ZOREEDA

Main information

  • Trade name:
  • ZOREEDA 25/125 Microgram Pressurised Inhalation Suspension
  • Dosage:
  • 25/125 Microgram
  • Pharmaceutical form:
  • Pressurised Inhalation Suspension
  • Prescription type:
  • Product subject to prescription which may be renewed (B)
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ZOREEDA 25/125 Microgram Pressurised Inhalation Suspension
    Ireland
  • Language:
  • English

Therapeutic information

  • Therapeutic area:
  • Adrenergics in combination with corticosteroids or other drugs, excl. Anticholinergics

Other information

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization status:
  • Authorised
  • Authorization number:
  • PA1963/009/001
  • Authorization date:
  • 06-04-2018
  • Last update:
  • 20-06-2018

Summary of Product characteristics: dosage,interactions,side effects

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Zoreeda 25 microgram/125 microgram per actuation pressurised inhalation, suspension.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each metered dose (ex valve) contains:

25 micrograms of salmeterol (as salmeterol xinafoate) and 125 micrograms of fluticasone propionate. This is equivalent

to a delivered dose (ex actuator) of 21 micrograms of salmeterol and 110 micrograms of fluticasone propionate.

For a full list of excipients see section 6.1

3 PHARMACEUTICAL FORM

Pressurised inhalation, suspension.

The canister contains a white to off-white suspension.

The canisters are fitted into white plastic actuators incorporating an atomising orifice and fitted with pink dust-caps.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Zoreeda is indicated for use in adults with asthma 18 years of age and older only.

Zoreeda is indicated in the regular treatment of patients with moderate to severe asthma where use of a combination

product (long-acting

agonist and inhaled corticosteroid) is appropriate:

- patients not adequately controlled on a lower strength corticosteroid combination product or

- patients already adequately controlled on an inhaled corticosteroid in a mid or high strength and a long-acting

agonist.

4.2 Posology and method of administration

Zoreeda is indicated in adults 18 years of age and older only.

Zoreeda is not indicated for use in children, 12 years of age or younger, or adolescents, 13 to 17 years of age.

Posology

Route of administration: Inhalation use.

Patients should be made aware that Zoreeda must be used daily for optimum benefit, even when asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of Zoreeda 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.

Note: Zoreeda is only available in two strengths, it is not available in a lower strength product containing salmeterol 25

microgram and fluticasone propionate 50 microgram, a strength which is available for other similar fixed-dose

combination products containing these two actives and currently available on the market. 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.

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Zoreeda should not be used for patients with mild asthma and may not be appropriate for patients with mild to

moderate asthma, in whom a low dose of the inhaled corticosteroid, either alone or with a long-acting

agonist, may

be required. Zoreeda could be considered for use in patients with moderate persistent asthma but only where control of

symptoms cannot be maintained with a lower strength product containing a lower dose of the corticosteroid.

Where the control of symptoms is maintained with the lowest strength of such an alternative fixed-dose combination

given twice daily then the next step could include a test of inhaled corticosteroid alone. As an alternative, patients

requiring a long-acting

agonist could be titrated to salmeterol and fluticasone propionate 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 Zoreeda containing the appropriate fluticasone propionate dosage for the

severity of their disease. If an individual patient should require dosages outside the recommended regimen, appropriate

doses of

agonist and/or corticosteroid should be

prescribed.

Adults 18 years and older:

- Two inhalations of 25 micrograms salmeterol and 125 micrograms fluticasone propionate twice daily.

A short-term trial of salmeterol and fluticasone propionate may be considered as initial maintenance therapy in adults

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. However Zoreeda is

not available in the lowest strength of this combination as currently available on the market and therefore an

alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose of the

inhaled corticosteroid would need to be prescribed for the initial maintenance therapy in adults with moderate

persistent asthma. Without the lowest strength (25/50 microgram) of this fixed-dose combination, initiation of therapy

in the majority of patients with asthma may be difficult and the lowest strength of the innovator product may be

required.

The dose of the inhaled corticosteroid may need to be increased to achieve control of asthma symptoms but once

control is attained treatment should be reviewed and the dose of the inhaled corticosteroid titrated downwards to the

lowest dose at which effective control of symptoms is maintained.

