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PAR Diagemet XL 500 mg prolonged release tablets PL 06831/0224

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DIAGEMET XL 500 MG PROLONGED RELEASE TABLETS (metformin hydrochloride)

PL 06831/0224

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

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Steps taken after authorisation – summary

Summary of Product Characteristics Page 14

Product Information Leaflet

Page 21

Labelling Page 23


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DIAGEMET XL 500 MG PROLONGED RELEASE TABLETS (metformin hydrochloride)

PL 06831/0224

LAY SUMMARY

On 07 February 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) granted Genus Pharmaceuticals Limited a licence for the medicinal product Diagemet XL 500 mg prolonged release tablets (PL 06831/0224). This is a prescription-only medicine (POM) used for the treatment of Type 2 (non-insulin dependent) diabetes mellitus when diet and exercise changes alone have not been enough to control blood glucose (sugar). The active ingredient in Diagemet XL 500 mg prolonged release tablets is metformin hydrochloride, which belongs to a group of medicines called biguanides. Metformin hydrochloride makes the body more sensitive to insulin and helps to lower your blood glucose levels. Insulin is a hormone that enables body tissues to take glucose from the blood and to use it for energy or for storage for future use. People with Type 2 diabetes do not make enough insulin in their pancreas or their body does not respond properly to the insulin it does make. This causes a build-up of glucose in the blood, which can cause a number of serious long-term problems. Diagemet XL 500 mg prolonged release tablets are specially made to release the drug slowly in your body and, therefore, are different to the immediate release type of tablets containing metformin hydrochloride which release the drug immediately. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Diagemet XL 500 mg prolonged release tablet outweigh the risks; hence a Marketing Authorisation has been granted.


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DIAGEMET XL 500 MG PROLONGED-RELEASE TABLETS (metformin hydrochloride)

(PL 06831/0224)

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk assessment Page 12


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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Genus Pharmaceuticals Limited a Marketing Authorisation for the medicinal product Diagemet XL 500 mg prolonged release tablets (PL 06831/0224) on 07 February 2011. The product is a prescription-only medicine (POM) used in the treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control. This product may be used as monotherapy, or in combination with other oral glucose lowering agents, or with insulin.

The application was submitted under Article 10.1 of Directive 2001/83/EC, claiming to be a generic medicinal product of Glucophage SR 500 mg prolonged release tablets (Merck Serono Limited, UK) which were first authorised on 26 November 2004. The active ingredient in Diagemet XL prolonged release tablets is metformin hydrochloride, which is a biguanide with glucose lowering effects. It lowers both basal and postprandial plasma glucose. It does not stimulate insulin secretion and, therefore, does not cause hypoglycaemia. No new non-clinical data have been submitted, which is acceptable given that the application was based on being a generic medicinal product of an originator product that has been in clinical use for over 10 years. Three bioequivalence studies (two single-dose and a multiple-dose) were submitted to support this application, comparing the test product Diagemet XL 500 mg prolonged release tablets (Genus Pharmaceutical Limited, UK) and the reference product Gluphage SR 500 mg prolonged release tablets (Merck Serono Limited, UK). The bioequivalence studies were carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence studies no new clinical studies were performed, which is acceptable given that the application was based on being a generic medicinal product of an originator product that has been in clinical use for over 10 years. No new or unexpected safety concerns arose during the assessment of this application and it was, therefore, judged that the benefits of taking Diagemet XL 500 mg prolonged release tablets outweigh the risks; hence a Marketing Authorisation has been granted.


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PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE INN: Metformin hydrochloride Chemical Name: 1) Imidodicarbonimidic diamide, N, N-dimethyl-, monohydrochloride 2) 1,1,-Dimethylbiguanide monohydrochloride Molecular Formula: C4H11N5.HCl Structure:

Molecular weight: 165.62 g/mol Appearance: A white crystalline powder, freely soluble in water, slightly soluble in

alcohol, practically insoluble in acetone and methylene chloride. Metformin hydrochloride is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance metformin hydrochloride, except for specifications of the packaging used and stability data to support a suitable retest period when stored in the proposed packaging are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with foodstuff. Appropriate stability data have been generated to support a suitable retest period for the active substance when stored in the proposed packaging. MEDICINAL PRODUCT Other ingredients Other ingredients consist of the pharmaceutical excipients in the tablet core and film coating, namely stearic acid, shellac, povidone K-30, isopropyl alcohol, colloidal anhydrous silica, magnesium stearate, hypromellose, hydroxy propyl cellulose, titanium dioxide, propylene glycol, macrogol 6000 and purified talc. Appropriate justification for the inclusion of each excipient has been provided. All excipients comply with their respective European Pharmacopoeia monograph, with the exception of stearic acid and shellac (which are controlled to suitable in-house specifications). Satisfactory Certificates of Analysis have been provided for all excipients. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients.


