Ziprasidone

Given the primary effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting medicinal products and alcohol.

In vitro and animal data suggest that ziprasidone may be a P-glycoprotein (p-gp) substrate. The in vivo relevance for humans remains unknown. 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 therapy, 200 mg b.i.d for 21 days, resulted in a decrease of approximately 35% in the exposure to ziprasidone.

In patients with hepatic insufficiency, lower doses should be considered.

There is a lack of experience in patients with severe hepatic insufficiency and ziprasidone should be used with caution in this group.

In isolated cases, there have been reports of serotonin syndrome temporally associated with the therapeutic use of ziprasidone in combination with other serotonergic medicinal products such as SSRIs. The features of serotonin syndrome can include confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea.

An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Ziprasidone should be used with caution in patients with risk factors for stroke.

Caution is advised in patients with significant bradycardia. Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for malignant arrhythmias and should be corrected before treatment with ziprasidone is started. If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.

Caution is recommended when treating patients with a history of seizures.

No studies have been conducted in pregnant women. 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 foetus.

Antipsychotic class labelling

Neonates exposed to antipsychotics (including ziprasidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. Geodon should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.

There are no adequate and well-controlled studies in lactating women. A single case report found that ziprasidone was detectable in breast milk. Patients should not breast feed an infant if they are taking ziprasidone. If treatment is necessary, breast-feeding should be discontinued.

Reproductive toxicity studies have shown undesirable effects on the reproductive process, at doses associated with maternal toxicity and/or sedation. There was no evidence of teratogenicity.

Fertility

There are no adequate and well-controlled studies in women and men exposed to ziprasidone.

Contraception

Women of childbearing potential receiving ziprasidone should be advised to use an appropriate method of contraception.

Ziprasidone may cause somnolence and may influence on the ability to drive and use machines. Patients likely to drive or operate machines should be cautioned appropriately.

Oral administration

Oral ziprasidone has been administered in clinical trials to approximately 6500 adult subjects. The most common adverse drug reactions in schizophrenia clinical trials were insomnia, somnolence, headache and agitation. In bipolar mania clinical trials, the most common adverse drug reactions were sedation, headache and somnolence.

The table below contains adverse drug reactions based on controlled schizophrenia and bipolar mania studies.

All adverse drug reactions are listed by class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

In short-term and long-term ziprasidone schizophrenia and bipolar mania clinical trials, the incidence of tonic clonic seizures and hypotension was uncommon, occurring in less than 1% of ziprasidone treated patients.

Ziprasidone causes a mild to moderate dose-related prolongation of the QT interval. In schizophrenia clinical trials, an increase of 30 to 60 msec was seen in 12.3% (976/7941)of ECG tracings from ziprasidone-treated and 7.5% (73/975) ofECG tracings from placebo-treated patients. A prolongation of >60 msec was seen in 1.6% (128/7941) and 1.2% (12/975) of tracings from ziprasidone and placebo-treated patients, respectively. The incidence of QTc interval prolongation above 500 msec was 3 in a total of 3266 (0.1%)in ziprasidone treated patients and 1 in a total of 538 (0.2%)in placebo treated patients.

Comparable findings were observed in bipolar mania clinical trials.

In long term maintenance treatment in schizophrenia clinical trials, prolactin levels in patients treated with ziprasidone were sometimes elevated, but, in most patients, returned to normal ranges without cessation of treatment. In addition, potential clinical manifestations (e.g. gynaecomastia and breast enlargement) were rare.

Paediatric population

In placebo-controlled bipolar disorder trials (ages 10-17 years), the most frequent adverse reactions (reported with a frequency >10%) were sedation, somnolence, headache, fatigue, nausea, dizziness, vomiting, decreased appetite and extrapyramidal disorder. In a placebo-controlled schizophrenia trial (ages 13-17 years), the most frequent adverse reactions (reported with a frequency >10%) were somnolence and extrapyramidal disorder. The paediatric safety profile of ziprasidone was generally similar to the adult profile. However high incidence of sedation and somnolence was observed in paediatric studies.

Ziprasidone was associated with a similar mild to moderate dose-related prolongation of the QT interval in paediatric clinical trials similar to that seen in the adult population. Tonic clonic seizures and hypotension were not reported in the placebo-controlled paediatric bipolar clinical trials.

IV administration

Clinical trials for intramuscular ziprasidone included 570 patients and/or normal subjects who received one or more injections of ziprasidone. Over 325 of these subjects participated in trials involving the administration of multiple doses.

Adverse reactions during exposure were obtained by collecting voluntarily reported adverse experiences, as well as results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.

Adverse Reactions Occurring at an Incidence of 1% or More Among Ziprasidone-Treated Patients in Short-Term Trials of Intramuscular Ziprasidone

The table below enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy with intramuscular ziprasidone in 1% or more of patients.

In these studies, the most commonly observed adverse reactions associated with the use of intramuscular ziprasidone (incidence of 5% or greater) and observed at a rate on intramuscular ziprasidone (in the higher dose groups) at least twice that of the lowest intramuscular ziprasidone group were headache (13%), nausea (12%), and somnolence (20%).

Treatment-Emergent Adverse Reaction Incidence In Short-Term Fixed-Dose Intramuscular Trials: