Public Assessment Report Decentralised Procedure … · PAR Equasym XL 40 mg, 50 mg and 60 mg modified-release capsules, hard UK/H/0819/004-6/DC 1. Public Assessment Report . Decentralised

PAR Equasym XL 40 mg, 50 mg and 60 mg modified-release capsules, hard UK/H/0819/004-6/DC

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Public Assessment Report

Decentralised Procedure

EQUASYM XL 40 MG MODIFIED-RELEASE CAPSULES, HARD

EQUASYM XL 50 MG MODIFIED-RELEASE CAPSULES,

HARD

EQUASYM XL 60 MG MODIFIED-RELEASE CAPSULES, HARD

(Methylphenidate hydrochloride)

Procedure No: UK/H/0819/004-6/DC

UK Licence No: PL 27303/0007-9

SHIRE PHARMACEUTICALS IRELAND LIMITED


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LAY SUMMARY This is a summary of the public assessment report (PAR) for Equasym XL 40 mg, 50 mg and 60 mg modified-release capsules, hard. These products will be referred to as Equasym XL in the remainder of this summary. This summary explains how Equasym XL was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Equasym XL. For practical information about using Equasym XL patients should read the package leaflet or contact their doctor or pharmacist. What is Equasym XL and what is it used for? Equasym XL is a hybrid generic medicine. This means that the capsules contain the same active substance (methylphenidate hydrochloride) as the reference product, Ritalin 10mg Tablets but contains a different amount of this active substance and the formulation allows for gradual release of the active substance in the body. Equasym XL 40 mg, 50 mg and 60 mg modified-release capsules, hard are additional strengths of previously approved Equasym XL 10 mg, 20 mg and 30 mg modified-release capsules. Equasym XL is used to treat attention deficit hyperactivity disorder (ADHD) in children and young people between the ages of 6 and 18 after treatments such as counselling and behavioural therapy. Children and young people with ADHD find it hard to sit still and concentrate. It is not their fault that they cannot do these things. Many children and young people struggle to do these things. However, with ADHD they can cause problems with everyday life. Children and young people with ADHD may have difficulty learning and doing homework. They find it hard to behave well at home, at school or in other places. ADHD does not affect the intelligence of a child or young person. How is Equasym XL used? Equasym XL should be given in the morning before breakfast. The capsules may be swallowed whole with a drink of water, or alternatively, may be opened and the capsule contents sprinkled onto a small amount (tablespoon) of applesauce and taken immediately and not stored for future use. If the medicine is taken with soft food, some fluids, e.g. water, should be taken afterwards. Equasym XL is a “modified release” form of methylphenidate which releases the medicine gradually over a time period corresponding to the school day (8 hours). It is intended to take the place of the same total daily dose of traditional (immediate release) methylphenidate taken at breakfast and lunchtime. In patients who have not taken methylphenidate before, their doctor will normally start treatment with traditional (immediate release) methylphenidate tablets. If the doctor feels it is necessary, methylphenidate treatment may be started with Equasym XL 10 mg once daily before breakfast. The doctor will usually start treatment with a low dose and increase it gradually as required, however, the maximum daily dose is 60 mg. Patients who do not feel better after 1 month of treatment should tell their doctor as they may


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need a different treatment. Equasym XL can only be obtained with a prescription. How do Equasym XL work? Equasym XL improves the activity of certain parts of the brain which are under-active. The medicine can help improve attention (attention span), concentration and reduce impulsive behaviour. The medicine is given as part of a treatment programme, which usually includes psychological, educational and social therapy. Equasym XL is prescribed only by doctors who have experience in children or young people’s behaviour problems. ADHD can be managed using treatment programmes. How has Equasym XL been studied? A study was conducted to determine that Equasym XL is bioequivalent to Equasym XL 10 mg, 20 mg and 30 mg modified release capsules. Equasym XL produces the same levels of active substance in the body as the reference medicines, relative to the capsule doses. What is the risk associated with Equasym XL? For the full list of all side effects reported with Equasym XL, see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet. Why is Equasym XL approved? It was considered that the benefits of using Equasym XL to treat ADHD outweigh the risks and the grant of Marketing Authorisations was recommended. What measures are being taken to ensure the safe and effective use of Equasym XL? A Risk Management Plan has been developed to ensure that Equasym XL is used as safely as possible. Based on this plan, safety information has been included in the Summary of Product Characteristics and the package leaflet for Equasym XL, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously. Other information about Equasym XL The MHRA agreed to grant Marketing Authorisations for Equasym XL on 5 February 2013. For more information about treatment with Equasym XL, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in August 2015.

