Amaryl (glimepiride) Side Effects, Warnings, and Drug Interactions

• Amaryl (glimepiride) is an oral diabetes medication used in addition to diet and exercise to control blood sugar in adults with type 2 diabetes.
• Management of blood sugar with Amaryl can help decrease the risk of eye, kidney, and nerve damage.
• Amaryl is not used for treating type 1 diabetes.

Common side effects of Amaryl include:

• dizziness,
• headache,
• nausea,
• vomiting,
• rash,
• allergic reactions,
• and flu-like symptoms.

Serious side effects of Amaryl include:

• anemia,
• low blood platelets,
• low sodium,
• sensitivity to sunlight,
• liver dysfunction,
• serious allergic reactions,
• and low blood sugar (hypoglycemia)
  • symptoms of low blood sugar include:
    • hunger,
    • nausea,
    • tiredness,
    • sweating,
    • headache,
    • heart palpitations,
    • numbness around the mouth,
    • tingling in the fingers,
    • tremors,
    • muscle weakness,
    • blurred vision,
    • chilliness,
    • excessive yawning,
    • irritability,
    • confusion,
    • and loss of consciousness

Drug interactions of Amaryl include medications that, when given in combination with Amaryl may reduce its ability to lower blood sugar, including:

• diuretics,
• corticosteroids,
• phenytoin,
• colesevelam,
• danazol,
• somatropin,
• and rifampin.

Beta-blockers can cause low or high blood sugar.

The following, when given in combination with Amaryl, may increase the risk of low blood sugar (hypoglycemia):

• Nonsteroidal anti-inflammatory drugs (NSAIDs),
• sulfa drugs,
• warfarin,
• miconazole,
• fluconazole,
• chloramphenicol,
• cimetidine,
• ranitidine,
• clarithromycin,
• monoamine oxidase inhibitors (MAOIs),
• probenecid,
• quinolone antibiotics,
• and selective serotonin reuptake inhibitors (SSRIs).

Combining Amaryl with insulin may increase risk of heart-related side effects. 

In animal studies, Amaryl and other sulfonylureas were associated with a higher risk of fetal death. However, there have been no good studies in women.

Abnormal blood sugar concentrations (high or low) during pregnancy increase the risk of abnormalities in the fetus. Physicians must carefully weigh the benefits and risks of Amaryl treatment during pregnancy. Insulin is the drug of choice for treating diabetes in pregnant women.

It is unknown if Amaryl is excreted in breast milk like other sulfonylureas. Because of the risk of low blood sugar in the infant, it is recommended that Amaryl be discontinued while breastfeeding. If therapy other than diet and exercise is needed, insulin is preferred.

Common side effects of glimepiride include:

• Headache
• Nausea
• Vomiting

A rash and allergic reactions also may occur. Flu-like symptoms have also been reported with glimepiride therapy.

Possible serious side effects of glimepiride include:

• Anemia
• Low blood platelets
• Low sodium
• Sensitivity to sunlight
• Liver dysfunction
• Serious allergic reactions

Low blood sugar (hypoglycemia) can occur during glimepiride therapy. Symptoms of low blood sugar include:

• Hunger
• Nausea
• Tiredness
• Perspiration
• Headache
• Heart palpitations
• Numbness around the mouth
• Tingling in the fingers
• Tremors
• Muscle weakness
• Blurred vision
• Chilliness
• Excessive yawning
• Irritability
• Confusion
• Loss of consciousness

Glimepiride is a derivative of a sulfonamide drug. People allergic to other sulfonamide-related drugs may develop an allergic reaction to glimepiride. Anyone who has an allergic reaction to sulfa drugs should not take glimepiride.

The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling:

• Hypoglycemia
• Hemolytic anemia

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 placebocontrolled 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.

Table 1: Eleven Pooled Placebo-Controlled Trials ranging from 13 weeks to 12 months : Adverse Events (Excluding Hypoglycemia) Occurring in ≥ 5% of Amaryl-treated Patients and at a Greater Incidence than with 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.
• 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.
• 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.

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).

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
• Hemolytic anemia in patients with and without G6PD deficiency
• 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

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 others:
  • 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.