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C B G M E B PUBLIC ASSESSMENT REPORT of the Medicines Evaluation Board in the Netherlands XTLuis, cutaneous solution 4% w/w Novum Pharma BV, the Netherlands dimeticone (100,000 cSt.) This assessment report is published by the MEB pursuant Article 21 (3) and (4) of Directive 2001/83/EC. The report comments on the registration dossier that was submitted to the MEB. It reflects the scientific conclusion reached by the MEB at the end of the evaluation process and provides a summary of the grounds for approval of a marketing authorisation. This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the latter category as the language in this report may be difficult for laymen to understand. This assessment report shall be updated by a following addendum whenever new information becomes available. General information on the Public Assessment Reports can be found on the website of the MEB. To the best of the MEB’s knowledge, this report does not contain any information that should not have been made available to the public. The MAH has checked this report for the absence of any confidential information. Registration number in the Netherlands: RVG 101389 16 December 2010 Pharmacotherapeutic group: ATC code: Route of administration: Therapeutic indication: Prescription status: Date of authorisation in NL: Application type/legal basis: other ectoparasiticides, incl. scabicides, insecticides and repellents P03AX cuteanous headlice infestations OTC 24 November 2009 Directive 2001/83/EC, Article 8(3) For product information for healthcare professionals and users, including information on pack sizes andpresentations, see Summary of Product Characteristics (SmPC), package leaflet and labelling. 1 of 9 C I B G M E B INTRODUCTION This is a national full application for XTLuis, cutaneous solution 4% w/w, submitted under E.C. Directive 2001/83/EC Article 8.3(i), for an existing active substance dimeticone. Dimeticone has been licensed for at least 33 years and it is widely used as an ingredient in a number of topical barrier cosmetic preparations. It is also used in pharmaceutical products indicated for the treatment of flatulence. However, this is the first time that an application in the Netherlands is filed claiming the use dimeticone as a pediculicidal agent. In the United Kingdom the same is registered as Hedrin®, it was already acknowledged as a medicinal product. This product has a physiological mode of action (see section on clinical pharmacology), however any pharmacological action cannot be ruled out. It was therefore decided that XTLuis should be assessed as a medicinal product. XTLuis solution acts on the lice by a physical process to cover the lice and disrupt the ability of the lice to manage its water balance so that treated insects fail to excrete surplus water. Hedrin activity is not diminished in insecticide resistant head lice. It is less effective in its ovicidal activity and therefore two applications 7 days apart are required. Based on the review of the quality, safety and efficacy data, the Netherlands has granted a marketing authorisation for XTLuis cutenaous solution 4% w/w, from Novum Pharma BV, the Netherlands. The date of authorisation was on 24 November 2009. The product is indicated for the eradication of headlice infestations (voor de bestrijding van besmettingen met hoofdluis). A comprehensive description of the indications and posology is given in the SmPC. II II.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Compliance with Good Manufacturing Practice The MEB has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation. Active substance The active substance is dimeticone 100,000 cSt, an established substance, described in the Ph.Eur.* The drug substance is practically insoluble in water and very slightly soluble to practically insoluble in glycerol, ethylene glycol, stearyl alcohol, methanol and ethanol. It is miscible in non-polar solvents such as hexane, heptane, toluene, xylene, ethyl acetate and methyl-ethyl-ketone. There are no chiral centres in the molecule. Full documentation on the active substance has been included. Manufacturing process Dimeticone 100,000 cSt fluid is manufactured at elevated temperatures by hydrolysis → polycondensation.The active substance has been adequately characterized and acceptable specifications have been adopted for the starting materials. Quality control of drug substance The drug substance specification is in line with the Ph.Eur. monograph for Silicone oil used as a lubricant. This is acceptable since the drug product lubricates the hairs. Batch analytical data demonstrating compliance with the Ph.Eur. monograph have been provided for three primary batches. The batches also comply with the proposed specification. 2 of 9 C B G M E B Stability of drug substance Stability data on the active substance have been provided for three primary batches stored at 25°C/60% RH (18 months) and 40°C/75% RH (6 months). The batches were stored in epoxy lined drums. The drug substance remained stable under accelerated and long term conditions for all parameters tested. No specific trends were observed. The proposed re-test period of 24 months is acceptable. * Ph.Eur. is an official handbook (pharmacopoeia) in which methods of analysis with specifications for substances are laid down by the authorities of the EU. Drug Product Composition The drug product is a clear and colourless cutaneous solution containing dimeticone 100,000 cSt (4.0% w/w). The drug product consists of 4.0% w/w Dimeticone 100,000 cSt and 96.0% w/w Cyclomethicone 5. The drug product is supplied in HDPE and glass bottles of varying