The full PAR for Equasym XL follows this summary.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 5 II Quality aspects Page 6 III Non-clinical aspects Page 10 IV Clinical aspects Page 11 V User consultation Page 13 VI Overall conclusion, benefit/risk assessment and

recommendation Page 14

Annex 1 - Table of content of the PAR update for MRP and DCP

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Scientific discussion I INTRODUCTION Based on the review of the data on quality, safety and efficacy the member states considered that the applications for Equasym XL 40 mg, 50 mg and 60 mg modified-release capsules, hard (PL 27303/0007-9; UK/H/0819/004-6/DC) could be approved. These applications were submitted by the decentralised procedure, with the UK as Reference Member State (RMS), and Belgium, Germany, Denmark, Spain, Finland, France, Ireland, Italy, Luxembourg, Netherlands, Norway and Portugal as Concerned Member States (CMS). These are prescription-only medicines (POM). Methylphenidate is indicated as part of a comprehensive treatment programme for attention-deficit/hyperactivity disorder (ADHD) in children aged 6 years of age and over when remedial measures alone prove insufficient. Treatment must be under the supervision of a specialist in childhood behavioural disorders. Diagnosis should be made according to DSM-IV criteria or the guidelines in ICD-10 and should be based on a complete history or evaluation of the patient. Diagnosis cannot be made solely on the presence of one or more symptom. These applications are made via the Decentralised Procedure (DCP), according to Article 10(3) of Directive 2001/83/EC, as amended, as hybrid applications. The reference medicinal product for these applications is Ritalin 10 mg tablets which was first authorised in the UK in August 1988 and underwent a change of ownership (CoA) to the current marketing authorisation holder (MAH) Novartis Pharmaceuticals UK Ltd on 31 October 1997 (PL 00101/00539). These applications are line extensions (additional strengths) of previously approved applications Equasym XL 10 mg, 20 mg and 30 mg modified release capsules which were originally approved on 11 February 2005 (UK/H/0819/001-3/MR; PL 00039/0528-30) to the MAH UCB Pharma BV (originally known as Celltech Pharmaceuticals Ltd) which underwent a CoA to Shire Pharmaceuticals Ireland Limited in June 2009. Equasym XL is a mild central nervous system (CNS) stimulant with more prominent effects on mental than on motor activities. Its mode of action in man is not completely understood but its effects are thought to be due to cortical stimulation and possibly to stimulation of the reticular activating system. No new non-clinical studies were conducted, which is acceptable given that these are hybrid applications cross-referring to a product that has been licensed for over 10 years. One bioequivalence study (single dose) was submitted to support these applications, comparing the test product Metadate CD 60 mg capsules (UCB, Inc) with the reference product Equasym XL 30 mg modified release capsules (Shire Pharmaceuticals Ireland Limited). The test product (Metadate CD 60 mg capsules, UCB, Inc), which was already commercially available, was taken from the US market. It has been confirmed that the product Metadate CD 60 mg capsules is the same as Equasym XL 60 mg modified release capsules (Shire Pharmaceuticals Ireland Limited). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence study, no new clinical studies were conducted, which is acceptable, given that the applications were for products that are hybrid applications cross-referring to a product that has been licensed for over 10 years. In addition, these


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applications are also line-extensions (additional strengths) of approved product licences containing a well-known active substance. The RMS has been assured that acceptable standards of GMP are in place for this product type at all sites responsible for the manufacture, assembly and batch release of this product. The RMS and CMS considered that the applications could be approved with the end of procedure (Day 210) on 20 December 2012. After a subsequent national phase, the marketing authorisations were granted in the UK on 05 February 2013. II QUALITY ASPECTS S. Active substance INN: Methylphenidate hydrochloride Chemical name:

