Second line treatment of type 2 diabetes mellitus in adult patients whose glycaemic control is inadequate after diet and exercise alone, and where combined therapy is metformine and glibenclamide is appropriate.

Oral route.

For use in adults only.

General:

As for all hypoglycaemic agents, the dosage should be adapted according to the individual metabolic response (glycemia, HbA1c).

Initiation of treatment:

Treatment should be initiated with a dose of the combination product equivalent to previous individual doses of metformin and glibenclamide; the dose being gradually increased depending on results on glycemic parameters.

Dose titration:

The dosage should be adjusted every 2 weeks or longer, by increments of 1 tablet, depending on glycemia results.

A gradual increase in the dosage may aid gastrointestinal tolerance and prevent the onset of hypoglycemia.

Maximum daily recommended dose:

The maximum daily recommended dose is 6 tablets of Diamet 500 mg/2.5 mg.

Dosage regimen:

The dosage regimen depends on the individual posology:

• Once a day, in the morning at breakfast, for a dosage of 1 tablet/day,

• Twice a day, morning and evening, for a dosage of 2 or 4 tablets/day,

• Three times a day, morning, noon and evening, for a dosage of 3, 5 or 6 tablets/day.

 

The tablets should be taken with meals. The dosage regimen should be adjusted according to the individual eating habits. However, any intake must be followed by a meal with a sufficiently high carbohydrate content to prevent the onset of hypoglycemic episodes.

Combination with insulin therapy:

No clinical data are available on the concomitant use of this product with insulin therapy.

Elderly subjects:

The dosage of Diamet should be adjusted depending on renal function parameters (start with 1 tablet of Diamet 500 mg/2.5 mg); regular checks on the renal function are necessary (see section 4.4).

Pediatric population:

Diamet is not recommended for use in children (see section 5.1).

• Hypersensitivity to metformin, glibenclamide or other sulphonylurea(s) and sulphonamides or to any of the excipients; • Type 1 diabetes (insulin-dependent diabetes), ketoacidosis, and 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; • 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; • Porphyria; • Lactation; • In association with miconazole (see section 4.5).

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, alcoholism, 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.

This can be followed by acidotic dyspnea, abdominal pain, hypothermia and 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, this medicinal product should be discontinued and the patient should be hospitalized immediately (see section 4.9).

Hypoglycemia

As it contains a sulphonylurea, Diamet exposes the patient to a risk of onset of hypoglycemic episodes. After treatment initiation, a progressive dose titration may prevent the onset of hypoglycemia. This treatment should only be prescribed if the patient adheres to a regular meal schedule (including breakfast). It is important that carbohydrate intake is regular since the risk of hypoglycemia is increased by a late meal, insufficient or unbalanced carbohydrate intakes. Hypoglycemia is more likely to occur in case of energy-restricted diet, after intensive or prolonged exercise, when alcohol intake or during the administration of a combination of hypoglycemic agents.

Diagnosis:

The symptoms of hypoglycemia are: headache, hunger, nausea, vomiting, extreme tiredness, sleep disorder, restlessness, aggression, impaired concentration and reactions, depression, confusion, speech impediment, visual disturbances, trembling, paralysis and paraesthesia, dizziness, delirium, convulsions, somnolence, unconsciousness, superficial breathing and bradycardia. Due to a counterregulation caused by the hypoglycemia sweating, fear, tachycardia, hypertension, palpitations, angina and arrhythmia can occur. These latter symptoms can be absent when the hypoglycemia is developed slowly, in case of autonomic neuropathy or when the patients take beta-blocking agents, clonidine, reserpine, guanethidine or other sympathomimetics.

Management of hypoglycemia:

Moderate hypoglycemic symptoms without loss of consciousness or neurological manifestations should be corrected by the immediate intake of sugar. An adjustment to the dosage and/or changes to meal patterns should be ensured. Severe hypoglycemic reactions with coma, seizures or other neurological signs are also possible and constitute a medical emergency requiring immediate treatment with intravenous glucose once the cause is diagnosed or suspected, prior to prompt hospitalization of the patient.

