Amaryl M SR

Amaryl M SR

Manufacturer:

Sanofi-Aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Glimepiride, metformin HCl.
Description
Each tablet contains glimepiride 2 mg and metformin HCl 500 mg. It also contains the following excipients: Lactose monohydrate, povidone K30, hypromellose, magnesium stearate, macrogol, titanium dioxide and sodium lauryl sulfate.
Action
Pharmacology: Pharmacodynamics: Glimepiride is a blood sugar-lowering agent belonging to the sulfonylurea group. The decrease in blood sugar is achieved principally by means of the stimulation of insulin release from pancreatic β-cells. This effect is predominantly based on improved responsiveness of these cells to the physiological glucose stimulus. Glimepiride augments the normal action of insulin on peripheral glucose uptake. Moreover, it mimics such action as well as the glucose output of the liver.
Metformin is a biguanide derivative of guanidine, used for treating type 2 diabetes mellitus. Defects which cause hyperglycaemia and type 2 diabetes mellitus include alterations in pancreatic insulin secretion, elevations in hepatic glucose production and peripheral insulin resistance. Metformin acts via mechanisms by reduction in hepatic glucose production, reduction in intestinal glucose absorption and increased insulin sensitivity (improved peripheral glucose uptake and utilization).
Pharmacokinetics: Glimepiride pharmacokinetics (Tmax and AUC) after meal was similar between a sustained-release formulation of Amaryl M SR 2/500 mg and an immediate-release formulation of single Amaryl M 2/500 mg or twice daily Amaryl M 1/250 mg. Meanwhile, metformin Tmax was delayed in sustained-release formulation compared to immediate-release formulation, but its elimination half-life was not prolonged. The extent of metformin exposure after meal was lower in sustained-release formulation than in immediate-release formulation and its twice daily treatment in divided doses by 14% and 23% on average, respectively. This effect on exposure is not considered clinically significant as there was no significant difference in safety between treatment groups.
Toxicology: Preclinical Safety Data: Metformin: Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 and 1500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose on a body surface area basis. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. However, an increased incidence of benign stromal uterine polyps was seen in female rats treated with 900 mg/kg/day.
No evidence of a mutagenic potential of metformin was found in Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), chromosomal aberration test (human lymphocytes) or in vivo micronuclei formation test (mouse bone marrow).
Fertility of male or female rats was unaffected by metformin administration at doses as high as 600 mg/kg/day, or approximately 2 times the maximum recommended human daily dose on a body surface area basis.
Glimepiride: In subchronic and chronic toxicity studies in rats, mice and dogs, a decline in serum glucose as well as a degranulation of the β-cells of the pancreas were noted; these where shown to be, in principle, reversible and are regarded as signs of the pharmacodynamic effect. In a chronic toxicity study in dogs, 2 of the animals receiving the highest dose (320 mg/kg body weight) developed cataracts. In vitro studies in the bovine lens and investigations in rats demonstrated no cataractogenic or co-cataractogenic potential.
Lifetime studies in rats revealed no carcinogenic potential. In mice, there was an increased incidence of islet cell hyperplasia and of islet cell adenomas; these are regarded as resulting from the chronic stimulation of the β-cells. Glimepiride did not show any mutagenic or genotoxic effects.
Administration to rats revealed no effects on fertility, course of pregnancy or delivery. Fetuses delivered by caesarean section were slightly retarded in growth. In spontaneously born progeny whose mothers had been treated with high doses, anomalies of the humerus, femur, shoulder and hip joint were observed. Oral administration in the late phase of pregnancy and/or during lactation led to increased numbers of fetal deaths and to the same limb deformities.
Glimepiride had no recognizable effects on the rearing, physical development, functional and learning behaviour, memory or fertility of the progeny. Glimepiride is ingested by the offspring in breast milk; high doses given to mother rats cause hypoglycaemia in suckling young rats.
Malformations (eg, eye malformations, fissures and bone anomalies) occurred in rats and rabbits and, in rabbits only, the numbers of abortions and intrauterine deaths were increased.
All reproduction toxicology findings are probably due to the pharmacodynamic effects of excessive doses and are not substance specific.
Indications/Uses
As an adjunct to diet and exercise in type 2 diabetes mellitus patients: In case that monotherapy with glimepiride or metformin does not result in adequate glycemic control; replacement of combination therapy of glimepiride and metformin.
Dosage/Direction for Use
In principle, the dosage of Amaryl M SR is governed by the desired blood glucose level. The starting dose of Amaryl M SR is 1 tab once a day before or with breakfast or first main meal. The dosage of Amaryl M SR must be the lowest which is sufficient to achieve the desired metabolic control.
During treatment with Amaryl M SR, glucose levels in blood and urine must be measured regularly. In addition, it is recommended that regular determinations of the proportion of glycated haemoglobin be carried out.
