PRODUCT INFORMATION

Fluticasone + Salmeterol Cipla 125/25

Fluticasone + Salmeterol Cipla 250/25

Fluticasone propionate/ Salmeterol (as xinafoate)

125 /25 microgram and 250 /25 microgram MDI

NAME OF THE MEDICINE

Fluticasone propionate/ Salmeterol (as xinafoate)

The chemical name of fluticasone propionate is S-Fluoromethyl 6α, 9α-difluoro-11ß-hydroxy-

16α-methyl-3-oxo-17 α-propionyloxy-androsta-1, 4-diene-17ß-carbothioate. It has a molecular
formula of C25H31F3O5S and a molecular weight of 500.6.

The chemical name of salmeterol xinafoate is (±)-4-Hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]-

methyl]-m-xylene-α, α′-diol 1-hydroxyl-2-naphthoate (salt). It has a molecular formula of
C25H37NO4.C11H8O3 and a molecular weight of 603.8.

The structural formula of fluticasone The structural formula salmeterol

propionate is: xinafoate is:

CAS Registry Number

Fluticasone propionate: 80474-14-2

Salmeterol xinafoate: 94749-08-3

DESCRIPTION

Fluticasone + Salmeterol Cipla contains the active ingredients fluticasone propionate and salmeterol
(as xinafoate).

Fluticasone propionate is a white or almost white powder. It is practically insoluble in water, sparingly
soluble in methylene chloride, slightly soluble in ethanol (96 per cent).

Salmeterol (as xinafoate) is a white or almost white powder. Practically insoluble in water, soluble in
methanol, slightly soluble in anhydrous ethanol.

Fluticasone + Salmeterol Cipla also contains the excipient norflurane (HFA 134a) which is a CFC-
free propellant.

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PHARMACOLOGY

This product contains fluticasone propionate and salmeterol (as xinafoate) which have differing modes
of action. Salmeterol provides symptomatic relief, while fluticasone propionate improves lung
function and prevents exacerbations of the condition. Fluticasone propionate/Salmeterol can offer a
more convenient regimen for patients on concurrent long-acting beta-agonist and inhaled
corticosteroid therapy. The respective mechanisms of action of both drugs are discussed below.

Fluticasone propionate
Fluticasone propionate given by inhalation at recommended doses has potent glucocorticoid activity
in the airway. The potent anti-inflammatory action improves the symptomatic control of asthma,
allows reduction of other drugs, such as rescue bronchodilators, and may limit the risk of decline in
lung function over time. The low systemic bioavailability of fluticasone propionate provides a better
risk: benefit outcome without the adverse effects that accompany systemically administered
corticosteroids.

Salmeterol
Salmeterol is a selective long-acting beta-2-adrenoceptor agonist and at dosages of less than 100
microgram twice daily has little measurable cardiovascular effect. Salmeterol xinafoate is a racemate,
the R-enantiomer being active.

The pharmacological properties of salmeterol offer a slower onset of action, but more effective
protection against histamine-induced bronchoconstriction and a longer duration of bronchodilation
(lasting for approximately 12 hours) than recommended doses of conventional short-acting beta-2
agonists. The onset of effective bronchodilation (> 15% improvement in FEV1) occurs within 10 to
30 minutes and peak effect occurs between 3 to 4 hours.

In vitro tests have shown salmeterol is a potent and long-lasting inhibitor of the release of mast
cell mediators, such as histamine, leukotrienes and prostaglandin D2, from human lung fragments. In
one study in man, salmeterol inhibits the early and late phase response to inhaled allergen; the latter
persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident.
Single dosing with salmeterol attenuates bronchial hyperresponsiveness. These properties indicate that
salmeterol has additional non- bronchodilator activity, but the full clinical significance is not yet clear.
The mechanism is different from the anti-inflammatory effect of corticosteroids.

Pharmacokinetics

There is no evidence in animal or human subjects that the administration of fluticasone propionate
and salmeterol together by the inhaled route affects the pharmacokinetics of either component. For
pharmacokinetic purposes therefore each component can be considered separately.

Even though plasma levels of fluticasone propionate/salmeterol are very low, potential interactions
with other substrates and inhibitors of CYP 3A4 cannot be excluded.

