Glibenclamide and Metformin HCl film-coated tablets
Description
Glucovance® 1.25 mg / 250 mg:
each film-coated tablet contains Glibenclamide 1.25 mg with Metformin Hydrochloride 250 mg
Glucovance® 2.5 mg / 500 mg:
each film-coated tablet contains Glibenclamide 2.5 mg with Metformin Hydrochloride 500 mg
Glucovance® 5 mg / 500 mg:
each film -coated tablet contains Glibenclamide 5 mg with Metformin Hydrochloride 500 mg
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. Metformin may act via 3 mechanisms:
- by reducing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
- in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization
- and by delaying intestinal glucose absorption.
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL-cholesterol and triglyceride levels. In clinical trials conducted so far with combination therapy with metformin and glibenclamide, these favourable effects on lipid metabolism have not been shown.
Glibenclamide is a second generation sulphonylurea with a medium half-life: it causes acute lowering of blood glucose by stimulating the release of insulin by the pancreas, this effect "being dependent on the presence of functioning beta cells in the islets of Langerhans.
The stimulation of insulin secretion by glibenclamide in response to a meal is of major importance.
The administration of glibenclamide to diabetics induces an increase in the postprandial insulin-stimulating response. The increased postprandial responses in insulin and C-peptide secretion persist after at least 6 months of treatment.
Metformin and glibenclamide have different mechanisms and sites of action, but their action is complementary. Glibenclamide stimulates the pancreas to secrete insulin, while metformin reduces cell resistance to insulin by acting on peripheral (skeletal muscle) and hepatic sensitivity to insulin.
Results from controlled, double blind clinical trials versus reference products in the treatment of type 2 diabetes inadequately controlled by monotherapy with metformin or glibenclamide combined with diet and exercise, have demonstrated that the combination had an additive effect on glucose regulation.
Paediatric patients:
In a 26-week, active controlled, double-blind, clinical study performed in 167 paediatric patients aged 9 to 16 years with type 2 diabetes not adequately controlled with diet and exercise, with or without an oral antidiabetic treatment, a fixed combination of metformin hydrochloride 250 mg and glibenclamide 1.25 mg was not shown more effective to either metformin hydrochloride or glibenclamide in reducing HbA 1c from baseline. Therefore, Glucovance should not be used in paediatric patients.
Pharmacokinetic properties
Related to the combination
The bioavailability of metformin and glibenclamide in the combination is similar to that noted when one tablet of metformin and one tablet of glibenclamide are taken simultaneously. The bioavailability of metformin in the combination is unaffected by the ingestion of food. The bioavailability of glibenclamide in the combination is unaffected by the ingestion of food, but the absorption speed of glibenclamide is increased by eating.
Related to metformin
Absorption:
After an oral dose of metformin. maximum plasma concentration (Cmax)is reached in 2.5 hours (Tmax). Absolute bioavailability of a 500 mg or 850 mg metformin tablet is approximately 50 - 60 % in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 μg/ml, even at maximum doses.
Distribution:
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution Vd ranged from 63 to 276l.
Metabolism:
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination:
Renal clearance of metformin is › 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged,leading to increased levels of metformin in plasma.
Related to glibenclamide
Absorption:
Glibenclamide is very readily absorbed l (› 95%) following oral administration. The peak plasma concentration is reached in about 4 hours.
Distribution:
Glibenclamide is extensively bound to plasma albumin (99%), which may account for certain drug interactions.
Metabolism:
Glibenclamide is completely metabolized in the liver to two metabolites. Hepatocellular failure decreases glibenclamide metabolism and appreciably slows down its excretion.
Excretion:
Glibenclamide is excreted in the form of metabolites via biliary route (60%) and urine (40%), elimination being complete within 45 to 72 hours. Its terminal elimination half-life is 4 to 11 hours.
Biliary excretion of the metabolites increases in cases of renal insufficiency, according to the severity of renal impairment until a creatinine clearance at 30 ml/min. Thus, glibenclamide elimination is unaffected by renal insufficiency as long as the creatinine clearance remains above 30 ml/min.
