Glimepiride + Metformin HCl

Transcription

1 Glimepiride + Metformin HCl Norizec Plus 2 mg/500 mg Sustained-Release Tablet oral hypoglycemic FORMULATION Each tablet contains: Metformin hydrochloride (in sustained-release form) mg Glimepiride 2 mg PRODUCT DESCRIPTION Capsule-shaped, biconvex, bilayered tablet with one layer white and the other layer yellow, plain on both sides CLINICAL PHARMACOLOGY Pharmacodynamics Metformin HCl SR + glimepiride fixed-dose combination (FDC) tablet combines in a single dosage form two antidiabetic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus. Metformin HCl Metformin is a biguanide antidiabetic agent that reduces both basal and postprandial plasma glucose concentrations in patients with type 2 diabetes mellitus by improving both peripheral and hepatic sensitivity to insulin. It does not stimulate insulin secretion and therefore does not produce hypoglycemia when used alone. Fasting insulin levels and day-long insulin response remain the same or may even decrease with metformin therapy. Metformin may act via three mechanisms: It reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; increases insulin sensitivity in the skeletal muscles and adipocytes, improving peripheral glucose uptake and utilization; delays intestinal glucose absorption. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. It also increases the transport capacity of all types of membrane glucose transporters. Glimepiride Glimepiride is a sulfonylurea antidiabetic agent. It lowers blood glucose primarily by stimulating the release of endogenous insulin from functioning pancreatic β-cells. Glimepiride exerts its extrapancreatic effects in two ways: by increasing rapidly the number of active glucose transport molecules in the plasma membranes of the muscle and fat cells resulting in stimulated glucose uptake and by increasing the intracellular concentration of fructose-2,6-bisphosphate, resulting in the inhibition of glucose production in the liver (gluconeogenesis). Pharmacokinetics Metformin HCl Metformin is slowly and incompletely absorbed from the gastrointestinal tract after oral administration. At steady-state, after administration of sustained-release metformin tablet, the AUC and peak plasma concentrations are not dose proportional within the range of 500 mg to 2,000 mg. Time to reach maximum plasma concentrations (T max ) is approximately 7 hours (range from 4 to 8 hours). The extent of metformin absorption (based on AUC) for metformin sustained-release tablet at 2,000 mg once a day dose is similar as that for metformin immediate-release tablet at 1,000 mg twice a day dose. 1 of 12

2 Metformin distributes rapidly to peripheral body tissues and fluids. It also appears to distribute slowly into erythrocytes and into a deep tissue compartment. Metformin is negligibly bound to plasma proteins. Steady-state plasma concentrations of metformin are generally <1 mcg/ml and are reached within 24 to 48 hours at usual clinical doses and dosing schedules. Renal elimination of metformin is via glomerular filtration and secretion by the proximal convoluted tubules as unchanged drug. The principal plasma elimination half-life of metformin is about 6.2 hours with 90% of the total dose being cleared within 24 hours in patients with normal renal function. In blood, the elimination half-life is about 17.6 hours. Glimepiride Glimepiride is completely (100%) absorbed from the gastrointestinal tract after oral administration. There was no change observed in the clearance of glimepiride at a dose range of 1 to 8 mg, exhibiting linear kinetics. Peak serum concentration is reached in about 2 to 3 hours. The time to reach C max (T max ) was slightly increased (12%) and the mean C max and AUC were slightly decreased (8% and 9%, respectively) when glimepiride was given with meals. Glimepiride has a very low volume of distribution (about 8.8 L), high protein binding (>99.5%), and low total body clearance (approximately 48 ml/min). It is likely to be only minimally removed by hemodialysis. Glimepiride is excreted in milk in animals. It is transferred to the placenta and passage through the blood-brain barrier is low. There was no relevant accumulation of glimepiride in the blood. Glimepiride is completely metabolized by oxidative biotransformation after oral administration. The