GEODON Powder for solution for injection Ref.[51057] Active ingredients: Ziprasidone

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 section 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

The safety and efficacy of ziprasidone intramuscular injection has not been evaluated in children and adolescents.

Elderly (>65 years)

Elderly patients have not been included in clinical trials in sufficient numbers. Thus, no recommendations as regards dosing could be given and intramuscular treatment in these patients is not recommended.

Neuroleptic malignant syndrome (NMS)

NMS is a rare but potentially fatal complex that has been reported in association with other 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 reactions occur.

Cardiovascular disease

Patients with cardiovascular disease have not been included in the clinical trials in sufficient numbers. Thus, the safe use of the intramuscular product has not been established (see section 4.3).

Blood pressure

Dizziness, tachycardia and postural hypotension are not unusual in patients following intramuscular administration of ziprasidone. Single cases of hypertension have also been reported. Caution should be exercised, particularly in ambulatory patients.

Tardive dyskinesia

There is a potential for ziprasidone to cause tardive dyskinesia and other tardive extrapyramidal syndromes after longterm treatment. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of ziprasidone should be considered.

Seizures

Caution is advised 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 section 4.2 and 5.2).

Increased risk of cerebrovascular accidents in the dementia population

An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebocontrolled 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 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.

Post-marketing Reports of Mortality

As with other IM antipsychotics, fatalities with the use of ziprasidone IM, generally in patients with multiple confounding risk factors, have been reported. Although a causal relationship has not been established, ziprasidone IM should be used with caution.

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).

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

All interaction studies have been conducted with oral ziprasidone.

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.

Effects of other medicinal products on ziprasidone

The CYP3A4 inhibitor ketoconazole (400mg/day) increased the serum concentrations of ziprasidone by <40%. The serum concentrations of S-methyl-dihydroziprasidone 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.

Carbamazepine therapy, 200mg 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 ziprasidone under 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 with ziprasidone 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. Women of child bearing potential should therefore be using an appropriate method of contraception. As human experience is limited, administration of ziprasidone is not recommended during pregnancy unless the expected benefit to mother outweighs the potential risk to the foetus.

Antipsychotic class labelling

Neonates exposed to antipsychotics 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.

Breast-feeding

It is not known whether ziprasidone is excreted in breast milk. Patients should not breast feed if they are receiving ziprasidone. If treatment is necessary, breast-feeding should be discontinued.

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.

Ziprasidone intramuscular

The table below contains adverse events with possible, probable or unknown relationship to ziprasidone in phase ⅔ trials. The most common reactions were nausea, sedation, dizziness, injection site pain, headache and somnolence. Additional reactions reported from the post-marketing experience are included as Frequency ‘Not known’ in italics in the list below.

All adverse 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).

The adverse reactions listed below may also be associated with the underlying disease and/or concomitant medications.

^* frequency estimated from three post-marketing open-label controlled clinical trials

The most common cardiovascular adverse events reported from fixed dose clinical trials with intramuscular ziprasidone were: dizziness (10mg – 11%, 20mg – 12%), tachycardia (10mg – 4%, 20mg – 4%) and postural dizziness (10mg – 2%, 20mg – 2%), orthostatic hypotension, 20mg – 5%) and hypotension (10mg – 2%).

In premarketing fixed dose clinical trials with ziprasidone intramuscular injection, increased blood pressure and hypertension were observed in 2.2% of patients receiving 10 mg and increased blood pressure was observed in 2.8% of patients receiving 20 mg.

Ziprasidone capsules

Oral ziprasidone has been administered in clinical trials (see section 5.1) to approximately 6500 subjects. The most common adverse reactions in schizophrenia clinical trials were sedation and akathisia. In bipolar mania clinical trials, the most common adverse reactions were sedation, akathisia, extrapyramidal disorder and dizziness.

The table below contains adverse events based on combined short term (4-6 week), fixed dose, schizophrenia studies and short term (3 week), flexible dose, bipolar mania studies with a probable or possible relationship to treatment with ziprasidone and which occur at an incidence greater than placebo. Additional reactions reported from the postmarketing experience are included as Frequency ‘Not known’ in italics in the list below.

All adverse 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).

The adverse reactions listed below may also be associated with the underlying disease and/or concomitant medications.

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) of ECG 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.

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, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie

This medicinal product must not be mixed with other medicinal products or solvents except Water for Injections mentioned in Section 6.6.