Consumer medicine information

Ziprox Capsules

Ziprasidone

BRAND INFORMATION

Brand name

Ziprox

Active ingredient

Ziprasidone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ziprox Capsules.

SUMMARY CMI

ZIPROX Capsules

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ZIPROX?

ZIPROX contains the active ingredient ziprasidone hydrochloride. ZIPROX is used to treat schizophrenia and bipolar disorder

For more information, see Section 1. Why am I using ZIPROX? in the full CMI.

2. What should I know before I use ZIPROX?

Do not use if you have ever had an allergic reaction to ZIPROX or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ZIPROX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ZIPROX and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take ZIPROX?

  • The usual starting dose is one 40 mg capsule taken twice daily with food.
  • Take your capsule(s) with food so in the morning with breakfast and in the evening with your evening meal.

More instructions can be found in Section 4. How do I take ZIPROX? in the full CMI.

5. What should I know while using ZIPROX?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking ZIPROX.
  • Talk to your doctor or mental health professional if you have thoughts or talk about death, suicide or self-harm.
  • Check with your doctor if you are pregnant or intend to become pregnant.
  • Talk to your doctor if you are breastfeeding or intend to breastfeed.
Things you should not do
  • Do not stop taking ZIPROX or change the dosage, even if you feel better, without checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ZIPROX affects you.
  • ZIPROX may cause drowsiness and sleepiness in some people
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Combining ZIPROX and alcohol can make you more sleepy, dizzy or light-headed. Your doctor may suggest you avoid alcohol while you are being treated with ZIPROX.
Looking after your medicine
  • Keep the capsules in their pack until it is time to take them.
  • Keep ZIPROX in a cool, dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using ZIPROX? in the full CMI.

6. Are there any side effects?

Speak to your doctor immediately if you notice any of the following: any worm-like movements of the tongue; uncontrolled movements of the tongue, mouth, cheeks or jaw; any uncontrolled movements spreading to the arms and legs. Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of the following: convulsions, seizures; trembling and shaking of the hands and fingers; shuffling walk and stiffness of the arms and legs; sudden uncontrollable muscle spasms in the eyes, head, neck and body. This is not a complete list of all possible side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ZIPROX Capsules

Active ingredient(s): ziprasidone hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using ZIPROX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ZIPROX.

Where to find information in this leaflet:

1. Why am I using ZIPROX?
2. What should I know before I use ZIPROX?
3. What if I am taking other medicines?
4. How do I take ZIPROX?
5. What should I know while using ZIPROX?
6. Are there any side effects?
7. Product details

1. Why am I using ZIPROX?

ZIPROX contains the active ingredient ziprasidone hydrochloride. It belongs to a group of medicines called atypical antipsychotics/neuroleptics.

ZIPROX is used to treat schizophrenia and bipolar disorder.

Schizophrenia

Schizophrenia is a mental illness. It varies from person to person, but can involve:

  • hallucinations: the person sees, hears, feels, smells or tastes something that is not actually there; most commonly a person may hear voices
  • delusions: a delusion is a false belief held by a person which is not held by others of the same cultural background
  • disturbed or disorganised thinking
  • poor memory and concentration
  • loss of emotion and expression
  • loss of motivation and energy
  • difficulty interacting with others, leading to social isolation.

Bipolar disorder

Bipolar disorder is a mental illness where a person cycles through:

  • 'manic' phases - with symptoms such as over-activity, irritability, elation and limited need for sleep
  • 'depressive' phases - with symptoms such as depressed mood, anxiety, difficulty making decisions, difficulty concentrating and hopelessness.

How ZIPROX works

Schizophrenia

Researchers do not know exactly what causes schizophrenia, but they do know that many people with it have high levels of some brain chemicals - including dopamine and serotonin.

ZIPROX is thought to work by helping to correct the imbalance of these chemicals, in turn, reducing the symptoms of schizophrenia.

Research has found ZIPROX can help reduce:

  • hallucinations
  • delusions
  • confused thoughts
  • social withdrawal
  • lack of motivation.

ZIPROX does not cure schizophrenia, but it can help manage the symptoms and help prevent further episodes.

Taking antipsychotic/neuroleptic medicine like ZIPROX can also allow you to try psychological therapies when recommended by your doctor. These may further help you manage your schizophrenia.

Bipolar disorder

Research has shown that there is a chemical imbalance in the brain in patients with bipolar disorder.

ZIPROX does not cure bipolar disorder. It is used as a short-term treatment for the manic phases. It is not used to treat the depressive phases of bipolar disorder.

Controlling the manic phase of bipolar disorder with medicine can also allow you to try psychological therapies when recommended by your doctor

Elderly patients

ZIPROX is not recommended for the treatment of elderly patients with dementia-related psychosis.

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

Use in children

ZIPROX is not recommended for children under 18 years of age as there is not enough information on its effects in this age group

2. What should I know before I use ZIPROX?

Warnings

Do not use ZIPROX if:

  • you have or have had any of the following:
    - a recent heart attack
    - heart failure that is not well-controlled
    - a condition that may lengthen your heart rhythm
    - a condition requiring medication to control (lengthen or shorten) your heart rhythm.
  • you are taking any other medications known to lengthen your heart rhythm.
  • you are hypersensitive to, or have had an allergic reaction to, ZIPROX or any of the ingredients listed at the end of this leaflet.
  • You produce symptoms of an allergic reaction may include
    - cough, shortness of breath, wheezing or difficulty breathing.
    - swelling of the face, lips, tongue, throat or other parts of the body
    - rash, itching or hives on the skin
    - fainting
    - hayfever-like symptoms
  • you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • the expiry date (EXP) printed on the pack has passed.
  • the packaging is torn, shows signs of tampering or it does not look quite right.