major metabolites are the cyclohexyl hydroxyl methyl derivative (M1) and carboxyl derivative (M2). Cytochrome P450 2C9 has been shown to be involved in the biotransformation of glimepiride to M1 which has one-third of the pharmacologic activity of its parent compound. However, it is not clear whether the glucose-lowering effect of M1 is clinically significant. M1 is further metabolized to inactive M2 metabolite by cytosolic enzymes. About 60% of glimepiride is recovered in the urine within 7 days with M1 (predominant) and M2 accounting for 80 to 90% of that recovered. About 40% is recovered in the feces; M1 and M2 (predominant) account for 70% of that recovered in the feces. No parent drug is recovered from urine or feces. The terminal half-lives of these metabolites were 3 to 6 and 5 to 6 hours, respectively. Significant biliary excretion of glimepiride or its M1 metabolite is not observed after intravenous dosing. Special Populations Hepatic Insufficiency There are no studies with the use of metformin or glimepiride in patients with hepatic impairment. However, the use of metformin in these patients has been associated with some cases of lactic acidosis. Its use in this population is therefore not recommended. Renal Insufficiency The plasma and blood half-life of metformin is prolonged and the renal clearance decreased in proportion to the decrease in creatinine clearance in patients with decreased renal function (based on measured creatinine levels). The relative total clearance of glimepiride is increased in patients with decreased renal function. The renal elimination of the two major glimepiride metabolites (M1 and M2) is reduced in patients with renal impairment. Geriatrics The limited pharmacokinetic data of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily related to a change in renal function. 2 of 12

3 There are no significant differences observed in glimepiride pharmacokinetics between patients with type 2 diabetes below or above 65 years old. Bioequivalence Study Metformin HCl 500 mg sustained-release (SR) + glimepiride 2 mg FDC (Norizec Plus) was shown to be bioequivalent to the reference product (innovator) of metformin HCl 500 mg SR and glimepiride 2 mg given as separate tablets in adults under fasting conditions. The following are important pharmacokinetic parameters of metformin HCl 500 mg SR + glimepiride 2 mg FDC (Norizec Plus) given as a single oral dose under fasting conditions: Pharmacokinetic Metformin HCl SR Glimepiride Parameters Mean ± SD 90% Confidence Interval Mean ± SD 90% Confidence Interval C max (ng/ml) ± ± AUC 0-t (ng-hr/ml) ± ± AUC 0-inf (ng-hr/ml) ± ± T max (hrs) 3.8 ± ± 0.9 K el (hrs -1 ) 0.2 ± ± 0.1 T 1/2 (hrs) 3.7 ± ± 9.58 C max = maximum plasma concentration of the drug at peak time AUC 0-t = area under the curve from blood level profile (from zero to sampling time point) AUC 0-inf = area under the curve from blood level profile (extrapolated to infinity) T max = time the drug reached its maximum concentration in the blood K el = elimination rate constant T 1/2 = elimination half-life INDICATION An adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who: Have inadequate glycemic control with metformin or glimepiride monotherapy or Are already treated with a combination of metformin and a sulfonylurea as separate tablets To maintain the efficacy of drug therapy, management of type 2 diabetes mellitus should also include nutritional counseling, appropriate exercise and weight reduction if obese or overweight. Secondary causes of poor glycemic control (e.g., infection) should be investigated and treated prior to initiation or escalation of oral antidiabetic therapy. DOSAGE AND MODE OF ADMINISTRATION The dose of metformin HCl SR + glimepiride FDC will vary, depending on a number of factors such as: patient s glycemic control, underlying medical conditions and other medications currently being taken. The dose of metformin HCl SR + glimepiride FDC should be individualized based on effectiveness and tolerability but not exceeding the maximum recommended daily dose of metformin HCl SR (2500 mg) and glimepiride (8 mg). The starting dose of metformin HCl SR + glimepiride tablet should be based on the patient s current regimen of metformin and/or sulfonylurea. Carefully monitor patients and adjust the dose accordingly in patients who may be more sensitive to hypoglycemic drugs. Monitor adverse events especially after initiation of the FDC or with dose increase. Consider dose reduction in patients who report hypoglycemia. Long-term efficacy should be monitored by measurement of glycosylated hemoglobin (HbA 1c ) levels. 3 of 12

