P-RMS FINAL ASSESSMENT REPORT Procedure number PL/H/PSUR/0005/002

Transcription

1 THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS 41 ZĄBKOWSKA STR.; WARSAW; POLAND; PHONE ; FAX P-RMS FINAL ASSESSMENT REPORT Procedure number PL/H/PSUR/0005/002 Active substance Innovator name of product in the P-RMS <for MRP products also procedure number> Metronidazole (topical) ROSEX, METRO- PL/H/PSUR/0005/002 Pharmaceutical form(s)/strength Gel, cream & lotion 7.5mg/g - 0,75%; Gel - 1% MAH(s) Galderma International HBD and DLP EU HBD: 22 Nov. 1988, DLP: Nov 2011 PSUR period 22 November 2008 to 30 November 2011 (PSURs 16,17, 18) P-RMS Assessor PL Justyna Hall, M.D. Contact point justyna.hall@urpl.gov.pl; fax: TIME TABLE Procedure Start Date Date of preliminary AR 09 May 2012 Deadline for comments to P-RMS Clockstop/ RFI / LoQ Procedure Restart Date Date of Draft Final AR Deadline for comments to P-RMS 08 June 2012 Date of Draft Final AR 11 June 2012 Date of Final AR 11 July 2012 Discussion at PhVWP DLP of the next PSUR submission and DLP according to PSUR Worksharing list Nov 2014 period of PSUR In addition to the innovator PSUR, the assessment report covers the following PSURs of additional products authorised in the P-RMS: MAHs MR procedure number Pharmaceutical form(s) Strength(s) (if applicable) Jelfa S.A. Gel, cream 10mg/g

2 The following PSURs of products not authorised in the P-RMS* have been submitted as part of the worksharing procedure. MAHs MR procedure number (if Period covered by the PSUR applicable) Laboratoires nationally authorized products (FR) 01 June 2009 to 30 November 2011 Bailleul-Biorga Gedeon Richter nationally authorized products (BG, CZ, HU, LV, LT, RO, SK) 01 December 2008 to 30 November 2011 Actavis nationally authorized products (SE, FI, DK) 01 December 2008 to 30 November 2011 * An overview table has been submitted to the P-RMS. INDICATIONS AUTHORISED IN THE P-RMS (INNOVATOR): Rosacea WORLDWIDE MARKETING AUTHORISATION STATUS AND UPDATE OF REGULATORY ACTIONS TAKEN FOR SAFETY REASONS (MAH, AUTHORITIES) Has there been a change to the marketing authorisation status or have regulatory actions been taken for safety reasons? Yes No If yes specify: NA Rozex/Metro 0,75% gel is registered in 67 countries (EU: AT, BE, DE, DK, EE, FI, FR, EL, HU, IE, IT, LT, LV, LU, MT, NL, NO, PL, PT, ES, SE, UK). Rozex/Metro 0,75% cream is registered in 41 countries (EU: BE, CZ, DK, EE, FI, FR, DE, EL, HU, IE, IT, LT, LU, NO, PL, PT, SK, SE, UK). Rozex/Metro 0,75% lotion is registered in 19 countries (EU: AT, BE, FR, DE, HU, IE, IT, LU, PL, PT, SK) and pending approval in UK. Metrogel Bioglan is registered 2 countries (EU: IE, UK). MetroGel 1% gel is registered in 6 non-european countries. SUMMARY OF RELEVANT PhVWP/CHMP DISCUSSIONS *, IF ANY: * During the period under review CHANGES TO REFERENCE SAFETY INFORMATION Is the CCDS the reference document? Yes No If not, please indicate which document is used as reference document: Date of the last reference document : 01 September 2010 Which sections of the reference safety document have been changed during the period covered by the PSUR?