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Pharmaceutical Development The objective of the development programme was to formulate a safe, efficacious, stable product that could be considered a generic medicinal product of the originator, Glucophage SR 500 mg prolonged release tablets (Merck Serono Limited, UK) A satisfactory account of the pharmaceutical development has been provided. Comparative in vitro dissolution and impurity profiles have been provided for this and the originator product. Manufacturing Process A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory based on process validation data and controls on the finished product. Process validation on batches of the product has been provided. Finished product specification The finished product specification is satisfactory. Test methods have been described and have been adequately validated, as appropriate. 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 tablets are packaged in either:

1. polyvinylchloride/polyvinylidene chloride/aluminium blisters strips in pack sizes of 20, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 180 and 600 tablets.

2. white opaque high-density polyethylene (HDPE) bottles, composed of two-piece plastic continuous closures with aluminium foil induction seals, in pack sizes of 20, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 180 and 600 tablets.

Not all pack sizes may be marketed. The Marketing Authorisation Holder has committed to submitting mock-ups for approval before marketing any pack size. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials suitable for contact with food. Stability of the Product Stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 3 years, with no special storage conditions. Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. Bioequivalence/Bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence study.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are pharmaceutically 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 Form The MAA form is satisfactory. Expert Report The pharmaceutical expert report is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion The grant of a Marketing Authorisation is recommended.


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NON-CLINICAL ASSESSMENT PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY No new non-clinical data were submitted, which is acceptable given that the proposed product is a generic medicinal product of an originator product that has been licensed for over 10 years. NON-CLINICAL EXPERT REPORT The non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the non-clinical aspects of the dossier. ENVIRONMENTAL RISK ASSESSMENT A suitable justification has been provided for non-submission of an Environmental Risk Assessment. As this product is intended for generic substitution with a product that is already marketed, no increase in environmental burden is anticipated. Thus, the justification for non-submission of an Environmental Risk Assessment is accepted. CONCLUSION The grant of a Marketing Authorisation is recommended.


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CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY The clinical pharmacology of metformin hydrochloride acid is well-known. With the exception of data from the below bioequivalence studies no new pharmacodynamic or pharmacokinetic data are provided or required for this application. PHARMACOKINETICS Section 5.1 of the Notes for Guidance on Modified Release Oral and Transdermal Dosage Forms (CPMP/EWP/280/96 Corr) requires the demonstration of bioequivalence after single dose and at steady state. In support of this application, the Marketing Authorisation Holder has submitted the following bioequivalence studies: Single-Dose Fasting Study A randomised, open-label, single-dose, two-treatment, two-sequence, two-period, crossover study comparing the pharmacokinetics of the test product Diagemet XL 500 mg prolonged release tablets (Genus Pharmaceuticals Limited, UK) and the reference product Glucophage SR 500 mg prolonged release tablets (Merck Serono Limited, UK) in healthy adults under fasting conditions The subjects were given a single dose (500 mg) of test or reference product with 240mL of 20% glucose solution in water after at least a 10-hour overnight fast. Blood samples were collected before and up to 48 hours after each administration. The washout period between the treatment arms was 8 days. The pharmacokinetic results (presented as geometric means, ratios and confidence intervals) are presented below:

Pharmacokinetic parameters (geometric mean), ratio and confidence intervals [CI]) of metformin hydrochloride

Diagemet XL 500 mg (Test)

Glucophage SR 500 mg (Reference)

Test/Ref Ratio (%)

90% CI

(Cmax) (pg/ml)

689.45 600.41 114.83 107.30-122.88

(AUC0-t) (ng.h/ml)

5275.32 5053.91 104.38 94.73-115.01

AUC0-inf) (ng.h/ml)

5562.95 5436.46 102.33 92.59-113.09

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration 90% geometric CI calculated from ln-transformed data Single-Dose Fed Study A randomised, open-label, single-dose, two-treatment, two-sequence, two-period, crossover study comparing the pharmacokinetics of the test product Diagemet XL 500 mg prolonged release tablets (Genus Pharmaceuticals Limited, UK) and the reference product Glucophage SR 500 mg prolonged release tablets (Merck Serono Limited, UK) in healthy adults under fed conditions The subjects were fasted for at least 10 hours prior to a standard high fat breakfast (about 1000 cal). The subjects were given one 500mg tablet of either the test or reference product with 240mL of 20% glucose solution in water 30 minutes after the start of breakfast.