configurations. Pharmaceutical development The development of the product has been adequately described. The key physicochemical characteristic for the drug substance is its high viscosity which is required for its pediculicidal activity in the drug product. Formulation studies focussed on the development of a lotion that was prepared from the drug substance in a suitable vehicle. A vehicle was required that could dissolve the required amount of dimeticone and could be readily volatile. Cyclomethicone 5 is a volatile silicone that is widely used in the cosmetic industry as a carrier for other silicones. Upon application, cyclomethicone evaporates, thus allowing a fine layer of dimeticone to be deposited on the hair, ensuring even distribution. Additionally, the vehicle should be simple, non-toxic and non-flammable. Cyclomethicones fulfils these requirements. The pharmaceutical development of the product has been adequately performed. Manufacturing process A description of the manufacturing process and a flow chart are included. During manufacturing Dimeticone 100,000 cSt and Cylomethicone 5 are mixed. Two sets of three batches were included in the manufacturing process validation. The results of the validation study indicated that the manufacturing process was able to consistently produce a product that met the product specification requirements and the method of mixing did not require further development. The manufacturing process can be regarded as sufficiently validated. Excipients Cyclomethicone 5 is described in the USP NF** and complies with the requirements in the monograph. Quality control of drug product The product specification includes tests for description, identity of product, identity of non-volatile drug substance, weight per ml at 20° C, refractive index at 20° C, Dimeticone content, viscosity, total viable aerobic count. The release and shelf-life requirements are identical and acceptable. The analytical methods have been adequately validated. Batch analysis data are included for six production scale batches. All batches comply with the proposed specification. Stability of drug product The MAH has started the stability studies with three batches packed into 100 ml white HDPE and Type III glass containers for the purpose of generating stability data. These data are presented as supportive data following the decision to change from a white to a neutral, translucent HDPE container. The batches were stored at 25°C/60% RH (40 months) and 40°C/75% RH (40 months). The batches were tested for appearance, identity by IR, Dimeticone content and viscosity. For none of these batches tested a significant change is observed at both long term and accelerated storage condition. An additional stability study was initiated and six further batches were packed into either natural, translucent HDPE or Type III glass bottles to generate primary stability data. The batches were stored at 25°C/60% RH (24 months), 30°C/65% RH (18 months) and 40°C/75% RH (24 months). These batches 3 of 9 C B G M E B were tested for appearance, Dimeticone content, viscosity, weight per ml and refractive index. For none of these batches tested a significant change is observed at long term, intermediate and accelerated storage condition. On the basis of the currently available data the proposed shelf-life of 36 months is acceptable. Other information There are no substances of ruminant animal origin present in the product nor have any been used in the manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded. ** United States Pharmacopoeia National Formulary II.2 Non clinical aspects Good Laboratory Practice All studies performed by the MAH for the current application are conform GLP regulations. It is presumed that all other studies referred to in this dossier are not conform GLP regulations. Additional studies that are required need to be conducted conform GLP regulations. Pharmacology Pharmacokinetics No absorption studies have been performed with dimeticon 100,000 cSt. Although dimeticons in general have been in use for many years in a wide range of products, including topical and oral applications, it is not clear if any of these products contain dimeticon 100,000 cSt, or a lower viscosity dimeticon. The absorption studies that have been performed with lower viscosity dimeticons show little absorption, and it is therefore unlikely that higher polymer sizes would be absorbed at a relevant level. Toxicology Single dose toxicity A dermal toxicity study was conducted in rats, in which low body weight gain or body weight loss was observed in treated female rats. This indicates that there may be some systemic toxicity due to absorption through the skin. However, an untreated control group is lacking, therefore body weights cannot be compared. Moreover, the systemic exposure due to dermal absorption is not determined, but it can be accepted that these exposures are clinically not relevant. Repeated dose toxicity No repeat dose toxicity studies have been conducted by the MAH. Genotoxicity No studies have been performed to assess the genotoxic potential of dimeticon 100,000 cSt. Instead, the slightly less viscous dimeticon 60,000 cSt has been evaluated in the Ames test. As dimeticon 100,000 cSt is a higher degree polymer, no difference in genotoxic potential is anticipated, and the results for dimeticon 60,000 can be used as evidence of lack of genotoxicity in the Ames test. No further studies have been reported concerning the genotoxic potential of dimenticon 100,000 cSt. Carcinogenicity No carcinogenicity studies have been performed with dimeticon 100,000 cSt. As this product is unlikely to be used more than two times, carcinogenicity studies are