public assessment report decentralised procedure … · assessment of renal function, liver...

PAR Methotrexate 2.5 mg Tablets UK/H/3935/002/DC

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Public Assessment Report

Decentralised Procedure

METHOTREXATE 2.5 MG TABLETS

UK/H/3935/002/DC UK Licence No: PL 20117/0163

MORNINGSIDE HEALTHCARE LIMITED


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LAY SUMMARY

On 22nd December 2011, the UK granted Morningside Healthcare Limited a Marketing Authorisation (licence) for Methotrexate 2.5 mg Tablets. Methotrexate 2.5 mg Tablets contain the active ingredient methotrexate. Methotrexate is an antimetabolite and immunosuppressant (medicine which affects the reproduction of the body’s cells and reduces the activity of the immune system). Methotrexate 2.5 mg Tablets are used to treat:

• Active rheumatoid arthritis • Severe psoriasis, especially plaque-type • Psoriatic arthritis in adult patients who have tried other treatments but their illness has

not improved No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of taking Methotrexate 2.5 mg Tablets outweigh the risks and a Marketing Authorisation was granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Patient Information Leaflet Page 11 Module 4: Labelling Page 13 Module 5: Scientific Discussion Page 14 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6: Steps taken after initial procedure Not applicable


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Module 1

Product Name

Methotrexate 2.5 mg Tablets

Type of Application

Generic application, Article 10.1

Active Substance

Methotrexate

Form

Tablets

Strength

2.5 mg

MA Holder

Morningside Healthcare Ltd 115 Narborough Road Leicester LE3 0PA United Kingdom

Reference Member State (RMS)

The United Kingdom (UK)

Concerned Member States (CMS)

Ireland (IE)

Procedure Number

UK/H/3935/002/DC

End of Procedure

Day 210: 10th November 2011


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Module 2 Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Methotrexate 2.5 mg Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5mg of methotrexate. Excipients: 11.88 mg lactose (as lactose monohydrate). For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet. Yellow, circular, biconvex, uncoated tablets plain on both sides, 4.50mm in diameter.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

- Active rheumatoid arthritis in adult patients. - Severe forms of psoriasis vulgaris, particularly of the plaque type, which cannot be sufficiently

treated with conventional therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis.

4.2 Posology and method of administration

For doses not realisable/practicable with this strength another strength of this medicinal product is available. Rheumatoid arthritis The usual dose is 7.5 - 15 mg once weekly. The planned weekly dose may be administered in three divided doses over 36 hours. The schedule may be adjusted gradually to achieve an optimal response but should not exceed a total weekly dose of 20 mg. Thereafter the dose should be reduced to the lowest possible effective dose which in most cases is achieved within 6 weeks. Psoriasis Before starting treatment it is advisable to give the patient a test dose of 2.5–5.0 mg to exclude unexpected toxic effects. If, one week later, appropriate laboratory tests are normal, treatment may be initiated. The usual dose is 7.5–15 mg taken once weekly. The planned weekly dose administered as three divided doses over 24 hours. As necessary, the total weekly dose can be increased up to 25 mg. Thereafter the dose should be reduced to the lowest effective dose according to therapeutic response which in most cases is achieved within 4 to 8 weeks. The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy which should be encouraged. Use in elderly Methotrexate should be used with extreme caution in elderly patients, a dose reduction should be considered due to reduced liver and kidney function as well as lower folate reserves which occurs with increased age. Patients with hepatic impairment Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol.

4.3 Contraindications

Methotrexate is contra-indicated in the presence of severe/significant renal or significant hepatic impairment, liver disease including fibrosis, cirrhosis, recent or active hepatitis; active infectious disease; and overt or laboratory evidence of immunodeficiency syndrome(s) and serious anaemia, leucopoenia or thrombocytopenia. Methotrexate Tablets should not be used concomitantly with drugs


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with antifolate properties (see section 4.5, Interactions with other Medicinal Products and other forms of Interaction). Methotrexate is teratogenic and should not be given during pregnancy or to mothers who are breast feeding (see Section 4.6., Pregnancy and Lactation). Following administration to a man or woman conception should be avoided by using an effective contraceptive method for at least 3 months after using Methotrexate 2.5mg Tablets (see Section 4.4, Special Warnings and Special Precautions for Use). Patients with a known allergic hypersensitivity to methotrexate or any of the excipients should not receive methotrexate.

