Composition
GLIMCIP 1
Each tablet contains:
Glimepiride……………….. ……………………………………1 mg
GLIMCIP 2
Each tablet contains:
Glimepiride……………….. ……………………………………2 mg
Dosage Form
Tablet
Pharmacology
Pharmacodynamics
Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta-cells. Sulphonylureas bind to the sulphonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.
In healthy subjects, the time to reach maximal effect (minimum blood glucose concentrations) was approximately 2–3 hours after single oral doses of glimepiride. The effects of glimepiride on HbA1c, fasting plasma glucose, and post-prandial glucose have been assessed in clinical trials.
Pharmacokinetics
Absorption
Studies with single oral doses of glimepiride in healthy subjects and with multiple oral doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours post-dose. When glimepiride was given with meals, the mean Cmax and area under the curve (AUC) were decreased by 8% and 9%, respectively.
Glimepiride does not accumulate in serum following multiple dosing. The pharmacokinetics of glimepiride does not differ between healthy subjects and patients with type 2 diabetes. Clearance of glimepiride after oral administration does not change over the 1–8 mg dose range, indicating linear pharmacokinetics.
In healthy subjects, the intra- and inter-individual variabilities of glimepiride pharmacokinetic parameters were 15–23% and 24–29%, respectively.
Distribution
After intravenous (I.V.) dosing in healthy 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%.
Metabolism
Glimepiride is completely metabolised by oxidative biotransformation after either an I.V. or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the biotransformation of glimepiride to M1. M1 is further metabolised to M2 by one or several cytosolic enzymes. M2 is inactive. In animals, M1 possesses about one-third of the pharmacological activity of glimepiride, but it is unclear whether M1 results in clinically meaningful effects on blood glucose in humans.
Excretion
When 14C-glimepiride was given orally to 3 healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 and M2 accounted for 80–90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in the faeces. M1 and M2 accounted for approximately 70% (ratio of M1 to M2 was 1:3) of the radioactivity recovered in the faeces. No parent drug was recovered from urine or faeces. After I.V. dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.
Special Populations
Geriatric: A comparison of glimepiride pharmacokinetics in patients with type 2 diabetes patients aged ≤65 years and those >65 years was evaluated in a multiple-dose study using glimepiride 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 approximately 11% higher than that for the younger patients.
Paediatric: The pharmacokinetics of glimepiride in paediatric patients with type 2 diabetes was comparable to historical data from adults. However, glimepiride is not recommended in paediatric patients because of its adverse effects on body weight and hypoglycaemia.
Gender: There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.
Renal Impairment: Studies in diabetes patients with renal impairment showed that glimepiride serum levels decreased as renal function decreased. However, mean AUCs for M1 and M2 increased 2.3-fold and 8.6-fold respectively in patients with severe renal impairment (CLcr<20 mL/min), as compared to those with mild renal impairment (CLcr>50mL/min). The apparent terminal half-life (T1/2) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as percent of dose, however, decreased, as renal function decreased.
Hepatic Impairment: It is unknown whether there is an effect of hepatic impairment on glimepiride pharmacokinetics because the pharmacokinetics of glimepiride has not been adequately evaluated in patients with hepatic impairment.
Obese Patients: The pharmacokinetics of glimepiride and its metabolites were measured in a single-dose study in type 2 diabetes patients who either had normal body weight or were morbidly obese. While the time to peak concentrations (tmax), clearance, and Vd of glimepiride in the morbidly obese patients were similar to those in the normal weight group, the morbidly obese had lower Cmax and AUC than those of normal body weight.
Race: No studies have been conducted to assess the effects of race on glimepiride pharmacokinetics. However, in placebo-controlled trials of glimepiride in patients with type 2 diabetes, the reduction in HbA1c was comparable in Caucasians, Blacks and Hispanics.
Indications
GLIMCIP is indicated as an adjunct to diet and exercise to improve glycaemic control in adult patients with type 2 diabetes (non-insulin-dependent diabetes mellitus ) whose hyperglycaemia cannot be controlled by diet and exercise alone. It should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.