Check with your doctor if you:

  • you have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  • you have or have had any other medical conditions
    - irregular heart rate
    - any heart or blood vessel problems
    - low blood levels of potassium or magnesium
    - a condition that may give you low blood pressure
    - seizures (fits)
    - liver problems
    - blood sugar level problems, e.g. diabetes
    - you are 65 years of age or over and have a condition known as 'dementia-related psychosis'
    - Neuroleptic Malignant Syndrome (NMS) - symptoms include sudden fever, fast breathing, blood pressure changes, sweating, confusion, muscle stiffness and drowsiness or sleepiness
    - Tardive Dyskinesia (TD) – symptoms include unusual movements (mainly of the face and tongue), or uncontrollable twitching or jerking of the arms and legs.
  • you are planning to have surgery or an anaesthetic.
  • you are currently receiving or are planning to receive dental treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Like most atypical antipsychotic/neuroleptic medicines, ZIPROX is not recommended for use during pregnancy.

For women of child-bearing age an appropriate method of contraception is recommended.

Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved

Babies exposed to antipsychotic drugs (including ZIPROX) during the third trimester of pregnancy are at risk of experiencing agitation, abnormal muscle tone, tremor, somnolence, breathing problems, difficulty in feeding and/or withdrawal symptoms after being born.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

ZIPROX is not recommended while you are breastfeeding. Do not take this medicine whilst breastfeeding until you and your doctor have discussed the risks and benefits involved. It is not known if it passes into breastmilk.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with ZIPROX and affect how it works.

Some medicines may interact with ZIPROX. These include:

  • lithium, a medicine used to treat bipolar disorders
  • medicines which act on the central nervous system (CNS), such as triptans, antipsychotics and antidepressants
  • alcohol
  • medicines used to control (lengthen or shorten) heart rhythm
  • ketoconazole, a medicine used to treat fungal infections
  • carbamazepine, a medicine used to treat epilepsy.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ZIPROX.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with ZIPROX.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ZIPROX.

4. How do I take ZIPROX?

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take.

This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

Schizophrenia

  • The usual starting dose is one 40 mg capsule taken twice daily with food.
  • Your doctor may increase your dose up to one 80 mg capsule twice daily with food.
  • To help you increase your dose, your doctor may give you a specially designed pack, known as a 'Titration Pack'.

Bipolar Disorder

  • The usual starting dose is one 40 mg capsule twice daily with food.
  • Your doctor may adjust your dose up to one 80 mg capsule twice daily with food.

When to take ZIPROX

Take your capsule(s) with food, in the morning with breakfast and in the evening with your evening meal.

You need to take ZIPROX with food because it helps your body absorb the medicine better. If you do not take with food, the medicine may have less effect.

Take this medicine at the same times each day. Taking it at the same times each day will have the best effect and will also help you remember when to take it.

How to take ZIPROX

Swallow the capsule(s) whole with a glass of water.

If you forget to use ZIPROX

ZIPROX should be used regularly at the same time each day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed

This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you use too much ZIPROX

If you think that you have used too much ZIPROX you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much ZIPROX, you may feel drowsy and show signs of tremor and uncontrollable movements of the tongue, jaw, arms and legs.

5. What should I know while using ZIPROX?

Things you should do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breast-feeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Call your doctor straight away if you:

  • become pregnant while taking ZIPROX

Remind any doctor, dentist or pharmacist you visit that you are using ZIPROX

Things you should not do

  • Do not take your medicine to treat any other condition unless your doctor or pharmacist tells you to
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours
  • Do not stop taking your medicine, or change the dosage, without first checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ZIPROX affects you.

ZIPROX may cause drowsiness and sleepiness in some people.

If you feel drowsy or sleepy while taking ZIPROX, do not drive or operate machinery, or do things that could be dangerous if you are not alert.

Drinking alcohol

Tell your doctor if you drink alcohol.

Be careful when drinking alcohol while taking ZIPROX.

Combining ZIPROX and alcohol can make you more sleepy, dizzy or light-headed. Your doctor may suggest you avoid alcohol while you are being treated with ZIPROX.

Looking after your medicine

  • Keep your medicine in its original packaging until it is time to take it.
  • If you take your medicine out of its original packaging it may not keep well.
  • Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half meters above the ground is a good place to store medicines

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking this medicine or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • headache
  • feeling sick (nausea)
  • sleepiness
  • difficulty sleeping
  • dizziness on standing up, especially when getting up from a sitting or lying position
  • dry mouth
  • too much saliva
  • indigestion
  • constipation
  • diarrhea
  • restlessness
  • muscle stiffness
  • blurred vision
  • palpitations
  • weakness or loss of strength
  • drowsiness
  • dizziness, blackouts or feeling faint
  • anxiety or agitation.
  • persistent painful erection of the penis or clitoris.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • any worm-like movements of the tongue
  • any other uncontrolled movements of the tongue, mouth, cheeks or jaw
  • any uncontrolled movements spreading to the arms and legs.
  • These are symptoms of a condition called Tardive Dyskinesia (TD).
  • If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.
  • These are very serious side effects and can also occur after you stop taking ZIPROX. You may need urgent medical attention or hospitalisation.
  • convulsions, fit or seizures
  • trembling and shaking of the hands and fingers
  • shuffling walk and stiffness of the arms and legs
  • sudden uncontrollable muscle spasms in the eyes, head, neck and body
  • symptoms of a condition called Neuroleptic Malignant Syndrome (NMS), which include: high fever, fast breathing, stiff muscles and confusion, drowsiness or sleepiness.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ZIPROX contains

Active ingredient
(main ingredient)		Ziprasidone Hydrochloride 20 mg, 40 mg, 60 mg or 80 mg per capsule
Other ingredients
(inactive ingredients)
  • sodium starch glycollate (type B)
  • macrogol 6000
  • lactose
  • sucrose
  • ammonium chloride
  • sodium lauryl sulfate
  • gelatin
  • titanium dioxide
  • indigo carmine (20 mg, 40 mg and 80 mg capsules only)
  • black printing ink
  • purified water.
Potential allergensLactose monohydrate
May contains trace amounts of sulfites and phenylalanine

Do not take this medicine if you are allergic to any of these ingredients.

