Amaryl M 1 mg+500 mg Bilayer Tablet

Uses

Amaryl M 1 mg+500 mg Bilayer Tablet used for the management of patients with type 2 diabetes mellitus when diet, exercise and single agent (glimepiride or metformin alone) do not result in adequate glycemic control.

Amaryl M 1 mg+500 mg Bilayer Tablet is also used to associated treatment for these conditions: Type 2 Diabetes MellitusPolycystic Ovaries Syndrome, Type 2 Diabetes Mellitus, Glycemic Control

How Amaryl M 1 mg+500 mg Bilayer Tablet works

ATP-sensitive potassium channels on pancreatic beta cells that are gated by intracellular ATP and ADP. The hetero-octomeric complex of the channel is composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing allows the formation of channels composed of varying subunit isoforms expressed at different concentrations in different tissues. In pancreatic beta cells, ATP-sensitive potassium channels play a role as essential metabolic sensors and regulators that couple membrane excitability with glucose-stimulated insulin secretion (GSIS). When there is a decrease in the ATP:ADP ratio, the channels are activated and open, leading to K+ efflux from the cell, membrane hyperpolarization, and suppression of insulin secretion. In contrast, increased uptake of glucose into the cell leads to elevated intracellular ATP:ADP ratio, leading to the closure of channels and membrane depolarization. Depolarization leads to activation and opening of the voltage-dependent Ca2+ channels and consequently an influx of calcium ions into the cell. Elevated intracellular calcium levels causes the contraction of the filaments of actomyosin responsible for the exocytosis of insulin granules stored in vesicles. Glimepiride blocks the ATP-sensitive potassium channel by binding non-specifically to the B sites of both sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits as well as the A site of SUR1 subunit of the channel to promote insulin secretion from the beta cell.

Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization . It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism . The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control.

After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios . These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism . Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit fructose-1,6-bisphosphatase enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting adenylate cyclase and decreasing the production of cyclic adenosine monophosphate (cAMP) , a derivative of ATP used for cell signaling . Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin .

In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose .

In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years .

Dosage

Amaryl M 1 mg+500 mg Bilayer Tablet dosage

General

In principle, the dosage of Amaryl M 1 mg+500 mg Bilayer Tablet is governed by the desired blood glucose level. The dosage of Amaryl M 1 mg+500 mg Bilayer Tablet must be the lowest which is sufficient to achieve the desired metabolic control. During treatment with Amaryl M 1 mg+500 mg Bilayer Tablet 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, e.g. 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. For the use only of a Registered Medical Practitioner or Hospital or a Laboratory This package insert is continually updated. Please read carefully before using a new pack As an improvement in control of diabetes is, in itself, associated with higher insulin sensitivity, glimepiride requirements may fall as treatment proceeds. To avoid hypoglycemia timely dose reduction or cessation of Amaryl M therapy must therefore be considered.

Amaryl M 1 mg+500 mg Bilayer Tablet is to be administered once per day during breakfast or the first main meal. The highest recommended dose per day should be 8mg of glimepiride and 2000mg of metformin. Daily doses of glimepiride of more than 6mg are more effective only in a minority of patients. In order to avoid hypoglycemia the starting dose ofAmaryl M 1 mg+500 mg Bilayer 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, Amaryl M 1 mg+500 mg Bilayer Tablet should be administered on the basis of dosage currently being taken.

Titration: The daily dose should be titrated based on the glycemic control ,in increments of 1 tablet only, corresponding to the lowest strength.

Duration of therapy: Treatment with Amaryl M 1 mg+500 mg Bilayer Tablet is normally a long-term therapy.

Special Populations: Children Data are insufficient to recommend pediatric use of Amaryl M 1 mg+500 mg Bilayer 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 (see Section Warnings) should be reviewed before considering initiation of metformin in patients with GFR<60 mL/min. If no adequate strength of Amaryl M 1 mg+500 mg Bilayer Tablet is available, individual monocomponents should be used instead of the fixed dose combination. GFR ml/min Metformin Glimepride 60-89 Maximum daily dose is 3000 mg Dose reduction may be considered in relation to declining renal function.

The highest recommended dose per day should be 8 mg of glimepiride 45-59 Maximum daily dose is 2000 mg The starting dose is at most half of the maximum dose. 30-44 Maximum daily dose is 1000 mg. The starting dose is at most half of the maximum dose. ˂30 Metformin is contraindicated Change-over to insulin is indicated, not least to achieve optimal metabolic control

Diaryl tablet must be swallowed without chewing and with sufficient amount of liquid (approximately ½ glass).

Due to prolonged release formulation, Amaryl M must be swallowed whole and not crushed or chewed.