4.4 Special warnings and precautions for use

Methotrexate should be used with extreme caution in patients with haematological depression, renal impairment, diarrhoea, and ulcerative disorders of the GI tract and psychiatric disorders. Hepatic toxicity has been observed, usually associated with chronic hepatic disease. The administration of low doses of methotrexate for prolonged periods may give rise, in particular, to hepatic toxicity. Liver function should be closely monitored. If hepatic function abnormalities develop, methotrexate dosing should be suspended for at least two weeks. It is only appropriate to restart methotrexate provided the abnormalities return to normal and the re-exposure is deemed appropriate. Particular care and possible cessation of treatment are indicated if stomatitis or GI toxicity occurs as haemorrhagic enteritis and intestinal perforation may result. Reversible eosinophilic pulmonary reactions and treatment resistant, interstitial fibrosis may occur, particularly after long-term treatment. Renal lesions may develop if the urinary flow is impeded and urinary pH is low, especially if large doses have been administered. Renal function should be closely monitored before, during and after treatment. Reduce dose of methotrexate in patients with renal impairment. High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 – 7 by oral or intravenous administration of sodium bicarbonate (5x625mg tablets every three hours) is recommended as a preventative measure. Haematopoietic suppression caused by Methotrexate may occur abruptly and with apparently safe dosages. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white cell or platelet count develops, methotrexate therapy should be withdrawn immediately and appropriate supportive therapy given (see Undesirable Effects section). Patients should be advised to report all symptoms or signs suggestive of infection. Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy. Methotrexate has been shown to be teratogenic; it has been reported to cause foetal death and/or congenital abnormalities. Therefore, it is not recommended in women of childbearing potential unless the benefits can be expected to outweigh the considered risks. If this drug is used during pregnancy for antineoplastic indications, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus. Following administration to a man or woman conception should be avoided by using an effective contraceptive method for at least 3 months after using Methotrexate 2.5mg Tablets (see section 4.3, Contraindications). Methotrexate has some immunosuppressive activity and therefore the immunological response to concurrent vaccination may be decreased. In addition, concomitant use of a live vaccine could cause severe antigenic reaction. Methotrexate should only be used by clinicians that are familiar with the various characteristics of the drug and its mode of action. Before beginning Methotrexate therapy or reinstituting Methotrexate after a rest period, a chest x-ray, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. This will include a routine examination of lymph nodes and patients should report any unusual swelling to the doctor.


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Patients receiving low-dose methotrexate should:

• Have a full blood count and renal and liver function tests before starting treatment. These should be repeated weekly until therapy is stabilised, thereafter patients should be monitored every 2-3 months throughout treatment.

• Patients should report all symptoms and signs suggestive of infection, especially sore throat.

If acute methotrexate toxicity occurs, patients may require treatment with folinic acid. The disappearance of methotrexate from plasma should be monitored, if possible. This is recommended in particular when high, or very high doses are administered in order to permit calculation of an adequate dose of leucovorin (folinic acid) rescue. Patients with pleural effusions and ascites should be drained prior to initiation of methotrexate therapy or treatment should be withdrawn. When to perform a liver biopsy in rheumatoid arthritis patients has not been established either in terms of a cumulative Methotrexate dose or duration of therapy. Pleuropulmonary manifestation of rheumatoid arthritis has been reported in the literature. In patients with rheumatoid arthritis, the physician should be specifically alerted to the potential for Methotrexate induced adverse effects in the pulmonary system. Patients should be advised to contact their physicians immediately should they develop a cough or dyspnoea (see Undesirable Effects section). Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry nonproductive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea. Methotrexate should be withdrawn from patient’s pulmonary symptoms, and a thorough investigation should be made to exclude infection. If methotrexate induced lung disease is Suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted. Lung manifestations of RA and other connective tissue disorders are recognised to occur. In patients with RA, the physician should be specifically alerted to the potential for methotrexate induced adverse effects on the pulmonary system. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Methotrexate is immunosuppressive and may therefore reduce immunological response to concurrent vaccination. Severe antigenic reactions may occur if a live vaccine is given concurrently. Methotrexate is extensively protein bound and may displace, or be displaced by, other acidic drugs. The concurrent administration of agents such as p-aminobenzoic acid, chloramphenicol, diphenyl hydantoins, acidic anti-inflammatory agents, salicylates, sulphonamides, tetracyclines, thiazide diuretics, probenecid, sulfinpyrazone or oral hypoglycaemics will decrease the methotrexate transport function of renal tubules, thereby reducing excretion and almost certainly increasing methotrexate toxicity. Methotrexate dosage should be monitored if concomitant treatment with NSAIDs is commenced, as concomitant use of NSAID's has been associated with fatal methotrexate toxicity. Concomitant administration of folate antagonists such as trimethoprim, co-trimoxazole and nitrous oxide should be avoided. Hepatic and nephrotoxic drugs should be avoided. Acitretin (a treatment for psoriasis) is metabolised to etretinate. Methotrexate levels may be increased by etretinate and severe hepatitis has been reported following concomitant use.