What ZIPROX looks like

ZIPROX 20 mg capsules: Blue/White size ‘4’ hard gelatin capsules imprinted in black ink with “CL62” on the cap and “20mg” on the body; filled with pale pink coloured powder. AUST R 201081

ZIPROX 40 mg capsules: Blue/Blue size ‘2’ hard gelatin capsules imprinted in black ink with “CL63” on the cap and “40mg” on the body; filled with pale pink coloured powder. AUST R 201082

ZIPROX 60 mg capsules: White/White size ‘1’ hard gelatin capsules imprinted in black ink with “CL64” on the cap and “60mg” on the body; filled with pale pink coloured powder. AUST R 201083

ZIPROX 80 mg capsules: Blue/White size ‘0’ hard gelatin capsules imprinted in black ink with “CL65” on the cap and “80mg” on the body; filled with pale pink coloured powder. AUST R 201084

All strengths are available in blister packs of 60 capsules.

Who distributes ZIPROX

Arrotex Pharmaceuticals Pty Ltd
15 – 17 Chapel Street
Cremorne VIC 3121

This leaflet was prepared in March 2025.

Published by MIMS April 2025

BRAND INFORMATION

Brand name

Ziprox

Active ingredient

Ziprasidone

Schedule

S4

 

1 Name of Medicine

Ziprasidone (as hydrochloride).

2 Qualitative and Quantitative Composition

Each capsule contains 20 mg, 40 mg, 60 mg or 80 mg ziprasidone (base).

Excipient(s) with known effect.

Each capsule contains lactose monohydrate and sucrose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

20 mg capsules.

Blue/White size '4' hard gelatin capsules imprinted in black ink with "CL62" on the cap and "20 mg" on the body; filled with pale pink coloured powder.

40 mg capsules.

Blue/Blue size '2' hard gelatin capsules imprinted in black ink with "CL63" on the cap and "40 mg" on the body; filled with pale pink coloured powder.

60 mg capsules.

White/White size '1' hard gelatin capsules imprinted in black ink with "CL64" on the cap and "60 mg" on the body; filled with pale pink coloured powder.

80 mg capsules.

Blue/White size '0' hard gelatin capsules imprinted in black ink with "CL65" on the cap and "80 mg" on the body; filled with pale pink coloured powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Ziprasidone is indicated:
for the treatment of schizophrenia, related psychoses, prevention of relapse and for maintenance of clinical improvement during continuation therapy;
as monotherapy for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder.

4.2 Dose and Method of Administration

Ziprox capsules are intended for oral administration. Ziprox capsules should be taken with food and swallowed whole without chewing, crushing or opening beforehand.

Schizophrenia.

The recommended dose in treatment of schizophrenia is 40 mg twice daily taken with food. Daily dosage may subsequently be adjusted on the basis of individual clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days. The maximum recommended dose of 80 mg twice daily may be reached as early as day 3 of treatment.
Ziprasidone is effective in the treatment of acutely exacerbated patients and in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response. In maintenance treatment, patients should be administered the lowest effective dose; in many cases a dose of 20 mg twice daily may be sufficient.
Long-term treatment with ziprasidone is effective in the prevention of recurrent exacerbation of the illness and is associated with an improvement of negative symptoms.

Bipolar mania.

The recommended dose in treatment of acute bipolar mania is 40 mg twice daily taken with food. Daily dosage may subsequently be adjusted on the basis of individual clinical status up to 80 mg twice daily. The maximum recommended dose of 80 mg twice daily may be reached as early as day 2 of treatment.

Children and adolescents.

Ziprasidone is not approved for use in paediatric patients and should not be used in children and adolescents younger than 18 years of age (see Section 4.8 Adverse Effects (Undesirable Effects), Paediatric population).

Dosage adjustment in renal impairment.

No dosage adjustment is required in patients with impaired renal function (see Section 5.2 Pharmacokinetic Properties).

Dosage adjustment in hepatic impairment.

In patients with mild to moderate impairment of liver function (Child Pugh A or B) caused by cirrhosis, lower doses should be considered. The serum concentrations after oral administration were 30% higher and the terminal half-life was about 2 hours longer than in normal patients.
A toxicity study in dogs showed intrahepatic cholestasis and elevation of serum ALT and alkaline phosphatase at oral doses producing exposure (plasma AUC) about twice the maximal clinical exposure. There is a lack of experience in patients with severe hepatic insufficiency and therefore, ziprasidone should be used with caution in this group.

Dosage adjustment in patients who smoke.

No dosage adjustment is required in patients who smoke (see Section 5.2 Pharmacokinetic Properties, Special populations).

4.3 Contraindications

Known hypersensitivity to any ingredient in the product.
Recent acute myocardial infarction.
Uncompensated heart failure.
Conditions with a potential to increase QT interval: QT-interval prolongation or history of QT prolongation; congenital long QT syndrome; use with other drugs known to increase the QT interval; arrhythmias treated with class IA and III antiarrhythmic drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

QT prolongation and pro-arrhythmias.