4 The sustained-release (SR) tablet should be swallowed whole. Do not chew or crush or divide the SR tablet. Metformin HCl SR + Glimepiride FDC should be given with meals to reduce the gastrointestinal side effects associated with metformin. Usual starting dose: One tablet once a day If glycemic control with the usual starting doses of metformin HCl 500 mg SR + glimepiride 2 mg FDC tablet remains unsatisfactory, the dose of metformin HCl SR + glimepiride may be increased (at an interval of 1 to 2 weeks) but should not exceed the maximum daily recommended adult oral dose for each component. Or, as prescribed by a physician. Elderly The initial and maintenance dose of metformin HCl SR + glimepiride FDC should be conservative in elderly patients, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin and glimepiride. Monitoring of renal function is necessary to aid in the prevention of metformin-associated lactic acidosis, particularly in the elderly. CONTRAINDICATIONS Hypersensitivity to metformin HCl and/or glimepiride, other sulfonylureas, or to any ingredient in the product Unstable and/or type 1 (insulin-dependent) diabetes mellitus History of lactic acidosis irrespective of precipitating factors Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Treat diabetic ketoacidosis with insulin. Severe renal impairment (egfr <30mL/min/1.73 m 2 ) Acute conditions with the potential to alter renal function such as: o Dehydration due to persistent or severe diarrhea, recurrent vomiting o Severe infection o Diagnostic examinations (e.g., intravenous urography, angiography) that would involve the use of iodinated contrast agents/media Acute or chronic disease which may cause tissue hypoxia such as: o Cardiac or respiratory failure o Recent myocardial infarction o Shock Acute or chronic alcoholism Severe hepatic impairment Pregnancy or breastfeeding WARNINGS AND PRECAUTIONS 4 of 12

5 Warning on Lactic Acidosis Lactic acidosis 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 be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, and any condition associated with hypoxia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/l), reduced blood ph, electrolyte disturbance with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/ml are generally found. Lactic acidosis is usually accompanied by nonspecific symptoms such as acidotic dyspnea, vomiting, abdominal pain with muscle cramps, and/or a general feeling of malaise with severe fatigue. Hypothermia followed by coma, hypotension, and resistant bradyarrhythmias may be seen with marked acidosis. Instruct patients to immediately alert their physicians if these symptoms occur. Serum electrolytes, ketones, blood glucose, and if indicated, blood ph, lactate levels, and even blood metformin levels may be useful. Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin HCl SR + glimepiride, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin HCl is dialyzable, prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. Do not use metformin HCl SR + glimepiride in patients with congestive heart failure receiving drugs such as digoxin and furosemide because of the risk of hypoperfusion and hypoxemia which may lead to lactic acidosis. Hypoglycemia Glimepiride in combination with insulin or other hypoglycemic agents may increase the risk of hypoglycemia. Regularly monitor glycemic control and reduce dose during therapy with metformin HCl SR + glimepiride FDC in patients susceptible to the hypoglycemic action of these agents (e.g., debilitated or malnourished and those with adrenal, liver and kidney dysfunction). Hypoglycemia may occur in patients when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as other sulfonylureas and insulin) or alcohol. Despite successful countermeasures, hypoglycemia may recur. Severe or prolonged hypoglycemia may be temporarily controlled by immediate intake of carbohydrates (artificial sweeteners have no effect). Immediate medical treatment and occasionally, hospitalization may be required. Loss of Control of Blood Glucose A loss of control of blood glucose may occur in patients stabilized on any antidiabetic regimen exposed to stress (e.g., fever, trauma, infection, or surgery). The efficacy of any oral hypoglycemic drug (including metformin HCl + glimepiride FDC) may be reduced in many patients over a period of time due to progression of severity of the diabetes or to diminished responsiveness to the drug. 5 of 12

