CMDh/223/2005 February 2014

Public Assessment Report

Scientific discussion

Zoreeda 25 Mikrogramm/125 Mikrogramm pro Dosis - Druckgasinhalation, Suspension Zoreeda 25 Mikrogramm/250 Mikrogramm pro Dosis - Druckgasinhalation, Suspension

Fluticasone propionate, Salmeterol xinafoate

Date: 11.05.2015

This module reflects the scientific discussion for the approval of Salmeterol plus Fluticason Propionat momaja 25 Mikrogramm/250 Mikrogramm Druckgasinhalator, Suspension and Salmeterol plus Fluticason-propionat momaja 25 Mikrogramm/125 Mikrogramm Druckgasinhalator, Suspension. The procedure was finalised at 04.08.2014. For information on changes after this date please refer to the module ‘Update’.

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I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Zoreeda 25 Mikrogramm/125 Mikrogramm pro Dosis - Druckgasinhalation, Suspension and Zoreeda 25 Mikrogramm/250 Mikrogramm pro Dosis - Druckgasinhalation, from Cipla Europe NV. The product is indicated in the regular treatment of asthma where use of a combination product (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate:

- patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short acting beta-2-agonist or - patients already adequately controlled on both inhaled corticosteroids and long-acting beta-2-agonist.

A comprehensive description of the indications and posology is given in the SmPC.

The marketing authorisation has been granted pursuant to Article 10(3)of Directive 2001/83/EC.

Fluticasone propionate is a glucocorticoid anti-asthmatic inhalant (anti-inflammatory). Salmeterol xinafoate is a selective beta-2-adrenoceptor agonist (bronchodilator).

II. QUALITY ASPECTS

II.1 Introduction

Salmeterol xinafoate and fluticasone propionate pressurised inhalation suspension comprises an aluminium canister with a suitable metering valve and a plastic actuator with dose indicator and fitted with dustcap in pouch with a silica gel bag.

II.2 Drug Substance

The active substances in Zoreeda 25 Mikrogramm/125 Mikrogramm pro Dosis - Druckgasinhalation, Suspension and Zoreeda 25 Mikrogramm/250 Mikrogramm pro Dosis - Druckgasinhalation are salmeterol xinafoate and fluticasone propionate. The specification of the active substances meets the current scientific requirements. The adequate quality of the active substances has been shown by submitting the appropriate control data. The stability of the active substances has been tested under ICH conditions. The results of the stability studies support the established retest-period.

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II.3 Medicinal Product

Zoreeda 25 Mikrogramm/125 Mikrogramm pro Dosis - Druckgasinhalation, Suspension and Zoreeda 25 Mikrogramm/250 Mikrogramm pro Dosis - Druckgasinhalation contains the following excipients:

Propellant: Norflurane (HFA 134a) The manufacturers responsible for batch release are S&D Pharma CZ spol.s.r.o. and Cipla (EU) Limited. The development of the product has been sufficiently made and deemed appropriate. The usage of all the excipients has been described. The release specification includes the check of all parameters relevant to this pharmaceutical form. Appropriate data concerning the control of the finished product support the compliance with the release specifications. The packaging of the medicinal product complies with the current legal requirements. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SmPC, with a shelf life of 2 years when stored below 30°C.

The pharmaceutical quality of Zoreeda 25 Mikrogramm/125 Mikrogramm pro Dosis - Druckgasinhalation, Suspension and Zoreeda 25 Mikrogramm/250 Mikrogramm pro Dosis - Druckgasinhalation has been adequately shown.

II.4 Discussion on chemical, pharmaceutical and biological aspects

Information on development, manufacture and control of active substance and medicinal product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics.

III. NON-CLINICAL ASPECTS

The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

III.1 Ecotoxicity/environmental risk assessment (ERA)

Since Zoreeda 25 Mikrogramm/125 Mikrogramm pro Dosis - Druckgasinhalation, Suspension and Zoreeda 25 Mikrogramm/250 Mikrogramm pro Dosis - Druckgasinhalation is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

III.2 Discussion on the non-clinical aspects

There are no objections to approval of Zoreeda 25 Mikrogramm/125 Mikrogramm pro Dosis - Druckgasinhalation, Suspension and Zoreeda 25 Mikrogramm/250 Mikrogramm pro Dosis - Druckgasinhalation from a non-clinical point of view.

