Decentralised Procedure. Public Assessment Report. Nasenspray sine AL 0,5 mg/ml Nasenspray, Lösung Nasenspray sine AL 1 mg/ml Nasenspray, Lösung

Transcription

1 Decentralised Procedure Public Assessment Report Nasenspray sine AL 0,5 mg/ml Nasenspray, Lösung Nasenspray sine AL 1 mg/ml Nasenspray, Lösung Xylometazoline hydrochloride DE/H/4485/ /DC Applicant: STADA Arzneimittel AG Stadastr.2-18 D Bad Vilbel Germany Reference Member State DE

2 TABLE OF CONTENTS I. INTRODUCTION... 5 II. EXECUTIVE SUMMARY... 5 II.1 Problem statement... 5 II.2 About the product... 5 II.3 General comments on the submitted dossier... 6 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.. 6 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 7 III.1 Quality aspects... 7 III.2 Non-clinical aspects... 7 III.3 Clinical aspects... 8 IV. BENEFIT RISK ASSESSMENT Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 2/12

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS Name of the drug substance (INN name): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number(s) for the Decentralised Procedure Reference Member State: Concerned Member States: Applicant (name and address) Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA Nasenspray sine AL 0,5 mg/ml Nasenspray, Lösung Nasenspray sine AL 1 mg/ml Nasenspray, Lösung Xylometazoline hydrochloride R01AA07 Nasal spray, solution; 0.05% + 0.1% DE/H/4485/ /DC DE BE, EE, HR, HU, LT, LV, LU, PT, RO SI STADA Arzneimittel AG Stadastr D Bad Vilbel Germany STADA Arzneimittel Aktiengesellschaft Stadastr D Bad Vilbel Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 3/12

4 LIST OF ABBREVIATIONS 4PR 4-phase rhinomanometry AAR active anterior rhinomanometry AE adverse event BZD benzydamin CPMP Committee for Proprietary Medicinal Products CNS central nervous system DB double blind DMD dimetinden GCP Good Clinical Practise GMP Good Manufacturing Practise HDPE High density polyethylene LCN lidocaine MC multicentre min minute NAR nasal airway resistance NaCl sodium chloride NP nasal patency NTI nasotracheal intubation NS not significant PC placebo-controlled PG parallel groups PLA placebo PNE phenylephrine PNIF peak nasal inspiratory flow R randomised; reference RC reference controlled RM rhinitis medicamentosa RQLQ Rhinoconjunctivitis Quality of Life Questionnaire SD single dose SmPC Summary of Product Characteristics TID three times daily VAS visual analogue scale XM xylometazoline XYL xylitol Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 4/12

5 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the applications for Nasenspray sine AL 1 mg/ml nasal spray and Nasenspray sine AL 0.5 mg/ml nasal spray, solutions in the indication of - for detumescing the nasal mucosa in the event of colds and attacks of runny colds (vasomotor rhinitis), allergic rhinitis - for facilitating the flow of secretion in inflammation of the paranasal sinuses as well as in catarrh of the tubal middle ear associated with colds / / 0.05 % is intended for children between ages 2 and 6 years / / 0.1 % is intended for adults and school-age children is approved. II. EXECUTIVE SUMMARY II.1 Problem statement These Decentralised procedures are hybrid applications for Nasenspray sine AL 1 mg/ml nasal spray and Nasenspray sine AL 0.5 mg/ml nasal spray conforming to Article 10(3) of Directive 2001/83/EC and based on the reference products Snup Schnupfenspray 0.1 % Nasenspray and Snup Schnupfenspray 0.05 % Nasenspray, approved on the 14 th of January Both applied products containing xylometazoline hydrochloride and are identical in composition to the approved reference products as documented in the Quality AR and in section 3.1. The products must not be used for longer than 7 days (rhinitis medicamentosa) unless prescribed by the clinician. II.2 About the product The applied products contain xylometazoline hydrochloride 0.1 % or 0.05 %. Xylometazoline is well known in monotherapy and has been used for many years as an over-the counter (OTC) drug. Both applied products are identical in composition to the approved reference products Snup Schnupfenspray 0.1 % Nasenspray and Snup Schnupfenspray 0.05 % Nasenspray as documented below. Xylometazoline Xylometazoline is a direct-acting α-adrenoceptor agonist with affinity to both, α 1 - and α 2 - adrenoceptors. Current evidence indicates that within the nasal mucosa xylometazoline stimulates α 2 - adrenoceptors located on postcapillary venules and α 1 -adrenoceptors which are largely concentrated on precapillary arterioles. An increased influx/liberation of calcium ions and phosphorylation of key enzymes following α-adrenoceptor stimulation produces vasoconstriction. Extracellular fluid that contributes to congestion and rhinorrhoea is reduced as a result of the blood flow reduction. In addition, the vasoconstriction reduces the blood volume in the mucosa and the mucosal volume and it prevents the rapid washout of xylometazoline from the nasal mucosa such that it is retained locally for a prolonged period. Among the available topical decongestants, xylometazoline (and oxymetazoline) have the longest duration of action of up to 10 h following a single spray application. Within the ATC system xylometazoline is classified as a nasal decongestant preparation of the plain sympathomimetic class and coded R01AA07. Proposed indications - for detumescing the nasal mucosa in the event of colds and attacks of runny colds (vasomotor rhinitis), - allergic rhinitis - for facilitating the flow of secretion in inflammation of the paranasal sinuses as well as in catarrh of the tubal middle ear associated with colds - / / 0.05 % is intended for children between ages 2 and 6 years - / / 0.1 % is intended for adults and school-age children Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 5/12