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Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.

4.6 Fertility, pregnancy and lactation

Methotrexate is contra-indicated in pregnancy. Methotrexate affects spermatogenesis and oogenesis and may therefore decrease fertility. This effect appears to be reversible after discontinuation of therapy. Patients and their partners should be advised to avoid pregnancy until 3 months after cessation of methotrexate therapy. Patients should not breast feed whilst taking methotrexate. Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks of effects on reproduction should be discussed with patients of child bearing potential (see section 4.4, Special Warnings and Special Precautions for Use and section 4.3, Contraindications).

4.7 Effects on ability to drive and use machines

None known. 4.8 Undesirable effects

In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions for the various systems are as follows: Skin: Stevens - Johnson syndrome, epidermal necrolysis, erythaematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques has been reported. The recall phenomenon has been reported in both radiation and solar damaged skin. Haematopoietic: Bone marrow depression is most frequently manifested by leucopoenia, thrombocytopenia (which are usually reversible) and anaemia, or any combination may occur. Infection or hypogammaglobulinaemia has been reported. Alimentary System: Mucositis (most frequently stomatitis although gingivitis, pharyngitis and even enteritis, intestinal ulceration and bleeding) may occur. In rare cases the effect of Methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon. Nausea, anorexia and vomiting and/or diarrhoea may also occur. Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital System: Renal failure and uraemia may follow methotrexate administration, particularly after high doses or prolonged administration. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported. Methotrexate can decrease fertility. This effect appears to be reversible after discontinuation of therapy (see section 4.6, Pregnancy and Lactation). Pulmonary System: Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses. In the treatment of rheumatoid arthritis, methotrexate induced lung disease is a potentially serious adverse drug reaction which may occur acutely at any time during therapy. It is not always fully reversible. Pulmonary symptoms (especially a dry, non productive cough) may require interruption of treatment and careful investigation.


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Central Nervous System: Headaches, drowsiness, ataxia and blurred vision have occurred following low doses of methotrexate, transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations have been reported occasionally. Aphasia, paresis, hemiparesis, and convulsions have also occurred following administration of higher doses. There have been reports of leukoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation. Other reports include eye irritation, malaise, undue fatigue, vasculitis, sepsis, arthralgia/myalgia, chills and fever, dizziness, loss of libido/impotence and decreased resistance to infection. Also opportunistic infections such as herpes zoster. Osteoporosis, abnormal (usually "megaloblastic") red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death in relation to or attributed to the use of methotrexate. Although very rare, anaphylactic reactions to methotrexate have been reported. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported (see Section 4.4, Special Warnings and Special Precautions for Use).

4.9 Overdose

Leucovorin is a specific antidote for methotrexate and, following accidental overdosage, should be administered within one hour at a dosage equal to, or greater than, the methotrexate dose. It may be administered by i.v. bolus or infusion. Further doses may be required. The patient should be observed carefully and blood transfusions, renal dialysis and reverse barrier nursing may be necessary. In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate is a phase specific substance, the main effect being directed during the S-phase of cell division. The inhibition of dihydrofolate reductase can be circumvented by the use of leucovorin (folinic acid; citrovorum factor) and protection of normal tissues can be carried out by properly timed administration of leucovorin calcium.

5.2 Pharmacokinetic properties

When given in low doses, methotrexate is rapidly absorbed from the GI tract giving plasma concentrations equivalent to those achieved after i.v. administration. Higher doses are less well absorbed. About 50% has been shown to be protein bound. Biphasic and triphasic plasma clearance has been shown. The majority of the dose is excreted within 24 hours in the urine mainly as unchanged drug.