3/26 IV. CLINICAL ASPECTS

IV.1 Introduction

Product profile:

4.1 Therapeutic indications Salmeterol and Fluticasone propionate pressurised inhalation suspension is indicated in the regular treatment of asthma where use of a combination product (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate: - patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short acting beta-2-agonist or

- patients already adequately controlled on both inhaled corticosteroids and long-acting beta- 2-agonist.

4.2 Posology and method of administration Recommended Doses: Adults and adolescents 12 years and older: • Two inhalations of 25 micrograms salmeterol and 125 micrograms fluticasone propionate twice daily. Or • Two inhalations of 25 micrograms salmeterol and 250 micrograms fluticasone propionate twice daily.

Pharmacodynamics (extracted from the Clinical overview)

Fluticasone propionate

Fluticasone propionate is a corticosteroid designed for topical use.

It is not suitable for oral administration as it is subject to almost 100% first-pass inactivation in the liver. It has a high affinity for the glucocorticoid receptor with negligible binding to the mineralocorticoid, estrogen, progesterone, and aldosterone receptors. Fluticasone propionate potentially has the effects anticipated for any corticosteroid: increasing protein catabolism, having anti-inflammatory actions, immunosuppressant action, being diabetogenic and impairing bone metabolism, thus promoting osteoporosis. Immunosuppressant activity was demonstrated by a decline in thymus weight in dog and rat studies. In common with other intranasal and inhaled steroids, fluticasone propionate has anti-inflammatory and immunosuppressant activity.

Salmeterol

Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist.

Salmeterol xinafoate has pharmacologic actions similar to those of other selective β2- adrenergic receptor agonists (e.g., albuterol). Salmeterol stimulates β2-adrenergic receptors and apparently has little or no effect on α-, β1-, or β3-adrenergic receptors. The principal effect following oral inhalation of salmeterol and other β2-adrenergic agonists is bronchodilation resulting from relaxation of smooth muscles of the bronchial tree. Salmeterol

4/26 produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Salmeterol, like other β2-adrenergic agonists, can produce changes in heart rate and blood pressure (dose-related increases in heart rate of 3–16 beats/minute). At higher dosages, salmeterol administration has been associated with prolongation of the QTc interval. Administration of salmeterol and other β-adrenergic agonists may cause dose-related increases in blood glucose and/or decreases in serum potassium concentrations.

Pharmacokinetics (extracted from the Clinical Overview)

Fluticasone propionate

Systemic absorption occurs mainly through the lungs and is initially rapid followed by a prolonged phase. 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 characterized by high plasma clearance (1150 ml/min), a large volume of distribution at steady-state (approximately 300 L) and a terminal half-life of approximately 8 hours. Plasma protein binding is 91%.

Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces. The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted in the faeces as metabolites and unchanged drug.

Salmeterol

Limited data have been published on the pharmacokinetics of salmeterol. Moreover, there is no data on the extent to which inhaled salmeterol undergoes first-pass metabolism. Larger inhaled doses give approximately proportionally increased blood concentrations. Plasma salmeterol concentrations of 0.1 to 0.2 and 1 to 2 mcg/L have been attained in healthy volunteers about 5 to 15 minutes after inhalation of a single dose of 50 and 400 mcg, respectively. In patients who inhaled salmeterol 50 mcg twice daily for 10 months, a second peak concentration of 0.07 to 0.2 mcg/L occurred 45 to 90 minutes after inhalation, probably because of the gastrointestinal absorption of the swallowed drug. Salmeterol xinafoate dissociates in solution to salmeterol and 1-hydroxy-2-naphthoic acid. The xinafoate moiety has no apparent pharmacological activity. The cytochrome P450 (CYP) isoform 3A4 is responsible for aliphatic oxidation of salmeterol base, which is extensively metabolised by hydroxylation with the major metabolite being α-hydroxysalmeterol, with subsequent elimination predominantly in the faeces.