Ziprasidone causes a mild to moderate prolongation of the QT interval.
A study directly comparing the QT/QTc prolonging effect of ziprasidone with several other drugs effective in the treatment of schizophrenia was conducted in patient volunteers. In the first phase of the trial, ECGs were obtained at the time of maximum plasma concentration when the drug was administered alone. The mean change in QTc from baseline was calculated, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for oral ziprasidone ranged from approximately 9-14 msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine and haloperidol), but was approximately 14 msec less than the prolongation observed for thioridazine.
In the second phase of the trial, ECGs were obtained at the time of maximum plasma concentration while the drug was co-administered with the appropriate inhibitor(s) of the CYP450 metabolism specific for each drug. The effect of oral ziprasidone on QTc length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg twice daily).
In placebo-controlled schizophrenia trials, ziprasidone increased the QTc interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg. In schizophrenia clinical trials with ziprasidone, the electrocardiograms of 3/3266 (0.1%) patients who received ziprasidone and 1/53 8 (0.2%) patients who received placebo revealed QTc intervals exceeding the potentially clinically relevant threshold of 500 msec. In the ziprasidone-treated patients, neither case suggested a role of ziprasidone.
Comparable findings were observed in the bipolar mania clinical trials. In the placebo-controlled bipolar mania studies, ziprasidone increased the QTc interval (QTcF) compared with placebo by 8 msec. No subject in these studies experienced a QTcF > 480 msec. The mean daily dose in these studies was 120 mg.
Some drugs that prolong the QT/QTc interval greater than 500 msec have been associated with the occurrence of torsades de pointes and with sudden unexplained death (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). There have been rare post-marketing reports of torsades de pointes in patients with multiple confounding risk factors taking ziprasidone. A causal relationship with ziprasidone has not been established.
As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in patients taking ziprasidone at recommended doses. Experience with ziprasidone has not revealed an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo.
Certain circumstances may increase the risk of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (i) bradycardia; (ii) hypokalaemia or hypomagnesaemia; (iii) concomitant use of other drugs that prolong the QTc interval; and (iv) presence of congenital prolongation of the QT interval (see Section 4.3 Contraindications).
It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances, hypokalaemia in particular, have baseline serum potassium and magnesium measurements. Hypokalaemia may result from diuretic therapy, diarrhoea and other causes. Patients with low serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment. Persistently prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, ziprasidone should be avoided in patients with histories of significant cardiovascular illness (see Section 4.3 Contraindications). Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements > 500 msec.
For patients taking ziprasidone who experience symptoms that could indicate the occurrence of torsades de pointes e.g. dizziness, palpitations, syncope or seizures, the prescriber should initiate further evaluation, e.g. Holter monitoring may be useful. The possibility of a malignant cardiac arrhythmia should also 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 Contraindications).

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.

Increased mortality in elderly patient with dementia-related psychosis.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death and/or potentially, cerebrovascular adverse events compared with placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6-1.7 x that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature. Ziprasidone is not approved for the treatment of elderly patients with dementia-related psychosis.

Cerebrovascular adverse events, including stroke, in elderly patients with dementia.

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

Neuroleptic malignant syndrome (NMS).

Neuroleptic malignant syndrome, a potentially fatal complex, has been reported in association with antipsychotic drugs, including ziprasidone. The clinical manifestations are hyperthermia, muscle rigidity, altered mental status and signs of autonomic instability, such as irregular pulse and blood pressure, tachycardia, cardiac arrhythmias and diaphoresis. Additional features may include elevated creatine phosphokinase, rhabdomyolysis and acute renal failure. If a patient develops signs and symptoms indicative of NMS or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic drugs, including ziprasidone, should be discontinued.

Severe cutaneous adverse reactions.

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with ziprasidone exposure. DRESS consists of a combination of: a) three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy; and b) one or more systemic complications (such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis).
Other severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome, have also been reported with ziprasidone exposure. SCARs are sometimes fatal and ziprasidone should be discontinued if SCARs occur.

Tardive dyskinesia.

In fixed-dose, placebo-controlled trials in patients with schizophrenia, of up to six weeks duration, the incidence of treatment emergent tardive dyskinesia was comparable in patients receiving ziprasidone and placebo and lower than patients treated with active comparator (0.4% ziprasidone, 1.2% haloperidol and 0.7% placebo). In a 52-week, placebo-controlled trial in patients with schizophrenia, only one out of 219 patients treated with ziprasidone experienced tardive dyskinesia. However, as with other antipsychotic agents, the risk of tardive dyskinesia and other tardive extrapyramidal syndromes may increase with long-term exposure and therefore, if signs or symptoms of tardive dyskinesia appear in a patient on ziprasidone, a dose reduction or drug discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Falls.

Antipsychotic drugs (which includes ziprasidone) may cause somnolence, postural hypotension, and motor and sensory instability, which could lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, a fall risk assessment should be completed when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Rash.

In pre-marketing schizophrenia trials with ziprasidone, about 5% of patients developed rash and/or urticaria, with discontinuation of treatment in about one-sixth of these cases. The occurrence of rash was related to dose of ziprasidone, although the finding might also be explained by the longer exposure time in the higher dose patients. Several patients with rash had signs and symptoms of associated systemic illness, e.g. elevated white blood cells. Most patients improved promptly with adjunctive treatment with antihistamines or steroids and/or upon discontinuation of ziprasidone and all patients experiencing these events were reported to recover completely. Upon appearance of rash for which an alternative aetiology cannot be identified, ziprasidone should be discontinued.

Orthostatic hypotension.

Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope was reported in 0.6% of the patients treated with ziprasidone in schizophrenia clinical trials.
Ziprasidone should be used with particular caution in patients with known cardiovascular disease, cerebrovascular disease or conditions which would predispose patients to hypotension.

Suicide.

The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder, and close supervision of high-risk patients should accompany therapy. Prescriptions for ziprasidone should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Akathisia.

The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse.

CNS drugs/alcohol.

Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting agents, including alcohol and drugs acting on the dopaminergic and serotonergic systems.

Seizures.

As with other antipsychotics, caution is recommended when treating patients with a history of seizures.

Hyperprolactinaemia.

As with other drugs that antagonize dopamine D2 receptors, ziprasidone elevates prolactin levels in humans. Increased prolactin levels were also observed in animal studies with this compound and were associated with an increase in mammary gland neoplasia in mice; a similar effect was not observed in rats (see Section 5.3 Preclinical Safety Data, Carcinogenicity). Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. Neither clinical nor epidemiological studies conducted to date have shown an association between chronic administration of this class of drugs and tumourigenesis in humans; the available evidence is considered too limited to be conclusive at this time. Although disturbances such as galactorrhoea, amenorrhoea, gynaecomastia and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long-standing hyperprolactinaemia when associated with hypogonadism may lead to decreased bone density.

