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Class IA and III Antiarrhythmic Drugs (See Contraindications and QT Interval under Precautions).
Concomitant use with other drugs that prolong QT Interval (See QT Interval under Precautions).
CNS Drugs/Alcohol (See CNS Drugs/Alcohol under Precautions).
Effect of Ziprasidone on Other Drugs: Using human liver microsomes, ziprasidone demonstrated no inhibitory effect on CYP1A2, CYP2C9 or CYP2C19. The concentration of ziprasidone required to inhibit CYP2D6 and CYP3A4 in vitro is at least 1000-fold higher than the free concentration that can be expected in vivo.
Dextromethorphan - Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not alter the CYP2D6 mediated metabolism of dextromethorphan to its major metabolite, dextrorphan.
Oral Contraceptives - Ziprasidone administration results in no significant change to the pharmacokinetics of estrogen (ethinyl estradiol, a CYP3A4 substrate) or progesterone components.
Lithium - Co-administration of ziprasidone has no effect on the pharmacokinetics of lithium.
Protein binding - Ziprasidone extensively binds to plasma proteins. The in vitro plasma protein binding of ziprasidone was not altered by warfarin or propranolol, two highly protein-bound drugs, nor did ziprasidone alter the binding of these drugs in human plasma. Thus, the potential for drug interactions with ziprasidone due to displacement is unlikely.
Effects of Other Drugs on Ziprasidone: In vitro and animal data suggest that ziprasidone may be a P-glycoprotein (P-gp) substrate. The in vivo relevance for humans remains unknown.
Ketoconazole (400 mg/day), a potent inhibitor of CYP3A4, which also inhibits P-gp, produced an increase of approximately 35% in ziprasidone exposure (AUC and Cmax). Since ziprasidone is a substrate of CYP3A4 and induction of CYP3A4 and P-gp is related, co-administration with inducers of CYP3A4 and P-gp, such as carbamazepine, rifampin and St. John's Wort could cause decreased concentrations of ziprasidone. Carbamazepine 200 mg twice daily, an inducer of CYP3A4, produced a decrease of 36% in ziprasidone exposure.
Cimetidine, a nonspecific CYP inhibitor, did not significantly affect ziprasidone pharmacokinetics.
Antacid - Multiple doses of aluminium- and magnesium-containing antacids did not affect the pharmacokinetics of ziprasidone.