not required. Reproductive and developmental toxicity Three studies in rats using subcutaneous administration are described. Since this route of administration is likely to result in much higher systemic exposure than the dermal route, these studies are not relevant for this application. In rabbits, there seems to be some dermal absorption of the lower viscosity dimeticons, as reproduction toxicity is observed in two studies using dimeticon 10 and 350 cSt. It can be accepted that dimeticon 100,000 cSt is not absorbed in significant amounts through human skin. 4 of 9 C B G M E B Local tolerance Two skin irritation studies and two eye irritation studies were performed in rabbits using dimeticon 60,000 and 100,000 cSt. The slight eye irritation observed after treatment, was most pronounced with treatment of dimeticon 60,000 cSt. Since the results with dimeticon 100,000 cSt are more relevant, and showed insignificant irritation, it is concluded that the dimeticon 100,000 cSt is not an eye or skin irritant, after single administration. Dimeticon 100,000 cSt showed no potential for skin sensitisation, after single administration. Other toxicity studies No other toxicity studies were performed. Environmental risk assessment As dimeticons are widely used in a large number of cosmetic and pharmaceutical products, this product is not likely to add to the overall burden to the environment. Therefore, no environmental risk assessment is deemed necessary. II.3 Clinical aspects Quality of clinical studies, compliance with GCP The MEB has been assured that GCP standards were followed in an appropriate manner in the studies conducted. Clinical Pharmacology The mechanism of action of dimeticone has not been fully elucidated. The available evidence suggests that the activity of Hedrin is physical and due to coating of the lice by dimeticone. Dimeticone enters the trachae of the lice and prevents excretion of water resulting in disruption of gut and other organ functions. This product has a physiological mode of action, however any pharmacological action cannot be ruled out. Clinical Efficacy One pivotal observer blind clinical efficacy study was conducted by the MAH to support the proposed indication. This study involved an active controlled comparison of the efficacy of Hedrin (=XT Luis® 4% w/w) and 0.5% phenothrin in patients with current active head louse infection. In addition to the pivotal efficacy study, the clinical development programme comprised of a dose-finding Phase II pilot study to evaluate optimum treatment-interval and follow-up regimen. In the two clinical studies conducted to evaluate Hedrin® 87.5% (35/40) and 84.6% (220/260) were children aged 4-18 years; in total 57.7% of these were aged less than 10 years in the pivotal study. The dose-finding pilot Phase II study was performed in total 35 children and 5 adults, (conducted during the winter season). It compared a 20minute application versus 8-hours/overnight application in a once-a-week application regimen of Hedrin for two weeks. The study indicated that 8 hours or overnight was the appropriate treatment exposure time to achieve the intended maximum (at least 90%) eradication of head lice infections, although the study was underpowered. The pivotal Phase III study therefore included application of the product for 8 hrs or overnight. In this study 130 and 125 individuals with a median age of 9 years with head louse infection were treated with Hedrin (=XT Luis® 4% w/w) and 0.5% phenothrin respectively according to the recommended regimen (two applications on day 0 and 7 respectively (conducted during the summer season). The primary endpoints of the study were not finding lice after the second treatment application (day 9 & day 14). The results showed that 78/121 (64.46%) on Hedrin were cured versus 83/116 (71.55%) on with 0.5% phenothrin liquid in the PP analysis. A further 6 (4.96%) with Hedrin and 7 (6.03%) with phenothrin were considered to have been cured by the two treatments but subsequently re-infected. The difference in cure rates is estimated as 8.16% with a 95% confidence interval (CI) of –3.02% to +19.34%. Thus, the two treatments were regarded as equivalent to within 20%. Ovicidal failure was reported in 5 cases (4.13%) on Hedrin and 2 cases (1.72%) on phenothrin. 5 of 9 C B G M E B Of note the cure rate was significantly lower than the expected 90% for Hedrin on the basis of the dosefinding studywhereas high cure rates >90% are documented in the literature for pediculicides such as permethrin containing products; see recent Cochrane publication (2007)1. High cure rates (>90%) are also described for Phenothrin containing products, however, only abstracts could be retrieved from a preliminary literature search. The presently observed low cure rate also for the used comparator has been adequately explained by the MAH. MAH offsets the lower cure rate on Hedrin with claimed advantage of Hedrin® over other products currently marketed for this application that in ex vivo tests Hedrin® was effective against insecticide resistant head lice (KER/LLE/D5D11.02). MAH’s explained that a high proportion of patients in the Phase III study had used insecticide products without success prior to entry to the trial and that this is evidence that the product is effective against head lice resistant to currently used products cannot be assessed appropriately in the light of better results with the comparator product and the used exclusion criteria. Finally, the comparator product 0.5% Phenothrin is not registered in the Netherlands, although it is registered in some other EU countries. In conclusion, the pivotal clinical trial has not demonstrated unequivocally