SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Bolamyn SR 500 mg Prolonged Release Tablets (metformin hydrochloride)

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

One prolonged-release tablet contains 500 mg metformin hydrochloride equivalent to 390 mg metformin.

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Prolonged-release tablet

White to off white, oval shaped tablet, debossed “93” on one side and “7267” on the other side.

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. Bolamyn SR may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.

4.2    Posology and method of administration

Posology

Monotherapy and combination with other oral antidiabetic agents:

•    The usual starting dose is one tablet 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 gastrointestinal tolerability. The maximum recommended dose is 4 tablets daily.

•    Dosage increases should be made in increments of 500mg every 10-15 days, up to a maximum of 2000mg once daily with the evening meal. If glycaemic control is not achieved on 2000mg of Bolamyn SR once daily, 1000mg of Bolamyn SR 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 3000mg daily.

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

• If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate Bolamyn SR 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 Bolamyn SR is one tablet once daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Older people: 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).

Paediatric population: In the absence of available data, Bolamyn SR should not be used in children.

4.3 Contraindications

•    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

•    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 section 4.4).

•    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:

The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders as abdominal pain and severe asthenia.

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 5mmol/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).

Physicians should alert the patients on the risk and on the symptoms of lactic acidosis.

Renal function:

As metformin is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) 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 level at the lower 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, diuretic therapy or when starting therapy with a non-steroidal antiinflammatory drug (NSAID).

Administration of iodinated contrast agent:

The intravascular administration of iodinated contrast agents in radiologic studies can lead to renal failure. This may induce metformin accumulation which may expose to increase the risk for lactic acidosis. Metformin must 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 section 4.5).

Surgery:

Metformin hydrochloride must be discontinued 48 hours before elective surgery under general, spinal or peridural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if normal renal function has been established.

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 do not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or other oral anti-diabetes (e.g. sulphonylureas or meglitinides).

• 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

Alcohol

Acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting or malnutrition and hepatic insufficiency.

Avoid consumption of alcohol and alcohol-containing medicinal products. Iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and an increased risk of lactic acidosis.

Metformin must be discontinued prior to or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.4).

Associations requiring precautions for use

Medicinal products with intrinsic hyperglycaemic activity as glucocorticoids (systemic or by local route) and sympathomimetics. More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during the therapy with the respective medicinal products.

Diuretics especially loop diuretics, may increase the risk of lactic acidosis due to their potential to decrease renal function.

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 Fertility, pregnancy and lactation

Pregnancy

Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality.

A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or post-natal development. When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin, but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.

Breast-feeding

Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breast-feeding should be made, taken into account the benefit of breast-feeding and the potential risk to adverse effects on the child.

Fertility

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

4.7 Effects on ability to drive and use machines

Bolamyn SR 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 or meglitinides).

4.8 Undesirable effects

In post marketing data and in controlled clinical studies, adverse event reporting in patients treated with Bolamyn SR was similar in nature and severity to that reported in patients treated with Metformin immediate-release. The following adverse reactions may occur under treatment 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, not known (cannot be estimated from the available data).

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 section 4.4.)

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

Very rare:    Isolated reports of liver function tests abnormalities or

hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders

Very rare:    Skin reactions such as erythema, pruritus, urticaria

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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

Pharmacotherapeutic group: Oral blood glucose lowering drugs, biguanides ATC code: A10BA02

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).

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

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.

Biotransformation

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination

Renal clearance of metformin is >400ml/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

Hypromellose (E454)

Ethylcellulose Cellulose, microcrystalline Magnesium stearate

6.2    Incompatibilities

Not applicable

6.3    Shelf life

30 months

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

Aluminium-aluminium blisters.

Blister packs of 1, 20, 28, 30, 56, 60, 90 & 120 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

TEVA UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1013

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/03/2008

10    DATE OF REVISION OF THE TEXT

23/10/2014