6 Proposed posology - Xylometazoline nasal spray 0.1 % - Unless otherwise prescribed, adults and school-age children from 6 years of age when - necessary should put 1 puff of nasal spray into each nostril up to three times daily - Xylometazoline nasal spray 0.05 % - Unless otherwise prescribed, children between 2-6 years when necessary are given 1 puff - of nasal spray into each nostril up to three times daily Duration of use - The recommended single dose of / / should not be given more than three times a day. - / / should not be used for longer than 7 days except on the advice of a doctor - A doctor should always be consulted about the duration of therapy in children - Chronic cold sufferers may use these medicinal products only with medical monitoring - because of the risk of atrophy of the nasal mucosa The restriction of use to no more than 7 days seeks to avoid the complication of rebound congestion and rhinitis medicamentosa. The recommended dose should not be exceeded. An interval of several days should elapse before re-administering the product. Xylometazoline is considered as a known substance and has been used for half a century since its approval, e.g. by the US Food and Drug Administration (FDA), in Xylometazoline remains one of the most frequently prescribed and used nasal decongestants. Actual exposure has been considerably higher, because xylometazoline nasal decongestants have been obtained without prescription for decades. II.3 General comments on the submitted dossier These Decentralised procedures are hybrid applications for Nasenspray sine AL 1 mg/ml nasal spray and Nasenspray sine AL 0.5 mg/ml nasal spray conforming to Article 10(3) of Directive 2001/83/EC and based on the reference products Snup Schnupfenspray 0.1 % Nasenspray and Snup Schnupfenspray 0.05 % Nasenspray, approved on the 14 th of January According to Appendix II of the current European Medicines Agency's Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr), section on Locally Acting Locally Applied Products, a waiver of the need to provide equivalence data may be acceptable in the case of solutions, e.g. nasal sprays, if the test product is of the same type of solution (aqueous or oily), and contains the same concentration of the same active substance as the medicinal product currently approved. Both applied products are identical in composition to the approved reference products Snup Schnupfenspray 0.1 % Nasenspray and Schnupfenspray 0.05 % Nasenspray. The Clinical Overview is assessed as adequate. There was a national Scientific Advice with the BfArM on 22-Jan II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles The RMS has been assured that acceptable standards of GMP are in place for these product types at the sites within the Community. The RMS has accepted copies of the current manufacturer authorisations and GMP certificates as certification that acceptable standards of GMP are in place at these sites. The manufacturing site outside the Community, i.e. the alternative secondary packaging site, has been deleted. This is accepted. A new declaration of the Qualified Person of Stada Arzneimittel AG (on behalf of all involved QPs of the other manufacturers) concerning GMP compliance for the active substance has been provided, based on an audit not older than 3 years. Compliance with GCP and agreed ethical principles: Not applicable, the Applicant has not submitted a confirmative study, conducted by his own. Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 6/12

