AMARYL is also indicated for use in combination with insulin to lower blood glucose in patients with type 2 diabetes whose hyperglycemia cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic agent alone.
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
Overdosage of sulfonylureas, including AMARYL (glimepiride), can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. In case of overdosage, current medical intervention for the treatment of hypoglycemia should be followed according to the condition of the patient. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery.
Dosage Forms, Composition and Packaging
Each pink, flat-faced, oblong tablet with notched sides at the bisect, imprinted with “AMARYL” on one side and plain with bisect on the other, contains: glimepiride 1 mg. Nonmedicinal ingredients: ferric oxide, lactose, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. Plastic bottles of 30.
Each blue, flat-faced, oblong tablet with notched sides at the bisect, imprinted with “AMARYL” on one side and plain with bisect on the other, contains: glimepiride 4 mg. Nonmedicinal ingredients: FD&C Blue #2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. Plastic bottles of 30.
Each green, flat-faced, oblong tablet with notched sides at the bisect, imprinted with “AMARYL” on one side and plain with bisect on the other, contains: glimepiride 2 mg. Nonmedicinal ingredients: FD&C Blue #2 Aluminum Lake, ferric oxide, lactose, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. Plastic bottles of 30.
Warnings and Precautions
In patients with renal insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions.
Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to hemolytic anemia. Since AMARYL belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a nonsulfonylurea alternative should be considered.
When a patient stabilized on any diabetic regimen is exposed to stress such as illness during therapy, fever, trauma, infection, or surgery, a loss of glycemic control may occur. At such times, it may be necessary to adjust the dosage of AMARYL, add insulin in combination with AMARYL or even use insulin monotherapy. The effectiveness of any oral hypoglycemic drug, including AMARYL, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon, known as secondary failure, is distinctive of primary failure in which the drug is ineffective in an individual patient when given for the first time. Should secondary failure occur or if target blood glucose levels are not attainable with AMARYL monotherapy, metformin may be added until the maximum dose of both agents is reached. Should secondary failure occur with AMARYL-metformin combination therapy, AMARYL-insulin combination therapy may be instituted.
Use of AMARYL (glimepiride) must be considered as treatment in addition to a proper dietary regimen and not as a substitute for diet.
Over a period of time, patients may become progressively less responsive to therapy with oral hypoglycemic agents because of deterioration of their diabetic state. Patients should therefore be monitored with regular clinical and laboratory evaluations, including blood glucose and glycosylated hemoglobin (HbA1C) determinations, to determine the minimum effective dosage and to detect primary failure (inadequate lowering of blood glucose concentrations at the maximum recommended dosage) or secondary failure (progressive deterioration in blood sugar control following an initial period of effectiveness). The rate of primary failure will vary greatly depending upon patient selection and adherence to diet and exercise. The etiology of secondary failure is multifactorial and may involve progressive β-cell failure as well as exogenous diabetogenic factors such as obesity, illness, drugs, or tachyphylaxis to the sulfonylurea. If a loss of adequate blood glucose lowering response to a sulfonylurea is detected, the addition of a different type of oral antidiabetic may be considered, although insulin is often required. Certain patients who demonstrate an inadequate response or true primary or secondary failure to one sulfonylurea may benefit from a switch to another sulfonylurea.
In initiating treatment for type 2 diabetes, non-pharmacologic therapy (proper dietary management, exercise and weight reduction) should be emphasized as the initial form of treatment. Caloric restriction, weight loss and exercise are essential in the obese diabetic patient. Proper dietary management and exercise alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. In addition to regular physical activity, cardiovascular risk factors should be identified and corrective measures taken when possible.
Fasting blood glucose should be monitored periodically to determine therapeutic response. Glycosylated hemoglobin (HbA1C) should also be monitored, usually every 3 to 6 months, to more precisely assess long-term glycemic control.
Driving a vehicle or operating machinery: Alertness and reactions may be impaired due to hypo- or hyperglycemia, especially when beginning or after altering treatment or when AMARYL (glimepiride) is not taken regularly. This may, for example, affect the ability to drive or to operate machinery.
All sulfonylurea drugs are capable of producing severe hypoglycemia. In the initial weeks of treatment, the risk of hypoglycemia seen with glimepiride may be even further increased and necessitates closer and more frequent monitoring.
Signs of severe hypoglycemia can include disorientation, loss of consciousness, and seizures. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly, debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of AMARYL. A starting dose of 1 mg once daily followed by appropriate dose titration is also recommended in those patients. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when other drugs causing lowering of blood glucose are used concomitantly with AMARYL (see Drug Interactions, Drug-Drug Interactions). In clinical trials, patients receiving AMARYL in combination with insulin reported more incidence of hypoglycemia than patients on monotherapy.
