SITUKA SR 750 MG PROLONGED-RELEASE TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Situka SR 750 mg prolonged release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One prolonged release tablet contains 750 mg metformin hydrochloride corresponding to 585 mg metformin base.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged release tablet.

White to off white capsule shaped 19.60 mm x 9.30 mm uncoated tablet debossed with ‘XR750’ one side and plain on 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. Situka 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

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

Monotherapy and combination with other oral antidiabetic agents:

Situka SR 750 mg is intended for patients who are already treated with metformin tablets (prolonged or immediate release).

The dose of Situka SR 750 mg should be equivalent to the daily dose of metformin tablets (prolonged or immediate release), up to a maximum dose of 1500 mg given with the evening meal.

After 10 to 15 days, it is recommended to check that the dose of Situka SR 750 mg is adequate on the basis of blood glucose measurements.

Combination with insulin:

For patients already treated with metformin and insulin in combination therapy, the dose of Situka SR 750 mg or Situka SR 1000 mg should be equivalent to the daily dose of metformin tablets up to a maximum of 1500 mg or 2000 mg respectively, given with the evening meal, 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).

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

Patients with 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.

Metformin is contraindicated in patients with severe renal failure (GFR <30 mL/min).

Method of administration

Situka SR 750 mg prolonged release tablet is for oral administration.

They should be taken whole with a glass of water. They should not be chewed or crushed.

These tablets should always be taken with food.

4.3 Contraindications

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

Diabetic pre-coma

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

Renal failure or renal dysfunction (creatinine clearance < 60 ml/min).

Severe renal failure (GFR <30 mL/min)

Acute conditions with the potential to alter renal function such as:

– dehydration,

– severe infection,

– shock,

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

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.

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.

Diagnosis:

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 patients should stop taking metformin and seek immediate medical attention.

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.

This can be followed by acidotic dyspnea, abdominal pain, hypothermia and coma.

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.

If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalised immediately (see section 4.9).

As metformin is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels 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 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 a non-steroidal antiinflammatory drug (NSAID).

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.

Intravascular administration of iodinated contrast agent 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 atleast 48 hours after, provided that renal function has been re-evaluated and found to be stable (see section 4.2 and 4.5).

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.

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 other oral antidiabetics (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 Concomitant use not recommended

Alcohol

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

Avoid consumption of alcohol and alcohol-containing medications.

Iodinated contrast media

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

Metformin hydrochloride 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 section 4.2 and 4.4).

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 other drug and upon its discontinuation.

Cationic medicinal products that are eliminated by renal tubular secretion (e.g., cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50 % and Cmax by 81 %. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered.

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclooxygenase (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.

They may increase the risk of lactic acidosis due to their potential to decrease renal function.

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.

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 fetal development, parturition or postnatal development (see section 5.3).

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 new-borns/infants. However, as only limited data are available, breast-feeding is not recommended during metformin treatment. A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breast-feeding and the potential risk to adverse effect on the child.

Fertility

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/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

Metformin has negligible influence on the 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 (e.g. sulphonylureas, insulin, or meglinitides).

4.8 Undesirable effects

All medicines can cause allergic reactions although serious allergic reactions are very rare. In post marketing data and in controlled clinical studies, adverse event reporting in patients treated with Situka SR was similar in nature and severity to that reported in patients treated with Situka immediate release.

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite, which resolve spontaneously in most cases.

The following adverse reactions may occur with Situka SR. Frequencies are defines as follows: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10000 to <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

i) Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.

ii) 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.

iii) Isolated reports of liver function test abnormalities or hepatitis resolving upon metformin discontinuation

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

Yellow Card Scheme

Website: www.mhra.gov.uk yellowcard or search  for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms:

Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis.

Management:

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 ANTI-DIABETICS

ATC code: 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.

Mechanism of action:

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.

Pharmacodynamic effects

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).

In clinical studies, the major non glycemic effect of metformin is either weight stability or modest weight loss.

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 and safety :

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.

Following a single oral administration of one tablet of Situka SR 1000 mg under fasting conditions, mean AUC of 7738 ng.hr/ml and a mean peak plasma concentration of 1165 ng/ml is achieved 3.9 hours (range 2 to 6.5 hours) after administration.

Following a single oral administration of one tablet of Situka SR 1000 mg under fed

conditions, mean AUC of 10744 ng.hr/ml and a mean peak plasma concentration of 1102

ng/ml is achieved 5.5 hours (range of 5 to 8 hours) after administration

Mean metformin absorption from the prolonged release formulation is almost 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 volume of distribution (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 > 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

Non-clinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity.

6.1

Magnesium stearate

Silica colloidal anhydrous

Povidone – K30

Hypromellose

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

Tablets are supplied in transparent PVC/Aluminium blister packs containing 28 or 56 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Mercury Pharmaceuticals Ltd,

Capital House, 85 King William Street,

London EC4N 7BL, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 12762/0492

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/08/2015