7 III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The drug substance is xylometazoline hydrochloride which is covered by a Ph. Eur. monograph. A valid certificate of suitability has been granted by the EDQM for xylometazoline hydrochloride from the drug substance manufacturer. The specification and the analytical procedures of the drug product manufacturer for the active substance are in line with Ph. Eur. and the certificate of suitability. The container closure system (double low-density polyethylene bags inside a fibre drum) and the retest period of 4 years are covered by the certificate of suitability. Drug Products The drug products of the current DCP procedures are two nasal spray solution strengths which contain 0.5 mg/ml and 1 mg/ml xylometazoline hydrochloride as active substance. The drug products are nonpreserved and are presented in multi-dose bottles. The function of the excipients is explained. Potassium dihydrogen phosphate is used as buffer substance, due to the ph sensitivity of the active substance. Sea water is added as isotonicity agent. Purified water is used as solvent. Nitrogen is the pressurized gas for sterile filtration (not present in the finished drug product). The drug products are filled into HDPE bottles with a nasal pump spray device. Both the 0.5 mg/ml and the 1 mg/ml strength are intended to be marketed in packages sizes of 10 ml and 15 ml nasal spray solution. The 3K pump system or alternatively the PFP N 90 pump system is used for both drug products. Both pump systems deliver a spray shot of 90 µl (90 mg). The applicant has confirmed that the test products of the current DCP procedures from STADA and the reference medicinal products from STADA (Snup 0.05 % and Snup 0.1 %) have the same qualitative and quantitative composition with regard to the drug substance and the excipients, the same pharmaceutical form (nasal spray solution), the same manufacture and manufacturers of the finished drug products and the same primary packaging. The drug products are manufactured as sterile products. The choice of the sterilization process has been justified (sterile filtration, followed by aseptic filling into pre-sterilized bottles which are fitted with the pre-sterilised pump system). The manufacturing process is described and process validation data are presented. The origin and the manufacture of the non-compendial excipient sea water are described, and the specification is accepted. All other excipients are specified according to Ph. Eur. The release and shelf-life specifications of the 0.5 mg/ml and the 1 mg/ml drug product are provided, and the non-compendial analytical procedures are described and validated. A shelf-life of 60 months without any storage conditions is accepted. The proposed in-use shelf-life of 12 months is supported by in-use data. III.2 Non-clinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of xylometazoline hydrochloride are well known. The applicant has not provided additional studies and further studies are not required. The provided non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. The available preclinical data are adequately mentioned in the SmPC, and the proposed recommendations for the use during pregnancy and lactation is endorsed. Environmental Risk Assessment (ERA) The applicant provided consumption data for 2012 to 2015 for the 4 concerned member states with the highest prevalence, which shows no significant increase. Considering these data, it is not expected that this MA will lead to an increase in the environmental exposure. An environmental assessment is not considered necessary. Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 7/12

