Glimepiride (glimepiride 2 mg) Dailymed

2 Dosage And Administration

• •Recommended starting dose is 1 or 2 mg once daily. Increase in 1 or 2 mg increments no more frequently than every 1-2 weeks based on glycemic response. Maximum recommended dose is 8 mg once daily. (2.1)
• •Administer with breakfast or first meal of the day. (2.1)
• •Use 1 mg starting dose and titrate slowly in patients at increased risk for hypoglycemia (e.g., elderly, patients with renal impairment). (2.1)

2.1 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.

3 Dosage Forms And Strengths

Glimepiride tablets USP are formulated as tablets of:

• •1 mg (Light pink capsule shaped flat-faced, bevelled edged tablets with breakline on both sides and debossed with ‘I’ and ‘1’ on either side of breakline only on one side)
• •2 mg (Yellow coloured capsule shaped flat-faced, bevelled edged tablets with breakline on both sides and debossed with ‘I’ and ‘2’ on either side of breakline only on one side)
• •4 mg (White capsule shaped flat-faced, bevelled edged tablets with breakline on both sides and debossed with ‘I’ and ‘4’ on either side of breakline only on one side)

Tablets (scored): 1 mg, 2 mg, 4 mg (3)

4 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)].
• •Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide derivatives may develop an allergic reaction to glimepiride tablets. Do not use glimepiride tablets in patients who have a history of an allergic reaction to sulfonamide derivatives.

• •Hypersensitivity to glimepiride or any of the product’s ingredients (4)
• •Hypersensitivity to sulfonamide derivatives (4)

5 Warnings And Precautions

• •Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications. (5.1)
• •Hypersensitivity Reactions: Postmarketing reports include anaphylaxis, angioedema and Stevens-Johnson Syndrome. If a reaction is suspected, promptly discontinue glimepiride tablets, assess for other potential causes for the reaction, and institute alternative treatment for diabetes. (5.2)
• •Hemolytic Anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider a non-sulfonylurea alternative. (5.3)
• •Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives. (5.4)
• •Macrovascular Outcomes: No clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride tablets or any other anti-diabetic drug. (5.5)

5.1 Hypoglycemia

All sulfonylureas, including glimepiride, 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 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.

5.2 Hypersensitivity Reactions

There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome [see Adverse Reactions (6.2)]. If a hypersensitivity reaction is suspected, promptly discontinue glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.

5.3 Hemolytic Anemia

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because glimepiride 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 glimepiride who did not have known G6PD deficiency [see Adverse Reactions (6.2)].

5.4 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 and a half 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 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.

5.5 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug.

6 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)]

Common adverse reactions in clinical trials (≥5% and more common than with placebo) include hypoglycemia, headache, nausea, and dizziness (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Lambda Therapeutics Research Ltd. at 1-855-642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Approximately 2,800 patients with type 2 diabetes have been treated with glimepiride in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with glimepiride for at least 1 year. In clinical trials, the most common adverse reactions with glimepiride were hypoglycemia, dizziness, asthenia, headache, and nausea.

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-treated patients and more commonly than in patients who received placebo.

Table 1: Eleven Pooled Placebo-Controlled Trials ranging from 13 weeks to 12 months: Adverse Events (excluding hypoglycemia) Occurring in ≥5% of Glimepiride-treated Patients and at a Greater Incidence than with PlaceboGlimepiride doses ranged from 1–16 mg administered daily

	Glimepiride N=745 %	Placebo N=294 %
Headache	8.2	7.8
Accidental InjuryInsufficient information to determine whether any of the accidental injury events were associated with hypoglycemia	5.8	3.4
Flu Syndrome	5.4	4.4
Nausea	5.0	3.4
Dizziness	5.0	2.4

Hypoglycemia

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 1 mg, 4 mg, 8 mg, or placebo. Patients randomized to glimepiride 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 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg and 0% for placebo. All of these events were self-treated.

