Glimepiride Metformin tablets India -Glucotaj glimepiride metformin combination pill glimepiride
Glimepiride Metformin tablets India -Glucotaj glimepiride metformin combination pill glimepiride m
After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5, 8.6)].
The maximum recommended dose is 8 mg once daily.
Patients being transferred to Glimepiride tablets from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for hypoglycemia.
When colesevelam is coadministered with Glimepiride, maximum plasma concentration and total exposure to Glimepiride is reduced. Therefore, Glimepiride tablets should be administered at least 4 hours prior to colesevelam.
Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g., anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea) [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].
Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 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 tablets-treated patients and
more commonly than in patients who received placebo.
Hypoglycemia
Weight Gain
The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including Glimepiride tablets, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving Glimepiride tablets, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving Glimepiride tablets, monitor the patient closely for hypoglycemia.
Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of Glimepiride tablets glucose-lowering effect.
Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of Glimepiride tablets in an unpredictable fashion.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine
The safety and efficacy of Glimepiride tablets in pediatric patients was evaluated in a single-blind, 24-week trial that randomized 272 patients (8 to 17 years of age) with type 2 diabetes to Glimepiride tablets (n = 135) or metformin (n = 137). Both treatment-naïve patients (those treated with only diet and exercise for at least 2 weeks prior to randomization) and previously treated patients (those previously treated or currently treated with other oral antidiabetic medications for at least 3 months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the time of study entry discontinued these medications before randomization without a washout period. Glimepiride tablets was initiated at 1 mg, and then titrated up to 2 mg, 4 mg or 8 mg (mean last dose 4 mg) through Week 12, targeting a self-monitored fasting fingerstick blood glucose < 126 mg/dL. Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily (mean last dose 1365 mg).
After 24 weeks, the overall mean treatment difference in HbA 1c between Glimepiride tablets and metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to + 0.6%). Based on these results, the trial did not meet its primary objective of showing a similar reduction in HbA 1c with Glimepiride tablets compared to metformin.
The profile of adverse reactions in pediatric patients treated with Glimepiride tablets were similar to that observed in adults [see Adverse Reactions (6)].
Hypoglycemic events documented by blood glucose values < 36 mg/dL were observed in 4% of pediatric patients treated with Glimepiride tablets and in 1% of pediatric patients treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).
Glimepiride tablets contain the active ingredient Glimepiride and the following inactive ingredients:lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate and sodium starch glycolate (potato). In addition, the 2 mgand 4 mg tablets contain D&C Yellow No. 10 Aluminum Lake and the 4 mg also contains D&C Red No. 27 Aluminum Lake.
In healthy subjects, the intra- and inter-individual variabilities of Glimepiride pharmacokinetic parameters were 15% to 23% and 24% to 29%, respectively.
Distribution
There was no effect of Glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (> 1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).
A total of 249 patients who were treatment-naïve or who had received
limited treatment with antidiabetic therapy in the past were randomized
to receive 22 weeks of treatment with either Glimepiride tablets(n =
123) or placebo (n = 126) in a multicenter, randomized, double-blind,
placebo-controlled, dose-titration trial. The starting dose of
Glimepiride tabletswas 1 mg daily and was titrated upward or downward at
2-week intervals to a goal FPG of 90 mg/dL to 150 mg/dL. Blood glucose
levels for both FPG and PPG were analyzed in the laboratory. Following
10 weeks of dose adjustment, patients were maintained at their optimal
dose (1 mg, 2 mg, 3 mg, 4 mg, 6 mg or 8 mg) for the remaining 12 weeks
of the trial. Treatment with Glimepiride tablets provided statistically significant improvements in HbA 1C and FPG compared to placebo (Table 4).
NDC 51079-425-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).
The 4 mg tablet is a peach, oval tablet debossed with G to the left of the score and 13 to the right of the score on one side of the tablet and MYLAN on the other side. They are available as follows:
NDC 51079-426-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Explain the symptoms and treatment of hypoglycemia as well as conditions that predispose to hypoglycemia. Patients should be informed that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.
Patients with diabetes should be advised to inform their healthcare provider if they are pregnant, contemplating pregnancy, breastfeeding, or contemplating breastfeeding.
, from their inceptions to 25 Mar 2013. All RCTs were selected according to pre- specified eligibility criteria. The quality of articles was assessed ...
Glimepiride Dosage and Administration
Recommended Dosing
Glimepiride tablets should be administered with breakfast or the first main meal of the day.
The recommended starting dose of Glimepiride tablets is 1 mg or 2 mg
once daily. Patients at increased risk for hypoglycemia (e.g., the
elderly or patients with renal impairment) should be started on 1 mg
once daily [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5, 8.6)].After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5, 8.6)].