The careful selection of patients and dosage and adequate instructions for the patient are important to reduce the risk of hypoglycemic episodes. If the patient encounters repeated episodes of hypoglycemia, which are either severe or associated with unawareness of the situation, antidiabetic treatment options other than Diamet should be taken into consideration. Factors favoring hypoglycemia:

• Concomitant administration of alcohol, especially combined with fasting,

• Refusal or (more particularly in elderly patients) inability of the patient to co-operate,

• Malnutrition, irregular meals, missed meals, fasting or changes to diet,

• Poor balance between physical exercise and carbohydrate intake,

• Renal failure,

• Severe liver failure,

• Overdose of Diamet,

• Certain endocrine disturbances: thyroid insufficiency, pituitary and adrenal gland insufficiency,

• Concomitant administration of certain other drugs (see section 4.5).

Renal and hepatic failure:

The pharmacokinetics and/or pharmacodynamics of Diamet may be modified in patients with hepatic failure or severe renal failure. If hypoglycemia occurs in such patients, it may be prolonged, and appropriate treatment must be initiated.

Patient Information:

The risks of hypoglycemia, its symptoms and its treatment, as well as its predisposing conditions, must be explained to the patient and his or her family. Similarly, the risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps accompanied by digestive disorders, abdominal pain and severe asthenia, dyspnoea attributed to acidose, hypothermia and coma.

In particular, the patient should be informed of the importance of adhering to a diet, following a programme of regular physical exercise and making regular checks on glycemia.

Blood sugar imbalance

In case of surgery or any other cause of diabetic decompensation, temporary insulin therapy should be envisaged instead of this treatment.

The symptoms of hyperglycemia are: increased urinating, raging thirst and a dry skin.

Kidney 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 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 or diuretic therapy, and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).

Administration of iodinated contrast media

The intravascular administration of iodinated contrast media in radiological studies can lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. Depending on the renal function, Diamet must be discontinued 48 hours before the test or at the time of the test and may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).

Concomitant use of glibenclamide with other medicinal products

The concomitant use of glibenclamide with alcohol, phenylbutazone or danazol is not recommended (see section 4.5).

Surgery

Because Diamet contains metformin hydrochloride, Diamet must be discontinued 48 hours before elective surgery under general, spinal or peridural anesthesia and may not be reinstituted earlier than 48 hours following surgery or resumption of oral nutrition and only after renal function has been re-evaluated and found to be normal .

Pancreatitis:

Diamet must be discontinued when pancreatitis is combined with sepsis or hypoxia.

Alcohol:

Alcohol is known to potentiate the effect of metformine in lactate metabolism. Patients should be warned against excessive alcohol intake, acute or chronic, while taking Diamet, due to the increase of the risk of lactic acidosis particularly in case of fasting or malnutrition or hepatic insufficiency.

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.

Regular physical exercise is as necessary as taking Diamet.

The usual laboratory tests for diabetes monitoring (glycemia, HbA1c) should be performed regularly,

Treatment of patients with G6PD-deficiency with sulphonylurea agents can lead to hemolytic anemia. Since glibenclamide belongs to the chemical class of sulphonylurea drugs, caution is recommended when using Diamet in patients with G6PD-deficiency and a non-sulphonylurea alternative may be considered.

Contraindicated combination

Related to glibenclamide

Miconazole (systemic route, oromucosal gel):

Increase in the hypoglycemic effect with possible onset of hypoglycemic manifestations, or even coma (see section 4.3).

Combinations not recommended

Related to sulphonylurea(s)

Alcohol:

Antabuse effect (intolerance to alcohol), notably for chlorpropamide, glibenclamide, glipizide, tolbutamide.

Increase of the hypoglycemic reaction (inhibition of compensation reactions), which may facilitate the onset of a hypoglycemic coma (see section 4.4).

