Glimepiride 4 mg Tablet, 90-count

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 antidiabetic drug. ( 5.5 )

5.1Hypoglycemia 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.

5.2Hypersensitivity 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.

5.3Hemolytic 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 ) ].

5.4Increased 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 plu…

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 Florida Pharmaceutical Products, LLC at 1-800-315-0985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 Placebo* Glimepiride N=745 % Placebo N=294 % Headache 8.2

7.8Accidental Injury † 5.8

3.4Flu Syndrome 5.4

4.4Nausea 5.0

3.4Dizziness 5.0 2.4 *Glimepiride doses ranged from 1-16 mg administered daily † Insufficient information to determine whether any of the accidental injury events were associated with hypoglycemia 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 aminotr…

7 DRUG INTERACTIONS Certain medications may affect glucose metabolism, requiring glimepiride tablets dose adjustment and close monitoring of blood glucose. ( 7.1 ) Miconazole: Severe hypoglycemia can occur when glimepiride tablets and oral miconazole are used concomitantly. ( 7.2 ) Cytochrome P450 2C9 interactions: Inhibitors and inducers of cytochrome P450 2C9 may affect glycemic control by altering glimepiride plasma concentrations.

( 7.3 ) Colesevelam: Coadministration may reduce glimepiride absorption. Glimepiride tablets should be administered at least 4 hours prior to colesevelam. ( 2.1 , 7.4 )

7.1Drugs Affecting Glucose Metabolism A number of medications affect glucose metabolism and may require glimepiride 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, 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 , monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving glimepiride , 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, 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, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for hypoglycemia. Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of glimepiride’s glucose-lowering effect.

Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of glimepiride in an unpredictable fashion. The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.

7.2Miconazole 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

7.3Cytochrome P450 2C9 Interaction 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.

7.4Concomitant 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 pr…