Consideration may be given as to whether patients should be stepped down to an inhaled corticosteroid alone from the

lowest strength combination product.

Regular review of patients as treatment is stepped down is important.

A clear benefit has not been shown as compared with 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. Zoreeda is not intended for the initial management of mild asthma or mild to moderate

asthma. It is recommended to establish the appropriate dosage of inhaled corticosteroid before any fixed-combination

can be used in patients with severe asthma.

Paediatric population

The safety and efficacy of Zoreeda in children, 12 years and younger and adolescents, 13-17 years of age have not been

established. No data are available. Zoreeda is not recommended for use in children and adolescents under 18 years of

age.

Note: Neither of the two available strengths of this fixed-dose combination of salmeterol xinafoate and fluticasone

propionate can be used in the management of asthma in children as the maximum authorised dose of fluticasone

Recommended Doses:

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propionate for use in children is 100 microgram twice daily. This dose of fluticasone propionate can only be attained

by use of a lower strength of this fixed-dose combination than is currently available for Zoreeda.

Use of a lower strength of this fixed-dose combination can only be obtained by downward dose titration to the lowest

strength of this fixed dose combination (containing 50 micrograms of fluticasone propionate). This is not available as

Zoreeda. Therefore the healthcare provider should down-titrate patients to the lowest strength (25/50 microgram) by

using the innovator product.

Spacer devices

Use of a spacer device with Zoreeda is recommended in patients who have, or are likely to have difficulties in

coordinating actuation of the inhaler with inspiration of breath. Limited data available from a single dose

pharmacokinetic study PRC/CRD/13/11 (with spacers washed in detergent solution and drip dried prior to use)

demonstrate an increase in systemic exposure when the Volumatic spacer device is used compared with the

AeroChamber Plus spacer device (see section 4.4). Patients should be instructed in the proper use and care of

their inhaler and spacer and their technique checked to ensure optimum delivery of the inhaled drug to the

lungs.

Either the Volumatic spacer device or the AeroChamber Plus spacer device can be used (depending on National

Guidance).

Use of a spacer device is recommended ONLY for Zoreeda containing salmeterol 25 microgram and fluticasone

propionate 250 microgram (the high strength inhaler). A spacer device is not recommended for use with Zoreeda

containing salmeterol 25 microgram and fluticasone propionate 125 microgram (the mid/lower strength inhaler). If a

spacer device is required for use with this mid/lower strength, the patient will have to change to an alternative fixed-

dose combination of salmeterol and fluticasone propionate containing salmeterol 25 microgram and fluticasone

propionate 125 microgram which is authorised for use with a spacer device.

Patients should continue to use the same make of spacer device, either the Volumatic spacer device or the

AeroChamber Plus spacer device, as switching between spacer devices can result in changes in the dose

delivered to the lungs (see section 4.4).

Re-titration to the lowest effective dose should always follow the introduction or change of a spacer device.

If a patient has previously used an alternative product and spacing device and is then transferred to these new

fixed-dose combination inhalers with or without a spacing device, re-titration of their dose to the lowest effective

dose should always be carried out.

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 in patients with hepatic impairment.

Instructions for Use:

Patients should be instructed in the proper use of their inhaler (see patient information leaflet) During inhalation, the

patient should preferably sit or stand. The inhaler has been designed for

use in a vertical position.

Testing the inhaler:

Before using for the first time patients should remove the mouthpiece cover by gently squeezing the sides of the cover,

shake the inhaler well, hold the inhaler between the fingers and thumb with their thumb on the base, below the

mouthpiece and release four puffs into the air to make sure

that it works. The inhaler should be shaken immediately before releasing each puff. If the inhaler has not been used for

a week or more remove the mouthpiece cover, the patients should shake the inhaler well and release two puffs into the

air.

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Use of the inhaler:

1. Patients should remove the mouthpiece cover by gently squeezing the sides of the cover.

2. Patients should check inside and outside of the inhaler including the mouthpiece for the presence of loose objects

3. Patients should shake the inhaler well to ensure that any loose objects are removed and that the contents of the

inhaler are evenly mixed.

4. Patients should hold the inhaler upright between fingers and thumb with their thumb on the base, below the

mouthpiece.

5. Patients should breathe out as far as is comfortable and then place the mouthpiece in their mouth between their teeth

and close their lips around it. Patients should be instructed not to bite the mouth piece.