Structure:

Molecular formula: C14H19NO2HCl Molecular weight: 269.77 Appearance: Methylphenidate hydrochloride is a white or almost white, fine

crystalline powder. Methylphenidate hydrochloride is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance methylphenidate hydrochloride are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. P. Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipients sugar spheres (consisting of sucrose, maize starch), povidone K29 to K32, Opadry Clear YS-1-7006 (consisting of hypromellose, macrogol 400 and macrogol 8000), ethylcellulose aqueous dispersion, dibutyl sebacate, gelatin, titanium dioxide (E171) and black printing ink [consisting of shellac glaze 45% (20% esterified) in ethanol, propylene glycol, ammonium hydroxide 28% and iron oxide black (E172)]. In addition:

• the 40 mg strength also contains yellow iron oxide (E172) • the 50 mg strength also contains indigo carmine (E132), red iron oxide (E172) and

white printing ink [consisting of shellac, propylene glycol, sodium hydroxide,


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povidone K16 and titanium dioxide (E171)]. All excipients comply with their respective European Pharmacopoeia monographs with the exception of Opadry Clear YS-1-7006 which is controlled to a suitable in-house specification and ethylcellulose aqueous dispersion and dibutyl sebacate which comply with National Formulary (NF) standards and iron oxide black (E172) which complies with the Japanese Pharmacopoeia (JP) monograph. In addition, the colourings yellow iron oxide (E172), indigo carmine (E132), red iron oxide (E172) and black iron oxide (E172) [present in the black printing ink] are in compliance with current EU Directives concerning the use of colouring agents. Satisfactory certificates of analysis have been provided for all excipients. Suitable batch analysis data have been provided for each excipient. With the exception of gelatin, none of the excipients contain materials of animal or human origin. The suppliers of gelatin have provided Certificates of Suitability from the European Directorate for the Quality of Medicines (EDQM) to show that they are manufactured in-line with current European guidelines concerning the minimising of risk of transmission of Bovine Spongiform Encephalopathy/transmissible Spongiform Encephalopathies (BSE/TSE). None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these products. Pharmaceutical Development The objective of the development programme was to formulate stable, robust, modified release hard capsules containing 40 mg, 50 mg or 60 mg methylphenidate hydrochloride, which could be considered hybrids of the reference product Ritalin 10 mg tablets (Novartis Pharmaceuticals UK Ltd). The MAH already has approved Equasym XL 10 mg, 20 mg and 30 mg modified release capsules. The higher strength capsules (40 mg, 50 mg and 60 mg) have been developed to increase patient compliance and convenience in situations where the patient requires a dose greater than 30 mg per day (but not exceeding the currently registered maximum daily dose of 60 mg per day). A satisfactory account of the pharmaceutical development has been provided. Comparative in vitro dissolution and impurity profiles have been provided for the proposed and originator products. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at commercial scale and has shown satisfactory results. Finished Product Specification The finished product specifications proposed are acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of analysis have been provided for all working standards used. Container-Closure System All strengths of finished product are packaged in clear polyvinyl chloride (PVC)/Aclar blisters with aluminium foil backing and vinyl seal coating in pack sizes of 28 and 30 modified-release hard capsules. It has been stated that not all pack sizes may be marketed, however, the marketing


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authorisation holder has committed to submitting the mock-ups for any pack size to the relevant regulatory authorities for approval before marketing. Satisfactory specifications and certificates of analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with foodstuff. Stability of the product Stability studies were performed in accordance with current guidelines on batches of the finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 3 years with the storage conditions ‘Store below 25°C.’ Bioequivalence/bioavailability Satisfactory certificates of analysis have been provided for the test and reference batches used in the bioequivalence studies. Summaries of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPCs, PIL and labels are acceptable. In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website.