that Hedrin (=XT Luis® 4% w/w) has a high efficacy in killing head lice in comparison with an established comparator. Clinical Safety For the intent to treat (ITT) population adverse events were reported by 13.1% (17) of the patients in the Hedrin group (in the phenothrin group: 20.2% (26) of the patients). Of the treatment-related adverse events a total of 3.8% (5) were reported by patients in the Hedrin group compared to a total of 8.5% (11) by patients in the phenothrin group. The adverse events related to Hedrin were 3 cases of scalp pruritis, 2 cases of transient mild eye irritation following accidental exposure. Eye irritation was also observed in non-clinical studies in rabbits. In the additional safety study carried out to determine skin irritation capacity of dimeticone (in 60 healthy volunteers treated with a combination of two silicone-based materials: dimethiconol - a similar compound to dimeticone-, and cyclometicone) no irritancy was observed after 16 hours of application. In conclusion, the Hedrin (XTLuis) treatment related adverse events were mild/moderate and transient and the incidence is lower than that of the comparator 0.5% phenothrin. Dimeticone (and cyclometicone) have been in use for many years in dermal cosmetic products. Discussion on clinical aspects In the Board meeting of 3 April 2008 it was medicinal product. It was concluded that acknowledged as a medicinal product. This pharmacological action cannot be ruled out. medicinal product. discussed whether XT Luis should be acknowledged as a in the United Kingdom XT Luis (Hedrin) was already product has a physiological mode of action, however any The Board decided that XT Luis should be assessed as a In the Board meetings held 26 November 2008 and 25 February 2009 it was decided to request the UK assessment reports, subsequently it was concluded that the submitted documentation for XT Luis was the same as Hedrin. In the Board meeting of 29 October 2009 the Board decided to register the product, based on the request of the MAH, the submitted data and fact that the product is on the market in the UK already for 4 years. The Board also acknowledged that this medicinal product has the non prescription status in the United Kingdom. There are no safety concerns, Therefore the Board decided that the legal status of supply could be set as non-prescription (UAD) in the Netherlands. 1 Strong M, Johnstone PW. Interventions for treating scabies. Cochrane Database of Systematic Reviews, 2007. 6 of 9 C B G M E B Product information SmPC The content of the SmPC approved during this national procedure in the Netherlands is in accordance with the SmPC of Hedrin (registered in the United Kingdom). Readability test 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 test consisted of a pilot test with 2 participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. The readability test has been sufficiently performed. III OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT XT Luis has a proven chemical-pharmaceutical quality. The MAH has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations. In the Board meeting of 3 April 2008 it was medicinal product. It was concluded that acknowledged as a medicinal product. This pharmacological action cannot be ruled out. medicinal product. discussed whether XT Luis should be acknowledged as a in the United Kingdom XT Luis (Hedrin) was already product has a physiological mode of action, however any The Board decided that XT Luis should be assessed as a In the Board meetings held 26 November 2008 and 25 February 2009 the application was discussed and it was decided to request the UK assessment reports, subsequently it was concluded that the submitted documentation for XT Luis was the same as Hedrin, the commercial name in the UK. The MEB, on the basis of the data submitted, considered that XTLuis demonstrated evidence of efficacy for the approved indication as well as a satisfactory risk/benefit profile acknowledging that XT Luis was a licensed medicinal product in the United Kingdom, and therefore granted a marketing authorisation. The board conluded that XT Luis can be approved with the legal status of supply non prescription (UAD in the Netherlands). 7 of 9 C B G M E B List of abbreviations ASMF ATC AUC BP CEP CHMP CI Cmax CMD(h) CV EDMF EDQM EU GCP GLP GMP ICH MAH MEB OTC PAR Ph.Eur. PIL PSUR SD SPC t½ tmax TSE USP Active Substance Master File Anatomical Therapeutic Chemical classification Area Under the Curve British Pharmacopoeia Certificate of Suitability to the monographs of the European Pharmacopoeia Committee for Medicinal Products for Human Use Confidence Interval Maximum plasma concentration Coordination group for Mutual recognition and Decentralised procedure for human medicinal products Coefficient of Variation European Drug Master File European Directorate for the Quality of Medicines European Union Good Clinical Practice Good Laboratory Practice Good Manufacturing Practice International Conference of Harmonisation Marketing Authorisation Holder Medicines Evaluation Board in the Netherlands Over The Counter (to be supplied without prescription) Public Assessment Report European Pharmacopoeia Package Leaflet Periodic Safety Update Report Standard Deviation Summary of Product Characteristics Half-life Time for maximum concentration Transmissible Spongiform Encephalopathy Pharmacopoeia in the United States 8 of 9 C B G M E STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Change of manufacturer Type of modification active substance II Date of start of the procedure Feb 2010 9 of 9 Date of end of the procedure April 2010 Approval/ non approval approved Assessment report attached N B