Professional Information

Pioglitazone Hydrochloride / Glimepiride

Pronouncation: (PYE-oh-GLI-ta-zone HYE-droe-KLOR-ide/glye-MEP-i-ride)
Class: Antidiabetic combination

Trade Names:
Duetact
- Tablets pioglitazone hydrochloride 30 mg (as base)/glimepiride 2 mg
- Tablets pioglitazone hydrochloride 30 mg (as base)/glimepiride 4 mg

Pharmacology

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Pioglitazone

Increases insulin sensitivity; inhibits hepatic gluconeogenesis.

Glimepiride

Stimulates insulin release from the pancreas; may decrease hepatic glucose production; increases sensitivity to insulin.

Indications and Usage

Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are already treated with pioglitazone plus a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or patients who have initially responded to pioglitazone alone and require additional glycemic control.

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

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 adequacy of therapeutic response.

General Advice

The max recommended daily dose of pioglitazone and glimepiride is 45 and 8 mg, respectively.

Storage/Stability

Store at 59° to 86°F. Keep container tightly closed. Protect from moisture and humidity.

Drug Interactions

Azole antifungal agents (eg, ketoconazole), trimethoprim

Pioglitazone plasma levels may be elevated, increasing pharmacologic effect and adverse reactions.

Beta-blockers (eg, propranolol)

Glimepiride plasma levels may be elevated, increasing the pharmacologic effect and adverse reactions. Because some signs and symptoms of hypoglycemia may be attenuated, hypoglycemia may be difficult to recognize.

Certain drugs tend to produce hyperglycemia (eg, corticosteroids, estrogens, isoniazid, phenothiazines, phenytoin, sympathomimetics, thiazide diuretics, thyroid products)

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

Ciprofloxacin, gatifloxacin

Severe and persistent hypoglycemia may occur.

Contraceptives, hormonal

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

Fluconazole, fluvoxamine, gemfibrozil, miconazole

Glimepiride plasma levels may be elevated, increasing the pharmacologic effect and adverse reactions.

Hypoglycemic action of sulfonylureas (eg, glimepiride) may be potentiated by certain drugs (eg, chloramphenicol, MAOIs, NSAIDs, probenecid, salicylates, sulfonamides)

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

Inducers of CYP2C8 (eg, rifampin)

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

Inhibitors of CYP2C8 (eg, gemfibrozil)

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.

Midazolam

Midazolam plasma levels may be reduced, decreasing the efficacy.

Rifamycins (eg, rifampin)

Glimepiride or pioglitazone plasma levels may be reduced, decreasing glycemic control.

Laboratory Test Interactions

Pioglitazone may reduce mean Hgb values by 2% to 4%, usually in first 4 to 12 wk of therapy, then stabilize thereafter; not associated with hematologic clinical reactions.

Adverse Reactions

Cardiovascular

CHF (postmarketing).

CNS

Headache (7%); asthenia, dizziness (2%).

EENT

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

GI

Diarrhea (6%); nausea, tooth disorder (5%).

Genitourinary

UTI (7%).

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

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 symptoms of heart failure.

Monitor

Monitor liver enzymes prior to the initiation of therapy and periodically thereafter; periodically perform fasting blood glucose and hemoglobin A _1c measurements to monitor glycemic control and therapeutic response.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Because elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering agents, the initial dosing, dose increment, and maintenance dosage should be conservative and based upon blood glucose levels prior to and after initiation of treatment.

Renal Function

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

Hepatic Function

Start with glimepiride 1 mg in patients with hepatic function impairment. Do not initiate therapy in patients with clinical evidence of active liver disease or increased serum transaminase levels at the start of therapy.

Special Risk Patients

Start with glimepiride 1 mg in elderly, debilitated, or malnourished patients, or in patients with renal or hepatic function impairment. In patients with systolic dysfunction, initiate therapy only after titration of pioglitazone 15 to 30 mg has been safely tolerated. If subsequent dose adjustment is needed, carefully monitor for weight gain, edema, or signs and symptoms of CHF exacerbation.

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 female patients taking pioglitazone.

Hematologic

Decreases in hemaglobin (2% to 4%) have been reported in patients receiving pioglitazone.

Hypoglycemia

Risk of hypoglycemia increases when used with other oral hypoglycemic agents or insulin; reduction in dose of concomitant agent may be necessary.

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

Instruct patient in signs, symptoms, and treatment of hypoglycemic reaction.
Review dietary and exercise guidelines for diabetes with patient.
Instruct patient 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 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.
Instruct patient to take this medication once daily with the first main meal.