6. Just after starting to breathe in through their mouth, patients should press firmly down on the top of the inhaler to

release the medicine while still breathing in steadily and deeply.

7. While holding their breath, patients should take the inhaler from their mouth and take their finger from the top of the

inhaler. Patients should continue holding their breath for as long as is comfortable.

8. To take a second inhalation, patients should keep the inhaler upright and wait about half a minute before repeating

steps 3 to 7.

9. Patients should immediately replace the mouthpiece cover in the correct orientation by firmly pushing and snapping

the cover into position. This does not require excessive force, the cover should click into position.

IMPORTANT

Patients should not rush stages 5, 6 and 7. It is important that patients start to breathe in as slowly as possible just

before operating their inhaler. Patients should practise in front of a mirror for the first few times. If they see "mist"

coming from the top of their inhaler or the sides of their mouth they should start again from stage 3.

Patients should get a replacement when the indicator shows the number ‘40’ and the colour on the dose indicator will

change from green to red. Stop using the inhaler when the indicator shows ‘0’ as any puffs left in the device may not be

enough to give a full dose. Never try to alter the

numbers on the indicator or detach the indicator from the actuator. The indicator cannot be reset and is permanently

attached to the actuator.

Patients should rinse their mouth out with water and spit out and/or brush their teeth after each dose of medicine, in

order to minimize the risk of oropharyngeal candidiasis and hoarseness.

Cleaning (also detailed in patient information leaflet): The inhaler should be cleaned at least once a week.

1. Remove the mouth piece cover.

2. Do not remove the canister from the plastic casing.

3. Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth or tissue.

4. Replace the mouthpiece cover in the correct orientation. This does not require excessive force, the cover should click

into position.

DO NOT PUT THE METAL CANISTER IN WATER

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4.3 Contraindications

Hypersensitivity (allergy) to either of the active substances or to the excipient listed in Section 6.1.

4.4 Special warnings and precautions for use

Zoreeda 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 Zoreeda 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 Zoreeda. Patients should be

asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after

initiation on Zoreeda.

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 Zoreeda. Regular

review of patients as treatment is stepped down is important. The lowest effective dose of salmeterol and fluticasone

propionate should be used (see section 4.2).

Treatment with Zoreeda 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, Zoreeda 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 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 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 (see section 4.8) 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. Zoreeda should be discontinued immediately, the patient assessed and alternative therapy

instituted if necessary.

The pharmacological side effects of

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

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children) (see Paediatric population sub-heading below for information on the systemic effects of inhaled

corticosteroids in children and adolescents). 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.

Spacer devices

Systemic absorption of salmeterol and fluticasone propionate is largely through the lungs. As the use of a spacer device

with a metered dose inhaler may increase drug delivery to the lungs it should be noted that this could potentially lead to

an increase in the risk of systemic adverse

effects. Only limited data are available investigating the increase seen in drug delivery to the lungs with Zoreeda when

used with either the Volumatic spacer device or the AeroChamber Plus spacer device. However, a single dose

pharmacokinetic study, Study PRC/CRD/13/11 (with spacers washed in detergent solution and drip dried prior to use)

has demonstrated that the systemic exposure to salmeterol and fluticasone propionate may be increased almost two-fold

when the Volumatic spacer device is used with Zoreeda as compared with the AeroChamber Plus spacer device.

Use of a spacer device is recommended only for Zoreeda containing salmeterol 25 microgram and fluticasone

propionate 250 microgram (the high strength inhaler). A spacer device is not recommended for use with Zoreeda

containing salmeterol 25 microgram and fluticasone propionate 125 microgram (the mid/lower strength inhaler). If a

spacing device is required for this mid/lower strength, the patient will have to change to an alternative fixed-dose

combination of salmeterol and fluticasone propionate containing salmeterol 25 microgram and fluticasone propionate

125 microgram which is authorised for use with a spacer device.

Patients should continue to use the same make of spacer device, either the Volumatic spacer device or the

AeroChamber Plus spacer device, as switching between spacer devices can result in changes in the dose

delivered to the lungs (see section 4.2).