6 Monitoring of Renal Function Impaired renal function would increase the risk of metformin accumulation and lactic acidosis. Renal function should be assessed and verified as normal before initiation of metformin HCl SR + glimepiride FDC therapy. Estimated glomerular filtration rate (egfr) should be determined at least annually in all patients taking metformin HCl SR + glimepiride FDC. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Initiating metformin HCl SR + glimepiride FDC therapy in patients with egfr between 30 to 45 ml/min/1.73 m 2 is not recommended. In patients taking metformin HCl SR + glimepiride FDC whose egfr later falls below 45 ml/minute/1.73 m 2, the benefits and risks of continuing treatment should be assessed. Discontinue metformin HCl SR + glimepiride FDC if the patient s egfr later falls below 30 ml/minute/1.73 m 2. Medications which may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin (i.e., cationic drugs) should be used with caution since these drugs are eliminated by renal tubular secretion. Radiologic Studies Administration of parenteral iodinated contrast agents has led to an acute decrease in renal function and the occurrence of lactic acidosis in patients receiving metformin, including metformin HCl SR + glimepiride FDC. Discontinue metformin HCl SR + glimepiride FDC at the time of, or prior to, an iodinated contrast imaging procedure in patients with an egfr between 30 and 60 ml/minute/1.73 m 2, history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate egfr 48 hours after the imaging procedure, and restart metformin HCl SR + glimepiride FDC if renal function is stable. Hepatic Impairment Metformin HCl SR + glimepiride FDC should generally be avoided in patients with clinical or laboratory evidence of hepatic disease since impaired hepatic function has been associated with lactic acidosis. Hemolytic Anemia Sulfonylureas may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Use sulfonylureas, including glimepiride, with caution and consider a non-sulfonylurea alternative in these patients. Hemolytic anemia has also been observed in patients who did not have known G6PD deficiency in postmarketing reports. Hypoxic States Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. Promptly discontinue metformin HCl SR + glimepiride FDC when such events occur. Surgical Procedures Temporarily discontinue metformin HCl SR + glimepiride FDC use in patients undergoing surgery associated with restricted food or fluid intake. Therapy may be reinstituted when the patient s oral intake has resumed and renal function has been found normal. Hypersensitivity Reactions Allergic reaction to glimepiride may be experienced by persons allergic to other sulfonamide derivatives. Hypersensitivity reactions, including serious reactions such as anaphylaxis, angioedema, and Stevens- Johnson syndrome (SJS) have been reported in postmarketing studies with glimepiride. Metformin HCl SR + glimepiride FDC should be immediately discontinued if hypersensitivity reaction is suspected. The patient should be assessed for other potential causes for the reaction, and institute alternative treatment for diabetes. 6 of 12

7 Alcohol Combined use of alcohol and metformin may increase the risk of hypoglycemia and lactic acidosis since alcohol decreases lactate clearance and hepatic gluconeogenesis, and may increase insulin secretion. Excessive alcohol intake on an acute or chronic basis should be avoided in patients receiving metformin HCl SR + glimepiride FDC. Vitamin B 12 Levels Evaluate hematologic parameters prior to initiation of metformin HCl SR + glimepiride FDC therapy and at least annually since decreases in serum vitamin B 12 have been associated with metformin use. Increased Risk of Cardiovascular Mortality Oral hypoglycemic drugs have been associated with increased cardiovascular mortality compared to treatment with diet