The maximum recommended dose is 8 mg once daily.
Patients being transferred to Glimepiride tablets from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for hypoglycemia.
When colesevelam is coadministered with Glimepiride, maximum plasma concentration and total exposure to Glimepiride is reduced. Therefore, Glimepiride tablets should be administered at least 4 hours prior to colesevelam.
Dosage Forms and Strengths
Glimepiride Tablets, USP are available containing 1 mg, 2 mg or 4 mg of Glimepiride, USP.
- The 1 mg tablet is a white to off-white, oval tablet debossed with G to the left of the score and 11 to the right of the score on one side of the tablet and MYLAN on the other side.
- The 2 mg tablet is a light yellow, oval tablet debossed with G to the left of the score and 12 to the right of the score on one side of the tablet and MYLAN on the other side.
- The 4 mg tablet is a peach, oval tablet debossed with G to the left of the score and 13 to the right of the score on one side of the tablet and MYLAN on the other side.
Contraindications
Glimepiride tablets are contraindicated in patients with a history of a hypersensitivity reaction to:
- Glimepiride or any of the product’s ingredients [see Warnings and Precautions (5.2)].
Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g., anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea) [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].
Warnings and Precautions
Hypoglycemia
All sulfonylureas, including Glimepiride tablets, can cause severe hypoglycemia [see Adverse Reactions (6.1)].
The patient's ability to concentrate and react may be impaired as a
result of hypoglycemia. These impairments may present a risk in
situations where these abilities are especially important, such as
driving or operating other machinery. Severe hypoglycemia can lead to
unconsciousness or convulsions and may result in temporary or permanent
impairment of brain function or death.
Patients must be educated to recognize and manage hypoglycemia. Use
caution when initiating and increasing Glimepiride tablets doses in
patients who may be predisposed to hypoglycemia (e.g., the elderly,
patients with renal impairment, patients on other anti-diabetic
medications). Debilitated or malnourished patients, and those with
adrenal, pituitary, or hepatic impairment are particularly susceptible
to the hypoglycemic action of glucose-lowering medications. Hypoglycemia
is also more likely to occur when caloric intake is deficient, after
severe or prolonged exercise, or when alcohol is ingested.Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
Hypersensitivity Reactions
There have been postmarketing reports of
hypersensitivity reactions in patients treated with Glimepiride tablets,
including serious reactions such as anaphylaxis, angioedema, and
Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected,
promptly discontinue Glimepiride tablets, assess for other potential
causes for the reaction, and institute alternative treatment for
diabetes.
Hemolytic Anemia
Sulfonylureas can cause hemolytic anemia in patients
with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because
Glimepiride tablets are a sulfonylurea, use caution in patients with
G6PD deficiency and consider the use of a non-sulfonylurea alternative.
There are also postmarketing reports of hemolytic anemia in patients
receiving Glimepiride tablets who did not have known G6PD deficiency [see Adverse Reactions (6.2)].
Increased Risk of Cardiovascular Mortality with Sulfonylureas
The administration of oral hypoglycemic drugs has been
reported to be associated with increased cardiovascular mortality as
compared to treatment with diet alone or diet plus insulin. This warning
is based on the study conducted by the University Group Diabetes
Program (UGDP), a long-term, prospective clinical trial designed to
evaluate the effectiveness of glucose-lowering drugs in preventing or
delaying vascular complications in patients with non-insulin-dependent
diabetes. The study involved 823 patients who were randomly assigned to
one of four treatment groups.
UGDP reported that patients treated for 5 to 8 years with diet plus a
fixed dose of tolbutamide (1.5 grams per day) had a rate of
cardiovascular mortality approximately 2-1/2 times that of patients
treated with diet alone. A significant increase in total mortality was
not observed, but the use of tolbutamide was discontinued based on the
increase in cardiovascular mortality, thus limiting the opportunity for
the study to show an increase in overall mortality. Despite controversy
regarding the interpretation of these results, the findings of the UGDP
study provide an adequate basis for this warning. The patient should be
informed of the potential risks and advantages of Glimepiride tablets
and of alternative modes of therapy.Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Macrovascular Outcomes
There have been no clinical studies establishing
conclusive evidence of macrovascular risk reduction with Glimepiride
tablets or any other anti-diabetic drug.
Adverse Reactions
The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling:
- Hypoglycemia [see Warnings and Precautions (5.1)]
- Hemolytic anemia [see Warnings and Precautions (5.3)]
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 tablets in the controlled clinical trials. In these
trials, approximately 1,700 patients were treated with Glimepiride
tablets for at least 1 year.Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 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 tablets-treated patients and
more commonly than in patients who received placebo.