Fluticasone propionate
Following oral administration 87-100% of the dose is excreted in the faeces, up to 75% as parent
compound depending on the dose. There is a non-active major metabolite. Following intravenous
administration there is rapid plasma clearance suggestive of extensive hepatic extraction. The plasma
elimination half-life is approximately 3 hours. The volume of distribution is approximately 250 litres.
Doses delivered by the dry powder inhalers and metered-dose inhalers may not have the same
systemic bioavailability; however, there is no difference in clinical efficacy between the inhalers in
controlled studies.

The absolute bioavailability of fluticasone propionate for each of the available inhaler devices has
been estimated from within and between study comparisons of inhaled and intravenous
pharmacokinetic data based on AUC(0-infinity) data. In healthy adult subjects the absolute
bioavailability has been estimated for fluticasone propionate Accuhaler (8%), fluticasone propionate

2
Diskhaler (9%) and fluticasone propionate Inhaler (10.9%) respectively. The absolute bioavailability
from fluticasone propionate/salmeterol Accuhaler and Inhaler are approximately 6%.

Salmeterol
Salmeterol acts locally in the lung, therefore plasma levels are not predictive of therapeutic effect. In
addition there are only limited data available on the pharmacokinetics of salmeterol because of the
technical difficulty of assaying very low plasma concentrations (approximately 200 pg/mL or less) of
the drug after inhaled dosing.

Following administration, salmeterol xinafoate is extensively bound (95-98%) to plasma proteins.

Elimination of radioactivity from plasma following oral administration of radiolabelled salmeterol
xinafoate is slow (mean t½ is 67 hours). Excretion is predominantly through the faeces and to a
lesser extent urine. Aliphatic hydroxylation appears to be the major route of metabolism in humans.

After regular dosing with salmeterol xinafoate, the xinafoate moiety, hydroxynaphthoic acid, can
be detected in the systemic circulation, reaching steady state concentrations of approximately 100
ng/mL. These concentrations are up to 1000-fold lower than steady state levels observed in toxicity
studies and in longer-term regular dosing (more than 12 months) trials in patients with airways
obstruction, there have not been adverse effects attributable to hydroxynaphthoic acid reported.

In a placebo-controlled, crossover drug interaction study in 20 healthy subjects, co- administration of

salmeterol (50 micrograms twice daily inhaled) and the CYP3A4 inhibitor ketoconazole (400 mg once
daily orally) for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax
and 15-fold AUC). There was no increase in salmeterol accumulation with repeat dosing. Three
subjects were withdrawn from salmeterol and ketoconazole co-administration due to QTc prolongation
or palpitations with sinus tachycardia. The increase in the QTc interval observed with the co-
administration o f salmeterol and ketoconazole compared with salmeterol and placebo administration
was not statistically significant. There were no clinically significant effects seen in heart rate or blood
potassium levels, which were the primary endpoints of the study (see PRECAUTIONS and
INTERACTIONS WITH OTHER MEDICINES).

CLINICAL TRIALS

Asthma

Two 12 week, double blind, double dummy, randomised, parallel group clinical studies were
performed in 1006 adult and adolescent patients aged ≥ 12 years. The first study compared the
50/25 micrograms strength fluticasone propionate/salmeterol metered dose inhaler (MDI; 165
patients) with the corresponding 100/50 micrograms Accuhaler (167 patients), while the second study
compared the 250/25 micrograms strength MDI (176 patients) with the 500/50 micrograms Accuhaler
(161 patients). The dosing regimen for the MDI is two inhalations twice daily whilst the Accuhaler is
one inhalation twice daily, ensuring the total daily dose of each active ingredient is the same for
both formulations. Both studies also included a comparison with CFC fluticasone propionate MDI
alone, at the same fluticasone propionate dose as the combination, to reaffirm the superiority of the
combination over fluticasone propionate alone despite the change in formulation. All patients had
reversible obstructive airways disease and were symptomatic on inhaled corticosteroids, with room
for improvement in lung function. No clinical trial was performed with the 125/25 micrograms MDI
strength because pharmaceutical and clinical pharmacology data have demonstrated dose
proportionality across the three strengths of the fluticasone propionate component.

The primary efficacy variable was change in mean morning PEF over weeks 1–12, and this met the
criterion for clinical equivalence between the MDI and Accuhaler combination formulations (95%
confidence limits for the difference between treatments contained within ±15 L/min) in both studies.
Comparable results were also seen for other time points in both studies, with almost all 95% confidence
intervals falling within ±15 L/min. In no cases were the confidence intervals greater than ±16L/min.
Large increases in mean PEF were seen over weeks 1-12 in both the MDI and the Accuhaler

3
combination groups.

