Public Assessment Report Decentralised Procedure Ketorolac trometamol 5 mg/ml eye drops, solution Procedure Nos: UK Licence No: PL 20812/0003 Biokanol Pharma GmbH
LAY SUMMARY On 09 August 2011, the MHRA granted Biokanol Pharma GmbH a Marketing Authorisation for the medicinal product Ketorolac trometamol 5 mg/ml eye drops, solution (PL 20812/0003; ). This is a prescription-only medicine (POM) used to prevent and reduce inflammation after eye surgery. The active ingredient, ketorolac trometamol belongs to a group of medicines known as non-steroidal anti-inflammatory drugs (NSAIDs), which are usually used as painkillers or to treat inflammation No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Ketorolac trometamol 5 mg/ml eye drops, solution outweigh the risks; hence a Marketing Authorisation has been granted. 2
TABLE OF CONTENTS Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 11 Module 4: Labelling Page 16 Module 5: Scientific Discussion Page 19 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6 Steps taken after initial procedure 3
Module 1 Product Names Ketorolac trometamol 5 mg/ml eye drops, solution Type of Application Hybrid, Article 10.3 Active Substance Pharmacotherapeutic classification (ATC code) Form Strength MA Holder Reference Member State (RMS) Concerned Member States (CMS) Procedure Number Ketorolac trometamol Antiinflammatory agents, non steroids (S01BC 05) Eye drops, solution 5 mg/ml Biokanol Pharma GmbH Kehler Str. 7, 76437 Rastatt Germany UK Austria, Germany, Greece, Italy, The Netherlands and Portugal Timetable Day 210 11 July 2011 4
Module 2 Summary of Product Characteristics 1 NAME OF THE MEDICINAL PRODUCT Ketorolac trometamol 5 mg/ml eye drops, solution 2 QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml of solution contains 5 mg ketorolac trometamol (0.5 % w/v) Excipient(s): contains benzalkonium chloride 0.1 mg/ml (0.01 %w/v) For a full list of excipients, see section 6.1. 3 PHARMACEUTICAL FORM Eye drops, solution. Clear and colourless solution 4 CLINICAL PARTICULARS 4.1 Therapeutic indications Ketorolac trometamol 5 mg/ml eye drops are indicated for the prophylaxis and reduction of inflammation and associated symptoms following ocular surgery. 4.2 Posology and method of administration Posology One drop instilled into the eye three times daily starting 24 hours pre-operatively and continuing for up to three weeks post-operatively. If Ketorolac trometamol 5 mg/ml eye drops are used concomitantly with other topical eye medications there must be an interval of at least 5 minutes between the two medications. No dose adjustment is necessary in elderly patients. Paediatric population Ketorolac trometamol 5 mg/ml eye drops are contraindicated in children under the age of 18 years (see section 4.3). Method of administration Ocular use. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients.. The potential exists for cross-sensitivity to acetylsalicylic acid and other non-steroidal antiinflammatory drugs. Ketorolac trometamol 5 mg/ml eye drops are contra-indicated in individuals who have previously exhibited sensitivities to these drugs. Ketorolac trometamol 5 mg/ml eye drops are contra-indicated in children under the age of 18 years and during pregnancy and breast-feeding. 4.4 Special warnings and precautions for use It is recommended that Ketorolac trometamol 5 mg/ml eye drops be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time, or patients with a known history of peptic ulceration. In common with other anti-inflammatory drugs, Ketorolac trometamol 5 mg/ml eye drops may mask the usual signs of infection. Concomitant use of Ketorolac trometamol 5 mg/ml eye drops and topical corticosteroids should be exercised with caution in patients susceptible to corneal epithelial breakdown. Ketorolac trometamol 5 mg/ml eye drops contain benzalkonium chloride as a preservative which may cause eye irritation and should not be used in patients continuing to wear soft (hydrophilic) contact lenses (since benzalkonium chloride is known to discolour this lens-type). Contact lenses should not be 5