The following text is the approved label text for the 40 mg capsules. The label text for the 50 mg and 60 mg capsules is in line with this text:


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MAA forms The MAA forms are satisfactory. Expert report The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion There are no objections to the approval of these products from a pharmaceutical view point. III NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of methylphenidate hydrochloride are well-known, no new non-clinical studies are required and none have been provided. In accordance with the Committee for Medicinal Products for Human Use (CHMP), Guideline on the Environmental Risk Assessment of Medicinal Products for Human use


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[EMEA/CHMP/SWP/4447/00], an environmental risk assessment (ERA) has been performed. The predicted environmental concentration (PEC) in surface water for methylphenidate hydrochloride (0. 26 µg /L) is above the threshold value of 0.01 µg/L and as a consequence, the MAH has committed to provide a Phase II risk assessment by September 2013. There are no objections to the approval of these products from a non-clinical viewpoint. IV CLINICAL ASPECTS Clinical Pharmacology The clinical pharmacology of methylphenidate hydrochloride is well-known. With the exception of the bioequivalence study detailed below, no new pharmacodynamic or pharmacokinetic data are provided or required for these applications. Pharmacokinetics In support of these applications, the marketing authorisation holder has submitted the following bioequivalence study: An open-label, randomised, two-treatment, two-sequence, two-period, crossover, single-dose bioavailability study to compare the test product Metadate CD 60 mg capsules (UCB, Inc) versus the reference product Equasym XL 30 mg modified release capsules (Shire Pharmaceuticals Ireland Limited) in healthy adult volunteers. The test product (Metadate CD 60 mg capsules, UCB, Inc), which was already commercially available, was taken from the US market. It has been confirmed that the product Metadate CD 60 mg capsules is the same as Equasym XL 60 mg modified release capsules (Shire Pharmaceuticals Ireland Limited). All volunteers received a single oral dose of either the test or reference product as a 1 x 60 mg capsule (test) or 2 x 30 mg capsule (reference) under fasting conditions. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 24 hours post dose. The washout period between treatment periods was at least 7 days. The pharmacokinetic results for methylphenidate (MPH) in the fasted state are presented below (log-transformed values; geometric least squares mean and 90% confidence intervals):

AUC0-t last area under the plasma concentration-time curve from time zero to t last hours AUC0-∞ area under the plasma concentration-time curve from time zero to infinity. Cmax maximum plasma concentration Tmax Time maximum plasma concentration is reached


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METADATE CD=Test product EQUASYM XL =Reference product

The arithmetic mean (± SD) plasma concentration-time profiles of methylphenidate following single doses of 1x60mg Metadate CD or 2x30mg Equasym XL Capsules for all subjects in the pharmacokinetic set: is presented below:

The above study is also applicable to the 40mg and 50mg dosage strengths. Methylphenidate hydrochloride is rapidly and almost completely absorbed from the capsules and AUC and Cmax are proportional to the dose over the therapeutic range. All strengths of the product contain identical formulations of immediate-release (IR) and extended-release (ER) beads in the same ratio, and, hence, no additional studies are required to support the current applications for the higher strengths. From the clinical point of view the standard multiple dose biowaiver criteria are met. A satisfactory argument could be made that no additional studies are required to support the current applications for the higher strengths. If all six strengths were being developed now, a package of pharmacokinetic (single dose fasting, single dose fed, steady state) studies performed just on the 30mg strength could be accepted as being applicable to all strengths. The submitted biostudy is therefore considered to be not essential to these applications. In addition the MAH provided additional information to confirm that the immediate-release and extended-release beads used in the 40/50/60 mg modified release capsules are the same as those used in the already marketed strengths (10/20/30 mg modified release capsules) and that the ratio between immediate/extended beads is unchanged. The results of the above study show that the 90% confidence intervals for AUC and Cmax for test versus reference product for methylphenidate hydrochloride are within predefined acceptance criteria specified in ”Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/, Corr**). In addition to these parameters, for a biphasic product such as this, the protocol should have specified parameters that reflect each of the two phases of drug release. In this case Cmax for example is a function purely of the delayed phase of drug release. Based on the data here, additional parameters addressing the early phase of drug release would appear to be plasma levels at about 1.5 to 2 hours, and AUC from zero to about 2 hours (after which the delayed phase of drug release starts to dominate). The MAH has also provided data to show that bioequivalence was demonstrated for both the early absorption phase and for the second phase of drug release. Furthermore the near concentration – time curves for the two strengths are virtually superimposable, supporting the position that formal demonstration of bioequivalence (including in this case for both phases of drug release) is not necessary. The two strengths (2 x 30mg and 1 x 60mg) clearly appear to be equivalent.


