Amaryl

1. Amaryl

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

• are allergic to Amaryl 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 Amaryl, 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 Amaryl. Alcohol can make the side effects from Amaryl worse.

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

If you take too much Amaryl, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Dosage Forms & Strengths

tablet

• 1mg
• 2mg
• 4mg

Type 2 Diabetes Mellitus

Initial: 1-2 mg PO qAM after breakfast or with first meal; may increase dose by 1-2 mg every 1-2 weeks; not to exceed 8 mg/day

Conversion from other oral hypoglycemic agents

• Observe patients carefully for 1-2 weeks when being converted from long half-life sulfonylureas to glimepiride, because of potential for overlapping of hypoglycemic effects

Dosing considerations

• Use in monotherapy or, if glycemic response to glimepiride is inadequate at maximum dose, with insulin or metformin

Dosing Modifications

Renal impairment: 1 mg PO qDay; titrate dose based on fasting blood glucose levels

Hepatic impairment: Not studied; not recommended in severe impairment; initiate therapy with 1 mg PO qDay and titrate carefully

Safety and efficacy not established

Prolonged hypoglycemia reported with use; titrate dose conservatively; monitor for hypoglycemic or hyperglycemic symptoms

Type 2 Diabetes Mellitus

1 mg PO qDay; titrate dose at weekly intervals to avoid hypoglycemia

Diabetes Mellitus

Used alone or in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 5 54 100 101 102 103 104 105 106 107 114 117

Used in fixed combination with rosiglitazone when treatment with both glimepiride and rosiglitazone is appropriate.114

Used in fixed combination with pioglitazone in patients with type 2 diabetes mellitus who are already receiving a thiazolidinedione and a sulfonylurea separately or who do not achieve adequate glycemic control with thiazolidinedione or sulfonylurea monotherapy.117

Many clinicians recommend metformin as the preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus.89 90 118 Sulfonylureas (e.g., glimepiride) are one of several second-line classes of agents used with other antidiabetic agents (e.g., metformin) in patients who are inadequately controlled on their current therapy.118

Oral antidiabetic agents not effective as sole therapy in patients with type 1 diabetes mellitus or diabetic acidosis, ketosis, or coma; insulin is necessary.1 14 28 29 42 45 114

Sulfonylurea antidiabetic agents not routinely recommended in hospitalized patients with diabetes mellitus.31 Long duration of action precludes rapid dosage adjustments.1 31 Increased risk of hypoglycemia in hospitalized diabetic patients with irregular eating patterns.31

General

• Adjust dosage according to tolerance and fasting glucose determinations.1 114 Monitor regularly (e.g., fasting blood or plasma glucose determinations) to determine therapeutic response and minimum effective dosage.1 114 Undertake any change in therapy with care and monitor appropriately.114 Monitor HbA1c every 3–6 months to determine the patient’s continued response to therapy.1 114

• Use lowest effective dosage (either as monotherapy or combined with metformin or insulin) to reduce both fasting glucose concentrations and HbA1c values to normal or near normal.1 17 18 24 31 28

• If inadequate glycemic control and/or secondary failure occurs during monotherapy with glimepiride, may consider add-on therapy with metformin, insulin, or rosiglitazone (e.g., as the fixed combination of glimepiride and rosiglitazone).1 114 With concomitant glimepiride and metformin therapy, adjust dosage to the minimum effective level for each drug.1

Administration

Oral Administration

Administer glimepiride alone or in fixed combination with rosiglitazone or pioglitazone once daily with the first main meal.1 5 6 114 117

Dispensing errors have occurred involving Amaryl (the trade name for glimepiride) and Reminyl (the former US trade name for galantamine hydrobromide, an acetylcholinesterase inhibitor used for treatment of Alzheimer’s dementia).111 112 Serious adverse events (e.g., severe hypoglycemia, death) have occurred because glimepiride was used in patients for whom the drug was not prescribed.111 The manufacturer of Reminyl changed the US trade name for galantamine hydrobromide from Reminyl to Razadyne.113