5.3 Preclinical safety data

No further preclinical safety data are available. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Anhydrous Calcium Hydrogen Phosphate Lactose Monohydrate Sodium starch glycolate Cellulose, microcrystalline Purified Talc Magnesium stearate

6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

18 months 6.4 Special precautions for storage

This medicine has no special storage temperature requirements. Store in the original container to protect from light

6.5 Nature and contents of container

Amber colour PVC /Aluminium blister- Blister packs of 7, 10, 14, 20, 24, 28, 30, 56, 60, 84, 90, 100 and 112 film coated tablets. Not all pack sizes may be marketed

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements 7 MARKETING AUTHORISATION HOLDER

Morningside Healthcare Ltd 115 Narborough Road Leicester LE3 0PA United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 2011/0163 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 22/12/2011 10 DATE OF REVISION OF THE TEXT

22/12/2011


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Module 3 Patient Information Leaflet


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Module 4 Labelling


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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, Ireland and the UK considered that the application for Methotrexate 2.5 mg Tablets could be approved. This prescription only medicine (POM) is indicated for:

• Active rheumatoid arthritis in adult patients • Severe forms of psoriasis vulgaris, particularly of the plaque type, which cannot

be sufficiently treated with conventional therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis

This application for Methotrexate 2.5 mg Tablets was submitted according to Article 10.1 of Directive 2001/83/EC, claiming to be a generic medicinal product of Methotrexate 2.5 mg Tablets, first authorised in the UK to Cyanamid of Great Britain Limited on 27th September 1989 (PL 00095/5079R). This licence then underwent a change of ownership to Goldshield Pharmaceuticals Limited on 5th May 2007 (PL 12762/0231). Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate is a phase specific substance, the main effect being directed during the S-phase of cell division. No new non-clinical studies were conducted, which is acceptable given that the product contains a widely-used, well-known active substance. No clinical studies, with the exception of the bioequivalence study, have been performed and none are required for this application as the pharmacology of methotrexate is well-established. 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. For manufacturing sites outside the community, the RMS has accepted copies of current GMP Certificates or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. The RMS considers that 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 justification has been provided for the absence of a Risk Management Plan.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Methotrexate 2.5 mg Tablets

Name(s) of the active substance(s) (INN) Methotrexate

Pharmacotherapeutic classification (ATC code)

Other immunosuppressive agents (L04AX)

Pharmaceutical form and strength(s) 2.5 mg Tablets

Reference numbers for the Decentralised Procedure UK/H/3935/002/DC

Reference Member State The United Kingdom (UK)

Member States concerned Ireland (IE)

Marketing Authorisation Number(s) PL 20117/0163

Name and address of the authorisation holder Morningside Healthcare Ltd 115 Narborough Road Leicester LE3 0PA United Kingdom


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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance INN name: Methotrexate Chemical name: (2S)-2-[[4-[[(2,4-Diaminopteridin-6-

yl)methyl]methylamino]benzoyl]amino] Pentanedioic acid Structural formula:

Molecular formula: C20H22N8O5 Appearance: Yellow powder. Molecular weight: 545.4 Solubility: Practically insoluble in water, ethanol, chloroform and diethyl ether;

freely soluble in dilute solutions of alkaline hydroxides and carbonates; soluble in dilute hydrochloric acid.

The source of methotrexate used in the product complies with the European Pharmacopoeia monograph for methotrexate. The manufacturer of the drug substance holds a valid EDQM (European Directorate for the Quality of Medicines and Healthcare) Certificate of Suitability. The quality of the substance is suitably controlled in line with the current edition of the relevant European Pharmacopoeia Monograph. The manufacturing process, control of materials, control of critical steps, validation and process development for methotrexate were assessed and approved by the EDQM in relation to the granting of the Certificate of Suitability and are therefore satisfactory. All potential known impurities have been identified and characterised. An appropriate specification with suitable test methods and limits is provided for the active substance. The methods of testing and limits for residual solvents are in compliance with current guidelines. Suitable Certificates of Analysis have been provided for all reference and impurity standards used. 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 current guidelines. Stability studies have been performed with the active substance and no significant changes were observed. On the basis of the results, a suitable re-test period could be approved.


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P. Medicinal Product Other Ingredients Other ingredients in the tablets consist of the pharmaceutical excipients anhydrous calcium hydrogen phosphate, lactose monohydrate, sodium starch glycolate, microcrystalline cellulose, purified talc and magnesium stearate. All excipients comply with their respective European Pharmacopoeia monographs. With the exception of lactose monohydrate, none of the excipients used contain material of animal or human origin. The applicant has provided a declaration that the milk used in the production of the lactose monohydrate is sourced from healthy animals under the same conditions as those intended for human consumption. Confirmation has been provided that the magnesium stearate used in this product is of vegetable 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 produce a safe, efficacious product containing methotrexate that could be considered a generic medicinal product of Methotrexate 2.5 mg Tablets. The applicant has provided suitable product development information. Valid justification for the use and amount of each excipient has been provided. Comparative in-vitro impurity and dissolution profiles have been provided for the proposed and reference products. The reference product used in the bioequivalence study was Maxtrex 2.5mg tablets, which was first authorised in the UK to Farmitalia Carlo Erba Limited (PL 03433/0071). This licence then underwent a change of ownership to Pharmacia Limited on 13th August 2002 (PL 00032/0343). This product is considered to be pharmaceutically equivalent to the reference product. Manufacturing Process A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results. Satisfactory process validation data on commercial-scale batches have been provided. The applicant has committed to perform process validation on future commercial-scale batches. Finished Product Specification The finished product specification is acceptable. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for any working standards used. Container-Closure System This product is packaged in amber colour blisters composed of polyvinyl chloride (PVC) and aluminium. Pack sizes are 7, 10, 14, 20, 24, 28, 30, 56, 60, 84, 90, 100 and 112 tablets.


