Metformininteractions

Strong CYP2C8 inhibitors (e.g., gemfibrozil): Limit pioglitazone and metformin hydrochloride dose to 15 mg/850 mg daily. CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin. Consider the benefits and risks of concomitant use.

Alcohol: Warn patients against excessive alcohol intake. Use of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction. Topiramate may decrease pioglitazone concentrations.

7.1 Strong CYP2C8

Inhibitors An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t 1/2 ) of pioglitazone. Therefore, the maximum recommended dosage of pioglitazone and metformin hydrochloride is 15 mg of pioglitazone and 850 mg of metformin hydrochloride once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

7.2 CYP2C8 Inducers

An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone and metformin hydrochloride, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dosage of pioglitazone and metformin hydrochloride (45 mg of pioglitazone and 2,550 mg of metformin hydrochloride).

7.3 Carbonic

Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with pioglitazone and metformin hydrochloride may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

7.4 Drugs that

Reduce Metformin Clearance Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

7.5 Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride.

7.6 Insulin

Secretagogues or Insulin Coadministration of pioglitazone and metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. If hypoglycemia occurs in a patient coadministered pioglitazone and metformin hydrochloride and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

7.7 Drugs Affecting

Glycemic Control Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving pioglitazone and metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving pioglitazone and metformin hydrochloride, the patient should be observed closely for hypoglycemia. 7.8 Topiramate A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate. The clinical relevance of this decrease is unknown; however, when pioglitazone and metformin hydrochloride and topiramate are used concomitantly, monitor patients for adequate glycemic control.