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Blood samples were collected before and up to 48 hours after each administration. The washout period between the treatment arms was 8 days. The pharmacokinetic results (presented as geometric means, ratios and confidence intervals) are presented below:

Pharmacokinetic parameters (geometric mean, ratio and confidence intervals [CI]) of metformin hydrochloride



Test/Ref Ratio (%)

90% CI

(Cmax) (pg/ml)

664.45 633.99 104.80 101.42-108.30

(AUC0-t) (ng.h/ml)

5619.99 6393.62 87.90 83.87-92.12

AUC0-inf) (ng.h/ml)

6259.05 7139.48 87.67 83.30-92.27

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration 90% geometric CI calculated from ln-transformed data

Multiple-Dose, Steady State Study A randomised, open-label, multiple-dose, two-treatment, two-sequence, two-period, crossover study comparing the pharmacokinetics of the test product Diagemet XL 500 mg prolonged release tablets (Genus Pharmaceuticals Limited, UK) and the reference product Glucophage SR 500 mg prolonged release tablets (Merck Serono Limited, UK) in healthy adults at steady state under fed conditions The subjects were fasted for at least 10 hours prior to a high fat breakfast (about 1000 Kcal). In the sitting position, the subjects were given one 500mg tablet of either treatment with 240mL of 20% glucose solution in water 30 minutes after the start of breakfast on Days 1 to 7.

Blood samples were collected 5 minutes prior to administration on Days 1 to 7 and up to 30 hours after administration on Day 7. The washout period between the treatment arms (last dose of period 1 and first dose of period 2) was 8 days. The pharmacokinetic results (presented as geometric means, ratios and confidence intervals) are presented below:

Pharmacokinetic parameters (geometric mean, ratio and confidence intervals [CI]) of metformin hydrochloride



Test/Ref Ratio (%)

90% CI

(Cmax)ss (pg/ml)

612.5280 610.0714 99.60 96.00-103.33

(AUC0-t)ss (ng.h/ml)

7312.7876 6672.7525 91.25 87.18-95.51

(Cmax)ss maximum plasma concentration at steady state (AUC0-t)ss area under the plasma concentration-time curve from time zero to t hours at steady state 90% geometric CI calculated from ln-transformed data

The 90% confidence intervals of the test/reference ratio of geometric means for (AUC0-t), (AUC0-t)ss, (AUC0-inf), (Cmax) and (Cmax)ss lie within the acceptable limits of 80-125% as required by the guideline on bioequivalence (CHMP/EWP/1401/98. Rev 1). Thus, the data support the claim that the test product Diagemet XL 500 mg prolonged release tablets (Genus Pharmaceuticals Limited, UK) is bioequivalent to the originator product Glucophage SR 500 mg prolonged release tablets (Merck Serono Limited, UK) in fasted, fed and multiple dose, steady states.


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EFFICACY The efficacy of metformin hydrochloride is well-known. No new efficacy data have been submitted and none are required for an application of this type. SAFETY With the exception of the safety data generated during the bioequivalence study, no new safety data were submitted and none are required for this type of application. No new or unexpected safety issues were raised by the bioequivalence data. 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 of the originator product. 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 The grant of a Marketing Authorisation is recommended.


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OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Diagemet XL 500 mg prolonged release 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. As the pharmacokinetics, pharmacodynamics and toxicology of metformin hydrochloride are well-known, no additional data were required. EFFICACY With the exception of the bioequivalence studies, no new data were submitted and none are required for an application of this type. Bioequivalence has been demonstrated between the applicant’s Diagemet XL 500 mg prolonged release tablets and the reference product Glucophage SR 500 mg prolonged release tablets (Merck Serono Limited, UK) for the fed, fasted and multi-dose, steady states. SAFETY With the exception of the safety data from the bioequivalence studies, no new data were submitted and none are required for an application of this type. As the safety profile of metformin hydrochloride is well-known, no additional data were required. No new or unexpected safety concerns arose from the bioequivalence studies. PRODUCT LITERATURE The SmPC, PIL and labelling are satisfactory, and consistent with that for the reference product, where appropriate, along with current guidelines. BENEFIT-RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. The data provided support the claim that this product is a generic medicinal product of the reference product, Glucophage SR 500 mg prolonged release tablets (Merck Serono Limited, UK). Extensive clinical experience with metformin hydrochloride is considered to have demonstrated the therapeutic value of the product. The benefit-risk is, therefore, considered to be positive.


