be considered for referral to an ophthalmologist for evaluation of possible causes, which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR)
which have been reported after use of systemic and topical corticosteroids.
Paediatric population
Children and adolescents <16 years taking high doses of fluticasone propionate (typically ≥
1000 micrograms/day) may be at particular risk. Systemic effects may occur, particularly at
high doses prescribed for long periods. Possible systemic effects include Cushing's syndrome,
Cushingoid features, adrenal suppression, acute adrenal crisis and growth retardation in
children and adolescents and more rarely, a range of psychological or behavioural effects
including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression.
Consideration should be given to referring the child or adolescent to a paediatric respiratory
specialist.
It is recommended that the height of children receiving prolonged treatment with inhaled
corticosteroid is regularly monitored. The dose of inhaled corticosteroid should be reduced
to the lowest dose at which effective control of asthma is maintained.

β adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective
and selective β blockers should be avoided in patients with asthma, unless there are
compelling reasons for their use. Potentially serious hypokalaemia may result from β2 agonist
therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated
by concomitant treatment with xanthine derivatives, steroids and diuretics.
Concomitant use of other β adrenergic containing drugs can have a potentially additive effect.
Fluticasone Propionate
Under normal circumstances, low plasma concentrations of fluticasone propionate are
achieved after inhaled dosing, due to extensive first pass metabolism and high systemic
clearance mediated by cytochrome CYP3A4 in the gut and liver. Hence, clinically significant
drug interactions mediated by fluticasone propionate are unlikely.
In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a
highly potent cytochrome CYP3A4 inhibitor) 100 mg b.i.d. increased the fluticasone
propionate plasma concentrations several hundred fold, resulting in markedly reduced serum
cortisol concentrations. Information about this interaction is lacking for inhaled fluticasone
propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases
of Cushing's syndrome and adrenal suppression have been reported. The combination should
be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side
effects.

In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole
increased the exposure of fluticasone propionate after a single inhalation by 150%. This
resulted in a greater reduction of plasma cortisol as compared with fluticasone propionate
alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole and cobicistatcontaining
products, and moderate CYP3A inhibitors, such as erythromycin, is also expected
to increase the systemic fluticasone propionate exposure and the risk of systemic side effects.
Combinations should be avoided unless the benefit outweighs the potential increased risk of
systemic corticosteroid side-effects, in which case patients should be monitored for systemic
corticosteroid side-effects.
Salmeterol
Potent CYP3A4 inhibitors
Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 micrograms
inhaled twice daily) in 15 healthy subjects for 7 days resulted in a significant increase in
plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in
the incidence of other systemic effects of salmeterol treatment (e.g. prolongation of QTc
interval and palpitations) compared with salmeterol or ketoconazole treatment alone.
Clinically significant effects were not seen on blood pressure, heart rate, blood glucose and
blood potassium levels. Co-administration with ketoconazole did not increase the elimination
half-life of salmeterol or increase salmeterol accumulation with repeat dosing.
The concomitant administration of ketoconazole should be avoided, unless the benefits
outweigh the potentially increased risk of systemic side effects of salmeterol treatment. There
is likely to be a similar risk of interaction with other potent CYP3A4 inhibitors (e.g.
itraconazole, telithromycin, ritonavir).
Moderate CYP 3A4 inhibitors
Co-administration of erythromycin (500 mg orally three times a day) and salmeterol (50
micrograms inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but nonstatistically
significant increase in salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Coadministration
with erythromycin was not associated with any serious adverse effects.

Fertility
There are no data in humans. However, animal studies showed no effects of salmeterol or
fluticasone propionate on fertility.
Pregnancy
A moderate amount of data on pregnant women (between 300 to 1000 pregnancy outcomes)
indicate no malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate.

Animal studies have shown reproductive toxicity after administration of β2 adrenoreceptor
agonists and glucocorticosteroids.
Administration of Salmeterol and Fluticasone propionate inhalation aerosol to pregnant
women should only be considered if the expected benefit to the mother is greater than any
possible risk to the fetus.
The lowest effective dose of fluticasone propionate needed to maintain adequate asthma
control should be used in the treatment of pregnant women..
Lactation
It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in
human milk.
Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are
excreted into the milk of lactating rats.
A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether
to discontinue breastfeeding or to discontinue Salmeterol and Fluticasone propionate
inhalation aerosol therapy taking into account the benefit of breastfeeding for the child and
the benefit of therapy for the woman.

Salmeterol and Fluticasone propionate inhalation aerosol, has no or negligible influence on
the ability to drive and use machines. 

