GLUMEFORM 1000 XR

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GLUMEFORM 1000 XR

Keep out of reach of children.

Read the directions carefully before use.

For prescription only.

QUALITATIVE AND QUANTITATIVE COMPOSITION:

Active ingredient: Metformin hydrochloride ..........1000 mg

Excipients: Hypromellose 2208, carboxymethylcellulose sodium, magnesium stearate, colloidal silicon dioxide.

PHARMACEUTICAL FORM: Extended release tablet.

Product description: A white to off-white, caplet-shaped tablet, plain on both sides, intact edges.

THERAPEUTIC INDICATIONS:

Treatment of type 2 diabetes mellitus (non-insulin dependent) in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.

Glumeform 1000 XR may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.

POSOLOGY AND METHOD OF ADMINISTRATION:

Note: Glumeform 1000 XR should be taken the whole tablet. Do not break or chew the tablet.

Recommended dosage:

The starting dose of metformin in patients who are not currently taking metformin is 500 mg orally, once daily. Increase the dose in 500 mg increments every 1-2 weeks if a higher dose of metformin is needed and there are no gastrointestinal adverse reactions. The dosage of metformin must be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2000 mg.

Adults: Glumeform 1000 XR is intended for patients who are already treated with metformin tablets (extended or immediate release).

The dose of Glumeform 1000 XR should be equivalent to the daily dose of metformin tablets (extended or immediate release), up to a maximum dose of 2000 mg, given with the evening meal.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements.

Combination with insulin:

For patients already treated with metformin and insulin in combination therapy, the dose of Glumeform 1000 XR should be equivalent to the daily dose of metformin tablets up to a maximum of 2000 mg, given with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements.

Elderly: The metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Paediatric population: In the absence of available data, Glumeform 1000 XR should not be used in children.

Recommendations for use in renal impairment:

Glumeform 1000 XR may be used in patients with moderate renal impairment (creatinine clearance [CrCl] 45 - 59 ml/min or estimated glomerular filtration rate [eGFR] 45-59 ml/min/1.73 m2) only in the absence of other conditions that may increase the risk of lactic acidosis and with the following dose adjustments: The starting dose is 500 mg or 750 mg metformin hydrochloride (equivalent to 1 tablet of Glumeform 500 XR or 1 tablet of Glumeform 750 XR), once daily. The maximum dose is 1000 mg daily (1 tablet of Glumeform 1000 XR). The renal function should be closely monitored (every 3 - 6 months).

Assess renal function prior to initiation of metformin and periodically thereafter.

Metformin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.

Initiation of metformin in patients with an eGFR between 30–45 mL/min/1.73 m2 is not recommended.

In patients taking metformin whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.

Discontinue metformin if the patient's eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications, Special warnings and precautions for use].

Discontinuation for iodinated contrast imaging procedures

Discontinue metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin if renal function is stable [see Special warnings and precautions for use].

CONTRAINDICATIONS:

Known hypersensitivity to metformin. Hypersensitivity of any components of the drug.

Severe renal failure (eGFR below 30 mL/min/1.73 m2) [see Special warnings and precautions for use].

Acute or chronic metabolic acidosis, including diabetic ketoacidosis.

Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular administration of iodinated contrast agents.

Acute disease which may cause tissue hypoxia such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock.

Hepatic insufficiency, acute alcohol intoxication, alcoholism.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE:

Lactic acidosis:

Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmia. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anyhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Posology and method of administration, Contraindications, Special warnings and precautions for use, Interactions and Use in special populations].

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin. In metformin treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue metformin and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Posology and method of administration, Clinical Pharmacology]:

- Before initiating metformin, obtain an estimated glomerular filtration rate (eGFR).

- Metformin is contraindicated in patients with an eGFR less than 30 mL/min/

1.73 m2 [see Contraindications].

- Initiation of metformin is not recommended in patients with eGFR between 30 -

45 mL/min/1.73 m2.

- Obtain an eGFR at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

- In patients taking metformin whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

Drug interactions: The concomitant use of metformin with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Interactions]. Therefore, consider more frequent monitoring of patients.

Age 65 or greater: The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiological studies with contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin if renal function is stable.

Surgery and other procedures:

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.

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Metformin should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic states: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue metformin.