Mistakes eg, forgetting to take a dose, must never be corrected by subsequently taking a larger dose.
Measures for dealing with such mistakes (in particular, forgetting a dose or skipping a meal) or situations where a dose cannot be taken at the prescribed time must be discussed and agreed between physician and patient beforehand.
As an improvement in 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 Amaryl M SR therapy must therefore be considered.
The highest recommended dose per day should be glimepiride 8 mg and metformin 2000 mg.
Daily doses of glimepiride of >6 mg are more effective only in a minority of patients.
In order to avoid hypoglycaemia, the starting dose of Amaryl M SR 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, Amaryl M SR should be administered on the basis of dosage currently being taken.
Titration: The daily dose should be titrated in increments of 1 tab only, corresponding to the lowest strength (in case various strengths are available).
Duration of Treatment: Treatment with Amaryl M SR is normally a long-term therapy.
Administration: Amaryl M SR should be administered once per day during breakfast or at the first main meal. Due to the sustained-release formulation, Amaryl M SR must be swallowed whole and not crushed or chewed.
Overdosage
Glimepiride: Acute overdosage as well as long-term treatment with too high a dose of glimepiride may lead to severe life-threatening hypoglycaemia.
Management: As soon as an overdose of glimepiride has been discovered, a physician must be notified without delay. The patient must immediately take sugar, if possible in the form of 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 eg, 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 IV injection of concentrated glucose solution is indicated (eg, for adults starting with 40 mL of 20% solution). Alternatively in adults, administration of glucagon eg, in doses of 0.5-1 mg IV, SC or IM may be considered.
In particular, when treating hypoglycaemia due to accidental intake of glimepiride in infants and young 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 (eg, gastric lavage and medicinal charcoal).
After acute glucose replacement has been completed, it is usually necessary to give an IV 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 hrs. In severe cases with a protracted course, hypoglycaemia or the danger of slipping back into hypoglycaemia, may persist for several days.
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.
Contraindications
Patients hypersensitive to glimepiride, metformin, other sulfonylureas, other sulfonamides or any of the excipients of Amaryl M SR.
Glimepiride: 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, changeover to insulin is indicated, not least to achieve optimal metabolic control.
Metformin: Diabetic ketoacidosis, diabetic pre-coma.
Renal failure or renal dysfunction (eg, serum creatinine levels >135 micromol/L in males and >110 micromol/L in females).
Acute conditions with the potential to alter renal function eg, dehydration, severe infection, shock, intravascular administration of iodinated contrast agents (see Precautions).
Acute or chronic disease which may cause tissue hypoxia eg, cardiac or respiratory failure, recent myocardial infarction, shock.
Hepatic insufficiency; acute alcohol intoxication, alcoholism.
Use in Pregnancy & Lactation: Glimepiride: Glimepiride must not be taken during pregnancy. Otherwise, there is risk of harm to the child. The patient must changeover to insulin during pregnancy.
Patients planning a pregnancy must inform their physician. It is recommended that such patients changeover to insulin.
To prevent possible ingestion with the breast milk and possible harm to the child, glimepiride must not be taken by breastfeeding women. If necessary, the patient must changeover to insulin or must stop breastfeeding.
Metformin: To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development.
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 fetal malformations associated with abnormal blood glucose levels.
Metformin is excreted into milk in lactating rats. Similar data are 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.
Special Precautions
Glimepiride: In exceptional stress situations (eg, trauma, surgery, febrile infections), blood glucose regulation may deteriorate and a temporary change to insulin may be necessary to maintain good metabolic control.
In the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates especially careful monitoring. Factors favouring hypoglycaemia include: Unwillingness or incapacity of the patient to cooperate (more commonly in older patients); undernourishment, irregular mealtimes or skipped meals; imbalance between physical exertion and carbohydrate intake; alterations of diet; consumption of alcohol, especially in combination with skipped meals; impaired renal function; severe impairment of liver function; overdosage with glimepiride; certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (eg, certain disorders of thyroid function and in anterior pituitary or corticoadrenal insufficiency); concurrent administration of certain other medicines (see Interactions); treatment with glimepiride in the absence of any indication.
If such risk factors for hypoglycaemia are present, it may be necessary to adjust the dosage of this drug or the entire therapy. This also applies whenever illness occurs during therapy or the patient's lifestyle changes.
Those symptoms of hypoglycaemia which reflect the body's adrenergic counter-regulation (see Adverse Reactions) may be milder or absent where hypoglycaemia develops gradually in the elderly, and where there is autonomic neuropathy or where the patient is receiving concurrent treatment with β-blockers, clonidine, reserpine, guanethidine or other sympatholytic drugs.
Hypoglycaemia can almost always be promptly controlled by immediate intake of carbohydrates (glucose or sugar).
It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur. Patients must, therefore, remain under close observation.
Severe hypoglycaemia further requires immediate treatment and follow-up by a physician and in some circumstances, in-patient hospital care.