Dosage and Administration
Dosage should be individualised on the basis of both effectiveness and tolerance. There is no fixed dosage regimen for the management of diabetes mellitus with GLIMCIP or any other hypoglycaemic agent.
The recommended starting dose of GLIMCIP is 1 mg or 2 mg once daily, administered with breakfast or the first main meal of the day. Patients at increased risk for hypoglycaemia (e.g. the elderly or patients with renal impairment) should be started on 1 mg once daily.
The usual maintenance dose is 1–4 mg once daily. The maximum recommended dose is 8 mg once daily. After reaching a daily dose of 2 mg, dosage increases should be made in increments of no more than 2 mg at 1- to 2-week intervals, based upon the patient's glycaemic response. A conservative titration scheme is recommended for patients at increased risk for hypoglycaemia.
Patients being transferred to GLIMCIP from sulphonylureas with longer half-life (e.g. chlorpropamide) may have overlapping drug effect for 1–2 weeks and should be appropriately monitored for hypoglycaemia.
Contraindications
GLIMCIP is contraindicated in patients with a history of a hypersensitivity reaction to glimepiride or any of product’s ingredients.
Patients who have developed an allergic reaction to sulphonamide derivatives may develop an allergic reaction to GLIMCIP. Do not use GLIMCIP in patients who have a history of an allergic reaction to sulphonamide derivatives.
Warnings and Precautions
Hypoglycaemia
All sulphonylurea drugs are capable of producing severe hypoglycaemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycaemic episodes. Severe hypoglycaemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. In patients predisposed to hypoglycaemia (e.g. elderly, patients with renal impairment, patients on other anti-diabetic medications) GLIMCIP must be used with caution, especially when doses are increased. Hypoglycaemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol in ingested. In patients with autonomic neuropathy, the elderly and those taking beta-adrenergic blocking medications or other sympatholytic agents, early symptoms of hypoglycaemia may be different or less pronounced and might result in severe hypoglycaemia before the patient is aware of the hypoglycaemia.
Haemolytic Anaemia
Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulphonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the class of sulphonylurea agents, caution should be practised when using GLIMCIP in patients with G6PD deficiency and a non-sulphonylurea alternative may be considered. In postmarketing reports, haemolytic anaemia has also been reported in patients receiving glimepiride and who did not have known G6PD deficiency.
Hypersensitivity Reactions
There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, including serious reactions such as anaphylaxis, angio-oedema, and Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, promptly discontinue GLIMCIP, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.
Increased Risk of Cardiovascular Mortality with Sulphonylureas
The administration of oral hypoglycaemic drugs (tolbutamide) has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Patients treated for 5–8 years with diet plus a fixed dose of tolbutamide (1.5 gm per day) had a rate of cardiovascular mortality approximately 2.5 times that of patients with diet alone. In view of close similarities like mode of action and chemical structure between drugs of the sulphonylurea class, this warning may also apply for all drugs in this class.
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug.
Drug Interactions
Drugs Affecting Glucose Metabolism
A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycaemia or worsening glycaemic control.
The following are examples of medications that may increase the glucose-lowering effect of sulphonylureas including glimepiride, increasing the susceptibility to and/or intensity of hypoglycaemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin-converting enzyme (ACE) inhibitors, H2-receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogues, anabolic steroids and androgens, cyclophosphamide, trophosphamide, iphosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, phenylbutazone, azapropazone, oxyfenbutazone, fenfluramine, allopurinol, sympatholytics, tritoqualine and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulphonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for hypoglycaemia. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for worsening glycaemic control.
The following are examples of medications that may reduce the glucose-lowering effect of sulphonylureas including glimepiride, leading to worsening glycaemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g. olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazine derivatives, chlorpromazine, thyroid hormones, oestrogens, progestogens, oral contraceptives, phenytoin, diazoxide, nicotinic acid and its derivatives, sympathomimetics (e.g. epinephrine, albuterol, terbutaline), acetazolamide and isoniazid. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for worsening glycaemic control. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for hypoglycaemia.
H2-antagonists, beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of glimepiride’s glucose-lowering effect.
Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of glimepiride in an unpredictable fashion.