Re-titration to the lowest effective dose should always follow the introduction or change of a spacer device. If a

patient has previously used an alternative product and spacing device and is then transferred to these new fixed-

dose combination inhalers with or without a spacing device, re-titration of their dose to the lowest effective dose

should always be carried out.

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 (see section 4.5).

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

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propionate as a fixed-dose combination administered via the Diskus/Accuhaler compared with placebo (see section

4.8). In a 3 year COPD study, older patients, patients with a lower body mass index (<25kg/m ) and patients with very

severe disease (FEV <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 Zoreeda should be re-evaluated. The safety

and efficacy of Zoreeda inhaler has not been established in patients with COPD and therefore Zoreeda is not indicated

for use in the treatment of patients with COPD.

Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research Trial, SMART) suggested African-

American patients were at increased risk of serious respiratory-related events or deaths when using salmeterol

compared with placebo (see section 5.1). It is not known if this was due to pharmacogenetic or other factors. Patients of

black African or Afro-Caribbean ancestry should therefore be asked to continue treatment but to seek medical advice if

asthma symptoms remain uncontrolled or worsen whilst using Zoreeda.

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 (see section 4.5).

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.

Zoreeda is only available in two strengths, it is not available in a lower strength containing salmeterol 25 microgram

and fluticasone propionate 50 microgram, the strength which would be prescribed for use in children. Furthermore,

there are no data available on the use of Zoreeda in children 12 years of age or younger or in adolescents aged 13 to 17

years.

Note: Neither of the two available strengths of this fixed-dose combination of salmeterol xinafoate and fluticasone

propionate can be used in the management of asthma in children as the maximum authorised dose of fluticasone

propionate for use in children is 100 microgram twice daily. This dose of fluticasone propionate can only be attained

by use of a lower strength of this fixed-dose combination than is currently available for Zoreeda.

The lack of data in the relevant age groups precludes use of Zoreeda in children and adolescents younger than 18 years

of age.

4.5 Interaction with other medicinal products and other forms of interaction

Beta adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective

blockers should be avoided in patients with asthma, unless there are compelling reasons for their use. Potentially

serious hypokalaemia may result from

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

adrenergic containing drugs can have a potentially additive effect.

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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 P450 3A4 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

P450 3A4 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 moderate CYP3A inhibitors, such as erythromycin, is also expected to increase the systemic fluticasone propionate

exposure and the risk of systemic side-effects. Caution is recommended and long-term treatment with such drugs

should if possible be avoided.

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 C

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 (see section 4.4).

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 non- statistically significant increase in salmeterol

exposure (1.4-fold C

and 1.2-fold AUC). Co- administration with erythromycin was not associated with any

serious adverse effects.

4.6 Fertility, pregnancy and lactation

Fertility

There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on

fertility.

A moderate amount of data on pregnant women (between 300 to 1000 pregnancy outcomes) indicates no malformative

or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity

after administration of

adrenoreceptor agonists and glucocorticosteroids (see section 5.3).

Fluticasone propionate

Salmeterol

Potent CYP3A4 inhibitors

Pregnancy

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Administration of salmeterol and fluticasone propionate 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.

Breastfeeding

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 therapy taking into account the benefit of

breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on ability to drive and use machines

Zoreeda has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

As Zoreeda 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.

System

Organ

Class

Adverse Event

Frequency

Infections &

Infestations

Candidiasis of the mouth and throat

Pneumonia

Bronchitis

Oesophageal candidiasis

Common

Common

Common

Rare

Immune

System

Hypersensitivity reactions with the following

manifestations:

Cutaneous hypersensitivity reactions

Uncommon

Rare

Disorders

Angioedema (mainly facial and oropharyngeal

oedema)

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Respiratory symptoms (dyspnoea)

Respiratory symptoms (bronchospasm)

Anaphylactic reactions including anaphylactic

shock

Uncommon

Rare

Rare

Endocrine

Disorders

Cushing's syndrome, Cushingoid features,

Adrenal suppression, Growth retardation in

children and adolescents, Decreased bone

mineral density

Rare

Metabolism &

Nutrition

Disorders

Hypokalaemia

Hyperglycaemia

Common

Uncommon

Psychiatric

Disorders

Anxiety

Sleep disorders

Behavioural changes, including psychomotor

hyperactivity and irritability (predominantly in

children)

Depression, aggression (predominantly in

children)

Uncommon

Uncommon

Rare

Not known

Nervous

System

Headache

Tremor

Very Common

Uncommon

Eye Disorders

Cataract

Uncommon

System Organ

Adverse Event

Frequency

Glaucoma

Rare

Cardiac Disorders

Palpitations

Tachycardia

Cardiac arrhythmias (including

supraventricular tachycardia and

extrasystoles).