The clinical overview on the clinical pharmacology, efficacy and safety is adequate.

IV.2 Clinical study reports

To support the application, the applicant has submitted as report 3 bioequivalence studies and 1 pharmakodynamic safety study.

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Study Objective of the study 1. Pharmacokinetic study To evaluate the efficacy and safety of the fluticasone moiety and safety of the salmeterol moiety 2. Pharmacodynamic study To evaluate the safety of the salmeterol moiety 3. Pharmacokinetic study with charcoal To evaluate the efficacy of the salmeterol blockade moiety 4. Pharmacokinetic study using a To evaluate the systemic exposure of spacing device fluticasone and salmereol moieties given via a spacing device

1. Pharmacokinetic study

One investigation centre was used and the 24 healthy male volunteers were studied after a single dose of 2 puffs (total inhaled dose of 50/500 mcg) on each of the treatment days. This dose was selected as it is the highest recommended dose to assess safety of the two active moieties. The washout period between the two treatment days was 14 days. Plasma samples were taken at pre-dose and at pre-defined intervals post dose on each occasion.” “All subjects who completed the study (n=24) were included for analysis of salmeterol (Table 6). There were 5 subjects in the fluticasone group who had predose concentrations greater than 5% of Cmax. Hence, the analysis was performed including (n=24) and excluding (n=19) the 5 subjects for fluticasone (Tables 7 and 8). The data of 19 subjects was considered as the primary analysis set.” “The 90% CI for salmeterol for Cmax was higher than the upper bioequivalence limit of 125%. However, this is likely due to high variance (> 30%) observed for plasma salmeterol in the study for Cmax. Since the upper limit of 90% CI was outside the bioequivalence limits, further evaluation of systemic exposure with salmeterol was performed in a safety pharmacodynamic study. The applicant would like to emphasize that AUC0-t for Salmeterol was within acceptable limits (80-125%), thereby confirming that the dose delivered is similar for the test and reference product.

Table 1. Pharmacokinetic parameters for Salmeterol (non-transformed values; arithmetic mean ± SD, tmax median, range), N=24

Treatment AUC0-12 AUC0-∞ Cmax tmax pg/ml/h pg/ml/h pg/ml h Test 330.15 411.23 142.64 0.08 (±139.65) (±177.33) (±99.97) (0.05-2.00) Reference 297.51 379.75 115.05 0.08 (±119.81) (±168.02) (±70.55) (0.08-2.00) *Ratio (90% CI) 110.73 109.29 117.01 (101.84-120.39) (100.77-118.55) (100.73-135.93) AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72h is reported instead of AUC0-t C max Maximum plasma concentration tmax Time until Cmax is reached *ln-transformed values

6/26 Table 2. Pharmacokinetic parameters for Fluticasone (non-transformed values; arithmetic mean ± SD, tmax median, range), N=19

Treatment AUC0-24 AUC0-∞ Cmax tmax pg/ml/h pg/ml/h pg/ml h Test 775.70 917.84 90.21 1.00 (±379.16) (±448.22) (±41.13) (0.25-6.00) Reference 801.08 891.86 93.58 1.50 (±358.50) (±400.30) (±42.16) (0.50-3.00) *Ratio (90% CI) 94.89 101.15 96.31 (84.80-106.17) (90.20-113.41) (84.38-109.93) AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72h is reported instead of AUC0-t C max Maximum plasma concentration tmax Time until Cmax is reached *ln-transformed values

Safety results

Both the Investigational products were well tolerated after self-administration of a single dose of two puffs i.e 50/500 µg (each puff releases 25/250 µg of salmeterol/fluticasone) by the subjects. There were no deaths and other serious adverse events reported during the conduct of the bioequivalence study.

