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4.5 Interactions with Other Medicinal Products and Other Forms of Interaction
Class IA and III Antiarrhythmic Drugs - see Section 4.3 Contraindications and Section 4.4 Special Warnings and Precautions for Use, QT Interval.

Concomitant Use with Other Drugs that Prolong QT Interval - see Section 4.4 Special Warnings and Precautions for Use, OT Interval.
 

CNS Drugs/Alcohol - see Section 4.4 Special Warnings and Precautions for Use, CNS Drugs/ Alcohol.

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. Ziprasidone is unlikely to cause clinically important drug interactions mediated by these enzymes.

Dextromethorphan - Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not after 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 after 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
Ziprasidone is metabolized by aldehyde oxidase and to a lesser extent by CYP3A4. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase.

Ketoconazole (400 mg/day), a potent inhibitor of CYP3A4, produced an increase of approximately 35% in ziprasidone exposure (AUC and Cmax). These changes produced by ketoconazole are unlikely to be clinically relevant.

Carbamazepine 200 mg twice daily, an inducer of CYP3A4, produced a decrease of 36% in ziprasidone exposure. These changes produced by carbamazepine are unlikely to be clinically relevant.

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.

Benztropine, Propranolol, Lorazepam - Pharmacokinetic evaluation of ziprasidone serum concentrations of patients in clinical trials has not revealed any evidence of clinically significant interactions with benztropine, propranolol or lorazepam.

4.6 Pregnancy and Lactation
Reproductive toxicity studies with oral ziprasidone have not shown adverse effects on the reproductive process, other than those secondary to maternal toxicity resulting from an exaggerated pharmacological effect at doses equal to or greater than 17.5 times the maximum recommended human dose (MRHD). There was no evidence of teratogenicity at any dose level (see Section 5.3 Preclinical Safety Data).

Use in Pregnancy
No studies have been conducted in pregnant women. Women of childbearing potential receiving ziprasidone should therefore be advised to use an appropriate method of contraception. As human experience is limited, administration of ziprasidone is not recommended during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus (see Section 5.3 Preclinical Safety Data).

Use in Lactation
It is not known whether ziprasidone is excreted in breast milk. Patients should be advised not to breastfeed an infant If they are receiving ziprasidone.

4.7 Effects on Ability to Drive and Use Machines
As with other psychoactive drugs, ziprasidone may cause somnolence, Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ziprasidone does not affect them adversely.

4.8 Undesirable Effects
Schizophrenia
The following table includes treatment-related adverse events occurring at a frequency of a 1 % and greater than placebo in ziprasidone short-term placebo-controlled schizophrenia trials.

Table 1: Treatment-related Adverse Events Occurring at a Frequency of a 1 % with Ziprasidone in Short-Term Placebo-Controlled Schizophrenia Trials

¹ Frequencies are categorized as follows : Very common ≥10%; common ≥1% and < 10%
 

The incidence of seizures was rare, occurring in less than 1 % of ziprasidone-treated patients.
In double-blind active-controlled clinical trials, the Movement Disorder Burden Scale, a composite measure of extrapyramidal symptoms, was statistically significant (p s 0.05) in favor of ziprasidone versus haloperidol and risperidone. Comparable changes were seen in the Simpson Angus and Barnes akathisia scales for ziprasidone and placebo-treated patients. In addition, the reported incidence of akathisia and use of anticholinergic drugs was greater in the haloperidol-and risperidonetreated patients relative to ziprasidone.

A low incidence of body-weight gain and loss has been reported during clinical trials.

There were only transient prolactin increases seen during chronic dosing with ziprasidone.

In a 52-week placebo-controlled clinical trial, the rate of discontinuations due to adverse events was similar in patients treated with ziprasidone to patients treated with placebo.

Bipolar Mania
The following table includes treatment-related adverse events occurring at a frequency of a ≥5% and greater than placebo in ziprasidone short-term placebo-controlled bipolar mania trials.
 

Table 2: Treatment-related Adverse Events Occurring at a Frequency of a ≥5% with Ziprasidone in Short-Term Placebo Controlled Bipolar Mania Trials

¹ Frequencies are categorized as follows : Very common ≥10%; common ≥1% and < 10%

The following adverse reactions have been reported during post-marketing experience:

Immune System Disorders: Allergic reaction, anaphylactic reaction
Cardiac Disorders: Tachycardia, torsade de pointes (see Section 4.4 Special Warnings and Precautions for Use)
Nervous System Disorders: Facial droop; neuroleptic malignant syndrome; serotonin syndrome (alone or in combination with serotonergic medicinal products); tardive dyskinesia

Psychiatric Disorders: Insomnia, mania/hypomania
Reproductive System and Breast Disorders: Galactorrhea, priapism
Skin and Subcutaneous Tissue Disorders: Angiodema, rash, hypersensitivity

Vascular Disorders: Postural hypotension, syncope

Gastrointestinal Disorders: Dysphagia, swollen tongue

Renal and Urinary Disorders: Enuresis, urinary incontinence

4.9 Overdose
Experience with ziprasidone overdosage is limited. The largest confirmed single ingestion is 12,800 mg. In this case, extrapyramidal symptoms and a QTc interval of 446 msec (with no cardiac sequelae) were reported. In overdose cases in general, the most commonly reported symptoms are extrapyramidal symptoms, somnolence, tremor, and anxiety.

In cases of suspected overdose, the possibility of multiple drug involvement should be considered. There is no specific antidote to ziprasidone. In cases of acute overdosage, establish and maintain an airway and ensure adequate ventilation and oxygenation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal, together with a laxative, should be considered. The possibility of obtundation, seizures 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. Given the high protein binding of ziprasidone, hemodialysis is unlikely to be beneficial in the treatment of overdose. Close medical monitoring and supervision should continue until the patient recovers.

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