3 posology and method of administration (4.2) contraindications(4.3) special warnings and precautions for use(4.4) interaction with other medicinal products and other forms of interaction(4.5) pregnancy and lactation (4.6) effects on ability to drive and use machines(4.7) undesirable effects(4.8) overdose (4.9) Please specify the safety relevant changes: On January 31 st 2009, Galderma submitted previous PSURs covering the period from November 22 nd 2005 to November 21 st During this PSUR worksharing procedure, some concerned Member States (Austria and Germany) raised few comments on the CSP. Subsequently, during the review period, the CDS has been updated according to the agreed CSP (CDS version 2.0 dated September, 1 st 2010 is presented in Appendix 2bis of PSUR 17 and in Appendix 2 of PSUR 18). Changes to the CDS are the following: - Warnings against prolonged duration of treatment and use in children were added in section 4.2 Posology and method of administration of the metronidazole CDS as follows: Metro/Rozex is not recommended for use in children due to a lack of data on safety and efficacy. The recommended duration of treatment should not be exceeded. - Warnings against UV exposure was added in section 4.4 Special Warnings and Special Precautions for Use of the metronidazole CDS as follows: The UV exposure (sunbathing, solarium, sunlamp) should be avoided during the therapy with metronidazole. - Section 4.8 Undesirable effects was updated to present adverse events according to the MedDRA System Organ Classes and frequencies. Furthermore, according to the agreed CSP, the following adverse events: tingling or numbness of the extremities, metallic taste and skin discomfort (burning and stinging) were respectively translated into paraesthesia, hypoesthesia, dysgeusia (metallic taste), skin discomfort (burning, pain of skin/stinging), and contact dermatitis was added. New version of section 4.8 is therefore presented as follows: The following spontaneous adverse experiences have been reported, and within each system organ class, are ranked by frequency, using the following convention: Very common ( 1/10) Common ( 1/100, < 1/10) Uncommon ( 1/ 1,000, < 1/100) Rare ( 1/10,000, < 1/1,000) Very rare (<1/10,000), including isolated reports Skin and subcutaneous tissue disorders Common: dry skin, erythema, pruritus, skin discomfort (burning, pain of skin/stinging), skin irritation, worsening of rosacea. Unknown frequency: contact dermatitis Nervous System disorders: Uncommon: hypoaesthesia, paraesthesia, dysgeusia (metallic taste) Gastrointestinal disorders: Uncommon: nausea Selected differences between RSI and proposed CSP: NA SUSPECTED ADVERSE DRUG REACTIONS (INNOVATOR) DURING THE PERIOD SERIOUS CASES AND ADRs

4 Total number of serious cases, incl. fatalities 18 Number of fatal cases 0 SUSPECTED ADVERSE DRUG REACTIONS, overview TABLE OF ADVERSE DRUG REACTIONS (ADRs) Serious Non-serious Total System Organ Class (SOC) Listed Unlisted Listed Unlisted Blood and lymphatic system disorders 1 1 Cardiac disorders 1 1 Congenital and familial and genetic disorders 0 Ear and labyrinth disorders 1 1 Endocrine disorders 0 Eye disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary disorders 1 1 Immune system disorders Infections and infestations 2 2 Injury poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified 0 Nervous system disorders Pregnancy, puerperium and perinatal conditions 2 2 Psychiatric disorders Renal and urinary disorders 0 Reproductive system and breast disorders 0 Respiratory thoracic and mediastinal disorders Social circumstances 0 Skin and subcutaneous tissue disorders Surgical and medical procedure Vascular disorders 1 1 Total TABLE OF SELECTED* SERIOUS UNLISTED ADRs : Serious unlisted ADRs Number of serious unlisted ADRs (MedDRA PT in agreed SOC order) EYE DISORDERS Uveitis 1* GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Face oedema 1 non serious (+1 from consumer)