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
|
In a randomized, double-blind, placebo-controlled
monotherapy trial of 14 weeks duration, patients already on sulfonylurea
therapy underwent a 3-week washout period then were randomized to
Glimepiride tablets 1 mg, 4 mg, 8 mg or placebo. Patients randomized to
Glimepiride tablets 4 mg or 8 mg underwent forced-titration from an
initial dose of 1 mg to these final doses, as tolerated [see Clinical Studies (14.1)]
. The overall incidence of possible hypoglycemia (defined by the
presence of at least one symptom that the investigator believed might be
related to hypoglycemia; a concurrent glucose measurement was not
required) was 4% for Glimepiride tablets 1 mg, 17% for Glimepiride
tablets 4 mg, 16% for Glimepiride tablets 8 mg and 0% for placebo. All
of these events were self-treated.
In a randomized, double-blind, placebo-controlled monotherapy trial
of 22 weeks duration, patients received a starting dose of either 1 mg
Glimepiride tablets or placebo daily. The dose of Glimepiride tablets
was titrated to a target fasting plasma glucose of 90 mg/dL to 150
mg/dL. Final daily doses of Glimepiride tablets were 1 mg, 2 mg, 3 mg, 4
mg, 6 mg or 8 mg [see Clinical Studies (14.1)]
. The overall incidence of possible hypoglycemia (as defined above for
the 14-week trial) for Glimepiride tablets vs. placebo was 19.7% vs.
3.2%. All of these events were self-treated.Weight Gain
Glimepiride tablets, like all sulfonylureas, can cause weight gain [see Clinical Studies (14.1)].
Allergic Reactions
In clinical trials, allergic reactions, such as
pruritus, erythema, urticaria, and morbilliform or maculopapular
eruptions, occurred in less than 1% of Glimepiride tablets-treated
patients. These may resolve despite continued treatment with Glimepiride
tablets. There are postmarketing reports of more serious allergic
reactions (e.g., dyspnea, hypotension, shock) [see Warnings and Precautions (5.2)].
Laboratory Tests
Elevated Serum Alanine Aminotransferase (ALT)
In 11 pooled placebo-controlled trials of Glimepiride
tablets, 1.9% of Glimepiride tablets-treated patients and 0.8% of
placebo-treated patients developed serum ALT greater than 2 times the
upper limit of the reference range.
Postmarketing Experience
The following adverse reactions have been identified
during post-approval use of Glimepiride tablets. 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, angioedema, and Stevens-Johnson Syndrome [see Warnings and Precautions (5.2)]
- Hemolytic anemia in patients with and without G6PD deficiency [see Warnings and Precautions (5.3)]
- 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
- Leukopenia, agranulocytosis, aplastic anemia, 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
Drug Interactions
Drugs Affecting Glucose Metabolism
A number of medications affect glucose metabolism and
may require Glimepiride tablets dose adjustment and particularly close
monitoring for hypoglycemia or worsening glycemic control.
The following are examples of medications that may increase the
glucose-lowering effect of sulfonylureas including Glimepiride tablets,
increasing the susceptibility to and/or intensity of hypoglycemia: oral
anti-diabetic medications, pramlintide acetate, insulin, angiotensin
converting enzyme (ACE) inhibitors, H 2
receptor antagonists, fibrates, propoxyphene, pentoxifylline,
somatostatin analogs, anabolic steroids and androgens, cyclophosphamide,
phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines,
clarithromycin, disopyramide, quinolones, and those drugs that are
highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory
drugs, salicylates, sulfonamides, chloramphenicol, coumarins,
probenecid and monoamine oxidase inhibitors. When these medications are
administered to a patient receiving Glimepiride tablets, monitor the
patient closely for hypoglycemia. When these medications are withdrawn
from a patient receiving Glimepiride tablets, monitor the patient
closely for worsening glycemic control.The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including Glimepiride tablets, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving Glimepiride tablets, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving Glimepiride tablets, monitor the patient closely for hypoglycemia.
Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of Glimepiride tablets glucose-lowering effect.
Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of Glimepiride tablets in an unpredictable fashion.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine
Miconazole
A potential interaction between oral miconazole and
sulfonylureas leading to severe hypoglycemia 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 hypoglycemia. Rifampin may induce the metabolism of
Glimepiride, causing decreased plasma concentrations of Glimepiride
which may lead to worsening glycemic control.
Concomitant Administration of Colesevelam
Colesevelam can reduce the maximum plasma concentration
and total exposure of Glimepiride when the two are coadministered.
However, absorption is not reduced when Glimepiride is administered 4
hours prior to colesevelam. Therefore, Glimepiride tablets should be
administered at least 4 hours prior to colesevelam.
