"The U.S. Food and Drug Administration today approved Farxiga (dapaglifozin) tablets to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes.
Type 2 diabetes affects about 24 million people and accounts for "...
All sulfonylureas, including AMARYL, can cause severe hypoglycemia [see ADVERSE REACTIONS]. 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 AMARYL 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.
There have been postmarketing reports of hypersensitivity reactions in patients treated with AMARYL, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue AMARYL, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.
Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because AMARYL is 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 AMARYL who did not have known G6PD deficiency [see ADVERSE REACTIONS].
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 2-½ 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 AMARYL 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.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with AMARYL or any other anti-diabetic drug.
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 4654 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).
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of AMARYL 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. AMARYL 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.
It is not known whether AMARYL is 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 AMARYL, taking into account the importance of AMARYL to the mother.
The pharmacokinetics, efficacy and safety of AMARYL have been evaluated in pediatric patients with type 2 diabetes as described below. AMARYL is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia.
The pharmacokinetics of a 1 mg single dose of AMARYL was 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±203 ng•hr/mL), Cmax (102±48 ng/mL) and t½ (3.1±1.7 hours) for glimepiride were comparable to historical data from adults (AUC(0-last) 315±96 ng•hr/mL, Cmax 103±34 ng/mL and t½ 5.3±4.1 hours).
The safety and efficacy of AMARYL in pediatric patients was evaluated in a single-blind, 24-week trial that randomized 272 patients (8-17 years of age) with type 2 diabetes to AMARYL (n=135) or metformin (n=137). Both treatment-na´ve 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. AMARYL was initiated at 1 mg, and then titrated up to 2, 4 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 HbA1c between AMARYL 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 HbA1c with AMARYL compared to metformin.
Table 2: Change from Baseline in HbA1C and Body Weight in
Pediatric Patients Taking Amaryl or Metformin
|Change from baseline (adjusted LS mean) +||-1.2||-1|
|Adjusted Treatment Difference** (95% CI)||0.2 (-0.3; 0.6)|
|Previously Treated Patients*||N=57||N=55|
|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|
|Change from baseline (adjusted LS mean)+||0.7||2|
|Adjusted Treatment Difference** (95% CI)||1.3 (0.3; 2.3)|
|* Intent-to-treat population using
last-observation-carried-forward for missing data (AMARYL, n=127; metformin,
n=126) + adjusted for baseline HbA1c and Tanner Stage
** Difference is AMARYL – metformin with positive differences favoring metformin
The profile of adverse reactions in pediatric patients treated with AMARYL was similar to that observed in adults [see ADVERSE REACTIONS].
Hypoglycemic events documented by blood glucose values < 36 mg/dL were observed in 4% of pediatric patients treated with AMARYL 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).
In clinical trials of AMARYL, 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].
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 and WARNINGS AND PRECAUTIONS]. Use caution when initiating AMARYL and increasing the dose of AMARYL in this patient population.
To minimize the risk of hypoglycemia, the recommended starting dose of AMARYL is 1 mg daily for all patients with type 2 diabetes and renal impairment [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
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 10-60 mL/min. The pharmacokinetics of AMARYL 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 AMARYL 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].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 2/15/2012
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