Side Effects

The following CIOMS frequency rating is used, when applicable :Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%;

Very rare<0.01%, Unknown ( cannot be estimated from available data).
For 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.
For 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 such as 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 such as nausea, vomiting, sensations of pressure or
fulness 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.
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 pseudoallergic reactions may occur, e.g. in the form of itching, urticaria
or rashes. Such mild reactions may develop into serious reactions with dyspnoea 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.

Investigations
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. 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%).
However, cases of peripheral neuropathy in patients with vitamin B12 deficiency have been
reported in post-marketing experience (frequency not known) (see Precautions)

• -Lactic acidosis (0.03 cases/1000 patient-years) is very rare (see Warnings).
• - Hemolytic anemia (frequency unknown)
• - Reduction of thyrotropin level in patients with hypothyroidism (see Precautions) (frequency
• unknown)
• - Hypomagnesemia in the context of diarrhea (frequency unknown)
• - Encephalopathy (frequency unknown)
• - Photosensitivity (frequency unknown)
• - Hepatobiliary disorders: Reports of liver function tests abnormalities and hepatitis resolving

upon metformin discontinuation

Toxicity

The oral LD50 value in rats is > 10000 mg/kg. The intraperitoneal LD50 value in rats is reported to be 3950 mg/kg . Although glimepiride is reported to have fewer risks of hypoglycemia compared to other sulfonylureas such as glyburide, overdosage of glimepiride may result in severe hypoglycemia with coma, seizure, or other neurological impairment may occur. This can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary since hypoglycemia may recur after apparent clinical recovery.

In a study of rats given doses of up to 5000 parts per million (ppm) in complete feed for 30 months, there were no signs of carcinogenesis. Meanwhile, the administration of glimepiride at a dose much higher than the maximum human recommended dose for 24 months in mice resulted in an increase in benign pancreatic adenoma formation in a dose-related manner, which was thought to be the result of chronic pancreatic stimulation. Glimepiride was non-mutagenic in in vitro and in vivo mutagenicity studies. In male and female rat studies, glimepiride was shown to have no effects on fertility.

Metformin (hydrochloride) toxicity data:

Oral LD50 (rat): 1 g/kg; Intraperitoneal LD50 (rat): 500 mg/kg; Subcutaneous LD50 (rat): 300 mg/kg; Oral LD50 (mouse): 1450 mg/kg; Intraperitoneal LD50 (mouse): 420 mg/kg; Subcutaneous LD50 (mouse): 225 mg/kg .

A note on lactic acidosis

Metformin decreases liver uptake of lactate, thereby increasing lactate blood levels which may increase the risk of lactic acidosis . There have been reported postmarketing cases of metformin-associated lactic acidosis, including some fatal cases. Such cases had a subtle onset and were accompanied by nonspecific symptoms including malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence. In certain cases, hypotension and resistant bradyarrhythmias have occurred with severe lactic acidosis . Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), as well as an increased lactate:pyruvate ratio; metformin plasma levels were generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase 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 .

A note on renal function

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased .

Metformin should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis . Lower doses should be used in the elderly and those with decreased renal function. Metformin decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Metformin may also have a positive effect on lipid levels.

A note on hypoglycemia

When used alone, metformin does not cause hypoglycemia, however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin when they are used together .

Use in pregnancy

Available data from post-marketing studies have not indicated a clear association of metformin with major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was ingested during pregnancy. Despite this, the abovementioned studies cannot definitively establish the absence of any metformin-associated risk due to methodological limitations, including small sample size and inconsistent study groups .

Use in nursing

A limited number of published studies indicate that metformin is present in human milk. There is insufficient information to confirm the effects of metformin on the nursing infant and no available data on the effects of metformin on the production of milk. The developmental and health benefits of breastfeeding should be considered as well as the mother’s clinical need for metformin and any possible adverse effects on the nursing child .

Precaution

PRECAUTIONS
For Glimepiride:
In the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates
especially careful monitoring. Factors favouring hypoglycaemia include:

• unwillingness or (more commonly in older patients) incapacity of the patient to cooperate.
• 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 (as for example in 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
glimepiride or the entire therapy. This also applies whenever illness occurs during therapy or the
patient's life-style 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 beta-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 hemolytic
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.
For Metformin: Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients
with hypothyroidism (see Adverse reactions)
Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum
levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is
recommended (see Adverse reactions)
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 sulfonylureas.

Interaction

For 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 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; paraaminosalicylic 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 gastro-intestinal tract. No interaction was observed when glimepiride was taken at least 4 hours before colesevelam. Therefore 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 case of fasting or 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 image 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 Dosage and Administration and Warnings).

