In principle, the dosage of Zoryl-MF is governed by the desired blood glucose level. The starting dose of Zoryl-MF is 1 tab once a day before or with breakfast or first main meal. The dosage of Zoryl-MF must be the lowest which is sufficient to achieve the desired metabolic control.
During treatment with Zoryl-MF, 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 (Zoryl-MF) requirements may fall as treatment proceeds. To avoid hypoglycaemia, timely dose reduction or cessation of Zoryl-MF therapy must therefore be considered.
The highest recommended dose per day should be Glimepiride (Zoryl-MF) 8 mg and Metformin (Zoryl-MF) 2000 mg.
Daily doses of Glimepiride (Zoryl-MF) of >6 mg are more effective only in a minority of patients.
In order to avoid hypoglycaemia, the starting dose of Zoryl-MF should not exceed the daily doses of Glimepiride (Zoryl-MF) or Metformin (Zoryl-MF) already being taken.
When switching from combination therapy of Glimepiride (Zoryl-MF) plus Metformin (Zoryl-MF) as separate tablets, Zoryl-MF 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 Zoryl-MF is normally a long-term therapy.
Administration: Zoryl-MF should be administered once per day during breakfast or at the first main meal. Due to the sustained-release formulation, Zoryl-MF must be swallowed whole and not crushed or chewed.
Metformin (Zoryl-MF) HCl: Cationic Drugs: Amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin that are eliminated by renal tubular secretion, theoretically may cause an increase in Metformin (Zoryl-MF) Cmax, whole blood concentrations and whole blood AUC by competing with Metformin (Zoryl-MF) for common renal tubular transport system. Concomitant administration of Metformin (Zoryl-MF) and cimetidine has been observed to result in reduced urinary Metformin (Zoryl-MF) excretion and increased plasma and Metformin (Zoryl-MF) concentrations.
Protein-Bound Drugs: Interaction of Metformin (Zoryl-MF) and highly protein-bound drugs (eg, salicylates, sulfonamides, chloramphenicol, probenecid) is unlikely because Metformin (Zoryl-MF) is negligibly bound to plasma proteins.
Antidiabetic Agents: Hypoglycemia may occur if used concomitantly with other antidiabetic agents such as sulfonylureas, glitazones or insulin.
Diuretics: Thiazide diuretics may exacerbate diabetes mellitus and may result in increased requirements of oral antidiabetic agents, including Metformin (Zoryl-MF). Temporary loss of diabetic control, or secondary failure to the antidiabetic agent may also occur. Potassium-sparing diuretics may be considered as substitute.
Furosemide may increase Metformin (Zoryl-MF) plasma and blood concentrations and blood AUC without significantly affecting Metformin (Zoryl-MF) renal clearance.
Nifedipine: Concomitant administration may result in increased plasma concentration of Metformin (Zoryl-MF) due to enhance absorption. Nifedipine may also increase urinary excretion of Metformin (Zoryl-MF).
β-Adrenergic Blocking Agents: β-adrenergic blocking agents may impair glucose tolerance and mask the true frequency or severity of hypoglycemia, block hypoglycemia-induced tachycardia but not hypoglycemic sweating, delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia, and impair peripheral circulation. Use these drugs with caution in patients with type 2 diabetes.
Angiotensin-Converting Enzyme (ACE) Inhibitors: ACE inhibitors (eg, captopril, enalapril, lisinopril, ramipril) may reduce fasting blood glucose concentrations. These drugs have also been associated with unexplained hypoglycemia in diabetic patients. Caution should be exercised when administering Metformin (Zoryl-MF) together with ACE inhibitors to prevent severe hypoglycemia.
Clomiphene: Ovulatory response may be increased when clomiphene and Metformin (Zoryl-MF) are used concomitantly in premenopausal patients with polycystic ovary syndrome.