In both studies, fluticasone propionate/salmeterol MDI was significantly more effective than
fluticasone propionate MDI alone in change from baseline in mean morning PEF throughout the
treatment period. This was manifest as early as week 1 (p<0.001). Mean treatment differences were
greater than 15L/min. These results demonstrate clinical superiority of the MDI combination over the
FP CFC formulation alone, reaffirming the superiority of the combination over fluticasone propionate
alone, despite the change in formulation. While a statistical comparison of fluticasone/salmeterol
Accuhaler was not conducted, the differences between these 2 treatment groups were of similar
magnitude to those observed for the combination MDI.

Both the fluticasone propionate/salmeterol MDI and Accuhaler formulations improved symptoms
scores, decreased rescue salbutamol usage and increased the percentage of symptom free days and
nights. Effects of the two treatments on these parameters were similar.

Chronic Obstructive Pulmonary Disease (COPD)

Three randomised, double blind, placebo-controlled trials have investigated the safety and efficacy of
fluticasone propionate/salmeterol Accuhaler in the treatment of patients with COPD. The studies used
two fluticasone propionate/salmeterol dose strengths (250/50 micrograms and 500/50 micrograms).
All studies comprised four treatment arms: fluticasone propionate/salmeterol, salmeterol, fluticasone
propionate, placebo. Salmeterol is currently registered for the treatment of COPD.

Fluticasone propionate/salmeterol vs salmeterol alone: The primary efficacy variable for the three
studies was mean change in morning pre-dose FEV1. In the ITT analysis, a statistically significant
difference in the primary endpoint in favour of fluticasone propionate/salmeterol was seen across all
three studies. For multiple measured secondary endpoints, fluticasone propionate/salmeterol 500/50
micrograms was superior by a clinically significant degree only for dyspnoea vs salmeterol alone. In
addition, fluticasone propionate/salmeterol 250/50 micrograms was statistically significantly superior
to salmeterol for % days without use of reliever medication and % of nights without awakening.

Post-hoc subgroup analyses were performed for those patients with severe COPD (FEV1<50%
predicted normal). There were 1724 patients in the severe subgroup, of whom 415 received fluticasone
propionate/salmeterol. A statistically significant treatment difference in favour of fluticasone
propionate/salmeterol (both doses) was seen in the primary endpoint in two of the three studies. The
clinical significance of these results is uncertain. For multiple measured secondary endpoints,
fluticasone propionate/salmeterol 500/50 micrograms produced a clinically significant improvement
in breathlessness and a clinically significant reduction in % of days without use of reliever medication
(1 time per day) compared with salmeterol alone.

INDICATIONS

For the regular treatment of asthma, where the use of a combination product is appropriate. This
may include the following:

 Patients on effective maintenance doses of long-acting beta-2 agonists and inhaled

corticosteroids
 Patients who are symptomatic on current inhaled corticosteroid therapy

For the symptomatic treatment of patients with severe COPD (FEV1<50% predicted normal)
and a history of repeated exacerbations who have significant symptoms despite regular beta-2
agonist bronchodilator therapy. Fluticasone propionate/salmeterol (125/25 microgram and 250 /25
microgram) is not indicated for the initiation of bronchodilator therapy in COPD.

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CONTRAINDICATIONS

Fluticasone propionate/salmeterol is contraindicated in patients with a history of hypersensitivity to

any ingredients of the preparation (see DESCRIPTION).

PRECAUTIONS

Use in asthma management plan

The management of asthma should normally follow a stepwise program and patient response should
be monitored clinically and by lung function tests. Treatment of asthma should be in accordance with
current National asthma treatment guidelines.

Fluticasone propionate/salmeterol is not for relief of acute symptoms for which a fast- and short-acting
inhaled bronchodilator (e.g. salbutamol) is required. Patients should be advised to have their relief
medication available at all times.

Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of 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 be reviewed by a physician. Consideration should be given to increasing corticosteroid
therapy. Also, where the current dosage of fluticasone propionate/salmeterol has failed to give
adequate control of asthma, the patient should be reviewed by a physician. For patients with asthma
or COPD, consideration should be given to additional corticosteroid therapies and administration of
antibiotics if an exacerbation is associated with infection.