Combinations requiring precautions for use: Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (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. Glucocorticoids (systemic and local routes), beta-2-agonists 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. Metformin may decrease the anticoagulant effect of phenprocoumon.

Therefore, a 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.

Volume of Distribution

Following intravenous dosing in healthy subjects, the volume of distribution was 8.8 L (113 mL/kg).

The apparent volume of distribution (V/F) of metformin after one oral dose of metformin 850 mg averaged at 654 ± 358 L .

Elimination Route

Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile. Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2 to 3 hours post-dose. Accumulation does not occur after multiple doses. When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8 to 9%, respectively. In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses. The absolute bioavailability of glimepiride is reported to be complete following oral administration.

Regular tablet absorption

The absolute bioavailability of a metformin 500 mg tablet administered in the fasting state is about 50%-60%. Single-dose clinical studies using oral doses of metformin 500 to 1500 mg and 850 to 2550 mg show that there is a lack of dose proportionality with an increase in metformin dose, attributed to decreased absorption rather than changes in elimination .

At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are achieved within 24-48 hours and are normally measured at Label.

Extended-release tablet absorption

After a single oral dose of metformin extended-release, Cmax is reached with a median value of 7 hours and a range of between 4 and 8 hours. Peak plasma levels are measured to be about 20% lower compared to the same dose of regular metformin, however, the extent of absorption of both forms (as measured by area under the curve - AUC), are similar .

Effect of food

Food reduces the absorption of metformin, as demonstrated by about a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute increase in time to peak plasma concentration (Tmax) after ingestion of an 850 mg tablet of metformin taken with food, compared to the same dose administered during fasting .

Though the extent of metformin absorption (measured by the area under the curve - AUC) from the metformin extended-release tablet is increased by about 50% when given with food, no effect of food on Cmax and Tmax of metformin is observed. High and low-fat meals exert similar effects on the pharmacokinetics of extended-release metformin .

Half Life

The elimination half-life of glimepiride is approximately 5 to 8 hours, which can increase up to 9 hours following multiple doses.

Approximately 6.2 hours in the plasma and in the blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution .

Clearance

A single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose proportionality (4 and 8 mg) study in patients with type 2 diabetes (T2D) were performed. In these studies, the total body clearance was 52.1 +/- 16.0 mL/min, 48.5 +/- 29.3 mL/min in patients with T2D given a single oral dose, and 52.7 +/- 40.3 mL/min in patients with T2D given multiple oral doses. Following intravenous dosing in healthy subjects, the total body clearance was 47.8 mL/min.

Renal clearance is about 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours .

Elimination Route

Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine. The ratio of M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3. No parent drug was recovered from urine or feces.

This drug is substantially excreted by the kidney .

Renal clearance of metformin is about 3.5 times higher than creatinine clearance, which shows that renal tubular secretion is the major route of metformin elimination. After oral administration, about 90% of absorbed metformin is eliminated by the kidneys within the first 24 hours post-ingestion .

Pregnancy & Breastfeeding use

For Glimepiride:

Glimepiride must not be taken during pregnancy. Otherwise there is 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: 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.

LACTATION

For Glimepiride: To prevent possible ingestion with the breast milk and possible harm to the child, glimepiride must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breast-feeding.

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.

Contraindication

For Glimepiride:
 in patients hypersensitive to glimepiride, other sulfonylureas, other sulfonamides, or any
of the excipients of Amaryl M 1 mg+500 mg Bilayer Tablet
 in pregnant women.
 in breast-feeding 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 (GFR˂30ml/min)
 Acute conditions with the potential to alter renal function such as:
- Dehydration
- severe infection

• - shock
• - Intravascular administration of iodinated contrast agents (see Precautions)

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.

Special Warning

For Glimepiride:In exceptional stress situations (e.g. trauma, surgery, febrile infections) blood glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control.

For Metformin:Lactic acidosis 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.

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 associated to 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 Section Contraindications and Section Interactions) Diagnosis:Patients and/or care-givers should be informed of the risk of lactic acidosis.

In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. 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.Renal function:GFR should be assessed before treatment initiation and regularly thereafter (see Section Dosage and Administration).

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 Contraindications).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 an NSAID.

Administration of iodinated contrast agent:Intravascular administration of iodinated contrast agents 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 48 hours after, provided that renal function has been re-evaluated and found to be stable (see Section Dosage and Administration and Section Interactions).

Surgery: 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.

Acute Overdose

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 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., s.c. or i.m. 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 (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

Storage Condition

Store below +25°C in a dry place.
Keep out of reach of children.

Innovators Monograph

You find simplified version here Amaryl M 1 mg+500 mg Bilayer Tablet