Glucophage 1000mg film-coated tablets

Updated the section 5.1 Pharmacodynamic properties for Mechanism of action

Internal Reference number: TW3355392

Change to section 4 for the side effect of vitamin B12 deficiency with metformin treatment.

Internal Reference: TW2998508

Update of sections 4.4 and 4.8 of the SmPC to include a warning and side effect of vitamin B12 deficiency with metformin treatment. 

Internal Reference: TW2998508

Update of section 4.6 of the SmPC to allow the use of metformin if clinically needed during pregnancy and in the periconceptional phase. 

Update of section 4.6 of the SmPC to allow the use of metformin if clinically needed during pregnancy and in the periconceptional phase. 

(Our ref: TW2762201)

4.2     Posology and method of administration

Posology

Adults with normal renal function (GFR≥ 90 mL/min)

Monotherapy and combination with other oral antidiabetic agents

The usual starting dose is 500 mg or 850 mg metformin hydrochloride 2 or 3 times daily given during or after meals.

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 of metformin hydrochloride is 3 g daily, taken as 3 divided doses.

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

Combination with insulin

Metformin and insulin may be used in combination therapy to achieve better blood glucose control. Metformin hydrochloride is given at the usual starting dose of 500 mg or 850 mg 2 or 3 times 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).

Renal impairment

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

Paediatric population

Monotherapy and combination with insulin

·                Glucophage can be used in children from 10 years of age and adolescents.

·                The usual starting dose is 500 mg or 850 mg metformin hydrochloride once daily, given during or after meals.

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 of metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses.

4.3         Contraindications

·                Hypersensitivity to metformin or to any of the excipients listed in section 6.1.

·                Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis).

·                Diabetic pre-coma.

·                Severe renal failure  (GFR < 30 mL/min).

·                Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock.

·                Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock.

·                Hepatic insufficiency, acute alcohol intoxication, alcoholism.

4.4     Special warnings and precautions for use

Lactic acidosis

Lactic acidosis, a very rare, but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis..

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (>5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.

Renal function

GFR should be assessed before treatment initiation and regularly thereafter, see section 4.2. Metformin is contraindicated in patients with GFR<30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function, see section 4.3.

Cardiac function

Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, metformin may be used with a regular monitoring of cardiac and renal function.

For patients with acute and unstable heart failure, metformin is contraindicated (see section 4.3).

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 4.5.

Surgery

Metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.

Paediatric population

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated.

No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially prepubescent children, is recommended.

Children aged between 10 and 12 years

Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.

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 does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulfonylureas or meglitinides).

4.5     Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Metformin must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 4.4.

Combinations requiring precautions for use

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.

Medicinal products with intrinsic hyperglycaemic activity (e.g. glucocorticoids (systemic and local routes) and sympathomimetics)

More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon its discontinuation.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2.

Co-administration of metformin with

·         Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.

·    Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.

·    Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.

·    Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.

Section 4.5 Interaction with other medicinal products and other forms of interaction:
..........

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2.

Co-administration of metformin with

·         Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.

·    Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.

·    Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.

·    Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.

Section 10 Date of revision of the text

12/2016

3.       PHARMACEUTICAL form

Film-coated tablet.

Glucophage 500 mg: White, circular, convex film-coated tablets, 11 mm in diameter and 5.7 mm high, engraved with GL 500.

Glucophage 850 mg: White, circular, convex film-coated tablets, 13.5 mm in diameter and 6.6 mm high, engraved with GL 850.

Glucophage 1000 mg: White, oval, biconvex film-coated tablets of dimensions 19 mm x 10.5 mm and 6.4 mm high with a score line on both sides with « 1000 » engraved on one side. The tablet can be divided into equal halves.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17 January 2015

To consolidate all SmPC's for the range so that details for tablets and powders are as similar as possible.

Ltd

Bedfont Cross

Stanwell Road

Feltham

Middlesex

TW14 8NX

UK

Adults: