Amaryl

Common Side Effects of Glimepiride

Glimepiride may cause changes in your blood sugar, which could cause blood sugar levels to fluctuate.

Symptoms of low blood sugar include:

• Sudden sweating
• Shaking
• Fast heartbeat
• Hunger
• Blurred vision
• Dizziness
• Tingling in the hands or feet

You may want to carry glucose tablets or gels with you to treat low blood sugar episodes.

Serious Side Effects of Glimepiride

Some side effects of glimepiride can be serious. You should call your doctor immediately if you experience:

• Yellowing of the skin or eyes (jaundice)
• Dark urine
• Light-colored stools
• Pain in the upper right part of the stomach
• Diarrhea
• Fever
• Sore throat
• Unusual bruising or bleeding

Many drugs can affect your blood sugar levels and make them more difficult to control.

You should talk with your doctor or pharmacist before you start, stop, or change any medication.

If you are taking another anti-diabetic drug such as chlorpropamide (Diabinese), follow your doctor's instructions carefully for stopping the old drug and starting on glimepiride.

The drug colesevelam (Welchol) can decrease the absorption of glimepiride. You will need to take glimepiride at least four hours before taking colesevelam.

You should tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs or supplements you are taking.

Glimepiride and Alcohol

Alcohol can worsen the side effects of glimepiride and may cause symptoms such as flushing, headache, chest pain, nausea, vomiting, weakness, blurred vision, mental confusion, sweating, choking, difficulty breathing, and anxiety.

Limit or avoid drinking alcohol while taking glimepiride.

You should also avoid unnecessary exposure to the sun while taking glimepiride because the drug can make your skin more sensitive to sunlight.

GENERIC AVAILABLE: Yes

Amaryl is a prescription medication used to treat type 2 diabetes.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Amaryl is part of the drug class:

• Sulfonamides, urea derivatives

>10%

Hypoglycemia (4-20%)

1-10%

Dizziness (1.7%)

Asthenia (1.6%)

Headache (1.5%)

Nausea (1.1%)

<1%

Allergic skin reactions

Erythema

Morbilliform or maculopapular eruptions

Pruritus

Urticaria

Diarrhea

Gastrointestinal pain

Vomiting

Agranulocytosis

Anemia

Aplastic anemia

Leukopenia

Pancytopenia

Thrombocytopenia, hemolytic

Cholestasis

Elevation of liver enzyme levels

Hepatic porphyria reactions

Jaundice (rare)

Disulfiram-like reactions

Hyponatremia

Postmarketing Reports

Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens- Johnson Syndrome

Hemolytic anemia in patients with and without G6PD deficiency

Hepatic impairment (eg, cholestasis, 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 <10,000/mcL) and thrombocytopenic purpura

Hepatic porphyria reactions and disulfiram-like reactions

Hyponatremia and SIADH, most often in patients on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone

Dysgeusia

Alopecia

Contraindications

Hypersensitivity; sulfa allergy

Type 1 diabetes

Diabetic ketoacidosis (with or without coma)

Complicated gestational diabetes mellitus

Cautions

Patients with risk of severe hypoglycemia: Elderly, debilitated, or malnourished; adrenal or pituitary insufficiency; patients with stress due to infection, fever, trauma, or surgery

If patient is exposed to stress, it may be necessary to discontinue glimepiride and initiate insulin

Use caution in hepatic/renal impairment

Pregnancy, lactation

Increased risk of cardiovascular mortality

Persons allergic to other sulfonamide derivatives may develop allergic reaction to glimepiride

Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy

Hemolytic anemia may occur with glucose 6-phosphate dehydrogenase (G6PD) deficiency when treated with sulfonylurea agents

Fluid retention, which may exacerbate or lead to heart failure, may occur

Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk of other cardiovascular effects

Potential risk of ischemic cardiovascular (CV) events relative to placebo reported in meta-analysis studies, but not confirmed in long-term CV outcome trial versus metformin or sulfonylurea

Dose-related edema, weight gain, and anemia may occur

Macular edema reported

Increased incidence of bone fracture reported

Postmarketing reports for glimepiride include anaphylaxis, angioedema, and Stevens-Johnson syndrome; promptly discontinue glimepiride, assess for other causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes

You may be more likely to have hypoglycemia (low blood sugar) if you take glimepiride with other drugs that can lower blood sugar, such as:

• exenatide (Byetta);

• probenecid (Benemid);

• aspirin or other salicylates (including Pepto Bismol);

• a blood thinner (warfarin, Coumadin, Jantoven);

• sulfa drugs (Bactrim, SMZ-TMP, and others);

• a monoamine oxidase inhibitor (MAOI); or

• insulin or other oral diabetes medications.

This list is not complete, and many other medicines can increase or decrease the effects of glimepiride on lowering your blood sugar. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with glimepiride. Not all possible interactions are listed in this medication guide.