Preclinical safety data
- No preclinical studies have been performed on the combination product. Preclinical evaluation of the constituents metformin and glibenclamide revealed no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential.
- Animal studies on metformin and glibenclamide do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ foetal development, parturition or postnatal development. (see section pregnancy and lactation).
Patients with Type 2 Diabetes
Multiple-dose studies with glibenclamide in patients with type 2 diabetes demonstrate drug level concentration-time curves similar to single-dose studies, indicating no buildup of drug in tissue depots.
In the presence of normal renal function, there are no differences between single-or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses,
Hepatic Insufficiency
No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either glibenclamide or metformin.
Renal Insufficiency
No information is available on the pharmacokinetics of glibenclamide in patients with renal insufficiency.
In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also, see WARNINGS).
Geriatrics
There is no information on the pharmacokinetics of glibenclamide in elderly patients.
Limited data from controlled pharmacokinetic studios of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced,
Table 1. Select Mean (± S.D.) Metformin Pharmacokinetic Paramaters Following Single or Multiple Oral Doses of Metformin
Subject Groups: Metformin
Dosea (Number of Subjects)
|
Cmaxb
(μg/mL)
|
Tmaxc
(hrs)
|
Renal Clearance
(mL/min)
|
Healthy, nondiabetic adults:
| |||
500 mg SDd (24)
| 1.03 (± 0.33) | 2.75 (± 0.81) | 600 (± 132) |
850 mg SD (74)e
| 1.60 (± 0.38) | 2.64 (± 0.82) | 552 (± 139) |
| 850 mg t.i.d for 19 dosesf (9) | 2.01 (± 0.42) | 1.79 (± 0.94) | 642 (± 173) |
| Adults with type 2 diabetes: | |||
| 850 mg SD (23) | 1.48 (± 0.5) | 3.32 (± 1.08) | 491 (± 138) |
| 850 mg SD t.i.d for 19 dosesf (9) | 1.90 (± 0.62) | 2.01 (± 1.22) | 550 (± 160) |
| Elderlyg healthy nondiabetic adults: | |||
| 850 mg SD (12) | 2.45 (± 0.70) | 2.71 (± 1.05) | 412 (± 98) |
| Renal-impaired adults : 850 mg SD | |||
| Mild (CLcrh 61-90 mL/min) (5) | 1.86 (± 0.52) | 3.20 (± 0.45) | 384 (± 122) |
| Moderate (CLcrh 31-60 mL/min) (4) | 4.12 (± 1.83) | 3.75 (± 0.50) | 108 (± 57) |
| Severe (CLcrh 10-30 mL/min) (6) | 3.93 (± 0.92) | 4.01 (± 1.10) | 130 (± 90) |
a-all doses given fasting except tho first 18 doses of the multiple-dose studies
b-Peak plasma concentration
c-time to peak plasma concentration
d-SD = single dose
e-Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
f-Kinetic study done following dose 19, given fasting
g-Elderly subjects, mean age 71 years (range 65-81 years)
h-Clcr = creatinine clearance normalized to body surface area of 1.73 m2
Pediatrics
There were no differences in pharmacokinetics of glibenclamide and metformin between paediatric patients and weight-and gender-matched healthy adults.
Gender
There is no information on the effect of gender on the pharmacokinetics of glibenclamide.
Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Race
No information is available on race differences in the pharmacokinetics of glibenclamide
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the anti hyperglycemic effect was comparable in whites (n=249), blacks (n=51),and Hispanics (n=24).
Indications
Glucovance® 1.25 mg /250 mg, Glucovance® 2.5 mg /500 mg:
Glucovance is indicated as initial therapy, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes with HbA1c above 8% whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone.
Glucovance® 1.25 mg /250 mg, Glucovance® 2.5 mg /500 mg, Glucovance®5 mg/500 mg: Glucovance® is indicated as second-line therapy when diet, exercise, and initial treatment with a sulfonylurea or metformin do not result in adequate glycemic control in patients with type 2 diabetes with HbA1c above 8%.