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Pharmacodynamics No new pharmacodynamic data were submitted and none were required for these applications. Efficacy No new efficacy data were submitted and none were required for these applications. Safety With the exception of the data generated during the bioequivalence study, no new safety data were submitted and none were required for these applications. No new or unexpected safety issues were highlighted by the bioequivalence data. Summaries of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPCs, PIL and labels are acceptable from a clinical perspective. The SmPCs are consistent with that for the reference product. The PIL is consistent with the details in the SmPCs and in-line with the current guidelines. The labelling is in-line with the current guidelines. Clinical Overview The clinical overview has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. 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 satisfactory Risk Management Plan has been submitted for these products. Conclusion The grant of Marketing Authorisations is recommended. V USER CONSULTATION The package leaflet for Equasym XL 10 mg, 20 mg and 30 mg modified release capsules (PL 27303/0004-6) has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. The package leaflet for Equasym XL 40 mg, 50 mg and 60 mg modified-release capsules, hard (PL 27303/0007-9) is in line with this package leaflet and is therefore acceptable.


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VI OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT AND RECOMMENDATION QUALITY The important quality characteristics of Equasym XL 40 mg, 50 mg and 60 mg modified-release capsules, hard 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. As the pharmacokinetics, pharmacodynamics and toxicology of methylphenidate hydrochloride are well-known, no additional data were required. EFFICACY With the exception of the bioequivalence study, no new clinical data were submitted and none are required for this type of application. Bioequivalence has been demonstrated between the applicant’s Metadate CD 60 mg capsules (which is the same as Equasym XL 60 mg modified-release capsules, hard) and the reference product 2 x Equasym XL 30 mg modified release capsules (Shire Pharmaceuticals Ireland Limited). As the 40 mg, 50 mg and 60 mg strengths of the product meet the criteria specified in “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/, Corr**), the results and conclusions of the bioequivalence study on the 60 mg strength can be extrapolated to the 40 mg and 50 mg strengths. SAFETY With the exception of the bioequivalence study, no new data were submitted and none are required for applications of this type. As the safety profile of methylphenidate hydrochloride is well-known, no additional data were required. No new or unexpected safety concerns arose from the safety data from the study. PRODUCT LITERATURE The SmPCs, PIL and labelling are satisfactory and consistent with those for the reference product, where appropriate, and consistent with current guidelines. BENEFIT/RISK ASSESSMENT The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with methylphenidate hydrochloride is considered to have demonstrated the therapeutic value of the products. The benefit/risk balance is, therefore, considered to be positive.

RECOMMENDATION The grant of Marketing Authorisations is recommended.


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Annex 1 - Table of content of the PAR update for MRP and DCP Steps Taken After The Initial Procedure With An Influence On The Public Assessment

Report (Type II variations, PSURs, commitments)

Scope Procedure numbers

Product Information affected

Date of start of the procedure

Date of end of procedure

Approval/ non approval

Assessment report attached

Type II variation to present an updated Environmental Risk Assessment dated 26 November 2012, and associated results of studies for methylphenidate.

UK/H/0819/001-006/II/048

Not applicable

26/11/2013 10/07/2015 Approval Yes


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VARIATION ASSESSMENT REPORT RECOMMENDATION Based on the review of the data on safety, the RMS considers that the variation to update the Environmental Risk Assessment (ERA) is approvable.