worn during instillation of the drug. After instillation there should be an interval of at least 15 minutes before reinsertion. Use of topical NSAIDS may result in keratitis. In some patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs and should be closely monitored for corneal health. Topical NSAIDs should be used with caution in patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g. dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time, as they may be at increased risk for corneal adverse events which may become sight threatening. Post marketing experience with topical NSAIDs also suggest that use more than 24 hours prior to surgery or use beyond 14 days post surgery may increase patient risk for the occurrence and severity of corneal adverse events. 4.5 Interaction with other medicinal products and other forms of interaction Ketorolac trometamol 5 mg/ml eye drops have been safely administered with systemic and ophthalmic medications such as antibiotics, sedatives, beta blockers, carbonic anhydrase inhibitors, miotics, mydriatics and cycloplegics. Ketorolac trometamol 5 mg/ml eye drops may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical corticosteroids may increase the potential for healing problems. If Ketorolac trometamol 5 mg/ml eye drops are used concomitantly with other topical eye medications there must be an interval of at least 5 minutes between the two medications. 4.6 Fertility, pregnancy and lactation Fertility There are no adequate data from the use of ketorolac trometamol on fertility in humans. Pregnancy There are no or a limited amount of data from the use of ketorolac trometamol in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Ketorolac trometamol 5 mg/ml eye drops are not recommended during pregnancy and in women of childbearing potential not using contraception. Lactation Ketorolac trometamol 5 mg/ml eye drops should not be used during breast-feeding. Ketorolac trometamol is excreted in human milk after systemic administration. 4.7 Effects on ability to drive and use machines Transient blurring of vision may occur on instillation of eye drops. Do not drive or use machinery unless vision is clear. 6
4.8 Undesirable effects Frequencies are defined as: Very common ( 1/10) Common ( 1/100 to <1/10) Uncommon ( 1/1,000 to <1/100) Rare ( 1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data). The most frequent adverse events reported with the use of Ketorolac are transient stinging and burning on instillation. MedDRA System organ class Very Common Common Rare Nervous system disorders Immune system disorders Eye disorders Ocular irritation or burning Hypersensitivity Superficial punctate keratitis (SPK), eye pain or stinging, eye and/or eyelid oedema, eye pruritus, conjunctival / ocular hyperaemia The events listed above are classified according to their incidence in clinical trials. Headache Corneal ulcer (ulcerative keratitis), corneal infiltrates, blurred and/or diminished vision, eye dryness, lacrimation increased Occasional post marketing reports of corneal damage including corneal thinning, corneal erosion, epithelial breakdown and corneal perforation have been received. These occurred mainly in patients using concomitant topical corticosteroids and/or with predisposing co-morbidity (see warnings and precautions section 4.4). None of the typical adverse reactions reported with the use of systemic non-steroidal anti-inflammatory agents (including ketorolac trometamol) have been observed at the doses used in topical ophthalmic therapy. 4.9 Overdose There is no experience of overdose by the ophthalmic route. Overdose is unlikely to occur via the recommended method of administration. Currently there are no reports available on overdosing with ketorolac trometamol either by use in the eye or after ingestion. Therefore, there is practically no risk of adverse effects due to accidental oral ingestion. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiinflammatory agents, non-steroids, ATC code: S01BC 05 Ketorolac trometamol is a non-steroidal anti-inflammatory agent demonstrating analgesic and antiinflammatory activity. Ketorolac trometamol inhibits the cyclo-oxygenase enzyme essential for biosynthesis of prostaglandins. Ketorolac has been shown to reduce prostaglandin levels in the aqueous humour after topical ophthalmic administration. Ketorolac trometamol given systemically does not cause pupil constriction. Results from clinical studies indicate that ketorolac has no significant effect on intra-ocular pressure. 7