Coumarin Anticoagulants: Metformin (Zoryl-MF) may affect the pharmacokinetic properties of coumarin anticoagulants when administered concomitantly. An increase in prothrombin time may occur upon cessation of Metformin (Zoryl-MF) therapy, with an increased risk of hemorrhage. Patients receiving phenprocoumon or other vitamin K anticoagulants should be carefully monitored.
Others: Drugs that may cause and exacerbate hyperglycemia over loss of glycemic control in patients with type 2 diabetes include corticosteroids, estrogen plus progesterone, oral contraceptives, phenytoin, thyroid products, sympathomimetics, phenothiazines, nicotinic acid, calcium-channel blockers and isoniazid. When such drugs are added to or withdrawn from therapy in patients receiving oral antidiabetic agents including Metformin (Zoryl-MF), patients should be observed closely for evidence of altered glycemic control.
The pharmacokinetics of Metformin (Zoryl-MF) and propanolol and ibuprofen were not affected when co-administered in a single dose.
Glimepiride (Zoryl-MF): Aspirin: Concomitant use with aspirin results in an increased mean AUC and decreased mean Cmax of Glimepiride (Zoryl-MF). However, there is no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of aspirin and other salicylates.
H2 Receptor Antagonists: Co-administration of either cimetidine or ranitidine with a single oral dose of Glimepiride (Zoryl-MF) did not significantly alter the absorption and disposition of Glimepiride (Zoryl-MF) and no differences were seen in hypoglycemic symptomatology.
Propanolol: Concomitant administration of propanolol may result in significant increase in the Cmax, AUC and t½ of Glimepiride (Zoryl-MF).
Miconazole: Potential interactions with oral hypoglycemic agents including Glimepiride (Zoryl-MF) leading to severe hypoglycemia have been reported. It is not known whether this interaction also occurs with the IV, topical or vaginal preparations of miconazole.
Coumarin Anticoagulants: The pharmacodynamic response to warfarin may be potentiated or weakened by concomitant administration with Glimepiride (Zoryl-MF). This may cause very small reductions in mean area under the prothrombin time (PT) curve and maximum PT values during Glimepiride (Zoryl-MF) treatment.
Cytochrome P450: Glimepiride (Zoryl-MF) is metabolized by cytochrome P450 2C9. This should be taken into account when Glimepiride (Zoryl-MF) is co-administered with inducers (eg, rifampicin), inhibitors (eg, fluconazole) or substrates of CYP2C9 (eg, amiodarone, tolbutamide, diclofenac, ibuprofen, naproxen).
Alcohol: Acute and chronic alcohol intake may unpredictably potentiate or reduce the activity of Glimepiride (Zoryl-MF).
Drugs that May Potentiate the Hypoglycemic Action of Glimepiride (Zoryl-MF) and Other Sulfonylureas in Addition to Insulin and Other
Oral Antidiabetic Agents: Nonsteroidal anti-inflammatory drugs, sulfonamides, highly protein-bound drugs, chloramphenicol, coumarins/coumarin derivatives, probenecid, monoamine oxidase inhibitors, β-blockers, aminosalicylic acid, anabolic steroids, male sex hormones, azapropazone, chloramphenicol, clofibrate, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluoxetine, guanethidine, ifosfamide, oxpentifylline (high dose parenteral), oxyphenbutazone, phenylbutazone, probenecid, quinolones, sulfinpyrazone, tetracyclines, tritoqualine and trofosfamide.
β-blockers, clonidine, guanethidine and reserpine may mask the warning symptoms of a hypoglycemic attack during concomitant treatment with Glimepiride (Zoryl-MF).
Drugs that Tend to Produce Hyperglycemia and May Lead to Loss of Glycemic Control when Co-Administered with Glimepiride (Zoryl-MF): Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogen, progestogens, oral contraceptives, phenytoin, nicotinic acid (high doses), sympathomimetics, barbiturates, calcium channel blockers, diazoxide, glucagons, laxatives (protracted use) and isoniazid.
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Information checked by Dr. Sachin Kumar, MD Pharmacology