Glimepiride

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of glimepiride, there are no specific foods that you must exclude from your diet when receiving this medication.

Before taking glimepiride, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to glimepiride or to any of its ingredients
• have or have ever had G6PD deficiency (an inherited condition causing premature destruction of red blood cells or hemolytic anemia)
• if you have hormone disorders involving the adrenal , pituitary, or thyroid gland
• have heart, kidney, or liver disease
• are pregnant or plan to become pregnant. If you become pregnant while taking glimepiride, call your doctor.
• are breast-feeding
• are having surgery, including dental surgery

Ask your doctor about the safe use of alcoholic beverages while you are taking glimepiride. Alcohol can make the side effects from glimepiride worse.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Glimepiride falls into category C. There are no well-controlled studies that have been done in pregnant women. Glimepiride should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if glimepiride crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using glimepiride.

Usual Adult Dose for Diabetes Type 2:

Initial dose: 1 to 2 mg orally once a day
Maintenance dose: Increase in 1 or 2 mg increments no more frequently than every 1 to 2 weeks based on glycemic response
Maximum dose: 8 mg per day

Comments:
-Administer with breakfast or first main meal of the day.
-In patients who are at increased risk for hypoglycemia, start with 1 mg orally once a day and titrate slowly.
-When patients are being transferred to this drug from a longer half-life sulfonylurea, monitor 1 to 2 weeks for overlapping drug effect.

Use: As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Usual Geriatric Dose for Diabetes Type 2:

Initial dose: 1 mg orally once a day; titrate slowly and monitor closely

Usual Pediatric Dose for Diabetes Type 2:

Not recommended because of adverse effects on body weight and hypoglycemia.

Antidiabetic agent; sulfonylurea.1 53

Storage

Oral

Glimepiride: Well-closed containers at 15–30°C.1

Fixed combination of glimepiride and rosiglitazone: Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).114

• If you have an allergy to glimepiride or any other part of glimepiride.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Acidic blood problem or type 1 diabetes.
• If you are breast-feeding or plan to breast-feed.
• If the patient is a child. Do not give this medicine to a child.

This is not a list of all drugs or health problems that interact with glimepiride.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad dizziness or passing out.
• Shortness of breath.
• Feeling very tired or weak.
• Low blood sugar can happen. The chance of low blood sugar may be raised when glimepiride is used with other drugs for high blood sugar (diabetes). Signs may be dizziness, headache, feeling sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating. Call your doctor right away if you have any of these signs. Follow what you have been told to do if you get low blood sugar. This may include taking glucose tablets, liquid glucose, or some fruit juices.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach.
• Dizziness.
• Feeling tired or weak.
• Headache.
• Weight gain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

7.1 Drugs 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, H2 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.

7.2 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.

7.3 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.

7.4 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 should be administered at least 4 hours prior to colesevelam.

12.1 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.

12.2 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. The effects of Glimepiride on HbA1c, fasting plasma glucose, and post-prandial glucose have been assessed in clinical trials [see Clinical Studies ( 14)].

12.3 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 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 in patients with type 2 diabetes, the reduction in HbA1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).

Renal Impairment:  A single-dose, open-label study Glimepiride 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 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 pharmacokinetics because the pharmacokinetics of Glimepiride has 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 ± 218 ng/mL vs. 410 ± 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 was administered. The Glimepiride doses were separated by a 14-day washout period. Co-administration of aspirin and Glimepiride 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 alone, Glimepiride with ranitidine (150 mg twice daily for 4 days; Glimepiride was administered on Day 3), or Glimepiride 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 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 was administered. The Glimepiride doses were separated by a 14-day washout period. Concomitant administration of propranolol and Glimepiride significantly increased Glimepiride 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 daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting Glimepiride and on Day 4 of Glimepiride administration. The concomitant administration of Glimepiride did not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in warfarin plasma protein binding. Glimepiride 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 treatment were 3.3% and 9.9%, respectively, and are unlikely to be clinically relevant.

Initial: 1 mg once daily; dose titration and maintenance dosing should be conservative to avoid hypoglycemia. Consider alternative therapy if eGFR <15 mL/minute/1.73 m2 (Alsahli 2015).

Administer once daily with breakfast or first main meal of the day. Patients that are NPO or require decreased caloric intake may need doses held to avoid hypoglycemia.

Administration advice:
-Take with breakfast or first main meal of the day
-When coadministered with colesevelam, this drug should be taken at least 4 hours prior

General:
-This drug should not be used in patients with type 1 diabetes or diabetic ketoacidosis.
-Hemolytic anemia may occur in glucose 6-phosphate dehydrogenase (G6PD) deficient patients; consider a non-sulfonylurea alternative.
-Improvement in glucose tolerance may take place after a few weeks of treatment, monitor clinical status closely within the first 4 to 8 weeks and at regular intervals thereafter to ascertain whether it is possible to reduce the dose.
-During periods of stress such as fever, trauma, infection, or surgery, patients may need to temporarily switch to insulin therapy.

Monitoring:
-Regular monitoring of blood glucose levels is necessary to ensure safety and efficacy

Patient advice:
-Patients should understand the importance of exercise and dietary control in the management of their disease.
-Patients should understand that alcohol ingestion, intense or prolonged exercise, skipping meals, illness, or lifestyle changes may increase their risks for hypoglycemia; they should know how to recognize the symptoms of hypoglycemia and be prepared to treat it.
-Patients should be careful about driving and use of machinery, especially when at risk for hypoglycemia.
-Patients should speak with their health care provider during periods of stress such as fever, trauma, or illness, as their diabetes management may need to be changed.
-Advise patients to speak to physician or health care professional if pregnant, intend to become pregnant, or are breastfeeding.

• Takes about two to three hours to reach maximal effect after a single dose.

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