Dosage

With the fixed combination of glimepiride and rosiglitazone maleate, dosage of rosiglitazone component expressed in terms of rosiglitazone.114

Adults

Initially, 1–2 mg once daily for previously untreated patients or patients transferred from other antidiabetic agents.1 In patients receiving 1 mg daily, increase dosage to 2 mg daily after 1–2 weeks if adequate glycemic control has not been achieved.53 Increase dosage in increments of no more than 2 mg daily at 1- to 2-week intervals up to a maximum of 8 mg once daily.1 Usual maintenance dosage is 1–4 mg once daily.1 53

Maximum initial dosage should not exceed 2 mg once daily.1

Initially, 1 mg of glimepiride and 4 mg of rosiglitazone once daily.114 May consider initial dosage of 2 mg of glimepiride and 4 mg of rosiglitazone once daily in patients already receiving a sulfonylurea or rosiglitazone.114

Initiate rosiglitazone component at the lowest recommended dosage.114

In patients previously receiving rosiglitazone monotherapy, allow approximately 1–2 weeks to assess therapeutic response to newly initiated glimepiride component before adjusting dosage.114 If additional glycemic control is needed after 1–2 weeks, increase dosage of the glimepiride component in increments of ≤2 mg.114 Assess response to increase in glimepiride component after 1–2 weeks to determine need for further dosage adjustment.114

In patients previously receiving sulfonylurea monotherapy, allow 2 weeks to observe reduction in blood glucose concentrations and 2–3 months to observe full therapeutic response to newly initiated rosiglitazone component.114 If additional glycemic control is needed after 8–12 weeks, increase dosage of the rosiglitazone component.114 If additional glycemic control is needed 2–3 months after an increase in rosiglitazone component, further titrate dosage.114

Patients switching from combined therapy with separate glimepiride and rosiglitazone preparations: Usual initial dosage of the fixed-combination is the same as the patient's existing dosage of the individual drugs.114

If hypoglycemia occurs, consider a reduced dosage of the glimepiride component.114

Select initial dosage based on patient’s current dosage of glimepiride (or another sulfonylurea agent) and/or pioglitazone.117

Patients currently receiving glimepiride monotherapy: Usual initial dosage is 2 or 4 mg of glimepiride and 30 mg of pioglitazone once daily.117

Patients transferring from monotherapy with other sulfonylureas: Initially, 2 mg of glimepiride and 30 mg of pioglitazone once daily.117 If patient is being transferred from a sulfonylurea with a long half-life (e.g., chlorpropamide), monitor closely for hypoglycemia during initial 1–2 weeks of the transition period.117

Patients currently receiving pioglitazone monotherapy: Usual initial dosage is 2 mg of glimepiride and 30 mg of pioglitazone once daily.117

Patients switching from combined therapy with separate glimepiride and pioglitazone preparations: Initiate fixed combination with 2 or 4 mg of glimepiride and 30 mg of pioglitazone once daily based on patient’s current dosage of glimepiride and pioglitazone.117 Carefully monitor patients whose hyperglycemia was not previously controlled with 15 mg of pioglitazone in combination with glimepiride during transfer.117

Gradually titrate dosage as needed based on therapeutic response.117 Allow sufficient time (e.g., 8–12 weeks) to assess response.117 If additional glycemic control is needed, may increase dosage until maximum daily dosage of 8 mg of glimepiride and 45 mg of pioglitazone is reached.117

Patients with type 2 diabetes mellitus and systolic dysfunction: Initiate glimepiride/pioglitazone fixed-combination at the lowest recommended dosage; use fixed combination preparation only after patient has previously received pioglitazone 15 mg once daily as monotherapy and has safely tolerated dosage titration to 30 mg once daily.117 Closely monitor for weight gain, edema, or other manifestations of CHF exacerbation if subsequent dosage adjustment required.117

Initially, 8 mg once daily and a low insulin dosage in patients whose fasting plasma or serum glucose concentration exceeds 150 mg/dL despite appropriate oral antidiabetic monotherapy, diet, and exercise.1 31