Atrial fibrillation

Angina pectoris

Uncommon

Uncommon

Rare

Uncommon

Uncommon

Respiratory,

Thoracic &

Mediastinal

Disorders

Nasopharyngitis

Throat irritation

Hoarseness/dysphonia

Very Common

Common

Common

Disorders

Class

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1. Reported commonly in placebo

2. Reported very commonly in placebo

3. Reported over 3 years in a COPD study

4. See section 4.4

Description of selected adverse reactions

The pharmacological side effects of

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. Zoreeda 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 Zoreeda.

Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression and growth

retardation in children and adolescents (see section 4.4). Children may also experience anxiety, sleep disorders and

behavioural changes, including hyperactivity and irritability.

Sinusitis

Common

Rare

Skin and

subcutaneous tissue

disorders

Contusions

Common

Musculoskeletal &

Connective Tissue

Disorders

Muscle cramps

Traumatic fractures

Arthralgia

Myalgia

Common

Common

Common

Common

Paradoxical bronchospasm

Paediatric population

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. Healthcare professionals are asked to report any

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4.9 Overdose

There are no data available from clinical trials on overdose with salmeterol and fluticasone propionate as a fixed dose

combination, 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 as a fixed dose combination therapy has to be withdrawn due

to overdose of the

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, Zoreeda therapy should be continued at a suitable

dosage for symptom control.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group:

Adrenergics in combination with corticosteroids or other drugs, excl. Anticholinergics.

ATC Code: R03AK06

Mechanism of action and pharmacodynamic effects

Zoreeda 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)

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

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.

suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax:

+353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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Salmeterol and fluticasone propionate asthma clinical trials

A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with

persistent asthma, compared the safety and efficacy of salmeterol and fluticasone propionate as a fixed-dose

combination 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 as a fixed-dose combination achieved asthma control than patients treated with inhaled corticosteroid (ICS)

alone and this control was attained at a lower corticosteroid dose.

*Well-controlled asthma was achieved more rapidly with the salmeterol and fluticasone propionate fixed-dose

combination than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual well-

controlled week was 16 days for the salmeterol and fluticasone propionate fixed-dose combination 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 fixed-dose combination treatment group compared to

23 days following treatment with ICS.

*Well controlled asthma; less than or equal to 2 days with symptom score greater than 1 (symptom score 1 defined as

'symptoms for one short period during the day') SABA use on less than or equal to 2 days and less than or equal to 4

occasions/week, greater than or equal to 80% predicted morning peak expiratory flow, no night-time awakenings, no

exacerbations and no side effects enforcing a change in therapy.

**Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted morning peak

expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy.

The results of this study suggest that salmeterol and fluticasone propionate 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 318 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 as a fixed-dose combination for two weeks. The study showed that doubling the inhalations of each strength

of the salmeterol and fluticasone propionate fixed-dose combination for up to 14 days resulted in a small increase in

agonist- related 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

agonist-related

adverse events should be taken into account if doubling the dose of the salmeterol and fluticasone propionate fixed-

dose combination is considered by the physician in adult patients requiring additional short-term (up to 14 days)

Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC)

Asthma over 12 months

Pre-Study Treatment

Salmeterol/FP

FP

WC

TC

WC

TC

No ICS (Short Acting

Agonist (SABA) alone)

Low dose ICS (

500 microgram BDP or equivalent/day)

Medium dose ICS (>500 to 1000 microgram

BDP or equivalent/day)

Pooled results across the 3 treatment levels

Clinical efficacy and safety

The overall study results showed:

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inhaled corticosteroid therapy.

The Salmeterol Multi-center Asthma Research Trial (SMART)

SMART was a multi-centre, randomised, double-blind, placebo-controlled, parallel group 28- week study in the US

which randomised 13,176 patients to salmeterol (50 micrograms twice daily) and 13,179 patients to placebo in addition

to the patients'

usual asthma therapy. Patients

were enrolled if

12 years of age, with asthma and if currently using asthma medication (but not a long acting beta

agonist (LABA)). Baseline ICS use at study entry was recorded, but not required

in the study. The primary endpoint in SMART was the combined number of respiratory-related

deaths and respiratory-related life-threatening experiences.