In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90–150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6, or 8 mg [see Clinical Studies (14.1)]. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride vs. placebo was 19.7% vs. 3.2%. All of these events were self-treated.

Weight gain

Glimepiride, 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-treated patients. These may resolve despite continued treatment with glimepiride. 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, 1.9% of glimepiride-treated patients and 0.8% of placebo-treated patients developed serum ALT greater than 2 times the upper limit of the reference range.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of glimepiride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• •Serious hypersensitivity reactions, including anaphylaxis, 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
• •Dysgeusia
• •Alopecia

• •Pediatric Patients: Not recommended because of adverse effects on body weight and hypoglycemia. (8.4)
• •Geriatric or Renally Impaired Patients: At risk for hypoglycemia with glimepiride. Use caution in dose selection and titration, and monitor closely. (8.5, 8.6)

8.1 Pregnancy

Risk Summary

Available data from a small number of published studies and postmarketing experience with glimepiride tablets use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glimepiride) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, glimepiride tablets should be discontinued at least two weeks before expected delivery (see Clinical Considerations). Poorly controlled diabetes in pregnancy is also associated with risks to the mother and fetus (see Clinical Considerations). In animal studies (see Data), there were no effects on embryo-fetal development following administration of glimepiride to pregnant rats and rabbits at oral doses approximately 4000 times and 60 times the maximum human dose based on body surface area, respectively. However, fetotoxicity was observed in rats and rabbits at doses 50 times and 0.1 times the maximum human dose, respectively.

The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7% and has been reported to be as high as 20% to 25% in women with a HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo-fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia-related morbidity.

Fetal/neonatal adverse reactions

Neonates of women with gestational diabetes who are treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4–10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.

Dose adjustments during pregnancy and the postpartum period

Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, glimepiride tablets should be discontinued at least two weeks before expected delivery (see Fetal/Neonatal Adverse Reactions).

Data

Animal data

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 was observed only at doses inducing maternal hypoglycemia and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride, as has been similarly noted with other sulfonylureas.

8.2 Lactation

Risk Summary

Breastfed infants of lactating women using glimepiride tablets should be monitored for symptoms of hypoglycemia (see Clinical Considerations). It is not known whether glimepiride is excreted in human milk and there are no data on the effects of glimepiride on milk production. Glimepiride is present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for glimepiride tablets and any potential adverse effects on the breastfed child from glimepiride tablets or from the underlying maternal condition.

Clinical Considerations

Monitoring for adverse reactions

Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Data

During prenatal and postnatal 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.

8.4 Pediatric Use

The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below. Glimepiride 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 glimepiride 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), C_max (102±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±96 ng∙hr/mL, C_max 103±34 ng/mL, and t_1/2 5.3±4.1 hours).

The safety and efficacy of glimepiride 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 glimepiride (n=135) or metformin (n=137). Both treatment-naive 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 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 glimepiride 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 glimepiride compared to metformin.

Table 2: Change from Baseline in HbA1c and Body Weight in Pediatric Patients Taking Glimepiride or Metformin

	Metformin	Glimepiride
Treatment-Naive Patients Intent-to-treat population using last-observation-carried-forward for missing data (glimepiride, n=127; metformin, n=126)	N=69	N=72
HbA1c (%)
Baseline (mean)	8.2	8.3
Change from baseline (adjusted LS mean)adjusted for baseline HbA1c and Tanner Stage	-1.2	-1.0
Adjusted Treatment DifferenceDifference is glimepiride – metformin with positive differences favoring metformin (95%CI)	0.2 (-0.3; 0.6)
Previously Treated Patients	N=57	N=55
HbA1c (%)
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)

The profile of adverse reactions in pediatric patients treated with glimepiride was 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 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).

8.5 Geriatric Use

In clinical trials of glimepiride, 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 and increasing the dose of glimepiride in this patient population.

8.6 Renal Impairment

To minimize the risk of hypoglycemia, the recommended starting dose of glimepiride 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 10–60 mL/min. The pharmacokinetics of glimepiride was 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 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)].