This combination tablet is indicated as an adjunct to diet and exercise in type 2 diabetes mellitus patients:

• In cases where monotherapy with glimepiride or metformin does not result in adequate glycemic control.
• Replacement of combination therapy of glimepiride and metformin.

Glimepiride is a sulfonylurea antidiabetic agent which decreases blood glucose concentration. The primary mechanism of action of Glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. Glimepiride acts in concert with glucose by improving the sensitivity of beta cells to physiological glucose stimulus, resulting in insulin secretion. In addition, extrapancreatic effects such as reduction of basal hepatic glucose production, increased peripheral tissue sensitivity to insulin, and glucose uptake may also play a role in the activity of Glimepiride. In non-fasting diabetic patients, the hypoglycaemic action of a single dose of Glimepiride persists for 24 hours.

Metformin Hydrochloride is a biguanide type oral antihyperglycemic drug used in the management of type 2 diabetes. It lowers both basal and postprandial plasma glucose. Its mechanism of action is different from that of sulfonylureas, and it does not produce hypoglycemia. Metformin Hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.

• The dosage of this tablet is governed by the desired blood glucose level. The dosage of this tablet must be the lowest which is sufficient to achieve the desired metabolic control. During treatment with this tablet, glucose levels in blood and urine must be measured regularly.
• Mistakes, e.g., forgetting to take a dose, must never be corrected by subsequently taking a larger dose.
• As improvement in the control of diabetes is, in itself, associated with higher insulin sensitivity, glimepiride requirements may fall as treatment proceeds. To avoid hypoglycaemia, timely dose reduction or cessation of this tablet therapy must therefore be considered.
• The highest recommended dose per day should be 8 mg of glimepiride and 2000 mg of metformin.
• In order to avoid hypoglycaemia, the starting dose of this tablet should not exceed the daily doses of glimepiride or metformin already being taken.
• When switching from combination therapy of glimepiride plus metformin as separate tablets, this combination should be administered on the basis of the dosage currently being taken.

Administration

This tablet must be swallowed whole and not crushed or chewed.

For Glimepiride:

• Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is coadministered with inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole) of CYP2C9.
• Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may occur when one of the following drugs is taken, for example: insulin and other oral antidiabetics; ACE inhibitors; anabolic steroids and male sex hormones; chloramphenicol; coumarin derivatives; cyclophosphamide; disopyramide; fenfluramine; fenyramidol; fibrates; fluoxetine; guanethidine; ifosfamide; MAO inhibitors; miconazole; fluconazole; para-aminosalicylic acid; pentoxifylline (high dose parenteral); phenylbutazone; azapropazone; oxyphenbutazone; probenecid; quinolones; salicylates; sulfinpyrazone; clarithromycin; sulfonamide antibiotics; tetracyclines; tritoqualine; trofosfamide.
• Weakening of the blood-glucose-lowering effect and, thus, raised blood glucose levels may occur when one of the following drugs is taken, for example: acetazolamide; barbiturates; corticosteroids; diazoxide; diuretics; epinephrine (adrenaline) and other sympathomimetic agents; glucagon; laxatives (after protracted use); nicotinic acid (in high doses); oestrogens and progestogens; phenothiazines; phenytoin; rifampicin; thyroid hormones.
• H₂ receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect. Under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent.
• Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering action of glimepiride in an unpredictable fashion.
• The effect of coumarin derivatives may be potentiated or weakened.
• Bile acid sequestrant: Colesevelam binds to glimepiride and reduces glimepiride absorption from the gastrointestinal tract. Glimepiride should be administered at least 4 hours prior to colesevelam.

For Metformin: Concomitant use not recommended:

• Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic insufficiency. Avoid consumption of alcohol and alcohol-containing medications.
• 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.
• Combinations requiring precautions for use: Some medicinal products can adversely affect renal function, which may increase the risk of lactic acidosis. When starting or using such products in combination with metformin, close monitoring of renal function is necessary. Glucocorticoids, beta-2-agonists, and diuretics have intrinsic hyperglycemic activity. Inform the patient and perform more frequent blood glucose monitoring. ACE inhibitors may decrease blood glucose levels. Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended. Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.

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 the efficacy of metformin.
• Inducers of OCT1 (such as rifampicin) may increase the rate of intestinal absorption and efficacy of metformin.
• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprim, 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 the efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are coadministered 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.

For Glimepiride:

• In patients hypersensitive to glimepiride, metformin, other sulfonylureas, other sulfonamides, or any of the excipients of this combination.
• In pregnant women.
• In breastfeeding women.
• No experience has been gained concerning the use of glimepiride in patients with severe impairment of liver function and in dialysis patients. In patients with severe impairment of hepatic function, change-over to insulin is indicated, not least to achieve optimal metabolic control.

For Metformin:

• Hypersensitivity to metformin or any of the excipients.
• Any type of acute metabolic acidosis such as lactic acidosis, diabetic ketoacidosis, diabetic pre-coma.
• Severe renal failure or renal dysfunction (e.g., serum creatinine levels >135 μmol/L in males and >110 μmol/L in females, GFR <30 mL/min).
• Acute conditions with the potential to alter renal function such as dehydration, severe infection, intravascular administration of iodinated contrast agents, etc.
• 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.