alone or diet plus insulin. In a long-term prospective study conducted by the University Group Diabetes Program (UGDP), it has been reported that diabetic patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g/day), a sulfonylurea, had a risk of cardiovascular mortality approximately 2.5 times that of patients treated with diet alone. In the United Kingdom Prospective Diabetes Study (UKPDS), however, intensive glycemic control with either sulfonylurea or insulin did not have an adverse effect on cardiovascular outcomes. Despite questions regarding the design of these studies and interpretation of the results, these studies provide a basis for caution especially in high risk patients with cardiovascular disease. More patients receiving glimepiride and insulin reported an increase in peripheral edema in clinical trials compared with patients receiving insulin alone. Patients using this combination therapy should be asked to report any edema or weight gain. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin or glimepiride. Metformin HCl SR + glimepiride FDC should not be prescribed to lower the risk of cardiovascular diseases (i.e., myocardial infarction and stroke) or to lower cardiovascular mortality for there is no study conducted using the combination. Effects on the Ability to Drive and Use Machines Although no studies have been conducted, patients who need to perform activities requiring mental alertness or physical coordination should avoid metformin HCl SR + glimepiride FDC since it may cause visual impairment as a result of hypoglycemia or hyperglycemia. INTERACTIONS WITH OTHER MEDICAMENTS Metformin HCl Cationic Drugs: Cationic drugs such as 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 peak plasma concentrations, whole blood concentrations and whole blood AUC by competing with metformin for common renal tubular transport systems. Concomitant administration of metformin and cimetidine has been observed to result in reduced urinary metformin excretion and increased plasma metformin concentrations. Other Antidiabetic Agents: Hypoglycemia may occur when metformin is used concomitantly with other antidiabetic agents such as sulfonylureas, meglitinides, glitazones, or insulin. Diuretics: Thiazide diuretics may exacerbate diabetes mellitus and may result in increased requirements of oral antidiabetic agents, metformin included. Temporary loss of diabetic control or secondary failure to the antidiabetic agent may also occur. Potassium-sparing diuretics, which are less diabetogenic, may be considered as a substitute. 7 of 12

8 Furosemide may increase metformin plasma and blood concentrations and blood AUC without significantly affecting metformin renal clearance. Nifedipine: Nifedipine increases the absorption, C max and AUC of metformin, and increases metformin excretion in the urine. Metformin has minimal effects on nifedipine pharmacokinetics. β-adrenergic Blocking Agents: β-adrenergic blocking agents (e.g., propranolol, nadolol) 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. Protein-Bound Drugs: Interaction of metformin and highly protein-bound drugs (e.g., salicylates, sulfonamides, chloramphenicol, probenecid) is unlikely because metformin is negligibly bound to plasma proteins. Angiotensin-Converting Enzyme (ACE) Inhibitors: ACE inhibitors (e.g., captopril, enalapril) 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 together with ACE inhibitors to prevent severe hypoglycemia. Alcohol: There is an increased risk of hypoglycemia and lactic acidosis when alcohol and metformin are used concomitantly since alcohol decreases lactate clearance and hepatic gluconeogenesis, and may increase insulin secretion. Acute or chronic intake of alcohol should be avoided in patients receiving metformin therapy. Clomifene: Ovulatory response may be increased when clomifene and metformin are used concomitantly in premenopausal patients with polycystic ovary syndrome. Anticoagulants: Metformin may affect the pharmacokinetic properties of coumarin anticoagulants when administered concomitantly. An increase in prothrombin time may occur upon cessation of metformin therapy, with an increased risk of hemorrhage. Patients receiving phenprocumon or other vitamin K anticoagulants should be carefully monitored. Iodinated Contrast Media: Intravascular