Avoid consumption of alcohol and alcohol-containing medications.

Phenylbutazone (systemic route):

Increase in the hypoglycemic effect of sulphonylurea(s) (displacement of sulphonylurea(s) from protein-binding sites and/or decrease in their elimination). Preferably use another anti-inflammatory agent exhibiting fewer interactions, or else warn the patient and step up self-monitoring; if necessary, adjust the dosage during treatment with the anti-inflammatory agent and after its withdrawal.

Related to all antidiabetic agents

Danazol:

If the combination cannot be avoided, warn the patient and step up self-monitoring of blood glucose. Possibly adjust the dosage of the antidiabetic treatment during treatment with danazol and after its withdrawal.

Related to metformin

Alcohol:

Acute alcoholic intoxication is associated with increased risk of lactic acidosis, particularly in cases of fasting (see section 4.4) or malnutrition and hepatocellular failure.

Avoid drinking alcoholic beverages and taking drugs that contain alcohol.

Combinations requiring precautions

Related to all antidiabetic agents

Chlorpromazine:

At high dosages (100 mg per day of chlorpromazine), elevation in blood glucose (reduction in release of insulin).

Precaution for use: warn the patient and step up self-monitoring of blood glucose. Possibly adjust the dosage of the antidiabetic treatment during treatment with the neuroleptic and after its withdrawal.

Corticosteroids (glucocorticoids) and tetracosactides (systemic and local routes):.

Elevation in blood glucose, sometimes accompanied by ketosis (decreased carbohydrate tolerance with corticosteroids).

Precaution for use: warn the patient and step up self-monitoring of blood glucose. Possibly adjust the dosage of the antidiabetic during treatment with corticosteroids and after their withdrawal.

Β2-agonists:

Elevation in blood glucose due to the β2-agonists.

Precaution for use: warn the patient, step up blood glucose monitoring and possibly transfer to insulin therapy.

Angiotensin converting enzyme inhibitors (e.g. captopril, enalapril):

ACE inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of Diamet during therapy with an ACE inhibitor and upon its discontinuation.

Related to metformin

Diuretics:

Lactic acidosis due to metformin triggered by any functional renal insufficiency, related to diuretics and more particularly to loop diuretics.

Iodinated contrast media:

Intravascular administration of iodinated contrast media may lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. Depending on the renal function, Diamet must be discontinued 48 hours before the test 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.

Related to glibenclamide

Beta-blockers:

All beta-blockers mask some of the symptoms of hypoglycemia : palpitations and tachycardia;

Most non-cardioselective beta-blockers increase the incidence and severity of hypoglycemia.

Warn the patient and step up blood glucose self-monitoring, especially at the start of treatment.

Fluconazole:

Increase in the half-life of sulphonylurea with possible onset of hypoglycemic manifestations.

Warn the patient and step up blood glucose self-monitoring, and possibly adjust the dosage of the antidiabetic treatment during treatment with fluconazole and after its withdrawal.

Bosentan:

Risk of decreased hypoglycemic effect of glibenclamide because bosentan reduces the plasma concentration of glibenclamide. An increased risk of liver enzyme elevations was reported in patients receiving glibenclamide concomitantly with bosentan.

Warn the patient, set-up monitoring of glycemia and liver enzymes and adjust the dosage of the antidiabetic treatment if necessary.

Other interaction: combination to be taken into account:

Related to glibenclamide

Desmopressin:

Reduction in antidiuretic activity.

Pregnancy

No preclinical and clinical data on exposed pregnancies are available for Diamet.

Risk related to diabetes

When uncontrolled, diabetes (gestational or permanent) gives rise to an increase in congenital abnormalities and perinatal mortality. Diabetes must be controlled as far as possible during the period of conception in order to reduce the risk of congenital abnormalities.

Risk related to metformin (see section 5.3)

Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or fetal development, parturition or postnatal development.

A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities.