(Risk in bold is statistically significant at the 95% level.)

(*=could not be calculated because of no events in placebo group. Risk in bold figures is statistically significant at the

95% level. The secondary endpoints in the table above reached statistical significance in the whole population.) The

secondary endpoints of combined all-cause death or life-threatening experience, all cause death, or all cause

Number of primary endpoint

events /number of patients

Relative Risk

(95%

confidence

intervals)

salmeterol

placebo

All patients

50/13,176

36/13,179

1.40 (0.91, 2.14)

Patients using inhaled steroids

23/6,127

19/6,138

1.21 (0.66, 2.23)

Patients not using inhaled steroids

27/7,049

17/7,041

1.60 (0.87, 2.93)

African-American patients

20/2,366

5/2,319

4.10 (1.54, 10.90)

Number of secondary endpoint events

/number of patients

Relative Risk

(95%

confidence

intervals)

salmeterol

placebo

Respiratory-related death

Patients using inhaled steroids

10/6127

5/6138

2.01 (0.69, 5.86)

Patients not using inhaled steroids

14/7049

6/7041

2.28 (0.88, 5.94)

Combined asthma-related death or life-threatening experience

Patients using inhaled steroids

16/6127

13/6138

1.24 (0.60, 2.58)

Patients not using inhaled steroids

21/7049

9/7041

2.39 (1.10, 5.22)

Asthma-related death

Patients using inhaled steroids

4/6127

3/6138

1.35 (0.30, 6.04)

Patients not using inhaled steroids

9/7049

0/7041

Key findings from SMART: primary endpoint

Key findings from SMART by inhaled steroid use at baseline: secondary endpoints

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hospitalisation did not reach statistical significance in the whole population.

Paediatric population

In trial SAM101667, in 158 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 [n=428], 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.

5.2 Pharmacokinetic properties

When salmeterol and fluticasone propionate were 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.

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 pre-

systemic 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 (1150mL/min), a large volume of

distribution at steady-state (approximately 300L) 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 the fixed-dose combination of salmeterol and fluticasone propionate 25/50

microgram administered via a pressurised metered dose inhaler (pMDI) (2 inhalations twice daily with or without a

spacer) or the fixed-dose combination of salmeterol and fluticasone propionate administered as an inhalation powder

Fluticasone propionate

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via the 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 when administered via the pMDI with spacer (107 pg hr/mL

[95% CI: 45.7, 252.2]) and when administered as an inhalation powder via the Diskus (138 pg hr/mL [95% CI: 69.3,

273.2]), but lower when administered via the pMDI without spacer (24 pg hr/mL [95% CI: 9.6, 60.2]).

Systemic exposure to salmeterol was similar when administered via the pMDI without spacer, via the pMDI with

spacer and as an inhalation powder via the 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).

5.3 Preclinical safety data

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 co-

administration, 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, norflurane, 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Propellant: norflurane (HFA 134a)

6.2 Incompatibilities

Not Applicable

6.3 Shelf life

2 Years

6.4 Special precautions for storage

Do not store above 25°C.

The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C, protect from direct

sunlight. Do not pierce or burn the canister even when empty.

As with most inhaled medicinal products in pressurised canisters, the therapeutic effect of this medicinal product may

decrease when the canister is cold.

6.5 Nature and contents of container

Aluminium canister with a suitable metering valve and a polypropylene white actuator with pink dust-caps having dose

indicator in a sealed pouch containing desiccant. The actuator has a counter attached which shows how many actuations

of medicine are left in the canister.

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Each container is filled to deliver 120 doses.

Pack sizes:

10 (bundled package 10x1) canisters containing 120 doses -hospital/pharmacy use only

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Cipla Europe NV

De Keyserlei 58-60, Box-19

2018 Antwerp

Belgium

8 MARKETING AUTHORISATION NUMBER

PA1963/009/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 10

March 2017

10 DATE OF REVISION OF THE TEXT

April 2018

1, 2 (bundled package 2x1) or 3 (bundled package 3x1) canisters containing 120 doses.

