Pioglitazone Hydrochloride / Glimepiride

Pronunciation: PYE-oh-GLI-ta-zone HYE-droe-KLOR-ide/glye-MEP-ir-ide
Class: Antidiabetic combination

Trade Names

Duetact
- Tablets, oral pioglitazone hydrochloride 30 mg (as base)/glimepiride 2 mg
- Tablets, oral pioglitazone hydrochloride 30 mg (as base)/glimepiride 4 mg

Pharmacology

Pioglitazone

Increases insulin sensitivity; inhibits hepatic gluconeogenesis.

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Glimepiride

Stimulates insulin release from the pancreas; increases sensitivity to insulin.

Indications and Usage

Adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus who are already treated with a thiazolidinedione (eg, pioglitazone) plus a sulfonylurea or who have inadequate glycemic control on a thiazolidinedione or sulfonylurea alone.

Contraindications

Diabetic ketoacidosis with or without coma; hypersensitivity to any component of the product; patients with established New York Heart Association (NYHA) class III or IV heart failure.

Dosage and Administration

Elderly, Debilitated, or Malnourished Patients, or Patients With Renal or Hepatic Function Impairment

The initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. The initial dose should be started at glimepiride 1 mg prior to prescribing pioglitazone/glimepiride.

Patients Currently on Glimepiride Monotherapy
Adults

PO Titrate the dose based on individual response to each component as monotherapy. Based on the usual starting dose of pioglitazone (15 or 30 mg daily), treatment may be started at 30 mg/2 mg or 30 mg/4 mg once daily and adjusted after assessing adequacy of therapeutic response.

Patients Currently on Pioglitazone Monotherapy
Adults

PO Titrate the dose based on individual response to each component as monotherapy. Based on the usual starting dose of glimepiride (1 or 2 mg daily) and pioglitazone 15 or 30 mg, treatment may be started at 30 mg/2 mg once daily and adjusted after assessing adequacy of therapeutic response.

Patients Switching From Combination Therapy of Pioglitazone Plus Glimepiride as Separate Tablets
Adults

PO Treatment may be started at 30 mg/2 mg or 30 mg/4 mg once daily based on the dose of pioglitazone and glimepiride already being taken.

Patients Currently on a Different Sulfonylurea Monotherapy or Switching From Combination Therapy of Pioglitazone Plus a Different Sulfonylurea
Adults

PO Based on the max starting dose of glimepiride 2 mg, treatment may be started at 30 mg/2 mg once daily and adjusted after assessing the adequacy of therapeutic response.

General Advice

• The max recommended daily dose of pioglitazone and glimepiride is 45 and 8 mg, respectively.
• Do not give more than once daily at any of the tablet strengths.
• Administer once daily with the first main meal.

Storage/Stability

Store between 59° and 86°F. Protect from moisture and humidity.

Drug Interactions

ACE inhibitors (eg, enalapril)

The risk of hypoglycemia may be increased. Closely monitor glycemic control when these agents are started or stopped.

Alcohol

Alcohol inhibits gluconeogenesis, so hypoglycemia may occur whenever gluconeogenesis is required to maintain glucose levels. Avoid coadministration.

Aspirin

Aspirin may decrease the glimepiride AUC. Blood glucose and C-peptide concentrations appear to be unaffected and no hypoglycemic symptoms are noted.

Atorvastatin

Coadministration of pioglitazone and atorvastatin may decrease pioglitazone and atorvastatin serum concentrations.

Azole antifungal agents (eg, ketoconazole), trimethoprim

Pioglitazone plasma levels may be elevated, increasing pharmacologic effect and adverse reactions. Monitor blood glucose and for clinical signs of hypoglycemia. Pioglitazone dosage reduction may be needed.

Bosentan

Toxic effects may be increased with coadministration. In addition, the risk for liver enzyme elevations may be increased. Coadministration is contraindicated.

Ciprofloxacin, gatifloxacin

Severe and persistent hypoglycemia may occur. Closely monitor for signs and symptoms of hypoglycemia.

Clofibrate

Plasma concentrations of glimepiride may be elevated, increasing the hypoglycemic effect. Closely monitor for hypoglycemia.

Contraceptives, hormonal

Ethinyl estradiol levels may be decreased slightly by pioglitazone; however, the clinical importance of this interaction has not been established.

Drugs that may potentiate the hypoglycemic action of sulfonylureas (eg, glimepiride), such as chloramphenicol, MAOIs, NSAIDs, probenecid, salicylates, and sulfonamides

Closely monitor glycemic control when these agents are started, stopped, or coadministered with glimepiride.

Drugs that tend to produce hyperglycemia (eg, beta-blockers [eg, propranolol], corticosteroids, diazoxide, estrogens, isoniazid, phenothiazines, phenytoin, sympathomimetics, thiazide diuretics, thyroid products)

Closely monitor glycemic control when these agents are started, stopped, or coadministered with glimepiride. Because some signs and symptoms of hypoglycemia may be attenuated in patients receiving beta-blockers, hypoglycemia may be difficult to recognize.

Inducers of CYP2C8 (eg, rifampin)

May decrease pioglitazone exposure, reducing the pharmacologic effect. Closely monitor glycemic control when these agents are started or stopped.

