Melanov-M

Melanov-M

Manufacturer:

Brown & Burk Phils

Distributor:

Brown & Burk Phils
Full Prescribing Info
Contents
Gliclazide, metformin hydrochloride.
Description
Each uncoated tablet contains: Gliclazide 80 mg, Metformin Hydrochloride 500 mg.
Action
Pharmacology: Pharmacokinetics: Metformin: Absorption: After an oral dose of metformin hydrochloride tablet, maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (tmax). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces 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 recommended metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 microgram/ml, even at maximum doses. Food decreases the extent and slightly delays the absorption of metformin. Following oral administration of a 850 mg tablet, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.
Distribution and Plasma protein binding: 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 between 63-276 L.
Metabolism: 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.
Gliclazide: Single oral dose of Gliclazide, 40 to 120 mg results in a Cmax of 2.2 to 8 mg/l within 2 to 8 hours. Steady state concentrations are achieved after 2 days of administration of 40-120 mg of Gliclazide. Administration of Gliclazide with food reduces Cmax and delays Tmax. The volume of distribution is low due to extensive protein binding (85-97%). The half life of Gliclazide varies from 8.1-20.5 hours after single dose administration. Gliclazide is extensively metabolised to 7 metabolites predominantly excreted in the urine, the most abundant being the carboxylic acid derivative; 60-70% of the dose is excreted in the urine and 10-20% in the faeces.
Indications/Uses
It is indicated for the non-insulin dependent diabetes mellitus; diabetes with or without obesity in adults.
Dosage/Direction for Use
1-2 tablets once or twice daily with meals to a maximum of 4 tablets/day.
Overdosage
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.
Gliclazide: An overdose of sulfonylureas may cause hypoglycaemia. Moderate symptoms of hypoglycaemia, without any loss of consciousness or neurological signs, must be corrected by carbohydrate intake, dose adjustment and/or change of diet. Strict monitoring should be continued until the doctor is sure that the patient is out of danger. Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as a medical emergency, requiring immediate hospitalisation.
If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid I.V. injection of 50 ml of concentrated glucose solution (20 to 30%). This should be followed by continuous infusion of a more dilute glucose solution (10%) at a rate that will maintain blood glucose levels above 1 g/l. Patients should be monitored closely and, depending on the patient's condition after this time, the doctor will decide if further monitoring is necessary. Dialysis is of no benefit to patients due to the strong binding of Gliclazide to proteins.
Contraindications
Insulin-dependent diabetes mellitus, renal or hepatic failure, alcoholism, NIDDM complicated by severe ketosis and acidosis, diabetic precoma and coma, patients undergoing surgery, after severe trauma or during infections, chronic obstructive pulmonary disease, coronary heart disease, cardiac failure, peripheral vascular disease, pregnancy, known hypersensitivity to any of the ingredients.
Warnings
Hypoglycemia may occur if the patient's dietary intake is reduced or after accidental or deliberate overdose or after severe exercise, trauma and stress. Hypoglycemic symptoms can be reduced by prescribing a diabetic meal plan. Immediate intervention should be done if signs and symptoms of hypoglycemia occur.
Special Precautions
Adjust dose of combination according to blood and urinary glucose levels during the first few months. However, there have been few reports of lactic acidosis in patients of renal or liver disease.
Use In Pregnancy & Lactation
Use in Pregnancy: There is no experience with the use of Gliclazide during pregnancy in humans, even though there are few data with other sulfonylureas. In animal studies, Gliclazide is not teratogenic. Control of diabetes should be obtained before the time of conception to reduce the risk of congenital abnormalities linked to uncontrolled diabetes. Oral hypoglycaemic agents are not suitable; insulin is the drug of first choice for treatment of diabetes during pregnancy. It is recommended that oral hypoglycaemic therapy is changed to insulin before a pregnancy is attempted, or as soon as pregnancy is discovered.
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.
Adverse Reactions
Based on the experience with Gliclazide and with other sulfonylureas, the following undesirable effects have to be mentioned. Hypoglycaemia: As for othersulfonylureas, treatment with Gliclazide can cause hypoglycaemia, if mealtimes are irregular and, in particular if meals are skipped. Possible symptoms of hypoglycaemia are: headache, intense hunger, nausea, vomiting, lassitude, sleep disorders, agitation, aggression, poor concentration, reduced awareness and slowed reactions, depression, confusion, visual and speech disorders, aphasia, tremor, paresis, sensory disorders, dizziness, feeling of powerlessness, loss of self-control, delirium, convulsions, shallow respiration, bradycardia, drowsiness and loss of consciousness, possibly resulting in coma and lethal outcome. In addition, signs of adrenergic counter-regulation may be observed: sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia. Usually, symptoms disappear after intake of carbohydrates (sugar). However, artificial sweeteners have no effect. Experience with other sulfonylureas shows that hypoglycaemia can recur even when measures prove effective initially. If a hypoglycaemic episode is severe or prolonged, and even if it is temporarily controlled by intake of sugar, immediate medical treatment or even hospitalisation is required. Gastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea and constipation have been reported. These can be avoided or minimised if Gliclazide is taken with a meal.