Risk related to glibenclamide (see section 5.3)

Studies in animals have shown no evidence of teratogenic activity. In the absence of a teratogenic effect in animals, fetal malformation in humans is not to be expected since to date, substances known to cause malformation in humans have proved to be teratogenic in well-conducted animal studies in two species.

In clinical practice, there are currently no relevant data on which to base an evaluation of potential malformation or fetotoxicity due to glibenclamide when administered during pregnancy.

Management

Adequate blood glucose control allows pregnancy to proceed normally in this category of patients. Diamet must not be used for the treatment of diabetes during pregnancy.

It is imperative that insulin be used to achieve adequate blood glucose control. It is recommended that the patient be transferred from oral antidiabetic therapy to insulin as soon as she plans to become pregnant or if pregnancy is exposed to this medicinal product. Neonatal blood glucose monitoring is recommended.

Lactation

Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants of mothers treated with metformin alone. However in humans, in the absence of data concerning passage of glibenclamide into breast milk, and in view of the risk of neonatal hypoglycemia, this medicinal product is contraindicated in the event of breast-feeding.

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.

Fertility of male or female rats was unaffected by glibenclamide when administered orally at dose of 100 and 300 mg/kg/day.

Patients should be alerted to the symptoms of hypoglycemia and should be advised to exercise caution when driving or using machines.

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To prevent them, it is recommended to take Diamet in 2 or 3 daily doses and to increase slowly the doses.

Transient visual disturbances may occur at the start of treatment due to a decrease in glycemia levels.

The following adverse reactions may occur under treatment with Diamet. 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.

Blood and lymphatic system disorders:

These are reversible upon treatment discontinuation.

Rare: Leucopenia, thrombocytopenia.

Very rare: Agranulocytosis, hemolytic anemia, bone marrow aplasia and pancytopenia.

Metabolism and nutrition disorders:

Hypoglycemia (see section 4.4).

Uncommon: Crises of hepatic porphyria and porphyria cutanea.

Very rare: Lactic acidosis (see section 4.4).

Decrease of vitamin B₁₂absorption with decrease of serum levels during long-term use of metformin. Consideration of such etiology is recommended if a patient presents with megaloblastic anemia.

Disulfiram-like reaction with alcohol intake.

Nervous system disorders:

Common: Taste disturbance.

Eye disorders:

Transient visual disturbances may occur at the start of treatment due to a decrease in glycemia levels.

Gastrointestinal disorders:

Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite. These undesirable effects occur more frequently during treatment initiation and resolve spontaneously in most cases. To prevent them, it is recommended that Diamet be taken in 2 or 3 daily doses. A slow increase of the dose may also improve gastrointestinal tolerability.

Skin and subcutaneous tissue disorders:

A cross reactivity to sulphonamide(s) and their derivatives may occur.

Rare: Skin reactions such as pruritus, urticaria, maculopapular rash.

Very rare: Cutaneous or visceral allergic angiitis, erythema multiforme, exfoliative dermatitis, photosensitization, urticaria evolving to shock.

Hepatobiliary disorders:

Very rare: Liver function test abnormalities or hepatitis requiring treatment discontinuation.

Investigations:

Uncommon: Average to moderate elevations in serum urea and creatinine concentrations.

Very rare: Hyponatremia.

Overdose may precipitate hypoglycemia due to the presence of the sulphonylurea (see section 4.4).

High overdose or the existence of concomitant risk factors may lead to lactic acidosis due to the presence of metformin (see section 4.4). Lactic acidosis is a medical emergency and must be treated in hospital. The most effective treatment is to remove lactate and metformin by haemodialysis.

The plasma clearance of glibenclamide may be prolonged in patients suffering from liver disease. Since glibenclamide is extensively bound to proteins, it is not eliminated by dialysis.

Pharmacotherapeutic group: Biguanides and sulphonamide(s) in combination. ATC code: A10BD02

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 hypoglycemia.