Treatment of patients with G6PD deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.
Metformin: Lactic Acidosis: Lactic acdosis 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 other associated risk factors eg, poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.
Diagnosis: Lactic acidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, 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 hospitalized immediately.
Renal Function: As metformin is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter: At least annually in patients with normal renal function; at least 2-4 times a year in patients with serum creatinine 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 eg, when initiating antihypertensive or diuretic therapy and when starting therapy with an NSAID.
Administration of Iodinated Contrast Agent: As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin should be discontinued prior to or at the time of the test and not reinstituted until 48 hrs afterwards and only after renal function has been re-evaluated and found to be normal.
Surgery: Metformin HCl should be discontinued 48 hrs before elective surgery with general anesthesia and should not be resumed earlier than 48 hrs afterwards.
Other: 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 sulfonylureas.
Effects on the Ability to Drive or Operate Machinery: Glimepiride: Alertness and reactions may be impaired due to hypoglycaemia or hyperglycaemia, especially when beginning or after altering treatment or when glimepiride is not taken regularly. This for example, may affect the ability to drive or operate machinery.
Metformin: Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or use machines.
However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (sulfonylureas, insulin, repaglinide).
Use in Children: Data are insufficient to recommend pediatric use of Amaryl M SR.
Use In Pregnancy & Lactation
Glimepiride: Glimepiride must not be taken during pregnancy. Otherwise, there is risk of harm to the child. The patient must changeover to insulin during pregnancy.
Patients planning a pregnancy must inform their physician. It is recommended that such patients changeover to insulin.
To prevent possible ingestion with the breast milk and possible harm to the child, glimepiride must not be taken by breastfeeding women. If necessary, the patient must changeover to insulin or must stop breastfeeding.
Metformin: To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development.
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 fetal malformations associated with abnormal blood glucose levels.
Metformin is excreted into milk in lactating rats. Similar data are 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.
Adverse Reactions
Glimepiride and Metformin: The use of a combination of both compounds, either as a free combination or as a fixed combination, is associated with the same safety characteristics as the use of each compound separately.
Glimepiride: Metabolism and Nutrition Disorders: As a result of the blood glucose-lowering action of glimepiride, hypoglycaemia may occur, which may also be prolonged.
Possible symptoms of hypoglycaemia include headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, impaired alertness and reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, pareses, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and including coma, shallow respiration and bradycardia.
In addition, signs of adrenergic counter-regulation may be present eg, sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.
The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.
The symptoms nearly always subside when hypoglycaemia is corrected.
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 turgidity and hence the refractive index of the lens, this being dependent on blood glucose level.
Gastrointestinal Disorders: Occasionally, gastrointestinal symptoms eg, 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 but can regress after withdrawal of glimepiride.
Blood and Lymphatic System Disorders: Changes in the blood picture may occur: Rarely, thrombopenia and in, isolated cases, leucopenia, haemolytic anaemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop.
General Disorders: Occasionally, allergic or pseudo-allergic reactions may occur eg, in the form of itching, urticaria or rashes. Such mild reactions may develop into serious reactions with dyspnea and a fall in blood pressure, sometimes progressing to shock. In the event of urticaria, a physician must therefore be notified immediately.
In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur.
Metformin: Gastrointestinal symptoms eg, 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. To prevent these gastrointestinal symptoms, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Metallic taste (3%) is common.
Mild erythema has been reported in some hypersensitive individuals. The incidence of such effects is regarded as very rare (<0.01%).
A 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 (<0.01%).
Lactic acidosis (0.03 cases/1000 patient-years) is very rare (see Precautions).
Drug Interactions
Glimepiride: Based on experience with glimepiride and on what is known of other sulfonylureas, the following interactions must be considered:
Glimepiride is metabolized by cytochrome P-450 2C9 (CYP2C9). This should be taken into account when glimepiride is co-administered with inducers (eg, rifampicin) or inhibitors (eg, 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 eg, insulin and other oral antidiabetics, angiotensin-convering enzyme (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 eg, 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, β-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood glucose-lowering effect.
Under the influence of sympatholytic drugs eg, β-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.
Metformin: Inadvisable Combinations: Alcohol: Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of fasting or malnutrition and hepatic insufficiency.
Avoid consumption of alcohol and alcohol-containing medications.
Iodinated Contrast Agents: Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis.
Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hrs afterwards, and only after renal function has been re-evaluated and found to be normal (see Precautions).
Associations Requiring Precautions for Use: Glucocorticoids (systemic and local routes), β-agonists (salbutamol, formoterol) and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.
ACE inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.
Incompatibilities: None.
Storage
Do not store above 30°C.
Shelf-Life: 2 years.
MIMS Class
ATC Classification
A10BD02 - metformin and sulfonylureas ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
Presentation/Packing
SR tab (white, oblong, biconvex, engraved with "SR25" on one side) 30's.
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