CYP3A inhibitors : Combining ketoconazole increases the Cmax and AUC of tegretol by 2.4-fold and 7.3-fold, respectively, and decreases the Cmax and AUC of the active metabolite by 89% and 56%, respectively; other strong inhibitors of CYP3A4 can have similar effects. Combination of this product with potent inhibitors of CYP3A (ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin) should be avoided (see [Contraindications] and [Pharmacokinetics]).
CYP3A inducers: Combined use of rifampicin reduced Cmax and AUC of tegretol by 73% and 86%, respectively, and Cmax of active metabolites was unchanged and AUC was reduced by 46%. Other CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, and phenobarbital) are also expected to reduce exposure to tegretol. This product should be avoided in combination with strong CYP3A inducers.
Aspirin : When combined with maintenance doses of aspirin greater than 100 mg, it decreases the clinical efficacy of tegretol in reducing composite endpoint events. Other: Clinical pharmacologic interaction studies have shown no effect on PK, ADP-induced platelet aggregation of tegretol or its active metabolites when tegretol is combined with heparin, enoxaparin and aspirin or desmopressin compared to tegretol alone.
Effects of Tegretol on other drugs.
Tegretol is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.
Simvastatin, lovastatin: Because of metabolism via CYP3A4, tegretol can increase their serum concentrations. Tegretol increases Cmax by 81% and AUC by 56% for simvastatin and Cmax by 64% and AUC by 52% for simvastatin acid, increasing to 2-3 fold in some patients. Simvastatin had no effect on the plasma concentration of Tegretol. Tegretol may have a similar effect on lovastatin. In combination with Tegretol, simvastatin and lovastatin should not be administered at doses greater than 40 mg.
Atorvastatin: The combination of atorvastatin and tegretol increased the Cmax of atorvastatin acid by 23% and the AUC by 36%. Similar increases in AUC and Cmax were seen for all atorvastatin acid metabolites. Consider that these increases are not clinically significant.
Drugs metabolized via CYP2C9: The combination of tegretol and mebendazole showed no change in plasma concentrations of either drug, suggesting that tegretol is not an inhibitor of CYP2C9 and is unlikely to alter the metabolism of CYP2C9-mediated drugs (e.g., warfarin and mebendazole).
Oral contraceptives: Tegretol in combination with levonorgestrel and ethinyl estradiol increases exposure to ethinyl estradiol by approximately 20%, but does not alter the PK of levonorgestrel. tegretol is not expected to have a clinically meaningful effect on the effectiveness of oral contraceptives when combined with levonorgestrel and ethinyl estradiol.
Digoxin (P-gp substrate): The combination of tegretol and digoxin resulted in a 75% increase in Cmax and a 28% increase in AUC of the latter. Therefore, it is recommended that the combination of Tegretol with P-gp-dependent drugs with a narrow therapeutic index (e.g., digoxin, cyclosporine) be subjected to appropriate clinical and/or laboratory monitoring.
Combination therapy with other drugs.
Drugs known to induce bradycardia: Because of the observation of asymptomatic ventricular intervals and bradycardia, caution should be exercised when combining tegretol with drugs known to induce bradycardia.
In the PLATO study, tegretol was often used in combination with aspirin, proton pump inhibitors, statins, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers for the long-term treatment of concomitant disease and with heparin, low-molecular heparin, and intravenous GpIIb/IIIa inhibitors for the short-term treatment of concomitant disease. No clinically significant adverse effects associated with these drugs have been observed to occur. Coadministration of tegretol with heparin, enoxaparin, or desmopressin had no effect on activated partial thromboplastin time (aPTT), activated clotting time (ACT), or factor Xa content measurements. However, due to potential pharmacodynamic interactions, caution should be exercised when combining tegretol with drugs known to alter hemostasis.
Because bleeding abnormalities have been reported with SSRI therapy (e.g., paroxetine, sertraline, and citalopram), it is recommended that SSRIs should be combined with tegretol with caution and that the combination may increase the risk of bleeding.
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