For Glimepiride:

Metabolism and nutrition disorders:

• As a result of the blood-glucose-lowering action of glimepiride, hypoglycaemia which may also be prolonged.
• The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Eye disorders: Especially at the start of treatment, there may be temporary visual impairment due to the change in blood glucose levels. The cause is a temporary alteration in the fluidity and hence the refractive index of the lens, thus being dependent on blood glucose level.

Gastrointestinal disorders:

• Occasionally, gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fullness in the epigastrium, abdominal pain and diarrhoea may occur.
• In isolated cases, there may be hepatitis, elevation of liver enzyme levels and/or cholestasis and jaundice, which may progress to life-threatening liver failure.
• Dysgeusia (frequency not known).

Blood and lymphatic system disorders:

• Changes in the blood picture may occur: Rarely, thrombocytopenia and, in isolated cases, leucopenia, haemolytic anaemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop. Cases of severe thrombocytopenia with platelet count less than 10,000/µl and thrombocytopenic purpura have been reported in post-marketing experience (frequency not known).

Skin and subcutaneous tissue disorders: Alopecia (frequency not known).

General disorders:

• Occasionally, allergic or pseudo-allergic reactions may occur, e.g., in the form of itching, urticaria or rash. Such mild reactions may develop into serious reactions with dyspnoea and a fall in blood pressure, sometimes progressing to shock.
• In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur.

Investigation: Glimepiride, like all sulfonylureas, can cause weight gain (frequency not known).

For Metformin:

• Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite (>10%) are very common. These occur most frequently during initiation of therapy and resolve spontaneously in most cases.
• Metabolic side effects include:

• Decrease of vitamin B12 absorption with decrease of serum levels has been observed in patients treated long-term with metformin and appears generally to be without clinical significance (<0.05%). However, cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post-marketing experience (frequency not known).

• Lactic acidosis (0.03 cases/1000 patient-years) is very rare.

• Haemolytic anaemia (frequency not known).

• Reduction of thyroxine level in patients with hypothyroidism (frequency not known).

• Hypomagnesaemia in the context of diarrhoea (frequency not known).

• Encephalopathy (frequency not known).

• Photosensitivity (frequency not known).

• Hepatobiliary disorders: Reports of liver function test abnormalities and hepatitis resolving upon metformin discontinuation.

Pregnancy:

• For Glimepiride: Glimepiride must not be taken during pregnancy. Otherwise, there is a risk of harm to the child. The patient must change over to insulin during pregnancy. Patients planning a pregnancy must inform their physician. It is recommended that such patients change over to insulin.

• For Metformin: When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.

Lactation:

• For Glimepiride: To prevent possible ingestion with breast milk and possible harm to the child, glimepiride must not be taken by breastfeeding women. If necessary, the patient must change over to insulin, or must stop breastfeeding.
• For Metformin: Metformin is excreted into milk in lactating rats. Similar data is not available in humans, and a decision should be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the compound to the mother.

Children: Data is insufficient to recommend paediatric use of this tablet.

Renal impairment: A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at 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. The maximum daily dose of metformin should preferably be divided into 2–3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering the initiation of metformin in patients with GFR <60 mL/min. If no adequate strength of this tablet is available, individual monocomponents should be used instead of the fixed dose combination.

GFR 60–89 mL/min:

• Metformin: Maximum daily dose is 3000 mg. Dose reduction may be considered in relation to declining renal function.

• Glimepiride: The highest recommended dose per day should be 8 mg of glimepiride.

GFR 45–59 mL/min:

• Metformin: Maximum daily dose is 2000 mg. The starting dose is at most half of the maximum dose.

GFR 30–44 mL/min:

• Metformin: Maximum daily dose is 1000 mg. The starting dose is at most half of the maximum dose.

GFR <30 mL/min:

• Metformin: Metformin is contraindicated.

• Glimepiride: Change-over to insulin is indicated, not least to achieve optimal metabolic control.

For Glimepiride: Acute overdoses, as well as long-term treatment with too high a dose of glimepiride, may lead to severe life-threatening hypoglycaemia. As soon as an overdose has been discovered, a physician must be notified without delay. The patient must immediately take appropriate steps to minimise the harm from the glucose unless a physician has already undertaken responsibility for treating the overdose. Careful monitoring is essential until the physician is confident that the patient is out of danger. It must be remembered that hypoglycaemia may recur after initial recovery. Admission to hospital may sometimes be necessary even as a precautionary measure. In particular, significant overdoses and severe reactions with signs such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and admission to hospital. If, for example, the patient is unconscious, an intravenous injection of concentrated glucose solution is indicated (for adults starting with 40 ml of 20% solution, for example). Alternatively, in adults, administration of glucagon, e.g., in doses of 0.5 to 1 mg i.v., is used. In children, the dose of glucose given must be very carefully adjusted in view of the possibility of producing dangerous hyperglycaemia, and must be controlled by close monitoring of blood glucose. Patients who have ingested life-threatening amounts of glimepiride require detoxification (e.g., by gastric lavage and medicinal charcoal). After acute glucose replacement has been completed, it is usually necessary to give an intravenous glucose infusion in lower concentration so as to ensure that the hypoglycaemia does not recur. The patient's blood glucose level should be carefully monitored for at least 24 hours. In severe cases with a protracted course, hypoglycaemia, or the danger of slipping back into hypoglycaemia, may persist for several days.

For Metformin: 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. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis. Pancreatitis may occur in the context of a metformin overdose.

Combination Oral hypoglycemic preparations

Store in a cool (not exceeding 25°C) and dry place, protected from light.