Antidiabetic agent; sulfonylurea.1 53

Contraindications

• Known hypersensitivity to glimepiride or any ingredient in formulation.1

• Diabetic ketoacidosis, with or without coma.1 114

Warnings/Precautions

Warnings

Increased cardiovascular mortality reported with certain other antidiabetic agents (i.e., tolbutamide, phenformin).1 99 114 However, the American Diabetes Association (ADA) considers the benefits of intensive glycemic control with insulin or sulfonylureas to outweigh the risks overall.31 58 64 99

General Precautions

Possible severe hypoglycemia, especially in geriatric, debilitated, or malnourished patients and those with adrenal, pituitary, hepatic, or renal insufficiency.1 114 Increased risk of hypoglycemia with strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other oral antidiabetic agents (e.g., rosiglitazone, metformin).1 114

Hypoglycemia may be difficult to recognize in geriatric patients and in those receiving β-adrenergic blocking agents.1 114

Appropriate patient selection and careful dosing are important to avoid glimepiride-induced hypoglycemia.1 114

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery); administration of insulin may be required.1 114 May reinstitute oral antidiabetic therapy after an acute episode has resolved.114

Efficacy of therapy may decrease over time (secondary failure).1 Addition of metformin or insulin to therapy may be required.1 54 (See Diabetes Mellitus under Uses.)

When used in fixed combination with rosiglitazone or pioglitazone, consider the cautions, precautions, and contraindications associated with rosiglitazone or pioglitazone.114 117

Specific Populations

Category C.1 114

Many experts recommend use of insulin during pregnancy to maintain optimum control of blood glucose concentrations.1 114

Distributed into milk in rats; other sulfonylureas distributed into human milk.1 Use not recommended.1 114 If oral antidiabetic therapy discontinued and diet alone is inadequate for optimal glycemic control, consider institution of insulin.1 114

Glimepiride: Safety and efficacy not established in children <16 years of age.1 53

Fixed combination with rosiglitazone: Safety and efficacy not established in children <18 years of age.114

Fixed combination with pioglitazone: Safety and efficacy not established in pediatric patients.117

ADA states that use of oral antidiabetic agents may be considered in children with type 2 diabetes mellitus because of the greater compliance and convenience and lack of evidence demonstrating better efficacy of insulin for type 2 diabetes mellitus.93

No substantial differences in safety, efficacy, or pharmacokinetics relative to younger adults, but increased sensitivity cannot be ruled out.1

Possible increased risk of adverse effects due to age-related decreases in renal function.1 Renal function monitoring recommended, and care should be taken in dosage selection.1 (See Geriatric Patients under Dosage and Administration.)

Increased risk of hypoglycemia; may be difficult to recognize in geriatric patients.1

Increased risk of hypoglycemia; conservative dosing recommended.1 (See Hepatic Impairment under Dosage and Administration.)

Decreased clearance.1

Increased risk of hypoglycemia; conservative dosing recommended.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Dizziness, asthenia, headache, nausea.1

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

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 Amaryl 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.

• 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.

Amaryl is formulated as tablets of:

• 1 mg (pink, flat-faced, oblong with notched sides at double bisect, imprinted with "AMA RYL" on one side)
• 2 mg (green, flat-faced, oblong with notched sides at double bisect, imprinted with "AMA RYL" on one side)
• 4 mg (blue, flat-faced, oblong with notched sides at double bisect, imprinted with "AMA RYL" on one side)

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)]

In clinical trials, the most common adverse reactions with Amaryl were hypoglycemia, dizziness, asthenia, headache, and nausea.

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 Amaryl in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with Amaryl for at least 1 year.

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

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 Amaryl 1 mg, 4 mg, 8 mg or placebo. Patients randomized to Amaryl 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 Amaryl 1 mg, 17% for Amaryl 4 mg, 16% for Amaryl 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 Amaryl or placebo daily. The dose of Amaryl was titrated to a target fasting plasma glucose of 90–150 mg/dL. Final daily doses of Amaryl 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 Amaryl vs. placebo was 19.7% vs. 3.2%. All of these events were self-treated.

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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Amaryl. 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

Amaryl is an oral sulfonylurea that contains the active ingredient glimepiride. Chemically, glimepiride is identified as 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea (C24H34N4O5S) with a molecular weight of 490.62. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water.

The structural formula is:

Amaryl tablets contain the active ingredient glimepiride and the following inactive ingredients: lactose (hydrous), sodium starch glycolate, povidone, microcrystalline cellulose, and magnesium stearate. In addition, Amaryl 1 mg tablets contain Ferric Oxide Red, Amaryl 2 mg tablets contain Ferric Oxide Yellow and FD&C Blue #2 Aluminum Lake, and Amaryl 4 mg tablets contain FD&C Blue #2 Aluminum Lake.

Amaryl tablets are available in the following strengths and package sizes:

• 1 mg (pink, flat-faced, oblong with notched sides at double bisect, imprinted with
  "AMA RYL" on one side) in bottles of 100 (NDC 0039-0221-10)
• 2 mg (green, flat-faced, oblong with notched sides at double bisect, imprinted with
  "AMA RYL" on one side) in bottles of 100 (NDC 0039-0222-10)
• 4 mg (blue, flat-faced, oblong with notched sides at double bisect, imprinted with
  "AMA RYL" on one side) in bottles of 100 (NDC 0039-0223-10)

Store at 25°C (77°F); excursions permitted to 20 – 25°C (68 – 77°F) (see USP Controlled Room Temperature).

Dispense in well-closed containers with safety closures.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

If you also take colesevelam, avoid taking it within 4 hours after you take Amaryl.

Avoid drinking alcohol. It lowers blood sugar and may interfere with your diabetes treatment.

Avoid exposure to sunlight or tanning beds. Amaryl can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Substance Name

Glimepiride

CAS Registry Number

93479-97-1

Drug Class

Hypoglycemic Agents

Sulfonylurea Compounds