administration of iodinated contrast media may lead to renal failure, resulting in metformin accumulation with the risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the procedure, and withheld for 48 hours afterwards. Metformin may be reinstituted only after renal function has been re-evaluated and found to be normal. Glyburide: Concomitant administration of metformin and glyburide produced no changes in metformin pharmacokinetics and pharmacodynamics. Decreases in C max, blood AUC of glyburide were observed, but were highly variable. The clinical significance of this finding was unclear. Others: Drugs that may cause hyperglycemia and may exacerbate loss of glycemic control in patients with diabetes include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. Close monitoring of glycemic control and metformin dose adjustments are recommended when such drugs are administered or withdrawn in patients. The pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies in healthy volunteers. Glimepiride 8 of 12

9 Aspirin: Coadministration of aspirin and glimepiride resulted in decreased mean AUC and mean C max of glimepiride. However, there is no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of aspirin and other salicylates. H 2 -Receptor Antagonists: Coadministration of either cimetidine or ranitidine with a single oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride, and no differences were seen in hypoglycemic symptomatology. Propranolol: Concomitant administration of propranolol and glimepiride may result in significant increases in the C max, AUC and T 1/2 of glimepiride. Miconazole: Potential interactions between oral miconazole and oral hypoglycemic agents including glimepiride leading to severe hypoglycemia have been reported. It is not known whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole. Anticoagulants: The pharmacodynamic response to warfarin may be potentiated or weakened by concomitant administration with glimepiride. This may cause very small reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment. Cytochrome P450: Glimepiride is metabolized by cytochrome P450 2C9. This should be taken into account when glimepiride is coadministered with inducers (e.g., rifampicin), inhibitors (e.g., fluconazole) or substrates of CYP2C9 (e.g., amiodarone, tolbutamide, diclofenac, ibuprofen, naproxen). In vivo, concomitant administration with fluconazole (a potent CYP2C9) resulted in a 2-fold increase in glimepiride s AUC. Sympatholytic Agents: Signs of adrenergic counter-regulation to hypoglycemia may be reduced or absent when glimepiride and sympatholytics (e.g., β-adrenergic blocking agents, clonidine, guanethidine, and reserpine) are taken concomitantly. Colesevelam: Absorption of glimepiride is reduced when concomitantly administered with colesevelam. However, absorption is not reduced when glimepiride is administered 4 hours before taking colesevelam. Alcohol: Acute and chronic alcohol intake may unpredictably potentiate or reduce the activity of glimepiride. Drugs that may potentiate the hypoglycemic action of glimepiride and other sulfonylureas: Nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., ibuprofen, phenylbutazone, oxyphenbutazone and azapropazone; clarithromycin, highly protein-bound drugs, coumarins, probenecid, β-adrenergic blocking agents, salicylates, aminosalicylic acid, anabolic steroids and male sex hormones, chloramphenicol, certain long-acting sulfonamides, tetracyclines, quinolone antibiotics, coumarin anticoagulants, fenfluramine, fibrates, ACE inhibitors, fluoxetine, monoamine oxidase (MAO) inhibitors, disopyramide, allopurinol, probenecid, sulfinpyrazone, sympatholytics, cyclophosphamide, trosphosphamide, ifosfamide, miconazole, fluconazole, pentoxifylline (high dose parenteral), tritoqualine, insulin, and other oral antibiabetic drugs Drugs that tend to produce hyperglycemia and may lead to loss of glycemic control when coadministered with glimepiride: Thiazides and other diuretics, corticosteroids, phenothiazines, chlorpromazine, thyroid products, estrogens, progestogens, nicotinic acid (high doses) and nicotinic acid derivatives, laxatives (long-term use), oral contraceptives, phenytoin, diazoxide, glucagons, barbiturates, rifampicin, acetazolamide, adrenaline, sympathomimetics, and isoniazid STATEMENT ON USAGE FOR HIGH-RISK GROUPS Pregnancy: Pregnancy Category C. Current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as 9 of 12