5 IMMUNE SYSTEM DISORDERS Anaphylactic reaction 1* Hypersensitivity 7 non serious (+ 1 from consumer) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 1* + 1 non serious Myalgia 1* + 1 non serious Systemic lupus erythematosus 1* NERVOUS SYSTEM DISORDERS Dizzines 2* + 1 non serious (+ 5 from consumers) Epilepsy 1* Facial paresis 1 non serious Headache 2* + 1 non serious (+ 3 from consumers) Neuropathy peripheral 2* + 2 non serious (+ 1 from consumer) SKIN AND SUBCUTANEOUS TISSUE DISORDERS Acne 3 non serious (+ 14 from consumers) Blister 2 non serious (+ 6 from consumers) Dermatitis 4 non serious (+ 6 from consumers) Dermatitis allergic 1 non serious Dermatitis contact 4 non serious (+1 from consumer) Dermatitis exfoliative 1* Drug rash with eosinophilia and systemic symptoms 1* Rash 5 non serious (+ 17 from consumers) Skin exfoliation 3 non serious (+ 22 from consumers) Swelling face 1* + 4 non serious (+ 5 from consumers) Urticaria 1* + 4 non serious * Selection is within the discretion of the P-RMS VALUABLE INFORMATION FROM PSURs FOR OTHER PRODUCTS AUTHORISED IN THE P-RMS Do any of the PSURs for other products authorised in the P-RMS contain information not addressed in the PSUR for the originator product(s)? Yes No If yes, specify in table below: TABLE OF SELECTED* SERIOUS UNLISTED ADRs IN OTHER PSURs AUTHORISED IN THE P- RMS Serious unlisted ADRs (MedDRA PT in agreed SOC order) Number of serious unlisted ADRs * Selection is within the discretion of the P-RMS Other information: OVERALL ASSESSOR COMMENTS ON CASE REPORTS (INCL. LITERATURE CASES) Describe and comment on ADRs of importance from individual case histories. There is no evidence of a significant increase in the frequency of any listed or unlisted reactions reported during

6 the reference period. Hypersensitivity, skin swelling /swelling face, skin exfoliation should be additionally closely monitored in the next PSUR. OVERALL ASSESSOR COMMENTS ON MAH SPONSORED STUDIES Describe and comment on studies of relevance to safety of the product(s) Three clinical studies were conducted and completed during the reference period. No major safety issued were reported and no treatment related serious adverse events or deaths occurred during the studies. One phase IV study has been initiated during the review period and was ongoing at the time of the report. No serious adverse events related to Metrogel was reported. Two clinical phase III studies are planned. OVERALL ASSESSOR COMMENTS ON STUDIES FROM THE LITERATURE Describe and comment on literature studies of relevance to safety of the product(s). No new important information. OVERALL ASSESSOR COMMENTS ON NEW INFORMATION REGARDING Special populations: No new information. Pregnancy/lactation: Seven reports of use during pregnancy were reported during the review period: six cases were medically confirmed: foetal growth retardation and oligohydramnios (1 case); one case was not medically confirmed: foetal heart activity cessation, missed abortion and curettage. Drug interaction: Two serious medically confirmed cases of possible interaction with alcohol have been reported. The analysis of these cases does not rise any safety concern. Overdose: Ten non serious medically confirmed cases and twenty medically unconfirmed non serious cases of off-label due to wrong dose administered (overdose) were reported during the review period. Abuse or misuse: Two medically confirmed cases and six not medically confirmed cases of misuse. All of them were non serious. Medication errors: Two reports, medically confirmed. Long-term treatment: No new information. Off label use: Seventeen medically confirmed reports and twenty five not medically confirmed cases. Items under monitoring: Three items are under monitoring: convulsions, peripheral neuropathy and paraesthesia/hypoaesthesia. A safety review of these items has been carried out. Convulsions No new case of convulsions was received during the review period. However, one case of epilepsy has been reported during the review period. In this case, although a role of metronidazole could not be excluded, limited information provided precludes a causality assessment. Peripheral neuropathy Total number of case reports received during the review period: 5 medically confirmed (2 serious + 2 non