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic EffectsPregnancy Category C
There are no adequate and well-controlled studies of
Glimepiride tablets in pregnant women. In animal studies there was no
increase in congenital anomalies, but an increase in fetal deaths
occurred in rats and rabbits at Glimepiride doses 50 times (rats) and
0.1 times (rabbits) the maximum recommended human dose (based on body
surface area). This fetotoxicity, observed only at doses inducing
maternal hypoglycemia, is believed to be directly related to the
pharmacologic (hypoglycemic) action of Glimepiride and has been
similarly noted with other sulfonylureas. Glimepiride tablets should be
used during pregnancy only if the potential benefit justifies the
potential risk to the fetus. Because data suggest that abnormal blood
glucose during pregnancy is associated with a higher incidence of
congenital abnormalities, diabetes treatment during pregnancy should
maintain blood glucose as close to normal as possible.
Nonteratogenic Effects
Prolonged severe hypoglycemia (4 to 10 days) has been
reported in neonates born to mothers receiving a sulfonylurea at the
time of delivery.
Nursing Mothers
It is not known whether Glimepiride tablets are
excreted in human milk. During pre- and post-natal studies in rats,
significant concentrations of Glimepiride were present in breast milk
and the serum of the pups. Offspring of rats exposed to high levels of
Glimepiride during pregnancy and lactation developed skeletal
deformities consisting of shortening, thickening, and bending of the
humerus during the postnatal period. These skeletal deformations were
determined to be the result of nursing from mothers exposed to
Glimepiride. Based on these animal data and the potential for
hypoglycemia in a nursing infant, a decision should be made whether to
discontinue nursing or discontinue Glimepiride tablets, taking into
account the importance of Glimepiride tablets to the mother.
Pediatric Use
The pharmacokinetics, efficacy and safety of
Glimepiride tablets have been evaluated in pediatric patients with type 2
diabetes as described below. Glimepiride tablets are not recommended in
pediatric patients because of its adverse effects on body weight and
hypoglycemia.
The pharmacokinetics of a 1 mg single dose of Glimepiride tablets
were evaluated in 30 patients with type 2 diabetes (male = 7; female =
23) between ages 10 and 17 years. The mean (± SD) AUC (0-last) (339 ng•hr/mL ± 203 ng•hr/mL), C max (102 ng/mL ± 48 ng/mL) and t 1/2 (3.1 ± 1.7 hours) for Glimepiride were comparable to historical data from adults (AUC (0-last) 315 ng•hr/mL ± 96 ng•hr/mL, C max 103 ng/mL ± 34 ng/mL and t 1/2 5.3 ± 4.1 hours).The safety and efficacy of Glimepiride tablets in pediatric patients was evaluated in a single-blind, 24-week trial that randomized 272 patients (8 to 17 years of age) with type 2 diabetes to Glimepiride tablets (n = 135) or metformin (n = 137). Both treatment-naïve patients (those treated with only diet and exercise for at least 2 weeks prior to randomization) and previously treated patients (those previously treated or currently treated with other oral antidiabetic medications for at least 3 months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the time of study entry discontinued these medications before randomization without a washout period. Glimepiride tablets was initiated at 1 mg, and then titrated up to 2 mg, 4 mg or 8 mg (mean last dose 4 mg) through Week 12, targeting a self-monitored fasting fingerstick blood glucose < 126 mg/dL. Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily (mean last dose 1365 mg).
After 24 weeks, the overall mean treatment difference in HbA 1c between Glimepiride tablets and metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to + 0.6%). Based on these results, the trial did not meet its primary objective of showing a similar reduction in HbA 1c with Glimepiride tablets compared to metformin.
Metformin
|
Glimepiride Tablets
|
|
Treatment-Naïve Patients*
|
N = 69
|
N = 72
|
HbA 1C (%)
|
||
Baseline (mean)
|
8.2
|
8.3
|
Change from baseline (adjusted LS mean) †
|
-1.2
|
-1.0
|
Adjusted Treatment Difference ‡
(95% CI) |
0.2 (-0.3; 0.6)
|
|
Previously Treated Patients*
|
N = 57
|
N = 55
|
HbA 1C (%)
|
||
Baseline (mean)
|
9.0
|
8.7
|
Change from baseline (adjusted LS mean) †
|
-0.2
|
0.2
|
Adjusted Treatment Difference ‡
(95% CI) |
0.4 (-0.4; 1.2)
|
|
Body Weight (kg)*
|
N = 126
|
N = 129
|
Baseline (mean)
|
67.3
|
66.5
|
Change from baseline (adjusted LS mean) †
|
0.7
|
2.0
|
Adjusted Treatment Difference ‡
(95% CI) |
1.3 (0.3; 2.3)
|
Hypoglycemic events documented by blood glucose values < 36 mg/dL were observed in 4% of pediatric patients treated with Glimepiride tablets and in 1% of pediatric patients treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).