Treatment should not be stopped abruptly in patients with asthma due to risk of exacerbation; therapy
should be titrated-down under physician supervision. For patients with COPD cessation of therapy
may be associated with symptomatic decompensation and should be supervised by a physician.

Pneumonia in COPD

There was an increased reporting of pneumonia in studies of patients with COPD receiving fluticasone
propionate/salmeterol (see ADVERSE EFFECTS). Physicians should remain vigilant for the possible
development of pneumonia in patients with COPD as the clinical features of pneumonia and
exacerbation frequently overlap.

As with all medications containing corticosteroids, fluticasone propionate/salmeterol should be

administered with caution in patients with active or quiescent pulmonary tuberculosis.

Fluticasone propionate/salmeterol should be administered with caution in patients with thyrotoxicosis.

Cardiovascular effects

Cardiovascular effects, such as increases in systolic blood pressure and heart rate, may occasionally
be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. For this
reason, fluticasone propionate/salmeterol should be used with caution in patients with pre-existing
cardiovascular disease.

Hypokalaemia

A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher
therapeutic doses. Therefore, fluticasone propionate/salmeterol should be used with caution in
patients predisposed to low levels of serum potassium.

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Ocular complications

Rare instances of glaucoma and increased intraocular pressure have been reported following
administration of inhaled corticosteroids.

Care should be taken when transferring patients to fluticasone propionate/salmeterol therapy,

particularly if there is any reason to suppose that adrenal function is impaired from previous systemic
steroid therapy.

Risks associated with salmeterol

Fluticasone propionate/salmeterol should not be initiated in patients with unstable or acutely

deteriorating asthma, which may be a life-threatening condition. Serious acute respiratory events,
including fatalities, have been reported when salmeterol has been initiated in this situation. Although
it is not possible from these reports to determine whether salmeterol contributed to these adverse
events or failed to relieve the deteriorating asthma, the use of salmeterol in this setting is
inappropriate.

Fluticasone propionate/salmeterol should not be used to transfer patients from oral to inhaled steroids.

In rare cases inhaled therapy may unmask underlying eosinophilic conditions (e.g. Churg Strauss
syndrome). These cases have usually been associated with reduction or withdrawal of oral
corticosteroid therapy. A direct causal relationship has not been established.

There have been very rare reports of increases in blood glucose levels (see ADVERSE EFFECTS)
and this should be considered when prescribing to patients with a history of diabetes mellitus.

Data from a large US study (SMART) comparing the safety of salmeterol (a component of
fluticasone propionate/salmeterol) or placebo added to usual therapy showed a significant increase in
asthma-related deaths in patients receiving salmeterol. Data from this study suggested that African-
American patients may be at greater risk of serious respiratory-related events or deaths when using
salmeterol compared to placebo. It is not known if this was due to pharmacogenetic or other factors.
The SMART study was not designed to determine whether concurrent use of inhaled corticosteroids
modifies the risk of asthma-related death.

It was observed in a drug interaction study that concomitant use of systemic ketoconazole increases
exposure to salmeterol. This may lead to prolongation in the QTc interval. Due to the potential
increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong
CYP3A4 inhibitors (e.g. ketoconazole, atazanavir, ritonavir, clarithromycin, indinavir, itraconazole,
nefazodone, nelfinavir, saquinavir) is nor recommended (see INTERACTIONS WITH OTHER
MEDICINES and Pharmacokinetics).

Risks associated with fluticasone propionate

A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450
3A4 inhibitor) can greatly increase fluticasone propionate 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 fluticasone propionate and ritonavir,
resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.
Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the
potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.

Paradoxical bronchospasm

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-acting inhaled bronchodilator.
Fluticasone propionate/salmeterol should be discontinued immediately, the patient assessed, and if

6
necessary alternative therapy instituted.

The pharmacological side-effects of beta-2 agonist treatment, such as tremor, subjective palpitations
and headache, have been reported, but tend to be transient and may reduce with regular therapy.

Spacer devices

Most patients will benefit from the consistent use of a spacer device with their metered dose inhaler
(MDI or ‘puffer’), particularly those with poor inhaler technique. Use of a spacer will also decrease
the amount of drug deposited in the mouth and back of the throat, and therefore reduce the
incidence of local side effects such as ‘thrush’ and a hoarse voice.

A change in the make of spacer may be associated with alterations in the amount of drug delivered to
the lungs. The clinical significance of these alterations is uncertain. However, in these situations, the
person should be monitored for any loss of asthma control.