As Salmeterol and Fluticasone propionate inhalation aerosol, contains salmeterol and
fluticasone propionate, the type and severity of adverse reactions associated with each of the
compounds may be expected. There is no incidence of additional adverse events following
concurrent administration of the two compounds.
Adverse events which have been associated with salmeterol/fluticasone propionate are given
below, listed by system organ class and frequency. Frequencies are defined as: very common
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to
<1/1000) and not known (cannot be estimated from the available data). Frequencies were
derived from clinical trial data. The incidence in placebo was not taken into account.

Description of selected adverse reactions
The pharmacological side effects of β2 agonist treatment, such as tremor, palpitations and
headache, have been reported, but tend to be transient and reduce with regular therapy.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate
increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm
responds to a rapid-acting bronchodilator and should be treated straightaway. Salmeterol and
Fluticasone propionate inhalation aerosol should be discontinued immediately, the patient
assessed and alternative therapy instituted if necessary.
Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the
mouth and throat and, rarely, of the oesophagus can occur in some patients. Both hoarseness
and incidence of mouth and throat candidiasis may be relieved by rinsing the mouth with
water and/or brushing the teeth after using the product. Symptomatic mouth and throat
candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the
Salmeterol and Fluticasone propionate inhalation aerosol.
Paediatric population
Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal
suppression and growth retardation in children and adolescents. Children may also experience
anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product.

To report any side effect, kindly contact:
The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc

There are no data available from clinical trials on overdose with Salmeterol and Fluticasone
propionate inhalation aerosol however data on overdose with both drugs are given below:
The signs and symptoms of salmeterol overdose are dizziness, increases in systolic blood
pressure, tremor, headache and tachycardia. If Salmeterol and Fluticasone propionate
inhalation aerosol therapy has to be withdrawn due to overdose of the β2 agonist component
of the drug, provision of appropriate replacement steroid therapy should be considered.
Additionally, hypokalaemia can occur and therefore serum potassium levels should be
monitored. Potassium replacement should be considered.
Acute: Acute inhalation of fluticasone propionate doses in excess of those recommended
may lead to temporary suppression of adrenal function. This does not need emergency action
as adrenal function is recovered in a few days, as verified by plasma cortisol measurements.
Chronic overdose of inhaled fluticasone propionate: Adrenal reserve should be monitored
and treatment with a systemic corticosteroid may be necessary. When stabilised, treatment
should be continued with an inhaled corticosteroid at the recommended dose. Refer to section
4.4: risk of adrenal suppression.
In cases of both acute and chronic fluticasone propionate overdose, Salmeterol and
Fluticasone propionate inhalation aerosol therapy should be continued at a suitable dosage for
symptom control.

Pharmacotherapeutic Group: Adrenergics in combination with corticosteroids or other drugs,
excluding Anticholinergics.

ATC Code: R03AK06

Mechanism of action and pharmacodynamic effects
Salmeterol and Fluticasone propionate inhalation aerosol contains salmeterol and fluticasone
propionate which have differing modes of action.
The respective mechanisms of action of both drugs are discussed below.
Salmeterol:
Salmeterol is a selective long-acting (12 hour) β2 adrenoceptor agonist with a long side chain
which binds to the exo-site of the receptor.
Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than
recommended doses of conventional short-acting β2 agonists.

Fluticasone propionate:
Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid
anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations
of asthma, with less adverse effects than when corticosteroids are administered systemically.
Clinical efficacy and safety
Salmeterol and fluticasone propionate inhalation aerosol Asthma clinical trials
A twelve month study (Gaining Optimal Asthma ControL, GOAL), in adult and adolescent
patients with persistent asthma, compared the safety and efficacy of salmeterol and
fluticasone propionate inhalation aerosol versus inhaled corticosteroid (fluticasone
propionate) alone to determine whether the goals of asthma management were achievable.
Treatment was stepped up every 12 weeks until **total control was achieved or the highest
dose of study drug was reached. GOAL showed more patients treated with salmeterol and
fluticasone propionate inhalation aerosol, achieved asthma control than patients treated with
ICS alone and this control was attained at a lower corticosteroid dose.
*Well controlled asthma was achieved more rapidly with salmeterol and fluticasone
propionate inhalation aerosol than with ICS alone. The time on treatment for 50% of subjects
to achieve a first individual well controlled week was 16 days for salmeterol and fluticasone
propionate inhalation aerosol, compared to 37 days for the ICS group. In the subset of steroid
naive asthmatics the time to an individual well controlled week was 16 days in the salmeterol
and fluticasone propionate inhalation aerosol treatment compared to 23 days following
treatment with ICS.