8 III.3 Clinical aspects Pharmacokinetics There are no published data on systemic human pharmacokinetics of xylometazoline hydrochloride after nasal application. Following nasal application, absorption into the nasal mucosa of the water soluble agent occurs rapidly and the decongestant effect can be observed within 10 minutes and last up to 10 hours a single spray application. There is only minimum systemic absorption of xylometazoline when it is used in the recommended dose and route of administration. Data on distribution, protein binding, metabolism and elimination of xylometazoline are not available. However, renal elimination of xylometazoline appears to occur if systemic availability of xylometazoline is suspected, e.g. after an overdose. Comparative pharmacokinetic data in Special Populations are not available. Pharmacodynamics Decongestant Effects Decongestant effects of single administrations of topical xylometazoline 0.1 % were compared with those of oral pseudoephedrine 120 mg in 10 patients with chronic sinusitis and in 10 healthy subjects (Caenen et al. 2005). Decongestion was measured before and 15 min, 30 min, 1, 2, 4, 6, and 8 hours after drug administration using AAR for objective measurement of NAR. Additionally, a MRI was performed before and about 90 min after drug administration in order to demonstrate decongestant effects on nasal and sinus mucosa. Xylometazoline reduced the NAR by an average of 37.3 % in all patients and healthy subjects during 8 hours. Pseudoephedrine did not show a clear and long-lasting decongestant effect. Effects on Nasal Resistance and Nasal Patency Clarke et al. (1995b) showed in 20 healthy volunteers that successive increase in doses of xylometazoline caused a progressive decrease in nasal airway resistance (NAR) measured by rhinomanometry and an increase in peak nasal inspiratory flow (PNIF), (table 1). Aliquots of 1. 2, and 4 ml of a 0.1 % solution was nebulised and administered via air brush and NAR and PNIF were measured 10 minutes after administration. Table 1: Nasal patency for different degrees of vasoconstriction by topical xylometazoline There were significant differences between all sets of NAR values (p < ) and between the pairs of PNIF values (p < ), except between 2 and 4 ml. There was a plateau effect with increasing intra-nasal vasoconstriction. The increase in air flow correlated well with nasal airflow sensation (p < 0.05). Rhinitis medicamentosa Mucociliary transport is the most important defence mechanism of the respiratory tract. It is able to clean the inspired air from dust, allergens, viral agents, and other pathogens. Prolonged use of nasal decongestants is limited by development of rhinitis medicamentosa (RM). This is a syndrome of rebound hyperaemia which follows prolonged courses of imidazoline derivatives, characterised by histologic changes, including oedema, congestion, inflammatory cell infiltration, epithelial degeneration, giblet cell hyperplasia, squamous cell metaplasia, and nasociliary loss with subsequent mucociliary dysfunction (Barnes et al. 2005; Eccles et al. 2008). The most prominent feature of prolonged use (overuse) of xylometazoline is rebound nasal congestion, which results in a reduction in treatment efficacy (tachyphylaxis). Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 8/12

9 Interactions As for all sympathomimetics, concomitant use of xylometazoline with monoamine oxidase inhibitors, tricyclic or tetracyclic antidepressants can result in increase in blood pressure, especially in case of overdose. Clinical efficacy Randomised Controlled Studies of Xylometazoline Four randomised controlled studies of xylometazoline in acute or chronic rhinitis are summarised in table 2. All trials included also a placebo group and two had additional active comparator groups. Duration of treatment varied from a single application till 10 days of double-blind treatment and, the primary efficacy variable was nasal patency in three studies and tubal patency in one study. In all studies, xylometazoline was more effective than placebo in increasing nasal conductance as measured by rhinomanometry (Cingi et al. 2014; Eccles et al. 2008; Maranta et al. 1996). Subjective feeling of better nasal patency was assessed using a visual analogue scale and, the scores confirmed the objective measurements (Cingi et al. 2014; Eccles et al. 2008). Quality of life increased significantly (p = 0.001) in xylometazoline group in one study (Cingi et al. 2014). Two trials of xylometazoline in situations where nasal decongestion is favourable are summarised in table 3. One study (El-Seify et al. 2010) assessed frequency and severity of epistaxis in children during and after nasotracheal intubation (NTI) and the other (McCluney et al. 2009) discomfort and anxiety in children with nasal endoscopy. Bleeding frequency was significantly (p < 0.01) reduced during and after NTI when xylometazoline was topically applied before the procedure and, no case of severe bleeding occurred following xylometazoline administration (El-Seify et al. 2010). No significant differences with regard to pain, discomfort, and anxiety were observed between a single application of xylometazoline 0.1% and a combination of phenylephrine plus lidocaine (McCluney et al. 2009). Table 2: Controlled studies of xylometazoline Table 3: Controlled studies of xylometazoline (special applications) Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 9/12