EXECUTIVE SUMMARY The original ERA report, dated January 2011, was updated and approved by the Health Authorities in September 2011 for Equasym XL 10 mg, 20 mg and 30 mg modified-release capsules, hard (UK/H/0819/001-003/II/037G). The ERA was further updated and reviewed during the Line Extension procedure for Equasym XL 40 mg, 50 mg and 60 mg modified-release capsules, hard in December 2012 (UK/H/0819/04-06/DC). Shire Pharmaceuticals Ireland Limited committed to provide results of the Phase II ERA as a post approval commitment. The aim of this variation is to present the results of the Phase II studies and an updated ERA Report. The updated ERA covers all strengths of Equasym® XL up to 60mg, in a joint variation application. The Marketing Authorisation Holder (MAH) states that there are no changes to the Summaries of Product Characteristics, Patient Leaflets or labelling as a result of this variation. SCIENTIFIC DISCUSSION Background Methylphenidate hydrochloride (MPH, marketed as Equasym®/Metadate®/ Quasym® worldwide), is a central nervous system (CNS) stimulant that has been extensively used to treat ADHD, particularly in children of school age. A maximum daily dose of 60 mg is recommended. MPH belongs to the piperidine class of compounds which increase the extracellular concentration of dopamine and noradrenaline in the brain primarily through inhibition of the monoamine transporters. At higher doses MPH may also directly increase the release of dopamine and noradrenaline from neuronal terminals. Non clinical aspects An environmental risk assessment report has been prepared and is presented in Section 1.6.1 of the dossier. In accordance with Article 8(3) of Directive 2001/83/EC, as amended, the potential environmental risks posed by medicinal products should be submitted for all new marketing authorisation applications. Surface water Predicted Environmental Concentration (PEC) values were previously calculated using refined Fpen values for EU countries where Equasym XL is marketed. Following refinement of the market penetration factor (Fpen), the PEC values were determined to be less than the action limit of 0.01μg/L in all countries except the UK. For the UK a PEC value of 0.0135μg/L was calculated, which exceeded the action trigger level of 0.01μg/L. These data will not be re-assessed here. The studies conducted are tabulated below:

Substance (INN/Invented Name): methylphenidate CAS-number (if available): PBT screening Result Conclusion


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Bioaccumulation potential- log Kow

OECD107 1.472 Potential PBT (N)

PBT-assessment Phase I Calculation Value Unit Conclusion PEC surfacewater , default or refined (e.g. prevalence, literature)

0.3 µg/L > 0.01 threshold (Y)

Other concerns (e.g. chemical class)

(Y/N)

Phase II Physical-chemical properties and fate Study type Test protocol Results Remarks Adsorption-Desorption OECD 106 or … Koc =119-210 ml/g

Kd = 2-9 ml/g MPH is unlikely to partition to sewage sludge and is likely to remain in the aqueous phase

Ready Biodegradability Test OECD 301 Aerobic and Anaerobic Transformation in Aquatic Sediment systems

OECD 308 DT50, water =11.5 hrs DT50, sediment = DT50, whole system =13.7 hrs

The main transformation product ritalinic acid is persistent in water (DT 50 (20°C) = 149 d).

Phase IIa Effect studies Study type Test protocol Endpoint value unit species

Algae, Growth Inhibition Test/ Species

OECD 201 NOEC 2.55 mg/L Pseudokirchneriella subcapitata

Daphnia sp. Reproduction Test OECD 211 NOEC 2.07

mg/L Daphnia magna

Fish, Early Life Stage Toxicity Test/Species

OECD 210

NOEC 7.31

mg/L In house brood fish

Activated Sludge, Respiration Inhibition Test

OECD 209 EC50 >420 mg/L

Sediment dwelling organism OECD 218 NOEC 1000 mg/kg Chironomus riparius

The MAH has included a discussion of the main characteristics of MPH, noting that it is rapidly and almost completely absorbed and, due to extensive first pass metabolism, its systemic availability amounts to only 30% (11-51%) of the dose. Metabolism is primarily by de-esterification to ritalinic acid which has little or no pharmacological activity. It is unlikely to partition to the sediment extensively. Evidence suggests that ritalinic acid is biodegradable and is not likely to persist in the environment. In addition to this, toxicity to the aquatic environment is not predicted based on the above study results and assessment of potential risks. Water solubility was found to be >100 mg /L methylphenidate (equivalent to 86 mg/L as free base) in treated mains water. This was determined as part of the Fish Early Life Stage study. The following results were obtained from the aquatic tests:


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The predicted no effect concentration (PNEC) for the aquatic compartment was calculated by applying an assessment factor (AF) to the no-observed-effect-concentration (NOEC). The PNECWATER was determined based on the lowest NOEC result from the base set chronic toxicity testing and applying an assessment factor of 10. PNECWATER = 0.169/10 mg/L (0.0169 mg/L) The PNECMICROORGANISM was determined based on the NOAEC from the activated sludge respiration inhibition test and applying an assessment factor of 10. PNECMICROORGANISM = 4/10 mg/L (0.4 mg/L) Entry into the groundwater is considered to occur via bank filtration, except for substances with an average Koc > 10,000 L/kg or for substances that are readily biodegradable, or for substances that have a DT90 < 3 days. Methylphenidate is not considered to be readily biodegradable and has a maximum Koc value of 210. As a result, a groundwater assessment will be carried out. The PNECGROUNDWATER was calculated by applying an assessment factor of 10 to the NOEC result from the chronic Daphnia test. PNECGROUNDWATER = 0.202/10 mg/L (0.0202 mg/L) PECGROUNDWATER was calculated using the formula and default values detailed in the EMA (2006) guideline. PECGROUNDWATER = 0.25 x PECSURFACEWATER = 0.25 x 0.0003 = 0.000075 mg/L The PEC:PNEC ratios were determined to be; PECSURFACEWATER:PNECWATER = 0.018 PECSURFACEWATER:PNECMICROORGANISMS = 0.75 x 10-3 PECGROUNDWATER:PNECGROUNDWATER = 3.71 x 10-3 The above PEC/PNEC ratios are below the trigger values of 1, 0.1 and 1, respectively. The above calculated PEC:PNEC ratios indicate that methylphenidate is unlikely to be a concern for the aquatic environment. The ratio PECSEDIMENT: PNECSEDIMENT ratio is 3.9×10-4. This is below the trigger of 1 and indicates that methylphenidate is unlikely to represent a risk to the sediment compartment. Discussion Based on the UK PEC value, a Tier A assessment was conducted. In these studies, the calculated PEC:PNEC ratios for water microorganisms and groundwater indicated that MPH is unlikely to be a concern for the aquatic environment; the PECSEDIMENT: PNECSEDIMENT ratio was below the trigger of 1, indicating that MPH is unlikely to represent a risk to the sediment compartment and the results from the biodegradation, distribution and persistence studies showed that MPH is unlikely to partition to sewage sludge but would remain in the aqueous phase, and therefore, MPH is unlikely to persist in natural water-sediment systems. The most widely accepted indication of bioaccumulation potential is a high log Kow value. For MPH the log Kow is 0.139 at pH 7 which is below the trigger of 3 suggesting the potential for bioaccumulation in aquatic organisms is likely to be minimal. In addition, MPH


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did not meet the criteria for PBT screening (Kow >4.5). In a review of several studies suggesting that MPH could present a risk of endocrine disruption, the NIH (2005) concluded that it was difficult to discern whether methylphenidate had direct effects on vaginal opening and hormone levels or if effects were secondary to delayed development and altered growth rates. Further, with regard to paediatric clinical studies and whether growth effects were due to appetite suppression or by endocrine alterations as well, the NIH (2005) review concluded that endocrinological data were outdated and used comparison drugs which stimulated prolactin, creating a possible artifact of lower hormone levels with methylphenidate. In light of the conclusions from the NIH review (2005), and considering that methylphenidate is de-esterified and primarily excreted as ritalinic acid, which has little or no pharmacological activity, the MAH has concluded that there is negligible potential for any relevant endocrine disruptor effects in the environment resulting from the indicated use of Equasym XL modified-release capsules. This can be accepted. Overall conclusion An ERA was conducted to assess the potential risk to surface water, groundwater, sediment and micro-organisms. Based on a maximum daily dose for methylphenidate of 60 mg, MPH is considered unlikely to represent a risk for the environment following the prescribed usage of the products.

Documents

Public Assessment Report Decentralised Procedure … · PAR Equasym XL 40 mg, 50 mg and 60 mg modified-release capsules, hard UK/H/0819/004-6/DC 1. Public Assessment Report . Decentralised