Adjust insulin dosage upward at approximately weekly intervals until adequate glycemic control is achieved.1 31 53 Periodic adjustments in insulin dosage may be necessary during continued combination therapy.1

Initially, 1–2 mg once daily.1 1 2 May discontinue other sulfonylurea agents immediately.1 2 3 96 During transfer from chlorpropamide (a sulfonylurea with a long elimination half-life), monitor closely for hypoglycemia during the initial 1–2 weeks of the transition period.1

The initial dosage of glimepiride during transfer from other therapy should not exceed 2 mg daily.1

Prescribing Limits

Adults

Glimepiride monotherapy: Maximum 8 mg daily.1

Fixed combination with rosiglitazone: Maximum 4 mg of glimepiride and 8 mg of rosiglitazone daily.114

Fixed combination with pioglitazone: Maximum 8 mg of glimepiride and 45 mg of pioglitazone daily.117

Special Populations

Hepatic Impairment

Glimepiride monotherapy: Initially, 1 mg once daily.1 Conservative initial and maintenance dosages recommended.1

Fixed-combination preparation with rosiglitazone: Initially, 1 mg of glimepiride and 4 mg of rosiglitazone daily.114 Conservative initial and maintenance dosages recommended in patients with mild hepatic impairment; these individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.114 Do not initiate therapy with fixed combination of glimepiride and rosiglitazone in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).114

Renal Impairment

Glimepiride monotherapy: Initially, 1 mg once daily.1 Titrate dosage upward based on fasting glucose concentrations.1 Dosages >1 mg daily may not be required if Clcr <22 mL/minute.1 8

Fixed-combination preparation with rosiglitazone: Initially, 1 mg of glimepiride and 4 mg of rosiglitazone daily.114 Conservative initial and maintenance dosages recommended; individuals with renal impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.114

Geriatric Patients

Geriatric individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.1 114

Glimepiride monotherapy: Initially, 1 mg once daily.1 Titrate dosage upward with care.1 114 Conservative initial and maintenance dosages recommended.1 53 114

Fixed-combination preparation with rosiglitazone: Initially, 1 mg of glimepiride and 4 mg of rosiglitazone daily.114 Conservative initial and maintenance dosages recommended.114

Adrenal Insufficiency

Fixed-combination preparation with rosiglitazone: Initially, 1 mg of glimepiride and 4 mg of rosiglitazone daily.114 Conservative initial and maintenance dosages recommended; these individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.114

Debilitated or Malnourished Patients

These individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.1 114

Glimepiride monotherapy: Initially, 1 mg once daily.1 Conservative initial and maintenance dosages recommended.1

Fixed-combination preparation with rosiglitazone: Initially, 1 mg of glimepiride and 4 mg of rosiglitazone daily.114 Conservative initial and maintenance dosages recommended.114

• Inform patients of the potential risks and advantages of glimepiride therapy and of alternative forms of treatment.1 114

• Importance of taking the medication each morning with breakfast or with the first main meal.1 114

• Importance of adhering to diet and exercise regimen.1 13 15 16 114

• Importance of hygiene and avoidance of infection.31

• Advise patients about the nature of diabetes mellitus, prevention and detection of complications, and importance of glycemic control.18 31 22

• Importance of appropriate management of hypoglycemia and hyperglycemia.1 Risks of hypoglycemia.1 114 Importance of patients and responsible family members understanding symptoms and treatment of hypoglycemic reactions and identifying conditions that predispose to the development of such reactions.1 114

• Importance of regular monitoring of blood glucose (preferably self-monitoring) and of HbA1c.1 114

• Discuss potential for alterations in dosage requirements in special situations (e.g., illness, fever, trauma, infection, surgery); importance of informing clinician promptly if such situations occur.114

• Importance of understanding primary and secondary failure to therapy.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 114

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements,1 as well as any concomitant illnesses (e.g., type 1 diabetes mellitus, kidney or liver disease).114

• Advise patients receiving β-adrenergic blocking agents about potential risk for hypoglycemia.114

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

In the U.S.