10 Conclusions on clinical efficacy Xylometazoline 0.05 % and 0.1 % nasal sprays administered in the symptomatic treatment of of nasal congestion caused by allergic rhinitis, rhinitis vasomotorica and rhinitis associated with the common cold is well established. The quantitative and qualitative composition of the xylometazoline nasal sprays is identical with that of the reference products 0.05 % and 0.1 % Snup Schnupfenspray. The applicant has not carried out biopharmaceutical or clinical efficacy studies with these products (Note for guidance on the clinical requirements for locally applied, locally acting products containing known constituents, CPMP/EWP/239/95) because the products applied for are identical with the reference products. Moreover, according to Appendix II of the current European Medicines Agency's Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr), bioequivalence cannot be demonstrated through bioavailability studies, because the products applied for and the reference products are locally acting (nasal mucosa). These procedures are acceptable. Also, the proposed single doses of 0.05 % and 0.1 % xylometazoline nasal sprays in children up to 2 years of age in the 0.05 % strength and for the 0.1 % strength in the age class over 6 years, are wellestablished for short term use in the indications applied for and showed an acceptable level of safety. Treatment duration exceeding 7 days should be avoided in order to prevent rhinitis medicamentosa. This point is realized in the wording of the applicant s informative texts. The SmPC/PL is in line with those of the reference products. Clinical safety The European population exposed to nasal xylometazoline sprays 0.1 % and 0.05 % strength has been extensive and sufficient within its approved indications. Xylometazoline have been approved for more than 5 decades and available without prescription. A burning sensation in the nose and throat, local irritation, dryness of the nasal mucosa, and sneezing have occasionally occurred with topical nasal decongestants. Rhinitis medicamentosa is a term used specifically to refer to a condition which occurs with persistent overuse of topical nasal decongestants. Overuse of these drugs may result in rebound congestion, nasal hyperactivity, tolerance, and histologic changes of the nasal mucosa. According to the German SmPC, rhinitis sicca or synonymously atrophic rhinitis is a contraindication against the use of xylometazoline nasal sprays. Atrophic rhinitis is characterised by atrophic changes of all parts of the nose which results in decreased lubrication ( dry nose ) and decreased vascularity of the nasal mucosa.xylometazoline has been shown to be safe in children in several clinical trials. Data from clinical trials and case reports indicates that frequency, type and severity of AEs in children are expected to be similar as in adults. The majority of AEs reported in children occurred after overdosing of xylometazoline. These include nervousness, insomnia, sleepiness/drowsiness, hallucinations and convulsions. Cases of irregular breathing have been recorded in infants and neonates. Regarding safety in children, "systemic absorption of the imidazolines (oxymetazoline, xylometazoline) has very rarely been associated with bradycardia, hypotension, and coma. Epistaxis is an uncommon AE of nasal xylometazoline use. With attention to precautions, no serious AEs are expected during the short term use of xylometazoline nasal spray within 7 days. Conclusions on clinical safety Xylometazoline as a topical α-adrenoceptor agonist is established in adults and children aged 2 years and older with regard to efficacy and safety. Intranasal use of xylometazoline has been associated with local burning, stinging, sneezing and dryness of the nasal mucosa. Long-term use with treatment duration over 7 days can cause nasal stuffiness and tolerance (rhinitis medicamentosa). A few and minor AE s occurred with xylometazoline therapy in the clinical studies, i.e. minor bloodtinged nasal secretion. Xylometazoline seldom produces significant systemic adverse effects. Palpitations have been infrequently observed. After overdose, significant cardiovascular effects may occur, including hypertension and arrhythmias. Nausea and vomiting has rarely been reported. The listed AEs are adequate in the submitted SmPCs. These points are implemented in the informative texts of the applicant, which are in line with those of the reference products. Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 10/12

11 There are no current safety issues or regulatory actions that would restrict the use of xylometazoline nasal spray 0.1 % and 0.05 % strengths within its approved indications. Legal Status In Germany: not subject to prescription User Testing Fifteen questions cover all critical aspects of the Patient Information Leaflet in a total of 20 volunteers. The first round of testing showed that 98.7 % of the information (296 out of 300 pieces) requested in the questions was found by the participants. Each of these participants showed they understood the information by answering the questions correctly 100 % (300 out of 300 pieces). No further test round was conducted. Thus, the tested Package Leaflet is adequate. Summary Pharmacovigilance system The Applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable. Risk Management Plan The applicant 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 for Nasenspray sine AL 0,5 mg/ml Nasenspray, Lösung and Nasenspray sine AL 1 mg/ml Nasenspray, Lösung. The RMP is approved. The applicant considers routine pharmacovigilance and routine risk minimisation measures as sufficient. This is agreed. The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module of the Marketing Authorisation and any agreed subsequent updates of the RMP. Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 11/12

12 An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures. Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account: PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list. IV. BENEFIT RISK ASSESSMENT Based on the review of the data on quality, safety and efficacy, the application is approved. For intermediate amendments see current product information. Nasenspray sine AL 0,5 mg/ml / 1 mg/ml Nasenspray, Lösung, DE/H/4485/ /DC Public AR Page 12/12