GEODON Capsule, hard Ref.[8280] Active ingredients: Ziprasidone

A medical history, including assessment of family history, and physical examination should be undertaken to identify patients for whom ziprasidone treatment is not recommended (see section 4.3).

QT interval

Ziprasidone causes a mild to moderate dose-related prolongation of the QT-interval (see section 4.8 and 5.1).

Ziprasidone should not be given together with medicinal products that are known to prolong the QT-interval (see sections 4.3 and 4.5). 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.

If cardiac symptoms, such as palpitations, vertigo, syncope or seizures occur, then the possibility of a malignant cardiac arrhythmia should be considered and a cardiac evaluation including an ECG should be performed. If the QTc interval is >500 msec, then it is recommended that the treatment should be stopped (see section 4.3).

There have been rare post-marketing reports of torsade de pointes in patients with multiple confounding risk factors taking ziprasidone.

Paediatric population

Safety and efficacy of ziprasidone in the treatment of schizophrenia in children and adolescents have not been established (see Section 5.1).

Neuroleptic malignant syndrome (NMS)

NMS is a rare but potentially fatal complex that has been reported in association with antipsychotic medicinal products, including ziprasidone. The management of NMS should include immediate discontinuation of all antipsychotic medicinal products.

Severe Cutaneous Adverse Reactions

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with ziprasidone exposure. DRESS consists of a combination of three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis.

Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported with ziprasidone exposure.

Severe cutaneous adverse reactions are sometimes fatal. Discontinue ziprasidone if severe cutaneous adverse reactions occur.

Tardive dyskinesia

There is a potential for ziprasidone to cause tardive dyskinesia and other tardive extrapyramidal syndromes after long-term treatment. Patients with bipolar disorder are known to be particularly vulnerable to this category of symptoms. This is more frequent with increased duration of treatment and increasing age. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of ziprasidone should be considered.

Falls

Ziprasidone may cause somnolence, dizziness, postural hypotension, gait disturbance, which may lead to falls. Caution should be taken when treating patients at higher risk, and a lower starting dose should be considered (e.g. elderly or debilitated patients) (see section 4.2).

Seizures

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

Hepatic Impairment

There is a lack of experience in patients with severe hepatic insufficiency and ziprasidone should be used with caution in this group (see sections 4.2 and 5.2).

Medicinal products containing lactose

As the capsule contains the excipient lactose (see section 6.1), patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Increased risk of cerebrovascular accidents in the dementia population

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. Geodon should be used with caution in patients with risk factors for stroke.

Increased Mortality in Elderly people with Dementia

Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death and/or potentially, cerebrovascular adverse events compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Geodon is not licensed for the treatment of dementia-related behavioural disturbances.

Venous Thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with ziprasidone and preventive measures undertaken.

Priapism

Cases of priapism have been reported with antipsychotic use, including ziprasidone. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with the duration of treatment.

Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, ziprasidone may elevate prolactin levels. Disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density.

Pharmacokinetic and pharmacodynamic studies between ziprasidone and other medicinal products that prolong the QT interval have not been performed. An additive effect of ziprasidone and these medicinal products cannot be excluded, therefore ziprasidone should not be given with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, arsenic trioxide, halofantrine, levomethadyl acetate, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron mesilate, mefloquine, sertindole or cisapride (see section 4.3).

No studies on the interaction of ziprasidone with other medicinal products have been performed in children

CNS medicinal products/alcohol

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

Effect of ziprasidone on other medicinal products

An in vivo study with dextromethorphan showed no marked inhibition of CYP2D6 at plasma concentrations 50% lower than those obtained after 40 mg ziprasidone twice daily. In vitro data indicated that ziprasidone may be a modest inhibitor of CYP2D6 and CYP3A4. However, it is unlikely that ziprasidone will affect the pharmacokinetics of medicinal products metabolised by these cytochrome P450 isoforms to a clinically relevant extent.

Oral contraceptives – Ziprasidone administration resulted in no significant change to the pharmacokinetics of oestrogen (ethinyl oestradiol, a CYP3A4 substrate) or progesterone components.

Lithium – Co-administration of ziprasidone had no effect on the pharmacokinetics of lithium. As ziprasidone and lithium are associated with cardiac conduction changes, the combination may pose a risk for pharmacodynamic interactions including arrhythmias, however, in controlled clinical trials, the combination of ziprasidone plus lithium has not demonstrated an increased clinical risk, compared to lithium alone.

There are limited data on co-medication with the mood stabiliser carbamazepine. A pharmacokinetic interaction of ziprasidone with valproate is unlikely due to the lack of common metabolic pathways for the two drugs. In a study in patients, the co-administration of ziprasidone and valproate showed that the mean concentrations of valproate were within the therapeutic range as compared to valproate administered with placebo.

Effects of other medicinal products on ziprasidone

The CYP3A4 inhibitor ketoconazole (400 mg/day), which also inhibits p-gp, increased the serum concentrations of ziprasidone by <40%. The serum concentrations of S-methyldihydroziprasidone and ziprasidone sulphoxide, at the expected T_max of ziprasidone, were increased by 55% and 8% respectively. No additional QTc prolongation was observed. Changes in pharmacokinetics due to co-administration of potent CYP3A4 inhibitors are unlikely to be of clinical importance, therefore no dosage adjustment is required. 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.

Antacid – multiple doses of aluminium and magnesium containing antacid or cimetidine have no clinically significant effect on the pharmacokinetics of ziprasidoneunder fed conditions.

Serotonergic medicinal products

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 (see section 4.8). The features of serotonin syndrome can include confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea.

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.

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 (see section 5.3).

Pregnancy

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.

Breast-feeding

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.

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 ziprasidone has been administered in clinical trials (see section 5.1) 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 (see section 5.1). 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance. Website: www.hpra.ie.

Not applicable.