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Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary product packaging complies with relevant EU directives. Stability of the product Stability studies were performed on batches of the finished products in the packaging proposed for marketing and in accordance with current guidelines. These data support a shelf-life of 18 months with the following storage instructions:

‘Store in the original container to protect from light.’ The SmPC states that there are no special storage temperature requirements. This is satisfactory. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are pharmaceutically acceptable. A representative sample of the UK PIL and label mock-ups are included in modules 3 and 4 of this report. User testing results have been submitted for the PIL for this product. The results indicate that the PIL is in accordance with Article 59 of Council Directive 2001/83/EC, as amended and 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 form The MAA form is pharmaceutically satisfactory. Quality Overall Summary The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion It is recommended that a Marketing Authorisation is granted for this application from a quality point of view.


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III.2 NON-CLINICAL ASPECTS The pharmacodynamics, pharmacokinetics and toxicological properties of methotrexate are well-known. As methotrexate is a widely used, well-known active substance, the applicant has not provided any new non-clinical data and none are required. An overview based on literature review is appropriate. The non-clinical overview has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. An Environmental Risk Assessment has not been provided and is not required for an application of this type. It is recommended that a Marketing Authorisation is granted for this application from a non-clinical point of view.


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III.3 CLINICAL ASPECTS CLINICAL PHARMACOLOGY With the exception of the following bioequivalence study, no new pharmacokinetic or pharmacodynamic data were submitted with this application and none were required. Pharmacokinetics A randomized, single dose, two-treatment, two-period, two-sequence, crossover study to compare the pharmacokinetics of the test product Methotrexate 2.5 mg Tablets versus the reference product Maxtrex (methotrexate) 2.5 mg Tablets (Pharmacia Limited, UK) in healthy subjects under fasting conditions. Blood samples were taken pre- and up to 24 hours post dose. There was a washout period of 7 days between each treatment period. Pharmacokinetic parameters were measured from the plasma and statistically analysed. Results for methotrexate are presented below as log-transformed values: Treatment AUC0-t

(ng.h/mL) AUC0-∞

(ng.h/mL) Cmax

(ng/mL)

Test (T) 313.044 ± 66.1847 319.765 ± 67.1800 85.505 ± 16.9133 Reference (R) 316.101 ± 64.2836 322.786 ± 65.5519 87.998 ± 18.9635

T/R Ratio (90 % CI) 94.89 – 102.81 94.97 – 102.82 90.37 – 104.99

The results for the primary variables indicate that the 90 % confidence intervals for the test/reference ratio of geometric means for AUC0-t, AUC0-∞ and Cmax for methotrexate lie within the acceptance criteria of 80.00 -125.00 %. Thus, bioequivalence has been shown between the test and reference products in this study. Efficacy No new efficacy data were submitted with this application and none were required. Safety With the exception of the data submitted during the bioequivalence study, no new safety data were submitted with this application and none were required. No new or unexpected safety concerns were raised during the bioequivalence study. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are clinically satisfactory and consistent with those for the reference product. 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. MAA Form The MAA form is clinically satisfactory. Conclusion It is recommended that a Marketing Authorisation is granted for this application from a clinical point of view.


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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Methotrexate 2.5 mg Tablets 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 an application of this type. EFFICACY Bioequivalence has been demonstrated between the applicant’s Methotrexate 2.5 mg Tablets and the reference product Maxtrex 2.5 mg tablets. No new or unexpected safety concerns arose from this application. The SmPC, PIL and labelling are satisfactory and consistent with those for the reference product. 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 methotrexate is considered to have demonstrated the therapeutic value of the compound. The benefit-risk balance is therefore considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

public assessment report decentralised procedure … · assessment of renal function, liver...

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