10 increased neonatal morbidity and mortality. Insulin is recommended to be used during pregnancy to maintain blood glucose levels as close to normal as possible. Metformin HCl SR + glimepiride FDC tablet should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Lactation: In studies performed on the individual components, metformin have been shown to be excreted into human milk; however, it is not known if glimepiride is excreted in human milk. Discontinue use in breastfeeding mothers because of potential hypoglycemia in breastfeeding infants. Consider insulin therapy if diet and exercise is inadequate to control blood glucose. Children: The safety and efficacy of the fixed dose combination of metformin HCl SR + glimepiride have not been established in children. Elderly: Since elderly patients may have decreased renal function and are more susceptible to hypoglycemia, dosage should be carefully titrated; conservative initial and maintenance dose are recommended. Monitor renal function regularly. UNDESIRABLE EFFECTS Metformin may provoke or augment lactic acidosis particularly if it is present in high concentrations in the blood. Some of the symptoms of lactic acidosis may mimic certain adverse effects of metformin. Physicians should instruct their patients to recognize the onset of symptoms of lactic acidosis to avoid this adverse reaction. There is a great potential risk for hypoglycemia to occur due to the sulfonylurea, i.e., glimepiride, component of the FDC. Possible symptoms 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. Metformin HCl The most frequent adverse effects reported with metformin include nausea, vomiting, diarrhea, abdominal pain and loss of appetite. These adverse effects occur during initiation of treatment and resolve spontaneously in most cases. Blood and lymphatic system disorders: Decrease in serum vitamin B 12, megaloblastic anemia (rare); serum folic acid concentrations do not appear to decrease substantially in patients receiving metformin Metabolism and nutrition disorders: Hyperglycemia, hypoglycemia (may occur when metformin is given concomitantly with sulfonylureas and/or alcohol), lactic acidosis, weight decreased Nervous system disorders: Agitation, dizziness, headache, lightheadedness Cardiac disorders: Chest discomfort, palpitations Vascular disorders: Flushing, hypertension Respiratory, thoracic and mediastinal disorders: Dyspnea, flu syndrome, pneumonitis with vasculitis, rhinitis, upper respiratory infection Gastrointestinal disorders: Abdominal discomfort (e.g., bloating, abdominal cramps), abdominal distention, abnormal stools/loose stools, anorexia, constipation, dry mouth, dyspepsia/heartburn, epigastric discomfort, flatulence, gastric disorder, gastric ulcer, gastrointestinal disorder, indigestion, taste disturbance specifically metallic taste in the mouth Hepatobiliary disorders: Abnormal liver function tests, autoimmune hepatitis, cholestasis, hepatic injury, hepatitis Skin and subcutaneous tissue disorders: Erythema, nail disorder, pruritus, rash, skin lesion, urticaria Musculoskeletal and connective tissue disorders: Asthenia, chills, musculoskeletal pain, myalgia Renal and urinary disorders: Urinary tract infection General disorders and administration site conditions: Fatigue, increased sweating 10 of 12

11 Glimepiride The most frequent adverse effects reported with glimepiride include hypoglycemia, headache, nausea, and dizziness. Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia, erythrocytopenia, granulocytopenia, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia (including severe cases with platelet count less than 10,000/microL), thrombocytopenic purpura Immune system disorders: Anaphylaxis, angioedema, cross-sensitivity reaction to other sulfonylureas or sulfonamide may also occur, hypersensitivity reactions worsening (e.g., dyspnea, hypotension, and shock) Metabolism and nutrition disorders: Aggravation of diabetes mellitus, anorexia, hyperglycemia, hyponatremia, increased appetite, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, weight gain Nervous system disorders: Disulfiram-like reactions, dry mouth, hot flashes, insomnia, nervousness, paresthesia, tremor