The signs of hypoglycaemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.
Glimepiride may either potentiate or weaken the effects of coumarin derivatives.
Concomitant Administration of Colsevelam
Colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride when the two are co-administered, as it binds to glimepiride and reduces glimepiride absorption from the gastrointestinal tract. No interaction was observed when glimepiride was taken at least 4 hours before colesevelam. Therefore, GLIMCIP should be administered at least 4 hours prior to colesevelam.
Miconazole
A potential interaction between oral miconazole and sulphonylureas leading to severe hypoglycaemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known.
Cytochrome P450 2C9 Interactions
There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g. rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride, which may lead to hypoglycaemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride, which may lead to worsening glycaemic control.
Aspirin
A study on healthy subjects demonstrated that co-administration of aspirin and glimepiride resulted in a 34% decrease in the mean glimepiride AUC and a 4% decrease in the mean glimepiride Cmax.
Cimetidine and Ranitidine
A study on healthy subjects demonstrated that co-administration of cimetidine or ranitidine with a single 4 mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride.
Propranolol
A study on healthy subjects demonstrated that concomitant administration of propranolol and glimepiride significantly increased glimepiride Cmax, AUC, and T1/2 by 23%, 22%, and 15%, respectively, and decreased glimepiride CL/f by 18%. The recovery of M1 and M2 from urine was not changed.
Warfarin
A study on healthy subjects demonstrated that the concomitant administration of glimepiride did not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in warfarin plasma protein-binding. Glimepiride resulted in a statistically significant decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment were 3.3% and 9.9%, respectively, and are unlikely to be clinically relevant.
Renal Impairment
To minimise the risk of hypoglycaemia, starting dose of 1 mg glimepiride may be given to diabetes patients with kidney disease and the dose may be titrated, based on fasting blood glucose levels. The results of multiple-dose titration studies revealed that the relative total clearance of glimepiride increased when kidney function was impaired and the elimination of the two major metabolites was reduced in patients with renal impairment. The initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycaemic reactions.
Hepatic Impairment
No studies were performed in patients with hepatic insufficiency.
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of glimepiride in pregnant women. Glimepiride should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Because data suggest that abnormal blood glucose during pregnancy is associated with a higher incidence of congenital abnormalities, diabetes treatment during pregnancy should maintain the blood glucose levels as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycaemia (4–10 days) has been reported in neonates born to mothers receiving a sulphonylurea at the time of delivery.
Lactation
It is not known whether glimepiride is excreted in human milk. Animal data reported that significant concentrations of glimepiride were present in breast milk and serum of the offspring. Skeletal deformities consisting of shortening, thickening and bending of the humerus during the postnatal period were developed in animal offspring exposed to high levels of glimepiride during pregnancy and lactation. Based on these animal data and the potential for hypoglycaemia in a nursing infant, a decision should be made whether to discontinue nursing or discontinue glimepiride, taking into account the importance of glimepiride to the mother.
Paediatric Use
The profile of adverse reactions in paediatric patients treated with glimepiride was similar to that observed in adults. In a study between glimepiride and metformin, hypoglycaemic events (blood glucose <36 mg/dL) were observed in 4% of paediatric patients treated with glimepiride and in 1% of paediatric patients treated with metformin. Glimepiride is not recommended in paediatric patients because of its adverse effects on body weight and hypoglycaemia.
Geriatric Use
In clinical trials of glimepiride conducted in patients >65 years of age, no overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The drug is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased renal function and it may be difficult to recognize hypoglycaemia in these patients. Thus, caution needs to be practiced during initiation and up-titration of glimepiride in this population.
Effects on Ability to Drive and Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However, the patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery). The patient should be informed of this potential side effect.
Undesirable Effects
The following serious adverse reactions are discussed in more detail below:
- Hypoglycaemia
- Haemolytic anaemia
In clinical trials, the most common adverse reactions with glimepiride were hypoglycaemia, dizziness, asthenia, headache, and nausea.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Approximately 2,800 patients with type 2 diabetes have been treated with glimepiride in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with glimepiride for at least 1 year.
