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Oral Contraceptives: Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (norethindrone 1 mg plus ethinyl estradiol 0.035 mg once daily) resulted in 11% and 11-14% decrease in ethinyl estradiol AUC and Cmax, respectively. Clinical significance of a high variability on ethinyl estradiol pharmacokinetics is unknown.
Insulin or Insulin Secretagogues: The dose of insulin and insulin secretagogues (eg, sulfonylurea) should be reduced since concomitant administration may result in hypoglycemia.
Midazolam: Administration of pioglitazone for 15 days followed by a 7.5 mg single dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.
Strong CYP2C8 Inhibitors: Gemfibrozil (an inhibitor of CYP450 2C8) resulted in a 3-fold increase in the plasma concentration of parent pioglitazone and also inhibited the further metabolism of M-III and M-IV. Careful blood glucose monitoring and dosage adjustments are suggested during co-administration of pioglitazone and gemfibrozil. If used in combination with gemfibrozil or other strong CYP2C8 inhibitors, a maximum dose of pioglitazone 15 mg should be used.
CYP2C8 Inducers: Co-administration of pioglitazone with rifampicin (an inducer of CYP450 2C8) resulted in a 54% reduction in pioglitazone's AUC. The dose of pioglitazone may need to be increased when rifampicin is co-administered and glycemic control closely monitored.
If an inducer of CYP2C8 is started or stopped during treatment with pioglitazone, the maximum recommended dose of 45 mg should not be exceeded and changes in diabetes treatment may be needed based on the patient's clinical response.
Drugs Metabolized via Cytochrome P-450: The cytochrome P-450 isoform, CYP3A4, is partially responsible for the metabolism of pioglitazone. Potential pharmacokinetic interaction (reduction in Cmax and AUC) with CYP3A4 substrates (eg, atorvastatin, nifedipine). Clinical significance of this finding is unknown.
Peak plasma concentration and area under the AUC of pioglitazone may increase when taken concomitantly with CYP3A4 inhibitors eg, ketoconazole. However, pharmacokinetic interaction is unlikely with ranitidine which is a relatively weak CYP3A4 inhibitor.
In vitro studies have shown no inhibition of any subtype of cytochrome P-450. Interactions with substances metabolized by these enzymes are unlikely: Ciclosporin, calcium channel blockers, and HMGCoA reductase inhibitors.
Co-administration of pioglitazone with the following drugs did not show pharmacokinetic interactions: Metformin, glipizide, digoxin, phenprocoumon, fexofenadine, CYP2C9 substrates (eg, warfarin), CYP1A2 substrates (eg, theophylline).