Reported Adverse events in the study were as follows: A total of four adverse events were reported in the study. One subject (in the test group) experienced dryness in mouth and throat in period 1 (Subject No. 07), one subject (in the reference group) experienced elevated liver enzymes levels of SGOT, SGPT in period 2 (Subject no. 11) and the third subject (in the test group) experienced fever and generalized weakness in period 2 (Subject No. 15). Subjects who had adverse events were followed up till recovery. During vital signs examination, there were no clinically significant deviations observed from the baseline values. There were no clinically significant changes in post-study laboratory data, ECG or results of physical examinations except subject no. 11 who had elevated liver enzymes levels of SGOT, SGPT as compared to pre-study screening values. Therefore he was called for repeat follow up on 17/09/2010 and subject was declared fit on l7/09/2010 based on the laboratory results obtained.

2. Pharmacodynamic study

A randomised double blind placebo controlled five-way cross over study was used to compare the cardiac safety and impact on metabolic parameters of the test product at two doses with two doses of the reference product. Placebo “Dummy” inhalers corresponding to each active treatment were also administered to maintain blinding. Additionally, the pharmacodynamic variables were objective assessments measured through a device (ECG for heart rate, QTc interval) or through blood sampling (blood glucose, serum potassium). In this context, the primary endpoint (i.e., change in heart rate) was evaluated by assessing the area under the curve (AUC) data for heart rate over a period of 4 hrs after drug administration. The heart rate AUC (0-4hrs) was analysed by dividing the AUC by 4 hrs to provide the average increase in heart rate between the test and the reference product over the period of 4 hours. In order to avoid any concerns which could arise from the influence of post-prandial effect on the study endpoints which is evident from published literature [Kemp et al, Cazzola et al], the applicant compared the safety parameters until 4 hours (i.e. before meal).

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Safety results

Test and reference product showed a similar dose related safety profile in healthy adult males. These results can only partially be extrapolated to the intended patient population.

3. Pharmacokinetic study with charcoal blockade

This pharmacokinetic study evaluated lung deposition of salmeterol after a single dose (2 puffs i.e. 500/50 mcg) in 42 healthy volunteers aged 18-45 years. This was an open-label, single dose, 4 way crossover (replicate) study conducted at a single centre. Since, the variation for Cmax was > 30% in the first PK study, this study was designed as a replicate study. As the efficacy of fluticasone was confirmed in the study PRC/CRD/07/10 with only 24 subjects, additional blood sampling for assay of fluticasone was not done. Further, the use of charcoal is unlikely to have a significant effect on the magnitude of bioavailability of fluticasone due to negligible oral bioavailability. In order to compare the results of this study (with charcoal blockade) with the without charcoal PK study (Study PRC/CRD/07/10), the dose used in the study was kept the same. All subjects inhaled the test or reference drug (dose of 50/500 mcg) in all 4 treatment periods as per the randomized treatment sequence. The treatment periods were separated by a 14 day washout period (same washout period was used in the without charcoal PK study). The subjects took 50 ml (approx 5 gm) of charcoal suspension 2 min prior to the first puff and 2 minutes after the first puff, followed by 100 ml (approx 10 gm) of charcoal suspension at 1.00, 2.00 and 3.00 hours post dose. Plasma samples were collected at pre-dose and at pre-defined intervals post dose on each occasion. For salmeterol, the 90% CI limits for both AUC0-t and Cmax lie within the conventional bioequivalence limit of 80-125% for the 250/25 mcg strength.

Table 1. Pharmacokinetic parameters for Salmeterol (non-transformed values; arithmetic mean ± SD, tmax median, range), T=82, R=83

Treatment AUC0-18 AUC0-∞ Cmax tmax pg/ml/h pg/ml/h pg/ml h Test 162.80 194.38 113.26 0.08 (0.05-0.50) (±78.96) (±92.20) (±72.94) Reference 146.58 177.39 101.88 0.08 (0.05-0.50) (±68.10) (±84.63) (±54.50) *Ratio (90% CI) 107.92 ___ 104.68 (98.52-118.23) (95.80-114.38) AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72h is reported instead of AUC0-t C max Maximum plasma concentration tmax Time until Cmax is reached *ln-transformed values

Safety results

A total of 19 adverse events were reported in the study. These were of mild to moderate intensity. Three adverse events (headache, throat pain and low serum cortisol) were related

8/26 to the treatment. All related adverse events are expected adverse reactions and are reported in the summary of product characteristics (SPC of the reference product).