7 serious) + 1 from consumer (non serious). Number of cumulative events of peripheral neuropathy received up to 30-NOV-2011: serious (+ 2 cases of peripheral sensory neuropathy and 1 case of mononeuropathy). Among the cases reviewed, only a few are really evocative of peripheral neuropathy (i.e. bilateral symptoms involving lower limbs, ascending symptomatology, time to onset of a few years). However alternative explanations have not been ruled out. Paraesthesia and Hypoaesthesia Total number of case reports received during the review period: 15 medically confirmed reports (2 serious + 13 non serious). Number of cumulative events of paraesthesia and hypoaesthesia reported up to 30-NOV-2011: 245 non serious + 8 serious. No particular signal has been identified with the available information. COMMENTS ON ANY CHANGE OF THE RISK BENEFIT BALANCE MAH conclusion: The safety information presented in PSUR is consistent with the known safety profile of topical metronidazole. The benefit/risk ratio remains favourable. Peripheral neuropathy, paraesthesia/hypothesia and convulsions will continue to be closely monitored. Assessors conclusions and comments: MAH conclusion is endorsed. Hypersensitivity, skin swelling /swelling face, skin exfoliation should be additionally closely monitored in the next PSUR. ACTION PLAN AND CONCLUSIONS A CHANGES OF THE BENEFIT RISK BALANCE Benefit/risk balance remains positive. Has the benefit risk balance changed? No Yes, please specify: B CHANGES REQUIRED IN THE CSP Is the CSP acceptable? Yes No In general CSP is acceptable, however small updates are justified. The updates are made in accordance with SE and HU comments. If not, specify the necessary changes (specific wordings): C REGULATORY ACTIONS * PROPOSED, IF ANY No regulatory action is needed * Regulatory options may include urgent safety restrictions, variations, suspension or revocation. Topics for close monitoring should be mentioned below in section E.

8 D SUMMARY OF COMMENTS FROM OTHER MSs Member State Comment Agreed action e.g. updating CSP, close monitoring AT No new safety concerns were identified from DK No new safety concerns were identified from FI No new safety concerns were identified from IE No new safety concerns were identified from SE No new safety concerns were identified from CSP update: The name of the product should not be stated in the CSP. The name of the substance should be stated HU DE In Section 4.4 special warnings and precautions for use an additional sentence can be found in the Hungarian SPC of Metrosa, which should be included in the CSP as well. No new safety concerns were identified from instead. CSP update: In section 4.4, after the sentence the UV exposure (sunbathing, solarium, sunlamp) should be avoided during the therapy with metronidazole an explanatory sentence would be helpful, such as Metronidazole transforms into inactive metabolite due to UV exposure, therefore its efficacy decreases significantly. Phototoxic side-effects haven t been reported in clinical trials in relation to metronidazole. E POINTS TO BE ADDRESSED IN THE NEXT PSUR Peripheral neuropathy, parasthesia/hypothesia and convulsions should be further closely monitored as agreed in the previous PSUR. Hypersensitivity, skin swelling /swelling face, skin exfoliation should be additionally closely monitored in the next PSUR. F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS Questions to be addressed by the MAH: MAH response: Galderma agrees to continue the monitoring of the events peripheral neuropathy, parasthesia/hypothesia and convulsions, and to closely monitor the events hypersensitivity, skin swelling /swelling face, skin exfoliation in the next PSUR. P-RMS assessment and conclusion: MAH conclusion is endorsed.

9 FINAL CONCLUSION (SUMMARY OF A-F) In the reporting period no new safety information concerning metronidazole topical use was identified. The benefit/risk balance remains positive for the drug. DLP according to PSUR Worksharing list is Nov Therefore, next PSUR (PSURs) is in January 2015 expected. MAH agrees to continue the monitoring of the events peripheral neuropathy, parasthesia/hypothesia and convulsions, and to closely monitor the events hypersensitivity, skin swelling /swelling face, skin exfoliation in the next PSUR. The CSP is updated according to Swedish comments. The name of the product is removed from the CSP. The name of the substance is stated instead. The CSP is also updated according to Hungarian comments: In section 4.4, after the sentence the UV exposure (sunbathing, solarium, sunlamp) should be avoided during the therapy with metronidazole an explanatory sentence would be helpful, such as Metronidazole transforms into inactive metabolite due to UV exposure, therefore its efficacy decreases significantly. Phototoxic side-effects haven t been reported in clinical trials in relation to metronidazole. DATE AND CONCLUSION OF PHVWP DISCUSSION CONCERNING THIS PSUR, IF ANY:

10 Annex I : CSP Metronidazole (topical) dated: 11/07/2012 In PAR: Proposed CSP with assessor comments, if any In Draft FAR: Proposed CSP with assessor comments In FAR: Agreed CSP 4.2 Posology and method of administration Metronidazole should be applied in a thin layer to the affected areas of the skin twice daily, morning and evening. Areas to be treated should be washed with a mild cleanser before application. Patients may use non comedogenic and non astringent cosmetics after application of metronidazole. The dosage does not need to be adjusted for elderly patients. Metronidazole is not recommended for use in children due to a lack of data on safety and efficacy. The average period of treatment varies according countries. It is usually of three to four months. The recommended duration of treatment should not be exceeded. However, if a clear benefit has been demonstrated continued therapy for a further three to four months period may be considered by the prescribing physician depending upon the severity of the condition. In clinical studies, topical metronidazole therapy for rosacea has been continued for up to 2 years. In the absence of a clear clinical improvement, therapy should be stopped. 4.3 Contraindications Topical metronidazole therapy is contraindicated in individuals with a history of hypersensitivity to metronidazole or other ingredients of the formulation. 4.4 Special warnings and precautions for use Contact with eyes and mucous membranes should be avoided. If irritation does occur the patient should be advised to use metronidazole less frequently or to stop temporarily and to seek medical advice if necessary. The UV exposure (sunbathing, solarium, sunlamp) should be avoided during the therapy with metronidazole. Metronidazole transforms into inactive metabolite due to UV exposure, therefore its efficacy decreases significantly. Phototoxic sideeffects haven t been reported in clinical trials in relation to metronidazole. Metronidazole is a nitro imidazole and should be used with caution in patients with an evidence of, or history of blood dyscrasia. Unnecessary and prolonged use of this medication should be avoided. Evidence suggests that metronidazole is carcinogenic in certain animal species. There is no evidence to date of a carcinogenic effect in human (see section preclinical safety data) 4.5 Interaction with other medications and other forms of interaction Interaction with systemic medication is unlikely because absorption of metronidazole following cutaneous application is low. Nevertheless, it should be mentioned that disulfiramlike reactions has been reported in small number of patients taking metronidazole and alcohol concomitantly. Oral metronidazole has been reported to potentiate the effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. The effect of topical metronidazole on prothrombin time is unknown.

11 4.6 Pregnancy and Lactation There has been no experience to date with the use of topical metronidazole in pregnant patients. In case of oral administration, metronidazole crosses the placental barrier and enters foetal circulation rapidly. No foetotoxicity was observed after oral metronidazole in either rats or mice. However because animal reproduction studies are not always predictive of human response and since oral metronidazole has been shown to be a carcinogen in some rodents this drug should be used in pregnancy only if clearly needed. After oral administration metronidazole is secreted in breast milk in concentration similar to those found in plasma. Even though blood levels are significantly lower with cutaneous application of metronidazole than those achieved after oral metronidazole in nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into importance of the drug to the mother. 4.7 Effects on ability to drive and use machines Based upon the pharmacodynamic profile and clinical experience performance related to driving and using machines should not to be affected. 4.8 Undesirable effects The following spontaneous adverse experiences have been reported, and within each system organ class, are ranked by frequency, using the following convention: Very common ( 1/10) Common ( 1/100, < 1/10) Uncommon ( 1/ 1,000, < 1/100) Rare ( 1/10,000, < 1/1,000) Very rare (<1/10,000), including isolated reports Skin and subcutaneous tissue disorders: Common: dry skin, erythema, pruritus, skin discomfort (burning, pain of skin/stinging), skin irritation, worsening of rosacea. Unknown frequency: contact dermatitis Nervous System disorders: Uncommon: hypoaesthesia, paraesthesia, dysgeusia (metallic taste) Gastrointestinal disorders: Uncommon: nausea 4.9 Overdose No data exist about overdose in humans. Acute oral toxicity studies with topical gel formulation containing 0.75% w/w metronidazole in rats have shown no toxic action with doses of up to 5g of finished product per kilogram body weight, the highest dose used. This dose is equivalent to the oral intake of 12 tubes of 30g packaging Rozex gel /Cream or more than 7 tubes of the 50g packaging of Rozex Cutaneous Emulsion for an adult weighing 72 kg, and 2 tubes of Gel/Cream and more than 1 tube of Cutaneous Emulsion for a child weighing 12kg.