Excessive alcohol intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving metformin.

Hepatic impairment: Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin in patients with clinical or laboratory evidence of hepatic disease.

Replacement of metformin with insulin should be given in severe infections, postoperative trauma, and pregnancy.

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.

USE IN PREGNANCY AND LACTATION:

Metformin is contraindicated in pregnant women. A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breast-feeding. 

EFFECTS ON ABILITY TO DRIVE AND USE MACHINE:

Glumeform 1000 XR does not cause hypoglycaemia as monotherapy. However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents.

INTERACTIONS:

Metformin concentration and toxicity may be potentiated by cephalexin, cimetidine, and iodinated contrast media.

Metformin concentration and effects may be decreased by corticosteroids (oral, inhaled, injected), hormone-like substances to release LH, somatropin.

Combined use of alcohol and metformin can increase the risk of hypoglycemia and lactic acidosis.

UNDESIRABLE EFFECTS:

The most common adverse reactions (ADRs) are gastrointestinal disorders. Adverse GI effects appear to be dose related, generally occur at initiation of therapy, and usually temporary.

Very common (ADR > 1/10): 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.

Common (1/100 ≤ ADR < 1/10): Taste disturbance.

Very rare (ADR < 1/10,000): Metabolism and nutrition disorders: lactic acidosis; decrease of vitamin B12 absorption. Skin and subcutaneous tissue disorders: erythema, pruritus, urticaria.

Treatment of ADRs:

Adverse GI effects can be diminished if metformin is taken with foods and the dose is increased gradually.

Decrease of vitamin B12 absorption (insignificantly and rarely), megaloblastic anaemia have been reported during long-term use of metformin. These cases are effectively treated with vitamin B12.

Metformin therapy should be discontinued if plasma lactate concentrations exceed 5mmol/l.

The drug must be discontinued if evidence of renal or hepatic impairment is present.

Metformin therapy should be withheld promptly in patients any condition associated with myocardial infarction or blood infection.

Patients should be advised not to consume excessive amounts of alcohol because of a risk of lactic acidosis.

If a patient during prolonged fasting conditions or treated with a very low caloric intake, metformin should be discontinued.

OVERDOSE:

Hypoglycemia has not been seen even with ingestion of up to 85 grams of metformin, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. The most effective method to remove lactate and metformin is haemodialysis.

PHARMACODYNAMIC PROPERTIES:

ATC code: A10BA02

Glumeform 1000 XR is an antidiabetic agent with the active ingredient - metformin. It belongs to biguanide class. Metformin lowers both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. Metformin may act via 3 mechanisms: reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization; 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).

Independently of its action on glycaemia, metformin has favourable effects on lipid metabolism in patients with type 2 diabetes. Metformin reduces total cholesterol, LDL cholesterol and triglyceride levels. A similar action has not been demonstrated with the extended release formulation.

PHARMACOKINETIC PROPERTIES:        

Absorption: After an oral dose of the extended release tablet, metformin absorption is significantly delayed compared to the immediate release tablet with a reported Tmax at approximately 7 hours (Tmax for the immediate release tablet is 2.5 hours).

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 2000 mg of metformin extended release tablets is similar to that observed after administration of 1000 mg of metformin immediate release tablets b.i.d.

Intrasubject variability of Cmax and AUC of metformin extended release is comparable to that observed with metformin immediate release tablets.

When the extended release tablet is administered in fasting conditions the AUC is decreased by 30% (both Cmax and Tmax are unaffected).

Mean Glumeform 1000 XR absorption is almost not altered by meal composition.

No accumulation is observed after repeated administration of up to 2000 mg of metformin hydrochloride as extended release tablets.

Following a single oral administration of one tablet of Glumeform 1000 XR under fasting conditions, a mean peak plasma concentration of 1214 ng/ml is achieved 5 hours (range 4 to 10 hours) after administration.

Glumeform 1000 XR was shown to be bioequivalent to Glumeform 500 XR at a 1000 mg dose with respect to Cmax and AUC in healthy fed and fasted subjects.

When metformine hydrochloride extended release tablet is administered in fed conditions the AUC is increased by 77% (Cmax is increased by 26% and Tmax is slightly prolonged by about 1 hour).

Distribution:

Plasma protein binding is negligible. Metformin partitions into erythrocy

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