The table summarizes adverse events, other than hypoglycaemia, that were reported in eleven pooled placebo-controlled trials, whether or not considered to be possibly or probably related to study medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported represent those that occurred at an incidence of ≥5% among glimepiride-treated patients and more commonly than in patients who received placebo.
Eleven pooled placebo-controlled trials ranging from 13 weeks to 12 months: Adverse events (excluding hypoglycaemia) occurring in ≥5% of glimepiride-treated patients and at a greater incidence than with placebo*
|
|
Glimepiride N=745 % |
Placebo N=294 % |
|
Headache |
8.2 |
7.8 |
|
Accidental Injury† |
5.8 |
3.4 |
|
Flu Syndrome |
5.4 |
4.4 |
|
Nausea |
5.0 |
3.4 |
|
Dizziness |
5.0 |
2.4 |
|
* Glimepiride doses ranged from 1 to 16 mg administered daily †Insufficient information to determine whether any of the accidental injury events were associated with hypoglycaemia |
||
Hypoglycaemia
In a randomised, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulphonylurea therapy underwent a 3-week washout period and, then, were randomised to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomised to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated. The overall incidence of possible hypoglycaemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycaemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg and 0% for placebo. All of these events were self-treated.
In a randomised, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90–150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6 or 8 mg. The overall incidence of possible hypoglycaemia (as defined above for the 14-week trial) for glimepiride versus placebo was 19.7% versus. 3.2%. All of these events were self-treated.
Weight Gain
Glimepiride, like all sulphonylureas, can cause weight gain.
Allergic Reactions
In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride-treated patients. These may resolve despite continued treatment with glimepiride. There are postmarketing reports of more serious allergic reactions (e.g. dyspnea, hypotension, shock).
Laboratory Tests
Elevated Serum Alanine Aminotransferase (ALT): In eleven pooled placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated patients and 0.8% of placebo-treated patients developed serum ALT greater than 2 times the upper limit of the reference range.
General
The following adverse reactions from clinical investigations were based on experience with glimepiride and other sulphonylureas:
- Blood and Lymphatic System Disorders (≥0.01% to <0.1% Incidence): Thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, erythropenia and pancytopenia, which were, in general, reversible upon discontinuation of medication.
- Immune System Disorders (<0.01% Incidence): Leucocytoclastic vasculitis, mild hypersensitivity reactions that may develop into serious reactions with dyspnoea, fall in blood pressure and, sometimes, shock.
- Gastrointestinal Disorders (<0.01% Incidence): Vomiting, diarrhoea, abdominal distention, abdominal discomfort, abdominal pain, which seldom lead to discontinuation of therapy.
- Hepato-biliary Disorders (<0.01% Incidence): Hepatic function abnormal (e.g. with cholestasis and jaundice), hepatitis and hepatic failure.
- Investigations (<0.01% Incidence): Blood sodium decrease.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of glimepiride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Serious hypersensitivity reactions, including anaphylaxis, angio-oedema, and Stevens-Johnson Syndrome
- Haemolytic anaemia in patients with and without G6PD deficiency
- Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure
- Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis
- Leucopenia, agranulocytosis, aplastic anaemia, and pancytopenia
- Thrombocytopenia (including severe cases with platelet count less than 10,000/µL) and thrombocytopenic purpura.
- Hepatic porphyria reactions and disulfiram-like reactions
- Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone
Overdosage
An overdosage of glimepiride, as with other sulphonylureas, can produce severe hypoglycaemia. Mild episodes of hypoglycaemia can be treated with oral glucose. Severe hypoglycaemic reactions constitute medical emergencies requiring immediate treatment. Severe hypoglycaemia with coma, seizure, or neurological impairment can be treated with glucagon or I.V. glucose. Continued observation and additional carbohydrate intake may be necessary because hypoglycaemia may recur after apparent clinical recovery.
Incompatibility
None.
Shelf-Life
3 years
Storage and Handling Instructions
Store in a cool, dry place.
Packaging Information
GLIMCIP 1: Strip of 10 tablets
GLIMCIP 2: Strip of 10 tablets
Last updated: August 2015
Last reviewed: August 2015