Indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM). Pioglitazone HCl is indicated for monotherapy. ioglitazone HCl is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet

and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.

Pioglitazone HCl exerts its antihyperglycemic effect only in the presence of insulin. Therefore, pioglitazone HCl should not be used in ... click here to view more

contraindicated in patients with known hypersensitivity to this product or any of its components

In worldwide clinical trials, over 3700 patients with type 2 diabetes have been treated with pioglitazone HCl. In U.S. clinical trials, over 2500 patients have received pioglitazone HCl, over 1100 patients have been treated for 6 months or longer, and over 450 patients for one year or longer.

The types of clinical adverse events reported when pioglitazone HCl was used in combination with sulfonylureas (N = 373), metformin (N = 168), or insulin (N = 379) were generally similar to those reported during pioglitazone HCl monotherapy with the exception of an increase in the occurrence of edema in the insulin combination study (pioglitazone 15% and placebo 7%). The incidence of withdrawals from clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or pioglitazone HCl (3.3%).
Mild to moderate hypoglycemia was reported during combination therapy with sulfonylurea or insulin. Hypoglycemia was reported for 1% of placebo-treated patients and 2% of patients when pioglitazone HCl was used in combination with a sulfonylurea. In combination with insulin, hypoglycemia was reported for 5% of placebo-treated patients, 8% for patients treated with 15 mg of pioglitazone HCl, and 15% for patients treated with 30 mg of pioglitazone HCl.
In U.S. double-blind studies, anemia was reported for 1.0% of pioglitazone HCl-treated patients and 0.0% of placebo-treated patients in monotherapy studies. Anemia was reported for 1.6% of pioglitazone HCl-treated patients and 1.6% of placebo-treated patients in combination with insulin. Anemia was reported for 0.3% of pioglitazone HCl-treated patients and 1.6% of placebo-treated patients in combination with sulfonylurea. Anemia was reported for 1.2% of pioglitazone HCl-treated patients and 0.0% of placebo-treated patients in combination with metformin.
In all U.S. clinical trials, edema was reported more frequently in pioglitazone HCl-treated patients than placebo-treated patients. In monotherapy studies, edema was reported for 4.8% of pioglitazone HCl-treated patients versus 1.2% of placebo-treated patients. Edema was reported most frequently in the insulin combination study (15.3% for pioglitazone HCl-treated patients versus 7.0% for placebo-treated patients). All events were considered mild or moderate in intensity.

Oral Contraceptives: Administration of another thiazolidinedione with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both hormones by approximately 30%, which could result in loss of contraception.

The pharmacokinetics of coadministration of pioglitazone HCl and oral contraceptives have not been evaluated in patients receiving pioglitazone HCl and an oral contraceptive. Therefore, additional caution regarding contraception should be exercised in patients receiving pioglitazone HCl and an oral contraceptive.
Glipizide: In healthy volunteers, coadministration of pioglitazone HCl (45 mg once daily) and glipizide (5.0 mg once daily) for seven days did not alter the steady-state pharmacokinetics of glipizide.
Digoxin: In healthy volunteers, coadministration of pioglitazone HCl (45 mg once daily) with digoxin (0.25 mg once daily) for seven days did not alter the steady-state pharmacokinetics of digoxin.
Warfarin: In healthy volunteers, coadministration of pioglitazone HCl (45 mg once daily) for seven days with warfarin did not alter the steady-state pharmacokinetics of warfarin. In addition, pioglitazone HCl has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy.
Metformin: In healthy volunteers, coadministration of metformin (1000 mg) and pioglitazone HCl (45 mg) after seven days of pioglitazone HCl (45 mg once daily) did not alter the pharmacokinetics of the single dose of metformin.
The cytochrome P450 isoform CYP3A4 is partially responsible for the metabolism of pioglitazone. Specific formal pharmacokinetic interaction studies have not been conducted with pioglitazone HCl and other drugs metabolized by this enzyme such as: erythromycin, astemizole, calcium channel blockers, cisapride, corticosteroids, cyclosporine, HMG-CoA reductase inhibitors, tacrolimus, trizolam, and trimetrexate, as well as inhibitory drugs such as ketoconazole and itraconazole. In vitro, ketoconazole appears to significantly inhibit the metabolism of pioglitazone. Pending the availability of additional data, patients receiving ketoconazole concomitantly with pioglitazone HCl should be evaluated more frequently with respect to glycemic control.

In the event of overdosage, appropriate supportive treatment should be initiated according to patient’s clinical signs and symptoms.

The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FBG alone. HbA1c reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with pioglitazone HCl for a period of time adequate to evaluate change in HbA1c (three months) unless glycemic control deteriorates.

Monotherapy
Pioglitazone HCl monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of pioglitazone HCl, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered.
Combination Therapy
Sulfonylureas: Pioglitazone HCl in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of pioglitazone HCl therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.
Metformin: Pioglitazone HCl in combination with metformin may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of pioglitazone HCl therapy. It is unlikely that the dose of metformin will require adjustment due to hypoglycemia during combination therapy with pioglitazone HCl.
Insulin: Pioglitazone HCl in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of pioglitazone HCl therapy. In patients receiving pioglitazone HCl and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dl. Further adjustments should be individualized based on glucose-lowering response.
Maximum Recommended Dose
The dose of pioglitazone HCl should not exceed 45 mg once daily since doses higher than 45 mg once daily have not been studied in placebo-controlled clinical studies. No placebo-controlled clinical studies of more than 30 mg once daily have been conducted in combination therapy.
Dose adjustment in patients with renal insufficiency is not recommended.
Therapy with pioglitazone HCl should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy. Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with pioglitazone HCl and periodically thereafter.

It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.

Patients should be told that blood tests for liver function will be performed prior to the start of therapy, every two months for the first year, and periodically thereafter. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine.Patients should be told to take pioglitazone HCl once daily. Pioglitazone HCl can be taken with or without meals. f a dose is missed on one day, the dose should not be doubled the following day.When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.In anovulatory, premenopausal women with insulin resistance, therapy with pioglitazone HCl may cause resumption of ovulation and contraceptive measures may need to be considered.