5.2 Pharmacokinetic properties a) General characteristics Absorption Rabbit aqueous humour bioavailability 0.856 μg-equiv./ml @ 0.5 hr Mean concentration of total radioactivity 1.607 μg-equiv./ml @ 2 hr T max 3.38 hr C max 1.905 μg-equiv./ml AUC (0-8 hr) 9.39 μg-equiv. hr/ml Total AUC 13.53 μg-equiv. hr/ml Half-life 3.77 hr Absolute ocular bioavailability 3.7% After topical ocular doses in the rabbit the half life of total radioactivity in aqueous humor was longer than after intracameral injection. This suggests that topical dosing may lead to a "reservoir" effect in the corneal epithelium and continued flux of drug from the reservoir into the aqueous humor. Distribution After ophthalmic doses were administered to rabbits, peak concentrations of radioactivity were achieved within 1 hour in the ocular tissues and were highest in the cornea (6.06 µg-eq/ml). At 1 hour, the majority of the radioactivity (0.9% of administered dose) was recovered from the sclera (0.58%) and cornea (0.24%), and smaller amounts were recovered from the aqueous humor (0.026%), vitreous humor (0.023%), retina-choroid (0.018%), iris-ciliary body (0.007%) and lens (0.002%). Relative to plasma AUC values, the AUC's in rabbits were higher for cornea (104 fold), sclera (27 fold), iris-ciliary body (5.8 fold), retina-choroid (5.6 fold) aqueous humor (3.3 fold) and approximately one-half in the vitreous humor and lens. After ophthalmic administration, concentrations of drugrelated radioactivity were higher in the ocular tissues and lower in plasma compared with those after IV dosing. Systemic Absorption After ophthalmic doses in the rabbit, ketorolac was absorbed rapidly into the systemic circulation (T max, 15 min). Plasma half-lives after ophthalmic doses (6.6-6.9 hr) were longer than those after IV administration (1.1 hr), suggesting that removal of drug from eye into the venous circulation may be rate-limiting. By comparison of drug levels in aqueous humor after intracameral injection vs. plasma levels after IV administration, ketorolac was shown to clear more rapidly from plasma (6 ml/min) than from the anterior chamber (11 µl/min). In the cynomolgus monkey, peak plasma levels of ketorolac occurred at 1.1 hr after the ophthalmic dose. The plasma half-life of ketorolac was similar after ophthalmic (1.8 hr) and IV doses (1.6 hr). The majority of the ophthalmic dose was excreted in urine (66% in rabbit and 75% in monkey) and a small amount in faeces (11% in rabbit and 2% in monkey). The extent of systemic absorption after ophthalmic dosing averaged 73% in the rabbit and 76% in the cynomolgus monkey. Metabolism After ophthalmic administration in rabbits, ketorolac represented the major component (more than 90%) of radioactivity in aqueous humor and plasma and the p-hydroxy metabolite accounted for 5% of radioactivity in plasma. Ketorolac was also the major component (96%) of plasma radioactivity after ophthalmic dosing in monkeys. After ophthalmic dosing in the rabbit, 72%, 17% and 6% of the total radioactivity in urine was comprised of intact ketorolac, p-hydroxy ketorolac and other polar metabolites, respectively. After IV dosing, the relative proportions of total radioactivity in urine averaged 6% as intact ketorolac, 68% as p-hydroxy ketorolac and 22% as polar metabolites. In the monkey, intact ketorolac and its polar metabolite accounted for 32% and 65% of the total radioactivity in urine, respectively, after ophthalmic dosing, and 50% and 49% of the radioactivity in urine, respectively, after IV dosing. Thus, the metabolism of ketorolac was qualitatively similar after ophthalmic and IV administration in the monkey and rabbit. 8
b) Characteristics in patients Ketorolac trometamol solutions (0.1% or 0.5%) or vehicle were instilled into the eyes of patients approximately 12 hours and 1 hour prior to surgery. Concentrations of ketorolac in aqueous humour sampled at the time of surgery were at the lower limit of detection (40 ng/ml) in 1 patient and below the quantitation limit in 7 patients dosed with 0.1% ketorolac trometamol. The average aqueous humor level of ketorolac in patients treated with 0.5% ketorolac trometamol was 95 ng/ml. Concentrations of PGE 2 in aqueous humour were 80 pg/ml, 40 pg/ml and 28 pg/ml in patients treated with vehicle, 0.1% ketorolac trometamol and 0.5% ketorolac trometamol, respectively. In the 21-day multiple dose (TID) tolerance study in healthy subjects, only 1 of 13 subjects had a detectable plasma level pre-dose (0.021 μg/ml). In another group of 13 subjects, only 4 subjects showed very low plasma levels of ketorolac (0.011 to 0.023 μg/ml) 15 minutes after the ocular dose. Thus, higher levels of ketorolac in the aqueous humor and very low or no detectable plasma levels after ophthalmic doses, suggest that the use of ketorolac trometamol by the ophthalmic route in treatment of ocular disorders results in quite low systemic absorption in patients. 