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycaemia or diabetes in patients treated with ziprasidone. Although fewer patients have been treated with ziprasidone, it is not known if this more limited experience is the sole reason for the paucity of such reports. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies which did not include ziprasidone, suggest an increased risk of treatment-emergent hyperglycaemia-related adverse events in patients treated with atypical antipsychotics included in these studies. Because ziprasidone was not marketed at the time these studies were performed, it is not known if ziprasidone is associated with this increased risk. Precise risk estimates for hyperglycaemia related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect medicine.

Sleep apnoea.

Sleep apnoea and related disorders have been reported in patients treated with antipsychotics, such as ziprasidone, with or without prior history of sleep apnoea, and with or without concomitant weight-gain. Caution should be taken in patients who have a history of or are at risk for sleep apnoea, or who are concomitantly using central nervous system depressants.

Priapism.

Cases of priapism have been reported with antipsychotic use, including ziprasidone.

Use in hepatic impairment.

In mild to moderate impairment of liver function (Child Pugh A or B) caused by cirrhosis, serum concentrations after oral administration were 30% higher and the terminal half-life was about 2 hours longer than in normal patients.
A toxicity study in dogs showed intrahepatic cholestasis and elevation of serum ALT and alkaline phosphatase at oral doses producing exposure (plasma AUC) about twice the maximal clinical exposure.
Therefore, ziprasidone should be used with caution in patients with hepatic impairment.

Use in renal impairment.

No dosage adjustment is required in patients with impaired renal function (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No dosage adjustment is required in elderly patients (65 years and over) for the treatment of schizophrenia.
Ziprasidone has not been systematically evaluated in subjects 65 years and older for the treatment of bipolar mania.

Paediatric use.

Ziprasidone is not approved for use in paediatric patients and should not be used in children and adolescents younger than 18 years of age (see Section 4.8 Adverse Effects (Undesirable Effects), Paediatric population).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 x higher than the free concentration that can be expected in vivo. Although the clinical relevance of this finding is uncertain, ziprasidone is unlikely to cause clinically important drug interactions mediated by these enzymes.

QTc prolongation.

As with other antipsychotic agents, there is an increased potential of QTc prolongation in the presence of Class IA and IIIA antiarrhythmics. Co-administration with the potent CYP3A4 inhibitor, ketoconazole, did not affect QTc, when compared to ziprasidone alone (see Section 4.4 Special Warnings and Precautions for Use; Section 4.3 Contraindications).

Dextromethorphan.

The pharmacokinetics and metabolism of dextromethorphan, a CYP2D6 substrate, were unaffected by ziprasidone.

Oral contraceptives.

Ziprasidone administration at a dose of 20 mg twice daily resulted in no significant change to the pharmacokinetics of oestrogen (ethinyloestradiol 0.03 mg, a CYP3A4 substrate) or progesterone components (levonorgesterol 0.15 mg).

Lithium.

Co-administration of ziprasidone at a dose of 40 mg twice daily had no effect on pharmacokinetics of lithium at a dose of 450 mg twice daily for 7 days. In this study, steady state lithium concentrations prior to co-administration of ziprasidone were 0.49 mEq/L.
As ziprasidone and lithium are associated with cardiac conduction changes, the combination may pose a potential for pharmacodynamic interaction, including arrhythmias. While there have been no reports of clinically significant QTc increases in clinical trials of adjunctive therapy involving ziprasidone and lithium, caution should be exercised in prescribing the two drugs together.

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.

Effects of other medicines on ziprasidone.

CYP3A4 inhibitors.

Co-administration of potent CYP3A4 inhibitors has the potential of increasing ziprasidone serum concentrations. The clinical importance of this potential has not been clearly defined.
In vitro data indicate that ziprasidone is a P-glycoprotein (P-gp) substrate. The in vivo relevance is unknown.
Ketoconazole a potent CYP3A4 inhibitor (400 mg/day); increased the serum concentrations of ziprasidone by approximately (35-40%). The serum concentration of S-methyl-dihydroziprasidone, at the expected Tmax of ziprasidone, was increased by 55% during ketoconazole treatment. No additional QTc prolongation was observed.
Cimetidine, a CYP3A4 inhibitor; a dose of 800 mg once daily for 2 days did not significantly alter the pharmacokinetics of ziprasidone.

CYP3A4 inducers.

Co-administration with inducers of CYP-3A4 and P-gp such as carbamazepine, rifampin and St John's Wort (Hypericum perforatum) could cause decreased concentrations of ziprasidone.
Carbamazepine, a CYP3A4 inducer; produced a decrease in AUC (36%) and Cmax (25%) of ziprasidone.

CNS drugs.

Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally-acting drugs. As it exhibits in vitro dopamine antagonism, ziprasidone may antagonise the effects of direct and indirect dopamine agonists.

Antacid.

Multiple doses of aluminium- and magnesium-containing antacid did not affect the pharmacokinetics of ziprasidone.

Other.

In addition, pharmacokinetic screening of patients in clinical trials has not revealed any evidence of clinically significant interactions with benztropine, propranolol or lorazepam.
Ziprasidone has not been studied for drug interaction with valproate or lamotrigine.