No serious adverse events were reported during the conduct of the study. All the adverse events resolved at the end of the study examination (except in case of subject no. 08, 13 and 23 who did not report for repeat post study examination). As these 3 subjects did not report for repeat post study due to personal reasons, even after repeated follow ups, therefore their health status was telephonically enquired and they confirmed that they did not have any health related complaints.

During vital signs examination, there were no clinically significant changes observed from the baseline values at the end of the study and no clinically significant changes were noted in post- study laboratory data (including serum cortisol) or results of post study physical examinations.

There were no clinically significant changes observed in rate/rhythm (increase/decrease) and intervals in post-study ECGs when compared with pre-study ECGs.

4. Pharmacokinetic study using a spacing device

This pharmacokinetic study evaluated the systemic exposure to fluticasone and salmeterol after a single dose (2 puffs; total dose = 50/500 mcg) in 24 healthy volunteers aged 18-45 years. This was an open-label, single dose, 4 way crossover study conducted at a single centre. All subjects inhaled the test or reference drug (total dose of 50/500 mcg) via the Volumatic spacer in the first 2 treatment periods and via the Aerochamber plus spacer in the subsequent 2 treatment periods using the deep breathing method. The treatment periods were separated by a 14 day washout period. Plasma samples were collected at pre-dose and at pre-defined intervals post dose on each occasion. The 90% confidence intervals for the ratios (T/R) of geometric least square means of test and reference product are within the bioequivalence limits of 80% to 125% for Cmax, AUC0-24 (Salmeterol) and AUC0-36 (Fluticasone). It is interesting to note that the variation reported for salmeterol (Cmax value) in this study with use of either spacer is approx 21%. This variation is significantly lower than the variation (> 30%) observed in the first pharmacokinetic study (Study code: PRC/CRD/07/10). Similar results are observed for the fluticasone component. This also supports our assessment made after the conduct of the study PRC/CRD/07/10 that the 90% CI for salmeterol for Cmax was higher than the upper bioequivalence limit of 125% due to greater variability and not due to any differences between the two products.

Table 1. Pharmacokinetic parameters for Salmeterol – volumatic spacer (non-transformed values; arithmetic mean ± SD, tmax median, range) T=23, R=23

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Treatment AUC0-24 AUC0-∞ Cmax tmax pg/ml/h pg/ml/h pg/ml h Test 1127.79 ± 322.01 1476.97 ± 690.32 1062.80 ± 311.11 0.08 (0.07-0.10)

Reference 1052.81 ± 332.80 1302.01 ± 437.50 992.77 ± 348.87 0.08 (0.08-0.10)

*Ratio (90% CI) 107.60 ------108.21 (98.33-117.75) (97.37-120.24) AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72h is reported instead of AUC0-t C max Maximum plasma concentration tmax Time until Cmax is reached *ln-transformed values

Table 2. Pharmacokinetic parameters for Salmeterol – AeroChamber (non- transformed values; arithmetic mean ± SD, tmax median, range) T=23, R=23

Treatment AUC0-24 AUC0-∞ Cmax tmax pg/ml/h pg/ml/h pg/ml h Test 736.01 ± 206.08 907.64 ± 274.66 520.28 ± 201.83 0.08 (0.05-0.15)

Reference 658.32 ± 166.13 803.23 ± 225.85 480.03 ± 188.50 0.08 (0.08-0.10)

*Ratio (90% CI) 111.03 ------110.28 (102.68-120.07) (98.75-123.14) AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72h is reported instead of AUC0-t C max Maximum plasma concentration tmax Time until Cmax is reached *ln-transformed values

Table 3. Pharmacokinetic parameters for fluticasone – volumatic spacer (non-transformed values; arithmetic mean ± SD, tmax median, range) T=23, R=23

Treatment AUC0-36 AUC0-∞ Cmax tmax pg/ml/h pg/ml/h pg/ml h Test 4528.42 ± 1093.84 4836.39 ± 1166.48 398.28 ± 96.40 2.00 (1.02-4.00)