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DIAGEMET XL 500 MG PROLONGEDRELEASE TABLETS (metformin hydrochloride)

(PL 06831/0224)

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the marketing authorisation applications on 08 December 2008

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 07 January 2009.

3 Following assessment of the application the MHRA requested further information relating to the clinical dossier on 27 January 2010, 28 April 2010, 30 September 2010 and 02 December 2010 and the quality dossier on 13 July 2009, 08 September 2010, 02 December 2010 and 24 January 2011.

4 The applicant responded to the MHRA’s requests, providing further information on the clinical dossier on 28 April 2010, 27 August 2010, 04 November 2010 and 26 January 2011, and on the quality dossier on 17 December 2009, 27 August 2010, 17 December 2010 and 25 January 2011.

5 The application was and granted on 07 February 2011


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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT Diagemet XL 500 mg prolonged release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION One prolonged release tablet contains 500mg metformin hydrochloride corresponding to 390 mg metformin base. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM Prolonged release tablet Off-white coloured, oval, biconvex, film coated tablets plain on both sides.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control. Diagemet XL prolonged release tablets may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.

4.2 Posology and method of administration • Monotherapy and combination with other oral antidiabetic agents: • The usual starting dose is one tablet of Diagemet XL once daily. • After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A

slow increase of dose may improve gastro-intestinal tolerability. The maximum recommended dose is 4 tablets of Diagemet XL 500 mg daily.

• Dosage increases should be made in increments of 500 mg every 10-15 days, up to a maximum of 2000 mg once daily with the evening meal. If glycaemic control is not achieved on 2000 mg once daily, 1000 mg twice daily should be considered, with both doses being given with food. If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000 mg daily.

• In patients already treated with metformin tablets, the starting dose of Diagemet XL should be equivalent to the daily dose of metformin immediate release tablets. In patients treated with metformin at a dose above 2000 mg daily, switching to Diagemet XL is not recommended.

• If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate Diagemet XL at the dose indicated above.

Combination with insulin: Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of Diagemet XL is one 500 mg tablet once daily, while insulin dosage is adjusted on the basis of blood glucose measurements. Elderly: Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see section 4.4). Children: In the absence of available data, Diagemet XL should not be used in children.


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4.3 Contraindications • Hypersensitivity to metformin hydrochloride or to any of the excipients. • Diabetic ketoacidosis, diabetic pre-coma. • Renal failure or renal dysfunction (creatinine clearance < 60 ml/min). • Acute conditions with the potential to alter renal function such as:

- dehydration, - severe infection, - shock,

- intravascular administration of iodinated contrast agents (see 4.4 Special warnings and precautions for use).

• Acute or chronic disease which may cause tissue hypoxia such as: - cardiac or respiratory failure, - recent myocardial infarction, - shock • Hepatic insufficiency, acute alcohol intoxication, alcoholism • Lactation (see section 4.6).

4.4 Special warnings and precautions for use

Lactic acidosis: Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia. Diagnosis: Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalised immediately (see section 4.9). Renal function: As metformin is excreted by the kidney, creatinine clearance (this can be estimated using the Cockcroft-Gault formula) and/or serum creatinine levels should be determined before initiating treatment and regularly thereafter: • at least annually in patients with normal renal function, • at least two to four times a year in patients with creatinine clearance levels at the limit of normal

and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with an NSAID. Administration of iodinated contrast agent: As the intravascular administration of iodinated contrast materials in radiological studies can lead to renal failure, metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal. Surgery: Metformin hydrochloride should be discontinued 48 hours before elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hours afterwards.


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Other precautions: • All patients should continue their diet with a regular distribution of carbohydrate intake during

the day. Overweight patients should continue their energy-restricted diet. • The usual laboratory tests for diabetes monitoring should be performed regularly. • Metformin alone never causes hypoglycaemia, although caution is advised when it is used in

combination with insulin or sulphonylureas. • The tablet shells may be present in the faeces. Patients should be advised that this is normal.

4.5 Interaction with other medicinal products and other forms of interaction

Inadvisable combinations Alcohol Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of: • fasting or malnutrition, • hepatic insufficiency.

Avoid consumption of alcohol and alcohol-containing medications. Iodinated contrast agents Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see 4.4 special warnings and precautions for use). Associations requiring precautions for use Glucocorticoids (systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation. ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.

