Ziprasidone intramuscular

Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using ziprasidone in combination with other drugs have been evaluated as described below. All interactions studies have been conducted with oral ziprasidone. Based upon the pharmacodynamic and pharmacokinetic profile of ziprasidone, possible interactions could be anticipated: Ziprasidone should not be used in combination with other drugs that have demonstrated QT prolongation. ( 4.1 , 7.3 ) The full prescribing information contains additional drug interactions. ( 7 )

7.1 Metabolic Pathway Approximately two-thirds of ziprasidone is metabolized via a combination of chemical reduction by glutathione and enzymatic reduction by aldehyde oxidase. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase. Less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation.

7.2 In Vitro Studies An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. There is little potential for drug interactions with ziprasidone due to displacement [see Clinical Pharmacology (12.3) ] .

7.3 Pharmacodynamic Interactions • Ziprasidone should not be used with any drug that prolongs the QT interval [ see Contraindications (4.1) ]. • Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs. • Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain antihypertensive agents. • Ziprasidone may antagonize the effects of levodopa and dopamine agonists. • Risk of serotonin syndrome with concomitant therapy with other serotonergic drugs such as SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St.

John’s Wort [ see Contraindications (4.3), Warnings and Precautions (5.4), Adverse Reactions (6.2 )].

7.4 Pharmacokinetic Interactions Carbamazepine Carbamazepine is an inducer of CYP3A4; administration of 200 mg twice daily for 21 days resulted in a decrease of approximately 35% in the AUC of ziprasidone. This effect may be greater when higher doses of carbamazepine are administered. Ketoconazole Ketoconazole, a potent inhibitor of CYP3A4, at a dose of 400 mg QD for 5 days, increased the AUC and C max of ziprasidone by about 35–40%. Other inhibitors of CYP3A4 would be expected to have similar effects. Cimetidine Cimetidine at a dose of 800 mg QD for 2 days did not affect ziprasidone pharmacokinetics.

Antacid The co-administration of 30 mL of Maalox ® with ziprasidone did not affect the pharmacokinetics of ziprasidone.

7.5 Lithium Ziprasidone at a dose of 40 mg twice daily administered concomitantly with lithium at a dose of 450 mg twice daily for 7 days did not affect the steady-state level or renal clearance of lithium. Ziprasidone dosed adjunctively to lithium in a maintenance trial of bipolar patients did not affect mean therapeutic lithium levels.

7.6 Oral Contraceptives In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of estrogen or progesterone components. Ziprasidone at a dose of 20 mg twice daily did not affect the pharmacokinetics of concomitantly administered oral contraceptives, ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg).

7.7 Dextromethorphan Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite, dextrorphan. There was no statistically significant change in the urinary dextromethorphan/dextrorphan ratio.

7.8 Valproate A pharmacokinetic interaction of ziprasidone with valproate is unlikely due to the lack of common metabolic pathways for the two drugs. Ziprasidone dosed adjunctively to valproate in a maintenance trial of bipolar patients did not affect mean therapeutic valproate levels.

7.9 Other Concomitant Drug Therapy Population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials has not revealed evidence of any clinically significant pharmacokinetic interactions with benztropine, propranolol, or lorazepam.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ziprasidone mesylate for injection, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary Neonates exposed to antipsychotic drugs, including ziprasidone mesylate for injection, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ). Overall available data from published epidemiologic studies of pregnant women exposed to ziprasidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ziprasidone mesylate for injection, during pregnancy (see Clinical Considerations ).

In animal studies, ziprasidone administration to pregnant rats and rabbits during organogenesis caused developmental toxicity at doses similar to recommended human doses, and was teratogenic in rabbits at 3 times the maximum recommended human dose (MRHD). Rats exposed to ziprasidone during gestation and lactation exhibited increased perinatal pup mortality and delayed neurobehavioral and functional development of offspring at doses less than or similar to human therapeutic doses ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal risk There is risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor,…