4.6 Fertility, Pregnancy and Lactation

Effects on 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 was shown to increase time to copulation in rats at doses of 10-160 mg/kg/day (0.5-8 x the maximum recommended human dose (MRHD) of 160 mg/kg/day on a mg/m2 basis). Fertility was impaired in rats dosed orally at 160 mg/kg/day (8 x the MRHD on a mg/m2 basis), with a no-effect dose level of 40 mg/kg/day (2 x the MRHD on a mg/m2 basis). The effect appeared to be in the female since the length of the oestrous cycle was increased, a pharmacological effect in rats of dopamine antagonists. Fertility was not impaired when males given 160 mg/kg/day were mated to untreated females and there were no treatment related findings in the testes of male rats given 200 mg/kg/day (11 x the MRHD on a mg/m2 basis).
(Category C)
Category C - Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
In animal studies ziprasidone crosses the placenta in rats and rabbits and demonstrated developmental toxicity, including possible teratogenic effects at doses similar to human therapeutic doses. When ziprasidone was administered to pregnant rabbits during the period of organogenesis, an increased incidence of foetal structural abnormalities (ventricular septal defects and other cardiovascular malformations and kidney alterations) was observed at a dose of 30 mg/kg/day (3 x the MRHD of 160 mg/day on a mg/m2 basis). There was no evidence to suggest that these developmental effects were secondary to maternal toxicity. The developmental no-effect dose was 10 mg/kg/day (equivalent to the MRHD on a mg/m2 basis). Studies in rats have not shown adverse effects on embryo-foetal development, other than those associated with maternal toxicity, when ziprasidone was administered during the period of organogenesis at oral doses up to 160 mg/kg/day, respectively (8 x the MRHD of 160 mg/day on a mg/m2 basis). The incidence of still births was increased when ziprasidone was administered at oral doses of 10 mg/kg/day or greater to rats throughout gestation (0.5 x the MRHD on a mg/m2 basis); estimated systemic exposure at the no-effect dose for perinatal mortality (5 mg/kg/day) was less than that in humans at the MRHD. Offspring showed increased postnatal mortality, suppression of growth and delayed development when ziprasidone 40 mg/kg/day was administered to rats orally during gestation and lactation (2 x the MRHD on a mg/m2 basis). The estimated systemic exposure in dams at the no-effect dose for offspring (5 mg/kg/day) was less than that in humans at the maximum recommended dose.
There are no adequate and well-controlled clinical trials in pregnant women. Women of child-bearing 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.

Non-teratogenic class effect.

Neonates exposed to antipsychotic drugs (including ziprasidone) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been post-market reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required additional medical treatment or monitoring.
Ziprasidone should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.
 There are no adequate and well-controlled studies in lactating women. Limited data indicate that ziprasidone and its active metabolites are excreted into breast milk at very low levels. Offspring showed increased postnatal mortality, suppression of growth and delayed development when ziprasidone 40 mg/kg/day was administered orally to rats during gestation and lactation (2 x the MRHD on a mg/m2 basis). The estimated systemic exposure in dams at the no-effect dose for offspring (5 mg/kg/day) was less than that in humans at the MRHD. Patients should not breast feed if they are taking ziprasidone.

4.7 Effects on Ability to Drive and Use Machines

As with other psychoactive drugs, ziprasidone may cause somnolence. Patients likely to drive or operate other machines should therefore be cautioned appropriately.

4.8 Adverse Effects (Undesirable Effects)

Table 1 contains treatment-emergent adverse events that occurred at an incidence of ≥ 1% in monotherapy, double-blind, placebo-controlled studies in patients with bipolar mania and short-term double-blind, placebo-controlled studies in patients with schizophrenia.
All adverse reactions are listed by class and frequency: very common (> 10%), common (1% to 10%), uncommon (0.1% to 1%), rare (< 0.1%).

General disorders and administration site conditions.

Uncommon: Gait abnormal, thirst, malaise. Rare: Chest pain, feeling hot, pyrexia, sluggishness.

Cardiac disorders.

Uncommon: Bundle branch block right, palpitation.

Gastrointestinal disorders.

Uncommon: Dysphagia, flatulence, gastritis. Rare: Gastro-oesophageal reflux, diarrhoea.

Blood and lymphatic system disorders.

Rare: Lymphopaenia.

Ear and labyrinth disorders.

Uncommon: Tinnitus, vertigo. Rare: Ear pain, vertigo positional.

Eye disorders.

Common: Visual impairment. Uncommon: Photophobia, oculogyric crisis. Rare: Amblyopia, eye pruritus.

Investigations.

Uncommon: Hepatic enzyme increased, increased appetite, heart rate increased, electrocardiogram QT interval prolonged. Rare: Blood lactate dehydrogenase increased, body temperature increased, eosinophil count increased, eosinophil count abnormal, hypocalcaemia, liver function test abnormal, heart rate increased.

Infections and infestations.

Uncommon: Rhinitis.

Metabolism and nutritional disorders.

Uncommon: Increased appetite.

Musculoskeletal and connective tissue disorders.

Uncommon: Joint stiffness, muscle spasms, pain in extremity, torticollis. Rare: Arthropathy, musculoskeletal discomfort, trismus.

Nervous system disorders.

Common: Tardive dyskinesia, hypertonia. Uncommon: Ataxia, bradykinesia, cogwheel rigidity, disturbance in attention, dizziness postural, drooling, dysarthria, generalized tonic-clonic seizures, hypokinesia, hypersomnia, hypoaesthesia, lethargy, oculogyric crisis, paraesthesia, speech disorders. Rare: Akinesia, paresis, restless legs syndrome.

Psychiatric disorders.

Common: Anxiety, agitation. Uncommon: Nightmare, nervousness, libido decreased. Rare: Anorgasmia, bradyphrenia, flat affect, panic attack, somnambulism.

Respiratory, thoracic and mediastinal disorders.

Uncommon: Dyspnoea, oropharyngeal pain, throat tightness. Rare: Hiccups, laryngospasm.

Renal and urinary disorders.

Uncommon: Dysuria, urinary incontinence, urinary hesitation. Rare: Urinary retention.

Reproductive system and breast disorders.

Common: Male sexual dysfunction. Uncommon: Galactorrhoea, gynaecomastia, amenorrhea.

Skin and subcutaneous tissue.

Common: Rash. Uncommon: Acne, maculopapular rash, urticaria. Rare: Alopecia, dermatitis allergic, erythema, psoriasis, skin irritation, swelling face, rash papular.

Other findings.

Extrapyramidal symptoms (EPS).

In double-blind active-controlled clinical trials in patients with schizophrenia, the Movement Disorder Burden Scale, a composite measure of EPS, was statistically significantly (p < 0.05) in favour of ziprasidone versus haloperidol and risperidone. In addition, the reported incidence of akathisia and use of anticholinergic drugs was greater in the haloperidol and risperidone groups relative to ziprasidone. The incidence of reported EPS for ziprasidone-treated patients in the short-term, placebo-controlled trials was 5% versus 1% for placebo.