4.6 Pregnancy and lactation Pregnancy: To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fœtal development, parturition or postnatal development (see also section 5.3) When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin, but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels. Lactation: Metformin is excreted into milk in lactating rats. Similar data is not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the compound to the mother.

4.7 Effects on ability to drive and use machines

Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines. However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (sulphonylureas, insulin, repaglinide).


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4.8 Undesirable effects In post-marketing data and in controlled clinical studies, adverse event reporting in patients treated with Diagemet XL was similar in nature and severity to that reported in patients treated with metformin immediate release tablets The following undesirable effects may occur with metformin: Frequencies are defined as follows: very common:>1/10; common >1/100, <1/10; uncommon >1/1,000, <1/100; rare >1/10,000, <1/1,000; very rare <1/10,000 and isolated reports.

Metabolism and nutrition disorders

very rare: Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such an aetiology is recommended if a patient presents with megaloblastic anaemia. Lactic acidosis (see 4.4. Special warnings and precautions for use).

Nervous system disorders

common: Taste disturbance

Gastrointestinal disorders

very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders

isolated reports: Liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders

very rare: Skin reactions such as erythema, pruritus, urticaria 4.9 Overdose

Hypoglycaemia has not been seen with metformin doses of up to 85g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

ORAL ANTI-DIABETICS (A10BA02: Gastrointestinal tract and metabolism) Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. Metformin may act via 3 mechanisms: (1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation (3) and delay of intestinal glucose absorption. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).


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In humans, independently of its action on glycaemia, immediate release metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: immediate release metformin reduces total cholesterol, LDL cholesterol and triglyceride levels. A similar action has not been demonstrated with the prolonged release formulation, possibly due to the evening administration, and an increase in triglycerides may occur. Clinical efficacy : The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in overweight type 2 diabetic patients treated with immediate release metformin as first-line therapy after diet failure. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:

• a significant reduction of the absolute risk of any diabetes-related complication in the metformin

group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034.

• a significant reduction of the absolute risk of diabetes-related mortality: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/ 1000 patient-years, p=0.017;

• a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/ 1000 patient-years (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/ 1000 patient-years (p=0.021);

• a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/ 1000 patient-years (p=0.01)

For metformin used as second-line therapy, in combination with a sulphonylurea, benefit regarding clinical outcome has not been shown. In type 1 diabetes, the combination of metformin and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.

5.2 Pharmacokinetic properties

Absorption After an oral dose of the prolonged release tablet, metformin absorption is significantly delayed compared to the immediate release tablet with a Tmax at 7 hours (Tmax for the immediate release tablet is 2.5 hours). At steady state, similar to the immediate release formulation, Cmax and AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2000mg of metformin prolonged release tablets is similar to that observed after administration of 1000mg of metformin immediate release tablets b.i.d. Intrasubject variability of Cmax and AUC of metformin prolonged release is comparable to that observed with metformin immediate release tablets. When the prolonged release tablet is administered in fasting conditions the AUC is decreased by 30% (both Cmax and Tmax are unaffected). Metformin absorption from the prolonged release formulation is not altered by meal composition. No accumulation is observed after repeated administration of up to 2000mg of metformin as prolonged release tablets. Distribution Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L. Metabolism Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.


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Elimination Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity reproduction.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Tablet core Stearic Acid Shellac Povidone K - 30 Isopropyl Alcohol Silica, colloidal Anhydrous Magnesium Stearate Tablet Coating Hypromellose Hydroxy Propyl cellulose Titanium dioxide Propylene Glycol Macrogol 6000 Talc purified

6.2 Incompatibilities

Not applicable 6.3 Shelf life

3 years 6.4 Special precautions for storage

This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container

20, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 180, 600 tablets in blister strips composed of PVC/PVDC 40g. 20, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 180, 600 tablets in HDPE (High Density Polyethylene) bottles. HDPE bottles are composed of a two-piece plastic continuous thread closure with aluminium-foil induction seal (innerseal). Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.


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7 MARKETING AUTHORISATION HOLDER Genus Pharmaceuticals Limited T/A Genus Pharmaceuticals Park View House 65 London Road Newbury Berkshire RG14 1JN, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 06831/0224 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 07/02/2011 10 DATE OF REVISION OF THE TEXT

07/02/2011

11 DOSIMETRY (IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)


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Labelling


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diagemet xl 500 mg prolonged release … diagemet xl 500 mg prolonged release tablets pl 06831/0224...

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