• Amaryl

Available Dosage Forms:

• Tablet

Therapeutic Class: Hypoglycemic

Chemical Class: 2nd Generation Sulfonylurea

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Difficulty with swallowing
• dizziness
• fast heartbeat
• hives
• itching
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• shortness of breath
• skin rash
• tightness in the chest
• unusual tiredness or weakness
• wheezing

• Abdominal or stomach pain
• agitation
• back, leg, or stomach pains
• bleeding gums
• blistering, peeling, or loosening of the skin
• bloating of abdomen
• blood in the urine or stools
• bloody, black, or tarry stools
• chest pain
• chills
• coma
• confusion
• cough or hoarseness
• dark urine
• decreased urine output
• depression
• diarrhea
• difficulty with breathing
• fever with or without chills
• fluid-filled skin blisters
• general body swelling
• general tiredness and weakness
• headache
• high fever
• hostility
• irritability
• joint or muscle pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• lethargy
• light-colored stools
• loss of appetite
• lower back or side pain
• muscle twitching
• nausea and vomiting
• nosebleeds
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rapid weight gain
• red, irritated eyes
• red skin lesions, often with a purple center
• seizures
• sensitivity to the sun
• skin thinness
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stupor
• swelling of face, ankles, or hands
• swollen or painful glands
• unusual bleeding or bruising
• upper right abdominal or stomach pain
• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

• Anxiety
• blurred vision
• cold sweats
• cool, pale skin
• increased hunger
• nightmares
• shakiness
• slurred speech

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Lack or loss of strength

• Redness or other discoloration of the skin
• severe sunburn

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• Tell all of your health care providers that you take Amaryl. This includes your doctors, nurses, pharmacists, and dentists.
• Low blood sugar may happen with this medicine. Very low blood sugar can lead to seizures, passing out, long lasting brain damage, and sometimes death. Talk with the doctor.
• Check your blood sugar as you have been told by your doctor.
• Be careful if you have G6PD deficiency. Anemia may happen.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Do not drive if your blood sugar has been low. There is a greater chance of you having a crash.
• Talk with your doctor before you drink alcohol.
• If you also take colesevelam, take it at least 4 hours after you take Amaryl.
• It may be harder to control your blood sugar during times of stress like when you have a fever, an infection, an injury, or surgery. A change in level of physical activity or exercise and a change in diet may also affect your blood sugar. Talk with your doctor.
• This medicine may raise the chance of death from heart disease. Talk with your doctor.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Amaryl while you are pregnant.

Amaryl is 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 Amaryl. Do not use Amaryl in patients who have a history of an allergic reaction to sulfonamide derivatives.

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)].

Hypoglycemia

All sulfonylureas, including Amaryl, 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 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.

Hypersensitivity Reactions

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.

Hemolytic Anemia

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 (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 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.

Macrovascular Outcomes

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

Drugs Affecting Glucose Metabolism

A number of medications affect glucose metabolism and may require Amaryl 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 Amaryl, 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 Amaryl, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving Amaryl, monitor the patient closely for worsening glycemic control.

The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including Amaryl, 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 Amaryl, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving Amaryl, monitor the patient closely for hypoglycemia.

Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of Amaryl's glucose-lowering effect.

Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of Amaryl 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, Amaryl should be administered at least 4 hours prior to colesevelam.

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 46–54 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).

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For type 2 diabetes:
    • Adults—At first, 1 to 2 milligrams (mg) once a day. Your doctor may adjust your dose until your blood sugar is controlled. However, the dose is usually not more than 8 mg per day.
    • Children—Use and dose must be determined by your doctor.

Breastfeeding is not recommended during use of this drug. Excreted into human milk: Unknown Excreted into animal milk: Yes Comments: If diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

While the excretion of other sulfonylureas into human milk has been demonstrated, the excretion of this drug into human milk is unknown. Significant concentrations of this drug have been found in rat milk as well as the serum of pups. In rat pups exposed to high doses during pregnancy and lactation, hypoglycemia and skeletal deformities consisting of shortening, thickening, and bending of the humerus have occurred. These skeletal deformations were determined to be the result of nursing from mothers exposed to this drug.