Eye disorders: Blurred vision, visual disturbance/abnormal vision Cardiac disorders: Bradycardia, palpitations, Vascular disorders: Allergic vasculitis, leukocytoclastic vasculitis, vasodilation Respiratory, thoracic and mediastinal disorders: Flu syndrome Gastrointestinal disorders: Abdominal discomfort, abdominal distention, abdominal pain, diarrhea, dyspepsia, gastrointestinal pain, gastrointestinal fullness, heartburn, metallic taste, vomiting Hepatobiliary disorders: Abnormal hepatic function, cholestasis, hepatic porphyria reactions, hepatitis which may lead to liver failure or hepatic dysfunction, increased hepatic enzyme levels, jaundice, Skin and subcutaneous tissue disorders: Allergic or pseudo-allergic reactions (e.g., pruritus, rash, urticaria, erythema multiforme, erythema nodosum, morbilliform, maculopapular skin eruptions), exfoliative dermatitis, photosensitivity reactions, porphyria cutanea tarda, Stevens-Johnson syndrome (SJS) Renal and urinary disorders: Increased urinary frequency, nocturia General disorders and administration site conditions: Asthenia, increased sweating, pain in extremity Investigations: Decrease in serum sodium concentration, laboratory test abnormal Injury, poisoning and procedural complications: Accidental injury OVERDOSE AND TREATMENT Metformin HCl There were no cases of overdose reported in clinical studies. Symptoms of metformin overdose include extensions of the common adverse effects (e.g., epigastric discomfort, nausea, vomiting, diarrhea, drowsiness, weakness, dizziness, malaise, and headache). Should these symptoms occur, lactic acidosis should be excluded. Metformin therapy should be discontinued and proper supportive therapy should be instituted. Metformin ingestion of up to 50 g has been reported. Hypoglycemia was reported in 10% of cases, but no causal relationship with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 ml/min under good hemodynamic conditions. Therefore, hemodialysis maybe useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. Glimepiride Like other sulfonylureas, glimepiride overdosage may manifest as hypoglycemia which may last for 7 to 12 hours and may recur after an initial recovery. Symptoms may not be present for up to 24 hours after ingestion. Aggressively treat mild hypoglycemic symptoms with oral glucose and adjust drug dosage and/or meal patterns. Continue close monitoring until the patient is out of danger. 11 of 12

12 Prevent absorption of glimepiride by inducing vomiting and then drinking water or lemonade with activated charcoal (adsorbent) and sodium sulfate (laxative). Gastric lavage followed by activated charcoal and sodium sulfate is recommended in case of large ingestions of glimepiride. In case of severe hypoglycemic reactions including coma, seizure or other neurological impairment, immediate hospitalization is required. In patients with diagnosed or suspected hypoglycemic coma, rapid intravenous injection of concentrated (50%) glucose solution followed by a continuous infusion of 10% glucose solution at a rate that will maintain blood glucose level at 100 mg/dl and above should be given. Monitor patients for 24 to 48 hours to prevent recurrence of hypoglycemia. In case of accidental ingestion of glimepiride in infants and children, treat hypoglycemic symptoms by giving a carefully controlled dose of glucose (to avoid the possibility of producing hyperglycemia) and close monitoring of blood glucose until the patient is out of danger. CAUTION Foods, Drugs, Devices, and Cosmetics Act prohibits dispensing without prescription. For suspected adverse drug reaction, seek medical attention immediately and report to the FDA at AND Unilab at (+632) or productsafety@unilab.com.ph. By reporting undesirable effects, you can help provide more information on the safety of this medicine. AVAILABILITY Glimepiride + Metformin HCl (Norizec Plus) 2 mg/500 mg Sustained-Release Tablet, in blister pack x 10s (box of 30s) STORE AT TEMPERATURES NOT EXCEEDING 30 C PROTECT FROM LIGHT AND MOISTURE KEEP THE PRODUCT OUT OF SIGHT AND REACH OF CHILDREN Manufactured by Inventia Healthcare Pvt. Ltd. F1-F1/1, Additional Ambernath M.I.D.C. Ambernath (East) , Dist. Thane, India Imported and distributed by UNILAB, Inc. No. 66 United Street, Mandaluyong City, Metro Manila, Philippines 12 of 12