Body weight.

The incidence of body-weight gain, recorded as an adverse event in short-term 4- and 6-week, fixed-dose, placebo-controlled schizophrenia trials, was low and identical in ziprasidone-treated and placebo-treated patients (both 0.4%). There was a small increase in median weight in ziprasidone-treated patients (0.5 kg) but not in placebo-treated patients.
In a one-year placebo-controlled schizophrenia study a median weight loss of 1-3 kg was observed in ziprasidone-treated patients compared to a 3 kg median loss in placebo-treated patients.

QT interval.

In schizophrenia clinical trials, a mean QT interval increase from screening of 3.3 msec was measured. A prolongation of > 60 msec was seen in 1.6% and 1.2% of tracings from ziprasidone- and placebo-treated patients, respectively. In the pre-marketing clinical trials database, the number of cases of clinically significant abnormalities in QTc prolongation (≥ 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.

Dose dependency of adverse events in short-term, placebo-controlled trials.

An analysis for dose response in this 4-study pool revealed an apparent relation of adverse event to dose for the following events: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash and abnormal vision.

Vital sign changes.

Ziprasidone is associated with postural hypotension (see Section 4.4 Special Warnings and Precautions for Use, Orthostatic hypotension).

Prolactin levels.

There were only transient prolactin increases seen during chronic dosing with ziprasidone. In Phase 2/3 clinical trials, prolactin levels in patients treated with ziprasidone were sometimes elevated (12%) compared with the placebo group (3%), but potential clinical manifestation (e.g. gynaecomastia 0.1%) were rare. In most patients, levels returned to normal ranges without cessation of treatment. In the clinical studies the degree and incidence of prolactin elevation was lower in ziprasidone patients than in patients treated with haloperidol (29%) or risperidone (60%).

Physical and psychological dependence.

Ziprasidone has not been systemically 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 behaviour, 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 behaviour).

Paediatric population.

In placebo-controlled clinical trials in bipolar disorder (aged 10-17 years) and schizophrenia (aged 13-17 years), the paediatric safety profile of ziprasidone was similar to the adult profile, except for an increased incidence of sedation and somnolence in paediatric patients. Ziprasidone is not approved for use in paediatric patients and should not be used in children and adolescents younger than 18 years of age.

Post-marketing experience.

The following adverse events have been reported during post-marketing experience and have not been listed above:

Immune system disorders.

Hypersensitivity.

Investigations.

Weight decreased, weight increased.

Endocrine disorders.

Hyperprolactinaemia.

Psychiatric disorders.

Mania/hypomania, somnambulism, sleep-related eating disorder.

Respiratory, thoracic and mediastinal disorders.

Sleep apnoea.

Nervous system disorders.

Syncope, facial droop, neuroleptic malignant syndrome (see Section 4.4 Special Warnings and Precautions for Use); serotonin syndrome (alone or in combination with serotonergic medicinal products), sedation.

Cardiac disorders.

Tachycardia, torsades de pointes (see Section 4.4 Special Warnings and Precautions for Use).

Vascular disorders.

Orthostatic hypotension, hypotension, embolism venous (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal disorders.

Dysphagia, tongue oedema, vomiting.

Skin and subcutaneous tissue disorders.

Angioedema, rash, drug reaction with eosinophilia and systemic symptoms (DRESS) vomiting.

Renal and urinary disorders.

Enuresis, urinary incontinence.

Reproductive system and breast disorders.

Galactorrhoea, priapism.

General disorders and administration site conditions.

Fatigue.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

Experience with ziprasidone in overdosage is limited. In overdose cases in general, the most commonly reported symptoms are extrapyramidal symptoms, somnolence, tremor and anxiety. Hypertension, hypotension, diarrhoea, tachycardia and prolongation of the QTc and QRS intervals have also been reported. Respiratory depression may occur following massive overdoses due to CNS depression. The largest confirmed single ingestion is 12.8 g. In this case, extrapyramidal symptoms and a QTc interval of 446 msec (with no cardiac sequelae) were reported.

Treatment of overdosage.

In cases of suspected overdose, the possibility of multiple drug involvement should be considered. There is no specific antidote to ziprasidone. In case of acute overdose, establish and maintain an airway and ensure adequate ventilation and oxygenation. Monitor respiratory function, vital signs and blood pressure. 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, adrenaline and dopamine should not be used, since beta stimulation combined with α1 antagonism associated with ziprasidone may worsen hypotension. Monitor for CNS depression, seizures and extrapyramidal reactions. In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Monitor liver function tests as increased serum liver enzymes may result following overdose.
The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis, therefore emesis is not recommended. Administration of activated charcoal should be considered and is most effective when administered within one hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected.
Given the high protein binding of ziprasidone, haemodialysis is unlikely to be beneficial in the treatment of overdose. Close medical monitoring and supervision should continue until the patient recovers.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ziprasidone exhibited high in vitro binding affinity for the dopamine D2 and D3, the serotonin 5HT2A, 5HT2C, 5HT1A and 5HT1D and α1-adrenergic receptors (Kis of 4.8, 7.2, 0.4, 1.3, 3.4, 2 and 10 nanoM, respectively) and moderate affinity for the histamine H1 receptor (Ki = 47 nanoM). Ziprasidone functioned as an antagonist at the D2, 5HT2A and 5HT1D receptors and as an agonist at the 5HT1A receptor. Ziprasidone inhibited synaptic reuptake of serotonin and noradrenaline. No appreciable affinity was exhibited for the other receptor/binding sites tested, including the cholinergic muscarinic receptor (IC50 > 1 microM).
The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. As with other drugs having efficacy in bipolar disorder, the mechanism of action of ziprasidone in bipolar disorder is unknown.
Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of ziprasidone. Ziprasidone's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Ziprasidone's antagonism of adrenergic α1 receptors may explain the postural hypotension observed with this drug.