Geriatric Use
In clinical trials of Glimepiride tablets, 1053 of 3491
patients (30%) were > 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.There were no significant differences in Glimepiride
pharmacokinetics between patients with type 2 diabetes ≤ 65 years (n =
49) and those > 65 years (n = 42) [see Clinical Pharmacology (12.3)].
Glimepiride is substantially excreted by the kidney. Elderly patients
are more likely to have renal impairment. In addition, hypoglycemia may
be difficult to recognize in the elderly [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)] . Use caution when initiating Glimepiride tablets and increasing the dose of Glimepiride tablets in this patient population.Renal Impairment
To minimize the risk of hypoglycemia, the recommended
starting dose of Glimepiride tablets is 1 mg daily for all patients with
type 2 diabetes and renal impairment [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].
A multiple-dose titration study was conducted in 16 patients with
type 2 diabetes and renal impairment using doses ranging from 1 mg to 8
mg daily for 3 months. Baseline creatinine clearance ranged from 10
mL/min to 60 mL/min. The pharmacokinetics of Glimepiride tablets were
evaluated in the multiple-dose titration study and the results were
consistent with those observed in patients enrolled in a single-dose
study. In both studies, the relative total clearance of Glimepiride
tablets increased when kidney function was impaired. Both studies also
demonstrated that the elimination of the two major metabolites was
reduced in patients with renal impairment [see Clinical Pharmacology (12.3)].Overdosage
An overdosage of Glimepiride tablets, as with other
sulfonylureas, can produce severe hypoglycemia. Mild episodes of
hypoglycemia can be treated with oral glucose. Severe hypoglycemic
reactions constitute medical emergencies requiring immediate treatment.
Severe hypoglycemia with coma, seizure, or neurological impairment can
be treated with glucagon or intravenous glucose. Continued observation
and additional carbohydrate intake may be necessary because hypoglycemia
may recur after apparent clinical recovery [see Warnings and Precautions (5.1)].
Glimepiride Description
Glimepiride tablets, USP are an oral sulfonylurea that
contains the active ingredient Glimepiride. Chemically, Glimepiride is
identified as 1-[[ p-[2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl]phenyl]sulfonyl]-3-( trans-4-methylcyclohexyl)urea (C 24H 34N 4O 5S)
with a molecular weight of 490.62. Glimepiride, USP is a white,
crystalline, odorless to practically odorless powder and is practically
insoluble in water.
The structural formula is:Glimepiride tablets contain the active ingredient Glimepiride and the following inactive ingredients:lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate and sodium starch glycolate (potato). In addition, the 2 mgand 4 mg tablets contain D&C Yellow No. 10 Aluminum Lake and the 4 mg also contains D&C Red No. 27 Aluminum Lake.
Glimepiride - Clinical Pharmacology
Mechanism of Action
Glimepiride primarily lowers blood glucose by
stimulating the release of insulin from pancreatic beta cells.
Sulfonylureas bind to the sulfonylurea receptor in the pancreatic
beta-cell plasma membrane, leading to closure of the ATP-sensitive
potassium channel, thereby stimulating the release of insulin.
Pharmacodynamics
In healthy subjects, the time to reach maximal effect
(minimum blood glucose concentrations) was approximately 2 to 3 hours
after single oral doses of Glimepiride tablets. The effects of
Glimepiride tablets on HbA 1c, fasting plasma glucose, and post-prandial glucose have been assessed in clinical trials [see Clinical Studies (14)].
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 (C max) 2 to 3 hours post-dose. When Glimepiride was given with meals, the mean C max and AUC (area under the curve) 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 mg to 8 mg dose
range, indicating linear pharmacokinetics.In healthy subjects, the intra- and inter-individual variabilities of Glimepiride pharmacokinetic parameters were 15% to 23% and 24% to 29%, respectively.
Distribution
After intravenous 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 metabolized by oxidative
biotransformation after either an intravenous 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 metabolized 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. M1 and M2 accounted
for 80% to 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 feces. M1 and M2 accounted for about 70% (ratio of M1 to M2 was 1:3)
of the radioactivity recovered in feces. No parent drug was recovered
from urine or feces. After intravenous dosing in patients, no
significant biliary excretion of Glimepiride or its M1 metabolite was
observed.
Geriatric Patients
A comparison of Glimepiride pharmacokinetics in
patients with type 2 diabetes ≤ 65 years and those > 65 years was
evaluated in a multiple-dose study using Glimepiride tablets 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 approximately 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.
Gender
There were no differences between males and females in
the pharmacokinetics of Glimepiride when adjustment was made for
differences in body weight.