Reference 4091.12 ± 882.61 4376.82 ± 946.49 367.03 ± 94.78 2.00 (0.25-6.00)

*Ratio (90% CI) 109.85 ------108.81 (103.48-116.60) (101.61-116.51) AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72 h is reported instead of AUC0-t C max Maximum plasma concentration tmax Time until Cmax is reached *ln-transformed values

10/26 Table 4. Pharmacokinetic parameters for fluticasone – AeroChamber (non- transformed values; arithmetic mean ± SD, tmax median, range) T=23, R=23

Treatment AUC0-36 AUC0-∞ Cmax tmax pg/ml/h pg/ml/h pg/ml h Test 2427.66 ± 1034.40 2594.11 ± 1113.20 235.29 ± 105.95 2.00 (0.25-4.02)

Reference 2299.97 ± 878.89 2464.39 ± 961.12 222.46 ± 78.29 1.50 (0.25-4.00)

*Ratio (90% CI) 104.24 ------102.81 (95.84-113.38) (93.71-112.78) AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72h is reported instead of AUC0-t C max Maximum plasma concentration tmax Time until Cmax is reached *ln-transformed values

Safety results

Test and Reference products were reasonably well tolerated after a single dose of 50/500 μg (25/250 μg per actuation X 2 puffs) in the healthy adult male human subjects under fasting conditions. A total of 19 adverse events were reported in the study. Most commonly reported were throat pain and headache which are known to be related to the investigational products, urticaria was reported for one subject. These were of mild to moderate intensity. All the other adverse events were unlikely to be related to the investigational products. All the adverse events resolved at the end of the study. No serious adverse events were reported during the conduct of the study. All the subjects were found to be fit in the post-study examination. During the study no abnormality was reported in any of the subjects during post dose examinations. During vital signs examination, there were no clinically significant changes observed from the baseline values and no clinically significant changes were noted in post- study laboratory data (including serum cortisol) or results of physical examinations. There were no clinically significant changes observed in rate/rhythm (increase/decrease) and intervals in post-study ECGs when compared with pre-study ECGs.

IV.3 Risk Management Plan

The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Salmeterol plus Fluticason Propionat momaja.

- Summary table of safety concerns as approved in RMP

Important identified risks  Pneumonia Important potential risks  Overdose  Adrenal suppression and acute adrenal crises that may result from prolonged treatment

11/26  Cardiac arrhythmia  Paradoxical bronchospasm  Systemic effects in paediatric population Missing information  Use in pediatric population  No data have elucidated if any phenotypes/genotypes might be at heightened risk of disease progression in patients treated with salmeterol/fluticasone  No studies of the effect on the ability to drive and use machines have been performed.  Lack of data in patients with hepatic impairment  Lack of data on fertility  Lack of specific data on lactating women

- Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP

Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures

Important Identified Risks

Pneumonia There was an increased None reporting of pneumonia in a 3 year study in patients with Chronic Obstructive Pulmonary Disease (COPD) receiving Salmeterol and Fluticasone pressurised inhalation suspension. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections and exacerbation frequently overlap. Reevaluation of treatment with Salmeterol and Fluticasone pressurized inhalation suspension has been advised in section 4.4 of the SPC if a patient with severe COPD

12/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures has experienced pneumonia. This risk has been known to occur commonly (≥1/100 to <1/10) as mentioned in SPC section 4.8 Undesirable effects and in section 4 (Possible effects) of PIL. The risk minimization measures include routine monitoring for reports of pneumonia and identification of trends in the severity and frequency of these reports to estimate the incidence of pneumonia.