Dosage and administration
General considerations
Dosage of Glucovance must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg Glibenclamide/2000 mg metformin. Glucovance should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to Glibenclamide), to reduce GI side effects (largely due to metformin), and to permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient.
With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to Glucovance and to identify the minimum effective dose for the patient. Thereafter, HbA1c should be measured at intervals of approximately 3 months to assess tho effectiveness of therapy. The therapeutic goal in all patients with type 2 diabetes is to decrease FPG, PPG, and HbA1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA1c (glycosylated hemoglobin), which is a better indicator of long-term glycemic control than FPG alone.
No studies have been performed specifically examining the safety and efficacy of switching to Glucovance therapy in patients taking concomitant Glibenclamide (or other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring.
Glucovance as initial therapy
Recommended starting dose: 1.25 mg/250 mg once or twice daily with meals.
For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of Glucovance is 1.25 mg/250 mg once a day with a meal. As initial therapy in patients with baseline HbA1c › 9% or an FPG › 200 mg/dL, a starting dose of Glucovance 1.25 mg/250 mg twice daily with the morning and evening meals may be used. Dosage increases should be made in increments of 1.25 mg/250 mg per day every twice weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. In clinical trials of glucovance as initial therapy, there was no experience with total daily doses greater than 10 mg/ 2000 mg per day.
Glucovance use in previous treated patients (second-line therapy)
Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals
For patients not adequately controlled on either Glibenciamide (or another sulfonylurea) or metformin alone, the recommended starting dose of Glucovance is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of Glucovance should not exceed the daily doses of Glibenclamide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.
For patients previously treated with combination therapy of Glibenclamide (or another sulfonylurea) plus metformin, if switched to glucovance, the starting dose should not exceed the daily dose of Glibenclamide (or equivalent dose of another sulfonylurea) and metformin already being taken. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of Glucovance should be titrated as described above to achieve adequate control of blood glucose.
Warnings
Metformin Hydrochloride
Lactic acidosis:
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Glucovance; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (›5 mmol/L), decreased blood pH, electrolyte disturbances 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 g/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient" age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Glucovance treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Glucovance should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Glucovance should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Glucovance, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, glucovance should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Glucovance should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of Glucovance, gastrointestinal symptoms, which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Glucovance do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking glucovance, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.
Precautions
General
Glucovance
Hypoglicemia. Glucovance is capable of producing hypoglycemia or hypoglycemic symptoms, therefore, proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol. Renal or hepatic insufficiency may cause elevated drug levels of both Glibenclamide and metformin hydrochloride and the hepatic insufficiency may also diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Metformin Hydrochloride
Monitoring of renal function - Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Glucovance. In patients with advanced age, Glucovance should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥ 80 years of age, renal function should be monitored regularly and, generally, Glucovance should not be titrated to the maximum dose. Before initiation of Glucovance therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Glucovance discontinued if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or metformin disposition - Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion,should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)-Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, Glucovance should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.
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 pre renal azotemia. When such events occur in patients on Glucovance therapy, the drug should be promptly discontinued.
Surgical procedures-Glucovance therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Alcohol intake - Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute chronic, while receiving Glucovance. Due to its effect on the gluconeogenic capacity of the liver, alcohol may also increase the risk of hypoglycemia.
Impaired hepatic function - Since impaired hepatic function has been associated with some cases of lactic acidosis, Glucovance should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels - In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B 12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin and any apparent abnormalities should be appropriately investigated and managed.
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these-patients, routine serum vitamin B12 measurements at two-to three-year intervals may be useful.
Change in clinical status of patients with previously controlled type 2 diabetes - A patient with type 2 diabetes previously well controlled on metformin who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Glucovance must be stopped immediately and other appropriate corrective measures initiated.
Treatment of patients with G6PD-deficiency with sulphonylurea agents can lead to haemolytic anaemia. Since glibenclamide belongs to the chemical class of sulphonylurea drugs, caution is recommended when using Glucovance in patients with G6PD-deficiency and a non-sulphonylurea alternative may be considered.