Race
No studies have been conducted to assess the effects of
race on Glimepiride pharmacokinetics but in placebo-controlled trials
of Glimepiride tablets in patients with type 2 diabetes, the reduction
in HbA 1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).
Renal Impairment
A single-dose, open-label study Glimepiride tablets 3
mg was administered to patients with mild, moderate and severe renal
impairment as estimated by creatinine clearance (CLcr): Group I
consisted of 5 patients with mild renal impairment (CLcr > 50
mL/min), Group II consisted of 3 patients with moderate renal impairment
(CLcr = 20 mL/min to 50 mL/min) and Group III consisted of 7 patients
with severe renal impairment (CLcr < 20 mL/min). Although,
Glimepiride serum concentrations decreased with decreasing renal
function, Group III had a 2.3-fold higher mean AUC for M1 and an
8.6-fold higher mean AUC for M2 compared to corresponding mean AUCs in
Group I. The apparent terminal half-life (T 1/2)
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 a percentage of dose decreased from 44.4% for Group I to 21.9%
for Group II and 9.3% for Group III.
Hepatic Impairment
It is unknown whether there is an effect of hepatic
impairment on Glimepiride tablets pharmacokinetics because the
pharmacokinetics of Glimepiride tablets have 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 involving 28 patients with type 2
diabetes who either had normal body weight or were morbidly obese. While
the t max, clearance, and volume of
distribution of Glimepiride in the morbidly obese patients were similar
to those in the normal weight group, the morbidly obese had lower C max and AUC than those of normal body weight. The mean C max, AUC 0-24, AUC 0-∞
values of Glimepiride in normal vs. morbidly obese patients were 547
ng/mL ± 218 ng/mL vs. 410 ng/mL ± 124 ng/mL, 3210 ± 1030 hours•ng/mL vs.
2820 ± 1110 hours•ng/mL and 4000 ± 1320 hours•ng/mL vs. 3280 ± 1360
hours•ng/mL, respectively.
Drug Interactions
Aspirin
In a randomized, double-blind, two-period, crossover
study, healthy subjects were given either placebo or aspirin 1 gram
three times daily for a total treatment period of 5 days. On Day 4 of
each study period, a single 1 mg dose of Glimepiride tablets were
administered. The Glimepiride tablets doses were separated by a 14-day
washout period. Co-administration of aspirin and Glimepiride tablets
resulted in a 34% decrease in the mean Glimepiride AUC and a 4% decrease
in the mean Glimepiride C max.
Colesevelam
Concomitant administration of colesevelam and Glimepiride resulted in reductions in Glimepiride AUC 0-∞ and C max
of 18% and 8%, respectively. When Glimepiride was administered 4 hours
prior to colesevelam, there was no significant change in Glimepiride AUC
0-∞ or C max, -6% and 3%, respectively [see Dosage and Administration (2.1) and Drug Interactions (7.4)].
Cimetidine and Ranitidine
In a randomized, open-label, 3-way crossover study,
healthy subjects received either a single 4 mg dose of Glimepiride
tablets alone, Glimepiride tablets with ranitidine (150 mg twice daily
for 4 days; Glimepiride tablets were administered on Day 3), or
Glimepiride tablets with cimetidine (800 mg daily for 4 days;
Glimepiride was administered on Day 3). Co-administration of cimetidine
or ranitidine with a single 4 mg oral dose of Glimepiride tablets did
not significantly alter the absorption and disposition of Glimepiride.
Propranolol
In a randomized, double-blind, two-period, crossover
study, healthy subjects were given either placebo or propranolol 40 mg
three times daily for a total treatment period of 5 days. On Day 4 or
each study period, a single 2 mg dose of Glimepiride tablets were
administered. The Glimepiride tablets doses were separated by a 14-day
washout period. Concomitant administration of propranolol and
Glimepiride tablets significantly increased Glimepiride tablets C max, AUC, and T 1/2
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
In an open-label, two-way, crossover study, healthy
subjects received 4 mg of Glimepiride tablets daily for 10 days. Single
25 mg doses of warfarin were administered 6 days before starting
Glimepiride tablets and on Day 4 of Glimepiride tablets administration.
The concomitant administration of Glimepiride tablets did not alter the
pharmacokinetics of R- and S-warfarin enantiomers. No changes were
observed in warfarin plasma protein binding. Glimepiride tablets
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 tablets
treatment were 3.3% and 9.9%, respectively, and are unlikely to be
clinically relevant.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Studies in rats at doses of up to 5000 parts per
million (ppm) in complete feed (approximately 340 times the maximum
recommended human dose, based on surface area) for 30 months showed no
evidence of carcinogenesis. In mice, administration of Glimepiride for
24 months resulted in an increase in benign pancreatic adenoma formation
that was dose-related and was thought to be the result of chronic
pancreatic stimulation. No adenoma formation in mice was observed at a
dose of 320 ppm in complete feed, or 46 mg/kg to 54 mg/kg body
weight/day. This is about 35 times the maximum human recommended dose of
8 mg once daily based on surface area.