Important Potential Risks Overdose The signs and symptoms of None salmeterol overdose are tremor, headache and tachycardia. The preferred antidotes are cardioselective beta- blocking agents, which should be used with caution in patients with a history of bronchospasm. Acute inhalation of fluticasone propionate doses in excess of those recommended may lead to temporary suppression of adrenal function. If salmeterol and fluticasone propionate pressurized inhalation suspension therapy has to be

13/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures withdrawn due to overdose of the beta agonist component of the drug, provision of appropriate replacement steroid therapy should be considered. This does not need emergency action as adrenal function is recovered in a few days, as verified by plasma cortisol measurements. Monitoring of adrenal reserve may be necessary. In cases of fluticasone propionate overdose salmeterol and fluticasone propionate pressurised inhalation suspension therapy may still be continued at a suitable dosage for symptom control. The risk of overdose is mentioned is mentioned section 4.9 (Overdose) and section 3 (How to use Salmetrol/Fluticasone). The risk minimization measures include routine monitoring for reports of overdose and identification of trends in the severity and frequency of these reports to estimate the incidence of overdose. Adrenal suppression and Prolonged treatment of None acute patients adrenal crises that may with high doses of result inhaled from prolonged treatment corticosteroids may result in adrenal suppression and acute adrenal crisis. Very rare cases of adrenal

14/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures 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. The risk of adrenal suppression and acute adrenal crises that may result from prolonged treatment is mentioned in section 4.4 (Special warnings and precautions for use), section 4.8 (Undesirable effects), section 4.9 (Overdose) and section 2 (What you need to know before you use Salmeterol/fluticasone

15/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures propionate), section 3 (How to use Salmeterol/fluticasone propionate). The risk minimization measures include routine monitoring for reports of adrenal suppression and acute adrenal crisis and identification of trends in the severity and frequency of these reports to estimate the incidence of adrenal suppression and acute adrenal crisis. Cardiac arrhythmia Rarely, salmeterol and None fluticasone propionate pressurised inhalation suspension may cause cardiac arrhythmias e.g supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Therefore Salmeterol and Fluticasone propionate pressurized inhalation, suspension should be used with caution in patients with severe cardiovascular disorders, heart rhythm abnormalities. Cardiac arrhythmias (including supraventricular tachycardia and extrasystoles) is rare (<1/10,000). The risk of cardiac arrhythmia is mentioned

16/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures in 4.4 (Special warnings and precautions for use), section 4.8 (Undesirable effects) of SPC and section 2 (What you need to know before you use Salmeterol/fluticasone propionate), section 3 (How to use Salmeterol/fluticasone propionate), section 4 (Possible side effects) in PIL. The risk minimization measures include routine monitoring for reports of cardiac arrhythmia and identification of trends in the severity and frequency of these reports to estimate the incidence of cardiac arrhythmia. Paradoxical bronchospasm As with other inhalation None therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Salmeterol and fluticasone propionate pressurised inhalation suspension should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. Paradoxical bronchospasm is rare (<1/10,000). The risk of Paradoxical bronchospasm is mentioned is mentioned section

17/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures 4.4 (Special warnings and precautions for use), section 4.8 (Undesirable effects) of SPC and section 4 (Possible side effects) in PIL. The risk minimization measures include routine monitoring for reports of paradoxical bronchospasm and identification of trends in the severity and frequency of these reports to estimate the incidence of paradoxical bronchospasm. Systemic effects in Systemic effects may None paediatric occur with any inhaled population corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest

18/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures dose at which effective control of asthma is maintained. The risk of Systemic effects in paediatric population is mentioned is mentioned section 4.4 (Special warnings and precautions for use), section 4.8 (Undesirable effects) of SPC and section 4 (What you need to know before you use Salmeterol/fluticasone propionate) in PIL. The risk minimization measures include routine monitoring for reports of systemic effects in paediatric population and identification of trends in the severity and frequency of these reports to estimate the incidence of systemic effects in paediatric population. Missing Information Use in pediatric A risk to breastfed None population newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue salmeterol and fluticasone propionate pressurised inhalation, suspension therapy taking into account the benefit of breastfeeding for the

19/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures child and the benefit of therapy for the woman. The risk of pediatric data is mentioned in section 4.4 (Special warnings and precautions for use) of SPC and section 4 (What you need to know before you use Salmeterol/fluticasone propionate) in PIL. The risk minimization measures include routine monitoring for reports with use in pediatric population and identification frequency of these reports to estimate the incidence of use in pediatric population. No data have elucidated A three year study None if any evaluating phenotypes/genotypes COPD patients and smoker might and be at heightened risk of non-smoker controls with disease progression in the patients purpose of characterizing treated with the salmeterol/fluticasone disease and defining predictive measures for disease activity and disease progression (2164 COPD subjects recruited). As no definitive data have been identified elucidating a clear physiologic mechanism by which salmeterol/fluticasone would heighten the risk of developing pneumonia in patients with COPD.