Metformin may act via 3 mechanisms:

(1) By reducing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis

(2) In muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization

(3) And by delaying 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 glycemia, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL-cholesterol and triglyceride levels. In clinical trials conducted so far with combination therapy with metformin and glibenclamide, these favorable effects on lipid metabolism have not been shown.

Glibenclamide is a second generation sulphonylurea with a medium half-life: it causes acute lowering of blood glucose by stimulating the release of insulin by the pancreas, this effect being dependent on the presence of functioning beta cells in the islets of Langerhans.

The stimulation of insulin secretion by glibenclamide in response to a meal is of major importance.

The administration of glibenclamide to diabetics induces an increase in the postprandial insulin-stimulating response. The increased postprandial responses in insulin and C-peptide secretion persist after at least 6 months of treatment.

Metformin and glibenclamide have different mechanisms and sites of action, but their action is complementary. Glibenclamide stimulates the pancreas to secrete insulin, while metformin reduces cell resistance to insulin by acting on peripheral (skeletal muscle) and hepatic sensitivity to insulin.

Results from controlled, double blind clinical trials versus reference products in the treatment of type 2 diabetes inadequately controlled by monotherapy with metformin or glibenclamide combined with diet and exercise, have demonstrated that the combination had an additive effect on glucose regulation.

Pediatric population:

In a 26-week, active controlled, double-blind, clinical study performed in 167 pediatric patients aged 9 to 16 years with type 2 diabetes not adequately controlled with diet and exercise, with or without an oral antidiabetic treatment, a fixed combination of metformin hydrochloride 250 mg and glibenclamide 1.25 mg was not shown more effective to either metformin hydrochloride or glibenclamide in reducing HbA1c from baseline. Therefore, Diamet should not be used in pediatric patients.

Related to the combination

The bioavailability of metformin and glibenclamide in the combination is similar to that noted when one tablet of metformin and one tablet of glibenclamide are taken simultaneously. The bioavailability of metformin in the combination is unaffected by the ingestion of food. The bioavailability of glibenclamide in the combination is unaffected by the ingestion of food, but the absorption speed of glibenclamide is increased by eating.

Related to metformin

Absorption:

After an oral dose of metformin tablet, maximum plasma concentration (C_max) is reached in approximately 2.5 hours (t_max). Absolute bioavailability of a 500 mg or 850 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (C_max) did not exceed 5 μg/ml, even at maximum doses.

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 from 63 to 276 l.

Metabolism:

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.

Related to glibenclamide

Absorption:

Glibenclamide is very readily absorbed (> 95%) following oral administration. The peak plasma concentration is reached in about 4 hours.

Distribution:

Glibenclamide is extensively bound to plasma albumin (99%), which may account for certain drug interactions.

Metabolism:

Glibenclamide is completely metabolized in the liver to two metabolites. Hepatocellular failure decreases glibenclamide metabolism and appreciably slows down its excretion.

Excretion:

Glibenclamide is excreted in the form of metabolites via biliary route (60%) and urine (40%), elimination being complete within 45 to 72 hours. Its terminal elimination half-life is 4 to 11 hours.

Biliary excretion of the metabolites increases in cases of renal insufficiency, according to the severity of renal impairment until a creatinine clearance at 30 ml/min. Thus, glibenclamide elimination is unaffected by renal insufficiency as long as the creatinine clearance remains above 30 ml/min.

Pediatric population

There were no differences in pharmacokinetics of glibenclamide and metformin between pediatric patients and weight-and gender-matched healthy adults.

No preclinical studies have been performed on the combination product. Preclinical evaluation of the constituents metformin and glibenclamide revealed no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential.

Animal studies on metformin and glibenclamide do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/ fetal development, parturition or postnatal development. (see section 4.6).

Avicel PH 101

Povidone K 90

Croscarmellose Sodium Type A

Magnesium Stearate

Not applicable

24Months/2Years

Store below 30°C.

This medicinal product does not require any special storage conditions.

30/pack

Clear PVC/PVDC Blister Strip and Aluminium Foil

No Special Disposal