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. Therefore, additional caution regarding contraception should be exercised in patients receiving pioglitazone and an oral contraceptive.
Zolid: Ketoconazole: Ketoconazole inhibited up to 85% of hepatic pioglitazone metabolism in vitro at a concentration equal molar to pioglitazone. Pending the availability of additional data. Patients receiving ketoconazole concomitantly with pioglitazone should be evaluated more frequently with respect to glycemic control.
Drug-Drug Relationships: Glipizide: Co-administration of pioglitazone and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide.
Metformin: Co-administration of a single dose of metformin (1000 mg) and pioglitazone after 7 days of pioglitazone did not alter the pharmacokinetics of the single dose of metformin.
Midazolam: Administration of pioglitazone for 15 days followed by a single 7.5-mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.
Nifedipine ER: In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.
ZolidPlus: Pioglitazone: An enzyme inhibitor of CYP2C8 (eg, gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (eg, rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response.
Metformin HCl: Cationic Drugs: Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of ZolidPlus and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Furosemide: Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance.
Co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively and increased the amount excreted in the urine. Tmax and t½ were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Others: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid. When such drugs are administered to a patient receiving ZolidPlus, the patient should be closely observed to maintain adequate glycemic control.