The following undesirable effects have been more rarely reported: Blood and lymphatic system disorders: Changes in haematology are rare. They may include anaemia, leukopenia, thrombocytopenia, granulocytopenia. These are in general reversible upon discontinuation of Gliclazide.
Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, erythema, maculo-papular rashes, bullous reactions, photosensitivity skin reactions.
Hepatobiliary disorders: Raised hepatic enzyme levels (ASAT, ALAT, alkaline phosphatase), hepatitis (isolated reports). Discontinue treatment if cholestatic jaundice appears.
These symptoms usually disappear after discontinuation of treatment.
Eye disorders: Transient visual disturbances may occur, especially on initiation of treatment, due to changes in blood glucose levels.
Metformin: During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To prevent them, it is recommended to take metformin in 2 or 3 daily doses and to increase slowly the doses.
Metabolism and nutrition disorders: Lactic acidosis. Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.
Nervous system disorders: Taste disturbance.
Gastrointestinal disorders: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, 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.
Hepatobiliary disorders: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.
Skin and subcutaneous tissue disorders: Skin reactions such as erythema, pruritus, urticaria.
Drug Interactions
The following products are likely to increase the risk of hypoglycaemia. Contraindicated combination: Miconazole (systemic route, oromucosal gel): increases the hypoglycaemic effect with possible onset of hypoglycaemic symptoms, or even coma.
Combinations which are not recommended: Phenylbutazone (systemic route): increases the hypoglycaemic effect of sulfonylureas (displaces their binding to plasma proteins and/or reduces their elimination). It is preferable to use a different anti-inflammatory agent, or else to warn the patient and emphasise the importance of self-monitoring. Where necessary, adjust the dose during and after treatment with the anti-inflammatory agent.
Alcohol: increases the hypoglycaemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Avoid alcohol or medicines containing alcohol.
Combinations requiring precautions for use: 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: Other Antidiabetic agents (insulin's, acarbose, biguanide), beta-blockers, fluconazole, angiotensin converting enzyme inhibitors (captopril, enalapril), H2-receptor antagonists, MAOIs, sulphonamides, and nonsteroidal anti-inflammatory agents.
The following products may cause an increase in blood glucose levels.
Combination which is not recommended: Danazol: diabetogenic effect of Danazol.
If the use of this active substance cannot be avoided, warn the patient and emphasise the importance of urine and blood glucose monitoring. It may be necessary to adjust the dose of the Antidiabetic agent during and after treatment with Danazol.
Combinations requiring precautions during use: Chlorpromazine (neuroleptic agent): high doses (>100 mg per day of chlorpromazine) increase blood glucose levels (reduced insulin release). Warn the patient and emphasise the importance of blood glucose monitoring. It may be necessary to adjust the dose of the Antidiabetic active substance during and after treatment with the neuroleptic agent.
Glucocorticoids (systemic and local route: intra-articular, cutaneous and rectal preparations) and tetracosactrin: increase in blood glucose levels with possible ketosis (reduced tolerance to carbohydrates due to glucocorticoids). Warn the patient and emphasise the importance of blood glucose monitoring, particularly at the start of treatment. It may be necessary to adjust the dose of the Antidiabetic active substance during and after treatment with glucocorticoids.
Ritodrine, salbutamol, terbutaline: I.V. Increased blood glucose levels due to beta-2 agonist effects. Emphasise the importance of monitoring blood glucose levels. If necessary, switch to insulin.
Combination which must be taken into account: Anticoagulant therapy (e.g. warfarin): Sulfonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of the anticoagulant may be necessary.
The hypoglycaemic effect of Gliclazide may be potentiated by salicylates, sulphonamides, Octreotide, Azapropazone, sulfinpyrazone, metabolism of Gliclazide may be accelerated by aminoglutethimide, testosterone, tetracycline compounds, chloramphenicol, Clofibrate, disopyramide, cimetidine. Co-trimoxazole rarely enhances the effect of Gliclazide. Gliclazide may be diminished by Rifamycins, oral contraceptives, thiazide diuretics, diazoxide, phenothiazine derivatives, thyroid hormones, loop diuretics, and abuse of laxatives. Calcium channel blockers (nifedipine) may occasionally impair glucose tolerance as well as Lithium may occasionally impair glucose tolerance.
Metformin: Concomitant use not with Alcohol is not recommended. Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of: Fasting or malnutrition, Hepatic insufficiency.
Avoid consumption of alcohol and alcohol-containing medications. Iodinated contrast agents lntravascular 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 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
Associations requiring precautions for use: 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.
Storage
Store at temperatures not exceeding 30°C.
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
Tab (white to off white oblong, shaped uncoated with a breakline on one surface and plain on the other surface) 30's.
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