The results of this study suggest that salmeterol and fluticasone propionate inhalation aerosol
50/100 microgram bd may be considered as initial maintenance therapy in patients with
moderate persistent asthma for whom rapid control of asthma is deemed essential.
A double blind, randomised, parallel group study in patients with persistent asthma aged ≥18
years evaluated the safety and tolerability of administering two inhalations twice daily
(double dose) of salmeterol and fluticasone propionate inhalation aerosol for two weeks. The
study showed that doubling the inhalations of each strength of salmeterol and fluticasone
propionate inhalation aerosol for up to 14 days resulted in a small increase in β agonistrelated
adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle
cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid-related adverse
events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to
one inhalation twice daily. The small increase in β-agonist-related adverse events should be
taken into account if doubling the dose of salmeterol and fluticasone propionate inhalation
aerosol is considered by the physician in adult patients requiring additional short-term (up to
14 days) inhaled corticosteroid therapy.
The Salmeterol Multi-center Asthma Research Trial (SMART)
The Salmeterol Multi-center Asthma Research Trial (SMART) was a 28-week US study that
evaluated the safety of salmeterol compared to placebo added to usual therapy in adult and
adolescent subjects. Although there were no significant differences in the primary endpoint of
the combined number of respiratory-related deaths and respiratory-related life-threatening
experiences, the study showed a significant increase in asthma-related deaths in patients
receiving salmeterol (13 deaths out of 13,176 patients treated with salmeterol versus 3 deaths
out of 13,179 patients on placebo). The study was not designed to assess the impact of
concurrent inhaled corticosteroid use, and only 47% of subjects reported ICS use at baseline.
Safety and efficacy of salmeterol-FP versus FP alone in asthma
Two multi-centre 26-week studies were conducted to compare the safety and efficacy of
salmeterol-FP versus FP alone, one in adult and adolescent subjects (AUSTRI trial), and the
other in paediatric subjects 4-11 years of age (VESTRI trial). For both studies, enrolled
subjects had moderate to severe persistent asthma with history of asthma-related
hospitalisation or asthma exacerbation in the previous year. The primary objective of each
study was to determine whether the addition of LABA to ICS therapy (salmeterol-FP) was
non-inferior to ICS (FP) alone in terms of the risk of serious asthma related events (asthmarelated
hospitalisation, endotracheal intubation, and death). A secondary efficacy objective of
these studies was to evaluate whether ICS/LABA (salmeterol-FP) was superior to ICS
therapy alone (FP) in terms of severe asthma exacerbation (defined as deterioration of asthma
requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalisation
or emergency department visit due to asthma that required systemic corticosteroids).
Subjects were randomized and received treatment in the AUSTRI and VESTRI trials,
respectively. For the primary safety endpoint, non-inferiority was achieved for both trials (see
Table below).

For the secondary efficacy endpoint, reduction in time to first asthma exacerbation for
salmeterol-FP relative to FP was seen in both studies, however only AUSTRI met statistical
significance:

Paediatric population
In trial SAM101667, in children aged 6 to 16 years with symptomatic asthma, the
combination of salmeterol/fluticasone propionate is equally efficacious to doubling the dose
of fluticasone propionate regarding symptom control and lung function. This study was not
designed to investigate the effect on exacerbations.
In a trial which randomized children aged 4 to 11 years, salmeterol/fluticasone propionate
Diskus (50/100 microgram, one inhalation twice daily) was compared with
salmeterol/fluticasone propionate MDI (25/50 microgram, two inhalations twice daily) over a
12-week treatment period. The adjusted mean change from baseline in mean morning peak
expiratory flow over Weeks 1-12 was 37.7L/min in the Diskus group and 38.6L/min in the
MDI group. Improvements were also seen in both treatment groups on rescue and symptom
free days and nights.

Fluticasone propionate containing medications in asthma during pregnancy
An observational retrospective epidemiological cohort study utilising electronic health
records from the United Kingdom was conducted to evaluate the risk of MCMs following
first trimester exposure to inhaled FP alone and salmeterol-FP relative to non-FP containing
ICS. No placebo comparator was included in this study.
Within the asthma cohort of 5362 first trimester ICS-exposed pregnancies, 131 diagnosed
MCMs were identified; 1612 (30%) were exposed to FP or salmeterol-FP of which 42
diagnosed MCMs were identified. The adjusted odds ratio for MCMs diagnosed by 1 year
was 1.1 (95%CI: 0.5 – 2.3) for FP exposed vs non-FP ICS exposed women with moderate
asthma and 1.2 (95%CI: 0.7 – 2.0) for women with considerable to severe asthma. No
difference in the risk of MCMs was identified following first trimester exposure to FP alone
versus salmeterol-FP. Absolute risks of MCM across the asthma severity strata ranged from
2.0 to 2.9 per 100 FP-exposed pregnancies which is comparable to results from a study of
15,840 pregnancies unexposed to asthma therapies in the General Practice Research Database
(2.8 MCM events per 100 pregnancies).