If using a spacer, the patient should be instructed to actuate the inhaler into the spacer and then slowly
breathe in as far as possible. Hold your breath for as long as comfortable, before breathing out slowly.
This should be repeated for each actuation of the drug into the spacer. Any delays between actuation
and inhalation should be kept to a minimum.

Static on the walls of the spacer may cause variability in drug delivery. Patients should be instructed
to wash the spacer in warm water and detergent and allow it to air dry without rinsing or drying with
a cloth. This should be performed before initial use of the spacer and at least monthly thereafter.

Possible systemic effects, including adrenocortical function, bone density and growth

Inhaled steroids are designed to direct glucocorticoid delivery to the lungs in order to reduce overall
systemic glucocorticoid exposure and side effects. With sufficient doses however, all inhaled steroids
can have adverse effects; possible systemic effects include Cushing’s syndrome, Cushingoid features,
depression of the hypothalamic-pituitary adrenal (HPA) axis, reduction of bone mineral density,
cataract, glaucoma and retardation of growth rate in children and adolescents (see
OVERDOSAGE).

The lowest dose of inhaled fluticasone that causes suppression of the HPA axis (as indicated by the
24 hour urinary cortisol concentrations), effects on bone mineral density or growth retardation in
children has not yet been established. Some depression of plasma cortisol may occur in a small number
of adult patients on higher doses (e.g. >1 mg/day). However, adrenal function and adrenal reserve
usually remain within normal range on inhaled fluticasone propionate therapy. To minimise the
systemic effects of inhaled corticosteroids, including fluticasone propionate, each patient should be
titrated down to the lowest dose that effectively controls his/her asthma (see DOSAGE AND
ADMINISTRATION).

Data regarding the effect of long term use of inhaled fluticasone on bone mineral density in elderly
patients are limited.

Patients in a medical or surgical emergency, who in the past have required high doses of inhaled
steroids and/or intermittent treatment with oral steroids, remain at risk of impaired adrenal reserve for
a considerable time. The extent of the adrenal impairment may require specialist advice before
elective procedures. The possibility of residual 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 OVERDOSAGE).

Effects on fertility

Neither fluticasone propionate nor salmeterol alone show significant effects on fertility. Studies to
detect such effects with co-administration have not been conducted.

7
Use in pregnancy

Pregnancy Category B3

There are limited data from clinical trials in pregnant women. However, extensive clinical experience
with drugs in this class has revealed no evidence of adverse effects on the mother or foetus at relevant
therapeutic doses of ICS. As with any medication, administration during pregnancy should only be
considered if the expected benefit to the mother is greater than any possible risk to the foetus.

An observational retrospective epidemiological cohort study utilising electronic health records from the
United Kingdom was conducted to evaluate the risk of major congenital malformations (MCMs)
following first trimester exposure to inhaled fluticasone propionate alone and salmeterol-fluticasone
propionate relative to non-fluticasone propionate containing inhaled corticosteroids. No placebo
comparator was included in this study.

Within the asthma cohort of 5362 first trimester inhaled corticosteroid-exposed pregnancies, 131
diagnosed MCMs were identified; 1612 (30%) were exposed to fluticasone propionate or salmeterol-
fluticasone propionate 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 fluticasone propionate exposed versus non-
fluticasone propionate inhaled corticosteroid 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 fluticasone propionate alone versus salmeterol-
fluticasone propionate. Absolute risks of MCM across the asthma severity strata ranged from 2.0 to 2.9
per 100 fluticasone propionate-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).

Results from the retrospective epidemiological study did not find an increased risk of MCMs following
exposure to fluticasone propionate when compared to other inhaler corticosteroids, during the first
trimester of pregnancy.

Reproductive toxicity studies in animals, either with single drug or in combination, revealed the foetal
effects expected at excessive systemic exposure levels of a potent beta-2-adrenoceptor agonist and
glucocorticosteroid – however these findings may not be relevant to humans taking inhaled steroids
and beta-2 agonist at the recommended dose.

Use in lactation

Fluticasone propionate and salmeterol concentrations in plasma after inhaled doses are very low and
therefore concentrations in human breast milk are likely to be correspondingly low. Studies in lactating
animals support this for salmeterol xinafoate, although after subcutaneous administration of
radiolabelled fluticasone propionate to lactating rats, levels of radioactivity in milk were 3 to 7 times
plasma levels. There are no data available for human breast milk.