5.3 Preclinical safety data Acute, sub-acute and chronic studies of ketorolac in experimental animals have established the safety of the drug. In addition, octoxynol 40 was separately evaluated for its ocular safety. Ketorolac was found to be non-irritating, it did not demonstrate a local anaesthetic effect, it did not influence the healing of experimental corneal wounds in rabbits, it did not enhance the spread of experimental ocular infections of Candida albicans, Herpes simplex virus type one, or Pseudomonas aeruginosa in rabbits, and it did not increase the ocular pressure of normal rabbit eyes. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium chloride Benzalkonium chloride Edetate disodium Octoxynol 40 Sodium hydroxide (for ph adjustment) Water for injection 6.2 Incompatibilities Not applicable. 6.3 Shelf life 30 months After first opening: 4 weeks. 6.4 Special precautions for storage This product does not require any special storage conditions 6.5 Nature and contents of container White low density polyethylene (LDPE) dropper bottles with transparent LDPE dropper tips and white high density polyethylene (HPDE) screw caps. Each bottle contains 5 ml eye drops. It is available in packs of 1 bottle. 6.6 Special precautions for disposal No special requirements. 7 MARKETING AUTHORISATION HOLDER Biokanol Pharma GmbH Kehler Str. 7, 76437 Rastatt Germany 9
8 MARKETING AUTHORISATION NUMBER(S) PL 20812/0003 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 09/08/2011 10 DATE OF REVISION OF THE TEXT 09/08/2011 10
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Module 5 Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the member states considered that the application for Ketorolac trometamol 5 mg/ml eye drops, solution (PL 20812/0003; ) could be approved. The product is a prescription-only medicine (POM) indicated for the prophylaxis and reduction of inflammation, and associated symptoms. following ocular surgery. This application was submitted using the decentralised procedure, with the UK as reference member state (RMS), and Austria, Germany, Greece, Italy, The Netherlands and Portugal as concerned member states (CMS). The application was submitted under Article 10.3 of Directive 2001/83/EC, as a hybrid application. The reference medicinal product for this application is Acular 5 mg Augentropfen (Allergan Pharmaceuticals, Ireland), which was first authorised in Germany on 17 February 1992. The corresponding reference product in the UK is Acular eye drops (Allergan Limited, UK), which was first authorised in the UK on 16 April 1996. Ketorolac trometamol is a non-steroidal anti-inflammatory drug (NSAIDs), demonstrating analgesic and anti-inflammatory activity. They are commonly used in the management and prevention of non-infectious ocular inflammation and cystoid macular oedema following cataract surgery, in the management of pain following refractive surgery, and other surgical procedures. The rationale for the use of NSAIDs is based on the inhibition of the release of prostaglandins by this substance group No new non-clinical or clinical data have been submitted, which is acceptable given that this is a hybrid application based on an originator product that has been in clinical use for over 10 years. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product at all sites responsible for the manufacture, assembly and batch release of this product. For manufacturing sites within the community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. The RMS and CMS considered that the application could be approved, with the end of procedure (Day 210) on 11 July 2011. After a subsequent national phase, a marketing authorisation was granted in the UK to Biokanol Pharma GmbH on 09 August 2011. 19
II. ABOUT THE PRODUCT Name of the product in the Reference Member State Name(s) of the active substance(s) (INN) Pharmacotherapeutic classification (ATC code) Pharmaceutical form and strength(s) Reference numbers for the Mutual Recognition Procedure Reference Member State Concerned Member States Ketorolac trometamol 5 mg/ml eye drops, solution Ketorolac trometamol Anti-inflammatory agents, non steroids (S01BC 05) Eye drops solution; 5 mg/ml United Kingdom Austria, Germany, Greece, Italy, The Netherlands and Portugal Marketing Authorisation Number(s) PL 20812/0003 Name and address of the authorisation holder Biokanol Pharma GmbH Kehler Str. 7, 76437 Rastatt Germany 20