When Salmeterol and Fluticasone propionate inhalation aerosolwere administered in
combination by the inhaled route, the pharmacokinetics of each component were similar to
those observed when the drugs were administered separately. For pharmacokinetic purposes
therefore each component can be considered separately.
Salmeterol
Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic
effects. In addition there are only limited data available on the pharmacokinetics of
salmeterol because of the technical difficulty of assaying the drug in plasma due to the low
plasma concentrations at therapeutic doses (approximately 200 picogram/mL or less)
achieved after inhaled dosing.
Fluticasone propionate
The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy
subjects varies between approximately 5 to 11% of the nominal dose depending on the
inhalation device used. In patients with asthma a lesser degree of systemic exposure to
inhaled fluticasone propionate has been observed.
Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged.
The remainder of the inhaled dose may be swallowed but contributes minimally to systemic
exposure due to the low aqueous solubility and presystemic metabolism, resulting in oral
availability of less than 1%. There is a linear increase in systemic exposure with increasing
inhaled dose.

The disposition of fluticasone propionate is characterised by high plasma clearance (1150
mL/min), a large volume of distribution at steady-state (approximately 300 L) and a terminal
half-life of approximately 8 hours.
Plasma protein binding is 91%.
Fluticasone propionate is cleared very rapidly from the systemic circulation. The main
pathway is metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450
enzyme CYP3A4. Other unidentified metabolites are also found in the faeces.
The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is
excreted in urine, mainly as metabolites. The main part of the dose is excreted in faeces as
metabolites and unchanged drug.
Paediatric population
The effect of 21 days of treatment with salmeterol and fluticasone propionate Inhaler 25/50
microgram (2 inhalations twice daily with or without a spacer) or salmeterol and fluticasone
propionate Diskus 50/100 microgram (1 inhalation twice daily) was evaluated in 31 children
aged 4 to 11 years with mild asthma. Systemic exposure to fluticasone propionate was similar
for salmeterol and fluticasone propionate Inhaler with spacer (107pg hr/mL [95% CI: 45.7,
252.2]) and salmeterol and fluticasone propionate Diskus (138pg hr/mL [95% CI: 69.3,
273.2]), but lower for salmeterol and fluticasone propionate Inhaler (24pg hr/mL [95% CI:
9.6, 60.2]). Systemic exposure to salmeterol was similar for salmeterol and fluticasone
propionate Inhaler, salmeterol and fluticasone propionate Inhaler with spacer, and salmeterol
and fluticasone propionate Diskus (126 pg hr/mL [95% CI: 70, 225], 103 pg hr/mL [95% CI:
54, 200], and 110 pg hr/mL [95% CI: 55, 219], respectively).

The only safety concerns for human use derived from animal studies of salmeterol and
fluticasone propionate given separately were effects associated with exaggerated
pharmacological actions.
In animal reproduction studies, glucocorticosteroids have been shown to induce
malformations (cleft palate, skeletal malformations). However, these animal experimental
results do not seem to be relevant for man given recommended doses. Animal studies with
salmeterol have shown embryofetal toxicity only at high exposure levels. Following coadministration,
increased incidences of transposed umbilical artery and incomplete
ossification of occipital bone were found in rats at doses associated with known
glucocorticoid-induced abnormalities.

The non-CFC propellant, HFA 134a has been shown to have no toxic effect at very high
vapour concentrations, far in excess of those likely to be experienced by patients, in a wide
range of animal species exposed daily for periods of two years.

Polyethylene glycol 1000
Propellant 1,1,1,2 Tetrafluoroethane (HFA 134a)

Not applicable

Store below 30°C. Do not Freeze. Avoid direct exposure to sunlight.
The metal canister is pressurized. Do not use or store near heat or open flame. Exposure to
temperature above 120°F (50°C) may cause bursting.

The immediate container is an aluminium can which is sealed with a metering valve. The
container is assembled with an actuator containing a mouthpiece dust cap. The actuator and
the dust cap are made of polypropylene.
Each inhaler delivers 120 metered doses/canister after initial priming

The canister should not be broken, punctured or burnt, even when apparently empty.