20/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures The risk minimization measures include routine monitoring for reports with disease progression due to any phenotypes/genotypes and identification of trends in the severity and frequency of these reports to estimate the incidence of disease progression due to any phenotypes/genotypes. No studies of the effect No studies of the effect None on the on the ability to drive and use ability to drive and use machines have been machines have been performed performed. The risk of effect on the ability to drive and use machines have been performed is mentioned section 4.7 (Effects on ability to drive and use machines) of SPC and section 2 (What you need to know before you use Salmeterol/fluticasone propionate) in PIL. The risk minimization measures include routine monitoring for reports affecting the ability to drive and use machines and identification of trends in the severity and frequency of these reports to estimate the incidence for inability to drive and use machines. Lack of data in patients Fluticasone propionate None with has high systemic hepatic impairment clearance mediated by cytochrome P450 3A4 in

21/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures the gut and liver. Hepatic impairment may affect the clearance of fluticasone propionate. However,there are no data available for use of Salmeterol and Fluticasone propionate pressurised inhalation suspension in patients with hepatic impairment. The risk of lack of data in patients with hepatic impairment is mentioned section 4.2 (Posology and method of administration) of SPC. The risk minimization measures include routine monitoring for reports with hepatic impairment and identification of trends in the severity and frequency of these reports to estimate the incidence of hepatic impairment. Lack of data on fertility There are no data in None humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility. The risk of lack of data on fertility is mentioned section 4.6 (Fertility, pregnancy and lactation) of SPC and section 2 (What you need to know before you use Salmeterol/fluticasone propionate) in PIL. The risk minimization measures include routine monitoring for reports

22/26 Safety Concern Routine Risk Minimisation Additional Risk Measures Minimisation Measures with effect on fertility and identification of trends in the severity and frequency of these reports to estimate the incidence of effect on fertility. Lack of specific data on Studies have shown that None lactating women salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats. It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk. The risk of Lack of specific data on lactating women is mentioned section 4.6 (Fertility, pregnancy and lactation) of SPC and section 2 (What you need to know before you use Salmeterol/fluticasone propionate) in PIL. The risk minimization measures include routine monitoring for reports with use in lactating women and identification of trends in the severity and frequency of these reports to estimate the incidence of adverse events associated with use in lactating women.

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IV.4 Discussion on the clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of salmeterol and fluticasone are well known. As salmeterol and fluticasone are widely used, well-known active substances, the applicant has not provided additional studies and further studies are not required. The application contains an adequate review of published clinical data and the bioequivalence has been shown.

V. USER CONSULTATION

The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

The pharmaceutical quality of Zoreeda 25 Mikrogramm/125 Mikrogramm pro Dosis - Druckgasinhalation, Suspension and Zoreeda 25 Mikrogramm/250 Mikrogramm pro Dosis - Druckgasinhalation has been adequately shown.

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Public Assessment Report

Update

Zoreeda 25 Mikrogramm/125 Mikrogramm pro Dosis - Druckgasinhalation, Suspension Zoreeda 25 Mikrogramm/250 Mikrogramm pro Dosis - Druckgasinhalation, Suspension

Fluticasone propionate, Salmeterol xinafoate

This module reflects the procedural steps and scientific information after the finalisation of the initial procedure.

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Scope Procedure number Product Information Date of start of the Date of end of Approval/ Assessment report affected procedure procedure non approval attached Change outside the approved specifications limits range - Assay limit AT/H/0517/001- No 14.08.2021 26.03.2021 approval No widening at release and shelf life 002/II/026

PAR Scientific discussion 26/26