III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS ACTIVE SUBSTANCE INN: Ketorolac trometamol Chemical name: (±)-5-Benzoyl-2,3-dihydro-1-H-pyrrolizine-1-carboxilic acid 1:1 salt with 2-amino-2-(hydroxymethyl)-1,3-propanediol Structure: Molecular formula: C 15 H 13 NO 3.C 4 H 11 NO 3 Molecular weight: 255.27 + 121.14= 376.41 Appearance: A white or almost white, crystalline powder, freely soluble in water and in methanol, slightly soluble in ethanol (96 per cent), and practically insoluble in methylene chloride. Ketorolac trometamol is the subject of a European Pharmacopoeia (Ph. Eur.) monograph. Synthesis of the drug substance from the designated starting materials has been adequately described, and appropriate in-process controls and intermediate specifications are applied. Satisfactory specifications are in place for all starting materials and reagents and these are supported by relevant certificates of analysis. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specification. Appropriate proof-of-structure data have been supplied for the active substance. All potential known impurities have been identified and characterised. Satisfactory certificates of analysis have been provided for all working standards. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specification. Batch analysis data are provided and comply with the proposed specification. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with Directive 2002/72/EC (concerning materials in contact with food), European Pharmacopoeia 3.1.3 (concerning polyolefines) and European Pharmacopoeia 3.1.4 (polyethylene without additives for containers for preparations for parenteral use and for ophthalmic preparations). Appropriate stability data have been generated, supporting a suitable retest period when stored in the proposed packaging. 21
MEDICINAL PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients sodium chloride, benzalkonium chloride, disodium edetate, octoxynol 40, sodium hydroxide, hydrochloric acid and water for injection. Appropriate justifications for the inclusion of each excipient have been provided. All excipients except octoxynol 40 comply with their respective European Pharmacopoeia monograph. Octoxynol 40 is controlled to a suitable in-house monograph. Certificates of Analysis are provided for each excipient showing compliance with their respective monograph. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Pharmaceutical Development The objective of the development programme was to formulate a stable ophthalmic preparation that is comparable in performance to the reference product Acular 5 mg Augentropfen (Allergan Pharmaceuticals, Ireland). Suitable pharmaceutical development data have been provided for this application. Comparative impurity profiles have been provided for this product and the UK originator product Acular eye drops (Allergan Limited, UK). Manufacturing Process A description and flow-chart of the manufacturing method has been provided. A satisfactory batch formula has been provided for the manufacture of the product. In-process controls are appropriate, considering the nature of the product and the method of manufacture. Process validation studies have been conducted and are satisfactory. Finished Product Specification The finished product specification proposed is acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for all working standards used. Container-Closure System The drug product is packaged in white low-density polyethylene (LDPE) dropper bottles, with transparent LDPE dropper tips and white high-density polyethylene (HDPE) screw caps. Each bottle contains 5 ml eye drops solution and is available in packs of one bottle. Satisfactory specifications and certificates of analysis have been provided for all packaging components. All primary packaging complies with Directive 2002/72/EC (concerning materials in contact with food), European Pharmacopoeia 3.1.3 (concerning polyolefines) and European Pharmacopoeia 3.1.4 (polyethylene without additives for containers for preparations for parenteral use and for ophthalmic preparations). Stability of the product Finished product stability studies were performed in accordance with current guidelines on batches of the finished product in the packaging proposed for marketing. The data support a 22
shelf-life of 30 months (unopened), with no special storage conditions. The shelf-life is 4 weeks after opening the product, with the no special storage conditions. The Marketing Authorisation Holder has provided a post-approval commitment to perform a water-loss study with freshly manufactured bottles, according to CPMP/QWP/122/02, rev 1. The commitment includes that any result exceeding the shelf-life limit for mass loss will be reported to the authority via variation with corrective action. Bioequivalence/Bioavailability As the product provides local therapeutic activity (that is, not systemic), investigation of bioequivalence is not appropriate for this product. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are satisfactory. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. MAA forms The MAA form is satisfactory. Expert report The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion There are no objections to the approval of this product from a pharmaceutical viewpoint. 23