Safety and efficacy in pediatric type 2 diabetes patients have not been established.
Careful selection of patients is important. Patients most likely to respond to sulfonylurea therapy are: obese or normal body weight; duration of diabetes less than 5 to 10 years before initiation of therapy; and, absence of ketoacidosis. It is imperative that there be careful attention to diet, careful adjustment of dosage, instruction of the patient on hypoglycemic reactions and their treatment, as well as regular, thorough follow-up examinations.
If non-pharmacologic therapy fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea should be considered. Use of AMARYL (glimepiride) must be viewed by both the physician and patient as a treatment in addition to diet and exercise and not as a substitute for proper dietary management, exercise and weight reduction or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet and exercise alone may be transient, thus requiring only short-term administration of AMARYL.
There are no adequate and well-controlled studies in pregnant women. On the basis of results from animal studies, AMARYL (glimepiride) should not be used during pregnancy. Recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Experts, including the Canadian Diabetes Association and the Canadian Medical Association recommend that insulin be used during pregnancy to maintain glucose levels as close to normal as possible.
Teratogenic Effects: Glimepiride did not produce teratogenic effects in rats exposed orally up to 4000 mg/kg body weight (approximately 4000 times the maximum recommended human dose based on surface area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times the maximum recommended human dose based on surface area). Glimepiride has been shown to be associated with intrauterine fetal death in rats when given in doses as low as 50 times the human dose based on surface area and in rabbits when given in doses as low as 0.1 times the human dose based on surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been similarly noted with other sulfonylureas, and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride.
Nonteratogenic Effects: In some studies in rats, offspring of dams exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformations consisting of shortening, thickening, and bending of the humerus during the postnatal period. Significant concentrations of glimepiride were observed in the serum and breast milk of the dams as well as in the serum of the pups. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride.
Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. Patients who are planning a pregnancy should consult their physician, and it is recommended that they change over to insulin for the entire course of pregnancy and lactation.
In rat reproduction studies, significant concentrations of glimepiride were observed in the serum and breast milk of the dams, as well as in the serum of the pups. Although it is not known whether AMARYL is excreted in human milk, other sulfonylureas are excreted in human milk. Since the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, AMARYL should be discontinued in nursing mothers. If AMARYL is discontinued, and if diet and exercise alone are inadequate for controlling blood glucose, insulin therapy should be considered (see Pregnant Women, Nonteratogenic Effects).
It has been suggested, based on a study conducted by the University Group Diabetes Program (UGDP), that certain sulfonylurea antidiabetic agents increase cardiovascular mortality in diabetic patients, a population at greater risk of cardiovascular disease. This finding was not confirmed by a more recent trial, the United Kingdom Prospective Diabetes Study (UKPDS) which showed that intensive glycemic control with either sulfonylureas or insulin did not have an adverse effect on cardiovascular outcomes. Despite questions regarding the design of these studies and interpretation of the results, the results of these studies provide a basis for caution, especially high risk patients with cardiovascular disease.
In clinical trials more patients receiving AMARYL and insulin reported an increase in peripheral edema compared to patients receiving insulin alone. Patients receiving this combination therapy should be asked to report any edema or weight gain.
Storage and Stability
Store between 15 and 30°C. Dispense in well-closed container.
Action and Clinical Pharmacology
After intravenous dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.
When 14C-glimepiride was given as a single dose orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and metabolites M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and metabolites M1 and M2 (predominant) accounted for about 70% of that recovered in feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.
There were no differences between males and females in the pharmacokinetics of glimepiride when adjusting for differences in body weight.
There were no important differences in glimepiride metabolism in subjects identified as phenotypically different drug-metabolizers by their metabolism of sparteine.
The pharmacokinetics of glimepiride in morbidly obese patients were similar to those in the normal weight group, except for a lower Cmax and AUC. However, since neither Cmax nor AUC values were normalized for body surface area, the lower values of Cmax and AUC for the obese patients were likely the result of their excess weight and not due to a difference in the kinetics of glimepiride.
Glimepiride is completely metabolized by oxidative biotransformation after either IV or oral administration. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2 C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful in humans is not clear.
A mild glucose-lowering effect first appeared following single oral doses as low as 0.5-0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [Tmin]) was about 2 to 3 hours. In type 2 diabetes (formerly known as non-insulin-dependent diabetes mellitus or NIDDM) patients, both fasting and 2-hour postprandial glucose levels were significantly lower with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours.