Administration during lactation should only be considered if the expected benefit to the mother is
greater than any possible risk to the child.

Paediatric use

Use in children less than 12 years is not recommended for this product. If the 50/25 microgram strength
formulation is required, an alternative brand may be used.

The growth of paediatric patients receiving corticosteroids, including fluticasone propionate, should
be monitored. The potential growth effects of prolonged treatment should be weighed against the
clinical benefits obtained. To minimise the systemic effects of inhaled corticosteroids, including
fluticasone propionate, each patient should be titrated down to the lowest dose that effectively controls

8
his/her asthma (see DOSAGE AND ADMINISTRATION).

In children taking recommended doses of inhaled fluticasone propionate, adrenal function and adrenal
reserve usually remain within the normal range. However, the possible effects of previous or
intermittent treatment with oral steroids should not be discounted. Nevertheless, the benefits of inhaled
fluticasone propionate should minimise the need for oral steroids.

Genotoxicity

Neither fluticasone propionate nor salmeterol showed evidence of mutagenic potential when tested
alone in a standard battery of genotoxicity assays. No studies examining the potential interaction
of fluticasone propionate and salmeterol to cause genetic toxicity when co-administered have been
conducted.

The non-CFC propellant, norflurane (HFA134a), 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.

Carcinogenicity

No studies on the carcinogenic potential of the combined formulation of fluticasone propionate:

salmeterol have been conducted in animals. With fluticasone alone, no evidence of a tumorigenic
effect was observed in either a 2 year study in rats receiving doses of fluticasone propionate up to 57
mg/kg/day by inhalation or in an 18 month study in mice receiving oral doses of fluticasone
propionate up to 1 mg/kg/day. With salmeterol alone, oral administration to mice at 0.2, 1.4 or 10
mg/kg/day for 18 months resulted in the development of smooth muscle tumours (leiomyomas and
possibly leiomyosarcomas) in the uterus. In rats, combined oral / inhalational administration for 24
months at total dose levels of 0.2, 0.7 and 2.6 mg/kg/day resulted in leiomyomas in the suspensory
ligament of the ovaries, as well as an increased incidence of benign pituitary tumours. The smooth
muscle tumours in both species are thought to result from chronic stimulation of beta-adrenoceptors
in these tissues, whereas the mechanism involved in the development of the pituitary tumours is
unknown.

Preclinical safety data

Fluticasone propionate and salmeterol have been extensively evaluated in animal toxicity tests.
Significant toxicities occurred only at doses in excess of those recommended for human use and
were those expected for a potent beta-2-adrenoreceptor agonist and glucocorticosteroid.

Co-administration of fluticasone propionate and salmeterol resulted in some cardiovascular lesions

not seen upon dosing with the individual drugs (mild atrial myocarditis and focal coronary arteritis
in rats and papillary muscle necrosis in dogs). However, these high dose changes were not
consistently observed across studies and are unlikely to be of clinical relevance.

Co-administration did not modify other class-related toxicities in animals.

Effects on ability to drive and use machinery

Fluticasone propionate/salmeterol is unlikely to produce an effect.

INTERACTIONS WITH OTHER MEDICINES

Both non-selective and selective beta-blockers should be avoided unless there are compelling reasons
for their use.

Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after

9
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 mediated by
fluticasone propionate are unlikely.

A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450
3A4 inhibitor) can greatly increase fluticasone propionate 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
propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome
and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should
be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid
side-effects.

Studies have 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. Nevertheless, care is advised when co-administering
potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic
exposure to fluticasone propionate.

Co-administration of ketoconazole and salmeterol resulted in a significant increase in plasma

salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This increase in plasma salmeterol may
cause a prolongation of QTc interval (see PRECAUTIONS and Pharmacokinetics).

ADVERSE EFFECTS

As this product contains fluticasone propionate and salmeterol the type and severity of adverse
reactions associated with each of the compounds may be expected. There is no evidence of additional
adverse events following concurrent administration of the two compounds.

Adverse events are listed below by system organ class and frequency. Frequencies are defined
as: very common (≥ 1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare
(≥1/10,000 and <1/1000) and very rare (<1/10,000).

Clinical trial data

Infections and infestations

Common: Candidiasis of mouth and throat, pneumonia (in COPD patients).