III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of ketorolac trometamol are well-known, no new non-clinical data have been submitted and none are required. The non-clinical expert report has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. As this product is intended for substitution with a product that is already marketed, no increase in environmental burden is anticipated and no Environmental Risk Assessment is necessary. Nevertheless, the applicant has submitted a Phase I Environmental Risk Assessment; the results raised no concerns. There are no objections to the grant of marketing authorisation on non-clinical grounds. 24
III.3 CLINICAL ASPECTS Clinical Pharmacology The clinical pharmacology of ketorolac trometamol is well-established. No clinical studies have been conducted to support the application. Essential similarity with the originator product is based on the comparative quality attributes of the product. The applicant refers to clarification provided from the Co-ordination Group for Mutual Recognition and Decentralised Procedures - human (CMD(h)) [CMD (h) minutes from meeting held on 20 and 21 April 2009], this application is made under Article 10.3 (hybrid) of Directive 2001/83/EC, which states that bioequivalence cannot be demonstrated through bioavailability studies for products for local use intended to act without systemic absorption - in this case after ocular administration. Efficacy The efficacy of ketorolac trometamol is well-known. Efficacy is reviewed in the clinical overview. No new efficacy data have been submitted and none are required for this type of application. Safety No new safety data were submitted and none were required for this application. The applicant has provided an adequate summary of the published literature with respect to safety. Pharmacovigilance System and Risk Management Plan The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. A suitable justification has been provided for not submitting a risk management plan for this product. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPC, PIL and labels are medically acceptable. The SmPC is consistent with that for the innovator product. The PIL is consistent with the details in the SmPC and is consistent with that for the innovator product. The labels are in-line with current requirements. Clinical Expert Report The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Conclusion There are no objections to the grant of a marketing authorisation on clinical grounds. 25
IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Ketorolac trometamol 5 mg/ml eye drops, solution are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit-risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for application of this type. The pharmacokinetic, pharmacodynamic and toxicological properties of ketorolac trometamol are well-known, and it has been used clinically for over 10 years. EFFICACY No clinical studies have been conducted to support the application. Essential similarity with the originator product is based on the comparative quality attributes of the product. The applicant refers to clarification provided from the Co-ordination Group for Mutual Recognition and Decentralised Procedures - human (CMD(h)) [CMD (h) minutes from meeting held on 20 and 21 April 2009], this application is made under Article 10.3 (hybrid) of Directive 2001/83/EC, which states that bioequivalence cannot be demonstrated through bioavailability studies for products for local use intended to act without systemic absorption in this case after ocular administration. SAFETY The safety profile of ketorolac trometamol is well-known. No new or unexpected safety concerns were raised from the clinical study submitted with this application. PRODUCT LITERATURE The approved SmPC is satisfactory and consistent with the innovator product. The final PIL and labelling text are satisfactory, and consistent with those for the innovator product and with the approved SmPC. BENEFIT-RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with ketorolac trometamol is considered to have demonstrated the therapeutic value of the product. The benefit/risk is, therefore, considered to be positive. 26
Module 6 STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted Application type Scope Outcome 27