Glimepiride was non-mutagenic in a battery of in vitro and in vivo
mutagenicity studies (Ames test, somatic cell mutation, chromosomal
aberration, unscheduled DNA synthesis, and mouse micronucleus test).There was no effect of Glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (> 1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).
Clinical Studies
Monotherapy
A total of 304 patients with type 2 diabetes already
treated with sulfonylurea therapy participated in a 14-week,
multicenter, randomized, double-blind, placebo-controlled trial
evaluating the safety and efficacy of Glimepiride tablets monotherapy.
Patients discontinued their sulfonylurea therapy then entered a 3-week
placebo washout period followed by randomization into one of four
treatment groups: placebo (n = 74), Glimepiride tablets 1 mg (n = 78),
Glimepiride tablets 4 mg (n = 76) and Glimepiride tablets 8 mg (n = 76).
All patients randomized to Glimepiride tablets started 1 mg daily.
Patients randomized to Glimepiride tablets 4 mg or 8 mg had blinded,
forced titration of the Glimepiride tablets dose at weekly intervals,
first to 4 mg and then to 8 mg, as long as the dose was tolerated, until
the randomized dose was reached. Patients randomized to the 4 mg dose
reached the assigned dose at Week 2. Patients randomized to the 8 mg
dose reached the assigned dose at Week 3. Once the randomized dose level
was reached, patients were to be maintained at that dose until Week 14.
Approximately 66% of the placebo-treated patients completed the trial
compared to 81% of patients treated with Glimepiride 1 mg and 92% of
patients treated with Glimepiride 4 mg or 8 mg. Compared to placebo,
treatment with Glimepiride tablets 1 mg, 4 mg and 8 mg daily provided
statistically significant improvements in HbA 1C compared to placebo (Table 3).
Placebo
(N = 74) |
Glimepiride Tablets
|
|||
1 mg (N = 78)
|
4 mg (N = 76)
|
8 mg (N = 76)
|
||
HbA 1C (%)
|
||||
n = 59
|
n = 65
|
n = 65
|
n = 68
|
|
Baseline (mean)
|
8.0
|
7.9
|
7.9
|
8.0
|
Change from Baseline (adjusted mean †)
|
1.5
|
0.3
|
-0.3
|
-0.4
|
Difference from Placebo (adjusted mean †)
95% confidence interval |
-1.2 ‡
(-1.5, -0.8) |
-1.8 ‡
(-2.1, -1.4) |
-1.8 ‡
(-2.2, -1.5) |
|
Mean Baseline Weight (kg)
|
||||
n = 67
|
n = 76
|
n = 75
|
n = 73
|
|
Baseline (mean)
|
85.7
|
84.3
|
86.1
|
85.5
|
Change from Baseline (adjusted mean †)
|
-2.3
|
-0.2
|
0.5
|
1.0
|
Difference from Placebo(adjusted mean †)
95% confidence interval |
2.0 ‡
(1.4, 2.7) |
2.8 ‡
(2.1, 3.5) |
3.2 ‡
(2.5, 4.0) |
Placebo (N = 126)
|
Glimepiride Tablets (N = 123)
|
|
HbA 1C (%)
|
n = 97
|
n = 106
|
Baseline (mean)
|
9.1
|
9.3
|
Change from Baseline (adjusted mean †)
|
-1.1 ‡
|
-2.2 ‡
|
Difference from Placebo (adjusted mean †)
95% confidence interval |
-1.1 ‡
(-1.5, -0.8) |
|
Body Weight (kg)
|
||
n = 122
|
n = 119
|
|
Baseline (mean)
|
86.5
|
87.1
|
Change from Baseline (adjusted mean †)
|
-0.9
|
1.8
|
Difference from Placebo (adjusted mean †)
95% confidence interval |
2.7
(1.9, 3.6) |
How Supplied/Storage and Handling
Glimepiride Tablets, USP are available containing 2 mg or 4 mg of Glimepiride, USP.
The 2 mg tablet is a light yellow, oval tablet debossed with G to the left of the score and 12 to the right of the score on one side of the tablet and MYLAN on the other side. They are available as follows:NDC 51079-425-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).
The 4 mg tablet is a peach, oval tablet debossed with G to the left of the score and 13 to the right of the score on one side of the tablet and MYLAN on the other side. They are available as follows:
NDC 51079-426-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Patient Counseling Information
Information for Patients
Inform patients about the importance of adherence to
dietary instructions, of a regular exercise program, and of regular
testing of blood glucose.