Such patients may find it helpful to rinse out their mouth with water after inhalation. Symptomatic
candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the fluticasone
propionate.

Rare: Oesophageal candidiasis

Immune system disorders

Hypersensitivity reactions:

Uncommon: Cutaneous hypersensitivity reactions, dyspnoea.

Rare: Anaphylactic reactions

Endocrine disorders

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Possible systemic effects include (see PRECAUTIONS):

Uncommon: Cataract

Rare: Glaucoma

Metabolism and nutrition disorders

Uncommon: Hyperglycaemia.

Psychiatric disorders

Uncommon: Anxiety, sleep disorders.

Rare: Behavioural changes, including hyperactivity and irritability (predominantly in children).

Nervous system disorders

Very common: Headache (see PRECAUTIONS).

Uncommon: Tremor (see PRECAUTIONS).

Cardiac disorders

Common: Palpitations (see PRECAUTIONS),

Uncommon: Tachycardia, atrial fibrillation.

Rare: Cardiac arrhythmias including supraventricular tachycardia and extrasystoles.

Peripheral vasodilation and a compensatory small increase in heart rate may occur in some patients.

Respiratory, thoracic and mediastinal disorders

Common: Hoarseness/dysphonia, throat irritation.

Skin and subcutaneous tissue disorders

Uncommon: Contusions.

Musculoskeletal and connective tissue disorders

Common: Muscle cramps, arthralgia.

Post-marketing data

Immune system disorders

Hypersensitivity reactions manifesting as:

Uncommon: Cutaneous hypersensitivity reactions.

Rare: Angioedema (mainly facial and oropharyngeal oedema) and respiratory symptoms (dyspnoea
and/or bronchospasm), anaphylactic reactions

Endocrine disorders

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Possible systemic effects include (see PRECAUTIONS):

Rare: Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children
and adolescents, decreased bone mineral density.

Metabolism and nutrition disorders

Uncommon: Hyperglycaemia.

Psychiatric disorders

Uncommon: Anxiety, sleep disorders.

Rare: Behavioural changes, including hyperactivity and irritability (predominantly in children).

Respiratory, thoracic and mediastinal disorders

Rare: Paradoxical bronchospasm (see PRECAUTIONS)

DOSAGE AND ADMINISTRATION

Note: Fluticasone + Salmeterol Cipla is not for use in patients aged under 12 years. A lower strength
fluticasone and salmeterol (50/25 microgram) inhalation can be available from other brand/s.

Fluticasone + Salmeterol Cipla is for inhalation only.

Fluticasone + Salmeterol Cipla must be used regularly for optimum benefit, even when
asymptomatic.

Patients should be regularly assessed by a doctor, so the dose of Fluticasone + Salmeterol Cipla they
are receiving remains optimal. Strength of dose should only be increased or decreased on medical
advice.

The use of one puff bd of the MDI has not been investigated in clinical trials.

Asthma

The dose of fluticasone propionate should be titrated to the lowest dose at which effective control
of symptoms is maintained.

Patients should be given the dose of Fluticasone + Salmeterol Cipla containing the appropriate
fluticasone propionate dosage for the severity of their disease.

Note: Salmeterol + Fluticasone Cipla is only available in two strengths (fluticasone propionate and
salmeterol 125/25 microgram and 250/25 microgram). It is not available in a lower strength product
containing salmeterol 25 microgram and fluticasone propionate 50 microgram. Therefore, when it is
appropriate to titrate down to a dose of inhaled corticosteroid below 125 micrograms, a change to an
alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose
of the inhaled corticosteroid is required.

Adults and adolescents over 12 years

The recommended dose for regular asthma management is 100/50 microgram to 500/50
microgram fluticasone propionate/salmeterol twice daily.

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Two inhalations (50/25 micrograms 125/25 micrograms or 250/25 micrograms) twice daily.

(Patients requiring dose below 250 micrograms of fluticasone will need to be prescribed an
alternative brand.)

Special patient groups

There is no need to adjust the dose in elderly patients or in those with renal or hepatic
impairment.

COPD

Adults

Two inhalations 250/25 micrograms twice daily.

OR

Two inhalations 125/25 micrograms twice daily may be a consideration in patients who are at a greater
risk of inhaled corticosteroid adverse effects (see CLINICAL TRIALS and DOSAGE AND
ADMINISTRATION).