Glucovance contains lactose. Therefore its use is not recommended in patients with rare hereditary problems of galactose-intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Undesirable effects
In double-blind clinical trials involving Glucovance, a total of 642 patients received Glucovance, 312 received metformin therapy, 324 received Glibenelamide therapy, and 161 received placebo. The percent of patients reporting events and types of adverse events reported in clinical trials of Glucovance (all strengths) as initial therapy and second-line therapy are listed in table 2
Table 2 GLUCOVANCE's Most Common Clinical Adverse Event ( › 5 %) when Compared to Pacebo, by Primary Term, in Double-Blind Clinical Studies
| Adverse Event | Number (%) of Patients | |||
Placebo
N = 161
|
Glibenclamide
N -324
|
Metformin
N - 312
|
GLUCOVANCE
N - 642
| |
| Upper respiratory infection | 22 (13.7) | 57 (17.6) | 51 (16.3) | 111 (17.3) |
| Diarrhea | 9 (5.6) | 20 (6.2) | 64 (20.5) | 109 (17.0) |
| Headache | 17 (10.6) | 37 (11.4) | 29 (9.3) | 57 (8.9) |
| Nausea/vomiting | 10 (6.2) | 17 (5.2) | 38 (12.2) | 49 (7.6) |
| Abdominal pain | 6 (3.7) | 10 (3.1) | 25 (8.0) | 44 (6.9) |
| Dizziness | 7 (4.3) | 18 (5.6) | 12 (3.8) | 35 (5.5) |
Disulfiram-like reactions have very rarely been reported in patients treated with glibenclamide tablets. Hypoglycemia
In controlled clinical trials of Glucovance there were no hypoglycemic episodes requiring medical intervention and/or pharmacologic therapy; all events were managed by the patients. The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy trial of Glucovance are summarized in Table 3. The frequency of hypoglycemic symptoms in patients treated with Glucovance 1.25 mg/250 mg was highest in patients with a baseline HbAlc ‹ 7%, lower in those with a baseline HbAlc of between 7 and 8%, and was comparable to placebo and metformin in those with a baseline HbAlc › 8%. For patients with a baseline HbA1c between 8% and 11% treated with Glucovance 2.5 mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30-35%. As second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% all patients treated with Glucovance experienced hypoglycemic symptoms.
Gastrointestinal reactions
The incidence of GI side effects (diarrhea, nausea/vomiting, and abdominal pain) in the initial therapy trial are summarized in Table 2. Across all Glucovance trials, GI symptoms were the most common adverse events with glucovance and were more frequent at higher dose levels. In controlled trials, ‹ 2% of patients discontinued Glucovance therapy due to GI adverse events.
Table 3 Treatment Emergent Symptoms of Hypoglycemia or Gastrointestinal Adverse Events in a Placebo-an Active-Controlled Trial of GLUCOVANCE as Initial Therapy
Variable
|
Placebo
(N = 161) |
Glibenclamide Tablets
(N = 160)
|
Metformin Tablets
(N = 159)
|
GLUCOVANCE 1.25 mg/ 250 mg Tablets
(N = 158)
|
GLUCOVANCE 2.5 mg/ 500 mg Tablets
(N = 162)
|
Mean Final Dose
|
0 mg
|
5.3 mg
|
1317 mg
|
2.78 mg/557 mg
|
4.1 mg/824 mg
|
| Number (%) of patients with symptoms of hypoglycemia |
5 (3.1)
|
34 (21.3)
|
5 (3.1)
|
18 (114)
|
61 (37.7)
|
| Number (%) of patients with gastrointestinal adverse events |
39 (24.2)
|
38 (23.8)
|
69 (43.3)
|
50 (31.6)
|
62(38.3)
|
Overdosage
Glibenclamide
Overdosage of sulfonylureas, including Glibenclamide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively 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. If hypoglycemic coma is diagnoses or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery.