Inform patients about the potential side effects of Glimepiride tablets including hypoglycemia and weight gain.Explain the symptoms and treatment of hypoglycemia as well as conditions that predispose to hypoglycemia. Patients should be informed that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.
Patients with diabetes should be advised to inform their healthcare provider if they are pregnant, contemplating pregnancy, breastfeeding, or contemplating breastfeeding.
Indications and Usage for Glimepiride
Glimepiride tablets are indicated as an adjunct to diet
and exercise to improve glycemic control in adults with type 2 diabetes
mellitus [see Clinical Studies (14.1)].
Important Limitations of Use
Glimepiride tablets should not be used for the
treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it
would not be effective in these settings.
Glimepiride + Metformin drug information | DrugsUpdate India
www.drugsupdate.com/generic/view/649/Glimepiride-+-Metformin
Glimepiride
stimulates the insulin release from functioning pancreatic β-cells and
inhibits gluconeogenesis at hepatic cells. It also increases insulin
sensitivity at peripheral target sites. Metformin decreases hepatic gluconeogenesis, decreases intestinal absorption of glucose and improves insulin sensitivity ( increases ...
Glimepiride + Metformin brands in India | DrugsUpdate India
www.drugsupdate.com/brand/showavailablebrands/649/2
203 records - Glimepiride + Metformin
brands in India - Bigan-GM from Sresan , Bigonyl from Indoco (Spera) ,
Blisto-1MF from Biocon , Blisto-2MF from Biocon , Blisto-4MF from Biocon
, Capril-M from Cutigen , Conpride-M from Concertina , Cupride-M from
Cubit (Cucard) , Cupride-SR from Cubit (Cucard) , Daoride-M from ...
[PDF]GLIMITAB M-1/GLIMITAB M-2 Tablets
www.centaurpharma.com/newwebsite/downloads/Glimitab-M.pdf
CLINICAL PHARMACOLOGY. Glimitab-M contains two oral anti-hyperglycemic drugs glimepiride and metformin hydrochloride used in the management of type- 2 diabetes (NIDDM). Pharmacodynamics. Glimepiride: The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on ...
Comparative efficacy of glimepiride and metformin in monotherapy of ...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834882/
by H Zhu - 2013 - Cited by 19 - Related articles
Nov 14, 2013 - A literature search for RCTs on glimepiride and metformin was conducted on the bibliographic databases, including PubMed, Cochrane Library and ScienceDirectEfficacy and Safety Comparison of Metformin/Glimepiride Combination ...
https://clinicaltrials.gov/ct2/show/NCT01459809
Oct 26, 2011 - Efficacy and Safety Comparison of Metformin/Glimepiride Combination Versus Each Compound Alone in New Diagnosed Type 2 Diabetes Patients ( RECOMMEND) ...
Study Type: Interventional (Clinical Trial)
Study Completion Date: January 2014
Study Start Date: February 2012
glimepiride + metformin: Indication, Dosage, Side Effect, Precaution ...
https://www.mims.com/india/drug/info/glimepiride%20%2B%20metformin/
Disclaimer: This information is independently developed by CIMS based on glimepiride + metformin
from various references and is provided for your reference only.
Therapeutic uses and prescribing information may vary between countries.
Please refer to CIMS Product Monographs for specific and locally
approved ...
Glimepiride (Amaryl) - Side Effects, Dosage, Interactions - Drugs
https://www.everydayhealth.com › Drugs › Sulfonylureas
Sep 3, 2014 - It may be used alone, or in combination with insulin or another oral medication such as metformin.
Your doctor will probably start you on a low dose of the medication and
gradually increase your dose if needed. If you've taken glimepiride for a long period of time, the drug may not control blood sugar as well ...
Glimepiride Versus Metformin as Monotherapy in Pediatric Patients ...
care.diabetesjournals.org/content/30/4/790
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RESULTS—Significant reductions from baseline A1C were seen in both the glimepiride (−0.54%, P = 0.001) and metformin (−0.71%, P = 0.0002) groups. A total of 42.4% (56 of 132) and 48.1% (63 of 131) of subjects in the glimepiride and metformin groups, respectively, in the intent-to-treat population achieved A1C <7.0% ...GLIMEPIRIDE 1MG AND METFORMIN HYDROCHLORIDE 500MG ...
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Glimepiride | Side Effects, Dosage, Uses, and More - Healthline
https://www.healthline.com/health/glimepiride/oral-tablet
Glimepiride (Amaryl) is an oral drug used to treat type 2 diabetes. Learn about side effects, warnings, dosage, and more.
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