Inhibitors of CYP2C8 (eg, gemfibrozil, trimethoprim)

May increase pioglitazone exposure, increasing the pharmacologic effect and adverse reactions. Closely monitor glycemic control when these agents are started or stopped.

Insulin

Incidence of edema may be increased, even after several months of combined therapy.

Miconazole

Severe hypoglycemia has been reported when oral hypoglycemic agents are coadministered with oral miconazole. Whether this interaction occurs with IV, topical, or vaginal miconazole preparations is not known.

Midazolam

Midazolam plasma levels may be reduced, decreasing the efficacy. Monitor the clinical response and adjust the midazolam dose as needed.

Nifedipine ER

Concurrent use of pioglitazone and nifedipine ER may result in a decrease in nifedipine concentrations. The clinical importance is unknown.

Rifamycins (eg, rifampin)

Glimepiride or pioglitazone plasma levels may be reduced, decreasing glycemic control. Close clinical and laboratory monitoring for signs of hypoglycemia is warranted, especially when a rifamycin is added to pioglitazone/glimepiride.

Warfarin

Coadministration of glimepiride and warfarin may result in a slight, but statistically significant, decrease in the pharmacodynamic response to warfarin. The magnitude of this change is unlikely to be clinically important. However, pioglitazone may increase or decrease the anticoagulant effect of warfarin. Closely monitor anticoagulant activity and adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

CHF (postmarketing).

CNS

Headache (7%).

EENT

Macular edema with blurred vision or decreased visual acuity (postmarketing).

GI

Diarrhea (6%); nausea (5%).

Genitourinary

UTI (7%).

Hematologic

Anemia; hemolytic anemia (postmarketing).

Hepatic

Hepatic enzyme elevations, hepatitis (postmarketing).

Musculoskeletal

Increased incidence of bone fractures in women (postmarketing).

Metabolic-Nutritional

Hypoglycemia (16%); weight gain (13%).

Respiratory

Upper respiratory tract infection (15%).

Miscellaneous

Lower limb edema (12%); limb pain (5%); edema and worsening of edema (postmarketing).

Precautions

Warnings Pioglitazone may cause or exacerbate CHF. Carefully observe patients for signs and symptoms of heart failure. Not recommended for use in patients with symptomatic heart failure.

Monitor Monitor liver enzymes prior to the initiation of therapy and periodically thereafter; periodically perform fasting blood glucose and HbA 1c measurements to monitor glycemic control and therapeutic response. Observe patients for signs and symptoms of heart failure (eg, excessive rapid weight gain, dyspnea, edema). Assess bone health. Perform eye exams regularly. Observe patients carefully for hypoglycemia (for 1 to 2 wk) after initiation of the therapy.

Pregnancy

Category C . Not recommended for use during pregnancy.

Lactation

Undetermined. Not recommended for use during breast-feeding.

Children

Safety and efficacy not established.

Elderly

Use with caution.

Renal Function

Start with glimepiride 1 mg in patients with renal function impairment.

Hepatic Function

Do not initiate therapy in patients with clinical evidence of active liver disease or if the ALT levels exceed 2.5 times the ULN. Use caution in mildly elevated liver enzymes.

Bladder cancer

Do not use in patients with active bladder cancer.

CV

Oral hypoglycemic agents have been associated with increased CV mortality compared with diet alone or diet plus insulin.

Edema

Use with caution; can cause fluid retention.

Fractures

An increased incidence of bone fracture was noted in women taking pioglitazone.

G6PD

Use with caution in patients with G6PD deficiency.

Hematologic

Decreases in Hgb (2% to 4%) have been reported in patients receiving pioglitazone. Hemolytic anemia has been reported with sulfonylurea agents.

Hypoglycemia

The risk of hypoglycemia increases when used with other oral hypoglycemic agents or insulin; reduction in the dose of the concomitant agent may be necessary. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.

Loss of glucose control

Exposure to stress, such as fever, trauma, infection, or surgery, may result in loss of blood glucose control.

Macular edema

Patients with diabetes should have regular eye exams by an ophthalmologist.

Ovulation

May result in ovulation in premenopausal, anovulatory women; adequate contraception is recommended.

Type 1 diabetes

Do not use in these patients.

Weight gain

Dose-related weight gain has been seen alone and in combination with other hypoglycemic agents.

Overdosage

Symptoms

Glimepiride

Coma, seizures, or other neurological impairment; hypoglycemia; loss of consciousness.

Patient Information

• Advise patients to read the Medication Guide before starting therapy and with each refill.
• Instruct patients to take this medication once daily with the first main meal.
• Instruct patients in signs, symptoms, and treatment of hypoglycemic reaction.
• Review dietary and exercise guidelines for diabetes with patients.
• Instruct patients to promptly seek medical advice during periods of stress, such as fever, trauma, infection, or surgery, because medication requirements may change.
• Instruct patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure to immediately report these symptoms to their health care provider.
• Instruct patients to seek immediate medical advice for abdominal pain, anorexia, dark urine, fatigue, unexplained nausea, or vomiting.
• Caution women that resumption of ovulation may occur in premenopausal, anovulatory women. Address adequate contraceptive measures.
• Advise patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.

Copyright © 2009 Wolters Kluwer Health.