Metformin Hydrochloride
Hypoglycemia has not been seen even with ingestion of up to 85 grams of metformin hydrochloride, although lactic acidosis has occurred in such circumstances. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been conducted with the combined products in Glucovance. The following data are based on findings in studies performed with the individual products.
Glibenclamide
Studies in rats with glibenclamide alone at doses up to 300 mg/kg/day (approximately 145 times the maximum recommended human daily dose of 20 mg for the glibenclamide component of Glucovance based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a two-year oncogenicity study of glibenclamide in mice, there was no evidence of treatment-related tumors.
There was no evidence of mutagenic potential of glibenclamide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay.
Metformin Hydrochloride
Long-term carcinogenicity studies were performed with metformin alone in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg of the metformin component of Gluovance based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone.
There was no evidence of a mutagenic potential of metformin alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin alone when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose of the metformin component of Glucovance based on body surface area comparisons.
Contraindications
Glucovance (Glibenclamide and metformin HCl tablets) is contraindicated in patients with:
Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
- Congestive heart failure requiring pharmacologic treatment.
- Known hypersensitivity to metformin hydrochloride or Glibenclamide
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
- Hepatic insufficiency, acute alcohol intoxication, alcoholism
- Porphyria
- Lactation
- In association with miconazole
Drug Interactions
Glucovance
Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phyenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isonazid. When such drugs are administrated to a patient receiving Glucovance, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving glucovance, the patient should be observed closely for hypoglycemia. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as compared to sulfonylureas, which are extensively bound to serum proteins.
Glibenclamide
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving Glucovance, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Glucovance, the patient should be observed closely for loss of blood glucose control.
A possible interaction between Glibenclamide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of Glibenclamide. The mechanism for this interaction is not known.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known.
Metformin Hydrochloride
Furosemide - A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.
Nifedipine - A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Cationic drugs - Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Glucovance and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Other-in healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.
Pregnancy
Teratogenic Effects: Pregnancy category B
Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used-during pregnancy to maintain blood glucose as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Glucovance should not be used during pregnancy unless clearly needed.
There are no adequate and well-controlled studies in pregnant women with Glucovance or its individual components. No animal studies have been conducted with the combined products in Glucovance, The following data are based on findings in studies performed with the individual products.
Glibenclamide
Reproduction studies were performed in rats and rabbits at doses up to 500 times the maximum recommended human daily dose of 20 mg of the glibenclamide component of Glucovance based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to Glibenclamide.
Metformin Hydrochloride
Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg of the metformin component of Glucovance based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentration demonstrated a partial placental barrier to metformin.
Nonteratogenic Effects
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. It is not recommended that Glucovance be used during pregnancy. However, if it is used, Glucovance should be discontinued at least two weeks before the expected delivery date.
Nursing mothers
Although it is not known whether Glibenclamide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue Glucovance, taking into account the importance of the drug to the mother. If Glucovance is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Pediatric use
Safety and effectiveness of Glucovance in pediatric patients have not been established.
Geriatric use
Of the 642 patients who received Glucovance in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. Of the 1302 patients who received Glucovance in open-label clinical studies, 20.7% were 65 and older while 2.5% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Metformin hydrochloride is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Glucovance should only be used in patients with normal renal function. Because aging is associated with reduced renal function, Glucovance should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Glucovance.
Storage
Store below 30°C
Presentations
Glucovance® 1.25 mg /250 mg: Box of 10 blisters @ 10 film-coated tablet
Glucovance® 2.5 mg /500 mg: Box of 10 blisters @ 10 film-coated tablet
Glucovance® 5 mg /500 mg : Box of 10 blisters @ 10 film-coated tablet
"Harus dengan resep dokter"
On medical prescription only
Manufactured by
Merck Sante SAS, France
Imported by
PT. Merck Tbk., Jakarta
Reg. Nos:
Glucovance 1.25 mg /250 mg: DKI1301600117A1
Glucovance 2.5 mg /500 mg: DKI1301600117B1
Glucovance 5 mg /500 mg: DKI1301600117C1
Date of revision: 14.10.11
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