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18-10-2018

Unauthorized "Surfaz-SN Triple Action Cream" seized from Mississauga store may pose serious health risks

Unauthorized "Surfaz-SN Triple Action Cream" seized from Mississauga store may pose serious health risks

Health Canada seized “Surfaz-SN Triple Action Cream”—an unauthorized skin cream promoted for antifungal, antibacterial and anti-inflammatory use—because it is labelled to contain prescription drugs (betamethasone dipropionate and neomycin sulphate). The product was seized from Kaf African Caribbean Market (2642 Liruma Road, Unit 2A) in Mississauga, Ontario.

Health Canada

1-8-2018

Unauthorized skin creams and lotions sold at various retailers in Quebec may pose serious health risks

Unauthorized skin creams and lotions sold at various retailers in Quebec may pose serious health risks

Health Canada seized eight unauthorized skin lotions and creams from Ayotai Canada because they are labelled to contain a prescription drug (clobetasol propionate or betamethasone dipropionate). The unauthorized lotions and creams were distributed by Ayotai and sold by various retailers in Quebec.

Health Canada

31-5-2018

Fluticasone Propionate Nasal Spray by Apotex Corp: Recall - Due to Potential for Small Glass Particles

Fluticasone Propionate Nasal Spray by Apotex Corp: Recall - Due to Potential for Small Glass Particles

The glass particles could block the actuator and impact the functionality of the pump and expose patients to the glass particles.

FDA - U.S. Food and Drug Administration

31-5-2018

Apotex Corp. Issues Voluntary Nationwide Recall of Fluticasone Propionate Nasal Spray USP 50 mcg Per Spray 120 Metered Sprays Due to Potential for Small Glass Particles

Apotex Corp. Issues Voluntary Nationwide Recall of Fluticasone Propionate Nasal Spray USP 50 mcg Per Spray 120 Metered Sprays Due to Potential for Small Glass Particles

Apotex Corp. is voluntarily recalling one (1) lot of Fluticasone Propionate Nasal Spray, USP, 50 mcg per spray, 120 Metered Sprays, to the consumer level. The Fluticasone Propionate Nasal Spray USP 50 mcg per spray 120 Metered Sprays has been found to contain small glass particles. The glass particles could block the actuator and impact the functionality of the pump. The issue was discovered through a customer complaint.

FDA - U.S. Food and Drug Administration

6-11-2018

Trelegy Ellipta (GlaxoSmithKline Trading Services Limited)

Trelegy Ellipta (GlaxoSmithKline Trading Services Limited)

Trelegy Ellipta (Active substance: fluticasone furoate/umeclidinium/vilanterol) - Centralised - 2-Monthly update - Commission Decision (2018)7416 of Tue, 06 Nov 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4363/WS/1369

Europe -DG Health and Food Safety

6-11-2018

Elebrato Ellipta (GlaxoSmithKline Trading Services Limited)

Elebrato Ellipta (GlaxoSmithKline Trading Services Limited)

Elebrato Ellipta (Active substance: fluticasone furoate/umeclidinium/vilanterol) - Centralised - 2-Monthly update - Commission Decision (2018)7417 of Tue, 06 Nov 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4781/WS/1369

Europe -DG Health and Food Safety

3-7-2018

Revinty Ellipta (Glaxo Group Ltd)

Revinty Ellipta (Glaxo Group Ltd)

Revinty Ellipta (Active substance: fluticasone furoate / vilanterol) - Corrigendum - Commission Decision (2014)3040 of Tue, 03 Jul 2018

Europe -DG Health and Food Safety

3-7-2018

Relvar Ellipta (Glaxo Group Ltd)

Relvar Ellipta (Glaxo Group Ltd)

Relvar Ellipta (Active substance: fluticasone furoate/vilanterol) - Corrigendum - Commission Decision (2013)8089 of Tue, 03 Jul 2018

Europe -DG Health and Food Safety

3-5-2018

Avamys (Glaxo Group Ltd)

Avamys (Glaxo Group Ltd)

Avamys (Active substance: Fluticasone furoate) - Centralised - Yearly update - Commission Decision (2018)2773 of Thu, 03 May 2018

Europe -DG Health and Food Safety