Use of the device

Fluticasone + Salmeterol Cipla is available with a dose indicator. The MDI comprises a suspension
of fluticasone propionate and salmeterol in a CFC-free propellant. The suspension is contained in an
aluminium canister with a suitable metering valve and a polypropylene actuator having dose indicator
and a dust cap in a sealed pouch containing desiccant.

The dose indicator will show number of actuations left in the canister through a window in the plastic
actuator.

Shake the inhaler well before use.

The patient should be instructed to prime four sprays before using it for the first time and two sprays
whenever it is not used for a week or more.

Inhaler should be cleaned at least once a week as follows.

 Remove the mouthpiece cover.
 Do not remove the canister from the plastic casing.
 Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth or tissue.
 Replace the mouthpiece cover.

For more detailed instructions for use refer to the patient information leaflet.

OVERDOSAGE

For information on the management of overdose contact the Poison Information Centre on
131126 (Australia)

The available information on overdose with fluticasone propionate/salmeterol, fluticasone and/or

salmeterol is given below:

It is not recommended that patients receive higher than approved doses of fluticasone
propionate/salmeterol. It is important to review therapy regularly and titrate down to the lowest dose
at which effective control of disease is maintained (see DOSAGE AND ADMINISTRATION).

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Symptoms and signs

The expected symptoms and signs of salmeterol overdosage are those typical of excessive beta-2-
adrenergic stimulation, including tremor, headache, tachycardia, increases in systolic blood pressure,
hypokalaemia and raised blood glucose levels.

Acute inhalation of fluticasone propionate doses in excess of those approved may lead to temporary
suppression of the hypothalamic-pituitary-adrenal axis. This does not usually require emergency
action as normal adrenal function typically recovers within a few days.

If higher than approved doses of fluticasone propionate/salmeterol are continued over prolonged
periods, significant adrenocortical suppression is possible. There have been very rare reports of acute
adrenal crisis, mainly occurring in children exposed to higher than approved doses over prolonged
periods (several months or years). Presenting symptoms are typically vague and may include anorexia,
abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased levels of consciousness,
hypoglycaemia and seizures. Situations which could potentially trigger acute adrenal crisis include
exposure to trauma, surgery, infection or any rapid reduction in the dosage of the inhaled fluticasone
propionate component. Additional systemic corticosteroid cover should be considered during periods
of stress or elective surgery.

Treatment

There is no specific treatment for an overdose of fluticasone propionate and salmeterol. If overdose
occurs, the patient should be treated supportively with appropriate monitoring necessary.

PRESENTATION AND STORAGE CONDITIONS

Fluticasone + Salmeterol Cipla 125/25 delivers 125 micrograms of fluticasone propionate and 25
micrograms of salmeterol (as xinafoate) per inhalation. Packs of 120 metered doses.

Fluticasone + Salmeterol Cipla 125/25 are a rigid, aluminium, container fitted with a
metered dose valve, containing a white homogeneous suspension, fitted to a plastic actuator
with a white coloured body and pink coloured cap, with a dose indicator.

Fluticasone + Salmeterol Cipla 250/25 delivers 250 micrograms of fluticasone propionate

and 25 micrograms of salmeterol (as xinafoate) per inhalation. Packs of 120 metered doses.

Fluticasone + Salmeterol Cipla 250/25 are a rigid, aluminium, container fitted with a
metered dose valve, containing a white homogeneous suspension, fitted to a plastic actuator
with a white coloured body and rubin red coloured cap, with a dose indicator.

Fluticasone + Salmeterol Cipla is available with a dose indicator (see DOSAGE AND
ADMINISTRATION).

Fluticasone + Salmeterol Cipla should be stored below 250C. Protect from frost and direct sunlight.

Do not store inhaler in a cold place as it may not work as well.

Replace the mouthpiece cover firmly and snap it into position.

As with most inhaled medications in pressurised canisters, the therapeutic effect of this fluticasone
propionate/salmeterol MDI may decrease when the canister is cold. The canister should not be
punctured, broken or burnt even when apparently empty.

NAME AND ADDRESS OF THE SPONSOR

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Cipla Australia Pty Ltd
Level 1, 132-136 Albert Road
South Melbourne, VIC 3205.

POISON SCHEDULE OF THE MEDICINE

Schedule 4 – Prescription Only Medicine

Date of First Inclusion in the Australian Register of Therapeutic Goods (ARTG)

15.12.2016

Date of Most Recent Amendment

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