In larger dose-ranging studies, blood glucose and glycosylated hemoglobin (HbA1C) were found to respond in a dose-dependent manner over the range of 1 to 4 mg of AMARYL once daily. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of AMARYL up to 8 mg once daily. No difference in the decrease in blood glucose and HbA1C concentrations were found when AMARYL was administered once or twice daily.
In two 14-week, placebo-controlled studies in 720 subjects, the average net reduction in HbA1C for AMARYL (glimepiride) patients treated with 8 mg once daily was 2.0% (0.02) in absolute units compared with placebo-treated patients. Efficacy results were not affected by age, gender, weight, or race.
In a 22-week, randomized, placebo-controlled study of Type 2 diabetic patients unresponsive to dietary management, AMARYL therapy improved postprandial insulin/C-peptide responses, and 75% of patients achieved and maintained control of blood glucose and HbA1C. The results of three long-term studies demonstrated that AMARYL, when administered over a prolonged treatment period of one-year (n=986), was effective in maintaining metabolic control in type 2 diabetic patients who were responders to sulfonylurea therapy. In an extension of long-term trials with patients previously treated with AMARYL, no meaningful deterioration in mean fasting blood glucose (FBG) or HbA1C levels was seen after up to 2.5 years of AMARYL therapy (n=445).
Combination therapy with AMARYL and metformin was compared with glimepiride and metformin monotherapy in Type 2 diabetic patients. The results of the study indicated that the combination of metformin and glimepiride was more effective than either treatment alone, with regards to improving HbA1C, fasting blood glucose and postprandial blood glucose levels.
Combination therapy with AMARYL and insulin (70% NPH/30% regular) was compared to placebo/insulin in secondary failure patients whose body weight was >130% of their ideal body weight. Initially, 5-10 units of insulin were administered with the main evening meal and titrated upward weekly to achieve predefined FPG values. Both groups in this double-blind study achieved similar reductions in FPG levels but the AMARYL/insulin therapy group showed an insulin sparing effect with a use of 38% less insulin.
AMARYL therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for Type 2 diabetes.
No studies were performed in pediatric patients.
Comparison of glimepiride pharmacokinetics in type 2 diabetic patients ≤65 years and those >65 years was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups. The mean AUC at steady state for the older patients was about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients (see Warnings and Precautions, General).
No studies were performed in patients with hepatic insufficiency.
The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extra-pancreatic effects may also play a role in the activity of glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which AMARYL (glimepiride) therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.
No pharmacokinetic studies to assess the effects of race have been performed, but in placebo-controlled studies of AMARYL (glimepiride) in patients with type 2 diabetes, the hypoglycemic effect was comparable in whites (n=536), blacks (n=63), and Hispanics (n=63).
A single-dose, open-label study was conducted in 15 patients with renal impairment. AMARYL (3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (CLcr): Group I, CLcr=77.7 mL/min (1.30 mL/sec), n=5; Group II, CLcr=27.7 mL/min (0.462 mL/sec), n=3; and Group III, CLcr=9.4 mL/min (0.16 mL/sec), n=7. AMARYL was found to be well tolerated in all 3 groups. The results showed that M1 and M2 metabolites serum levels (mean AUC values) increased 2.2 and 6.1 times from Group I to Group III as renal function decreased. The apparent terminal half-life (T1/2) for glimepiride did not change, while the half-lives for metabolites M1 and M2 increased as renal function decreased. Mean urinary excretion of metabolites M1 plus M2 as percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to III).
A multiple-dose titration study was also conducted in 16 type 2 diabetic patients with renal impairment using doses ranging from 1-8 mg daily for 3 months. The results were consistent with those observed after single doses. All patients with a CLcr less than 22 mL/min (0.37 mL/sec) had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this study suggested that a starting dose of 1 mg AMARYL may be given to type 2 diabetic patients with kidney disease, and the dose may be titrated based on fasting blood glucose levels (see Warnings and Precautions, Renal).
These data indicate that glimepiride did not accumulate in serum, and the pharmacokinetics of glimepiride were not different in healthy volunteers and in type 2 diabetic patients. Oral clearance of glimepiride did not change over the 1-8-mg dose range, indicating linear pharmacokinetics.
Contraindications
AMARYL (glimepiride) is contraindicated in patients with:
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Type 1 diabetes (formerly known as insulin-dependent diabetes mellitus or IDDM).
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Known hypersensitivity or allergy to any sulfonylurea or sulfonamides or any other component of the formulation. For a complete listing, see Dosage Forms, Composition and Packaging.
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Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
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Pregnant or breast-feeding women.
No experience has been gained concerning the use of AMARYL in patients with severe impairment of liver function and in dialysis patients. In patients with severe impairment of renal or hepatic function, change-over to insulin is indicated, to achieve optimal metabolic control.
