- (1) Ziprasidone should not be used with any drug that prolongs the QT interval (see CONTRAINDICATIONS).
- (2)Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs.
- (3)Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain antihypertensive agents.
- (4)Ziprasidone may antagonize the effects of levodopa and dopamine agonists.
The Effect of Other Drugs on Ziprasidone
Carbamazepine is an inducer of CYP3A4; administration of 200 mg BID 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, a potent inhibitor of CYP3A4, at a dose of 400 mg QD for 5 days, increased the AUC and Cmax of ziprasidone by about 3540%. Other inhibitors of CYP3A4 would be expected to have similar effects.
Cimetidine at a dose of 800 mg QD for 2 days did not affect ziprasidone pharmacokinetics.
The coadministration of 30 mL of Maalox® with ziprasidone did not affect the pharmacokinetics of ziprasidone.
In addition, 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.
In premarketing trials involving more than 5400 patients and/or normal subjects, accidental or intentional overdosage of oral ziprasidone was documented in 10 patients. All of these patients survived without sequelae. In the patient taking the largest confirmed amount, 3240 mg, the only symptoms reported were minimal sedation, slurring of speech, and transitory hypertension (200/95).
In post-marketing use, adverse events reported in association with ziprasidone overdose generally included extrapyramidal symptoms, somnolence, tremor, and anxiety.
Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Intravenous access should be established and gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizure, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects that might be additive to those of ziprasidone.
Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, epinephrine and dopamine should not be used, since beta stimulation combined with alpha1 antagonism associated with ziprasidone may worsen hypotension. Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of ziprasidone, resulting in problematic hypotension.
In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. There is no specific antidote to ziprasidone, and it is not dialyzable. The possibility of multiple drug involvement should be considered. Close medical supervision and monitoring should continue until the patient recovers.
Because of ziprasidone's dose-related prolongation of the QT interval and the known association of fatal arrhythmias with QT prolongation by some other drugs, ziprasidone is contraindicated in patients with a known history of QT prolongation (including congenital long QT syndrome), with recent acute myocardial infarction, or with uncompensated heart failure (see WARNINGS).
Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not been performed. An additive effect of ziprasidone and other drugs that prolong the QT interval cannot be excluded. Therefore, ziprasidone should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. Ziprasidone is also contraindicated with drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bolded warning (see WARNINGS).
Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Ziprasidone is not a controlled substance.
Physical and Psychological Dependence
Ziprasidone has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which ziprasidone will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ziprasidone misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).
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