Positron emission tomography studies.

At 12 hours following a 40 mg dose of ziprasidone, receptor blockade was greater than 80% for 5HT2A and greater than 50% for D2 using positron emission tomography (PET).

Clinical trials.

Schizophrenia.

The efficacy of ziprasidone in the management of the manifestations of psychotic disorders was established in three short-term (4 and 6 week) and one long-term (52-week) controlled trials of psychotic in-patients who met DSM-III-R criteria for schizophrenia or schizoaffective disorder. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS), both multi-item inventories of psychopathology traditionally used to evaluate the effects of drug treatment in psychosis.
Another traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Scale for the Assessment of Negative Symptoms (SANS) and the Montgomery-Asberg Depression Rating Scale (MADRS) were employed in some clinical trials.
In the 52-week, placebo-controlled maintenance trial (n = 294), ziprasidone doses of 20 mg, 40 mg and 80 mg twice daily were statistically superior to placebo in the prevention of recurrent exacerbation of the illness, as well as in the BPRS total and psychosis cluster, the CGI, the PANSS total and negative subscale and Global Assessment of Functioning. Discontinuations due to adverse events were 7-10% in the ziprasidone groups and 15% in the placebo group.
An analysis of the effect of ziprasidone on patients with clinically significant depressive symptoms (MADRS) ≥ 14 was conducted in two multi-centre placebo-controlled studies in acute schizophrenia. A statistically significant improvement versus placebo (p < 0.05) in the MADRS was observed in patients receiving ziprasidone 60 mg twice daily in one study and 80 mg twice daily in another study.

Bipolar mania.

The efficacy of ziprasidone in mania was established in two placebo-controlled, double-blind, 3-week studies which compared ziprasidone with placebo and one double-blind, 12-week study which compared ziprasidone to haloperidol and placebo. These studies included 850 patients meeting DSM-IV criteria for Bipolar I Disorder with an acute manic or mixed episode with or without psychotic features. Primary rating instruments used for assessing manic symptoms in these trials were: (i) the Mania Rating Scale (MRS), which is derived from the Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-CB) with items grouped as the Manic Syndrome subscale (elevated mood, less need for sleep, excessive energy, excessive activity, grandiosity), the Behaviour and Ideation Subscale (irritability, motor hyperactivity, accelerated speech, racing thoughts, poor judgment) and impaired insight; and (ii) the Clinical Global Impression-Severity of Illness Scale (CGI-S), which was used to assess the clinical significance of treatment response.
In a 3-week placebo-controlled, double-blind trial (n = 210), the dose of ziprasidone was 40 mg twice daily on Day 1 and 80 mg twice daily on Day 2. Titration within the range of 40-80 mg twice daily (in 20 mg twice daily increments) was permitted for the duration of the study. Ziprasidone was significantly more effective than placebo in reduction of the MRS total score and the CGI-S score (p ≤ 0.01).
In a second 3-week placebo-controlled, double blind trial (n = 205), the dose of ziprasidone was 40 mg twice daily on Day 1. Titration within the range of 40-80 mg twice daily (in 20 mg twice daily increments) was permitted for the duration of study (beginning on Day 2). Ziprasidone was significantly more effective than placebo in reduction of the MRS total score and the CGI-S score (p ≤ 0.01 and p ≤ 0.001 respectively).
In the 12-week placebo-controlled, double-blind, double-dummy trial (n = 437), patients were randomized to ziprasidone, haloperidol, or placebo in a ratio of 2:2:1. Patients randomized to ziprasidone or haloperidol took their assigned drug for the 12-week study period. Patients randomized to placebo took placebo for the first 3 weeks of treatment and were then switched to ziprasidone for the remaining 9 weeks of the study. During the first 3 weeks of randomized study medication, the dose of ziprasidone was within the range of 40-80 mg twice daily and the dose of haloperidol was within the range of 4-15 mg twice daily. During the last 9 weeks of treatment, drug dosages could be reduced to as low as 20 mg twice daily for ziprasidone and 2 mg twice daily for haloperidol. Ziprasidone was significantly more effective than placebo in reduction of the MRS total score (p < 0.001) and CGI-S score (p = 0.002) at Week 3. In ziprasidone-treated patients, significant treatment differences were shown in MRS total score at Day 2 (p = 0.001) and maintained at Day 7 (p = 0.016) and Day 14 (p = 0.001) and in CGI-S scores starting at Day 14 (p < 0.001). Haloperidol was also significantly more effective than placebo in reduction of the MRS total score (p ≤ 0.01) and CGI-S score (p ≤ 0.01) at Week 3.
Maintenance of effect over the 12-week period was observed for both ziprasidone- and haloperidol-treated groups. 92.5% of the subjects who responded (subjects with at least a 50% decrease from baseline in the MRS at any given visit) in the ziprasidone-treated group at the end of week 3 were still in response by week 12. Subjects in ziprasidone and haloperidol treatment groups had similar percentages of responders at each visit through week 12.
Based on the MADRS derived scores through week 4-12, more subjects in the haloperidol treatment group (5.0%) switched to depression than subjects in the ziprasidone treatment group. (See Tables 2 and 3.)
An additional randomized, placebo-controlled study (n = 205) compared the efficacy, tolerability and safety of ziprasidone and placebo in the presence of adjunctive lithium. All patients were either already receiving lithium or initiated treatment with lithium on Day 1. Patients were randomized to either ziprasidone or placebo in a ratio of 1:1. The dose of ziprasidone was 40 mg twice daily on Day 1 and 80 mg twice daily on Day 2 and adjusted within the range 40-80 mg twice daily thereafter. Lithium treatment in patients not already receiving lithium was initiated at 900 mg daily on Day 1. Lithium was dosed as needed thereafter to maintain a serum level of 0.8-1.2 mEq/L, but serum levels were not mandatory during the study. Treatment with ziprasidone plus lithium was not more efficacious than placebo plus lithium, based upon the lack of a statistically significant difference in the rate of change in MRS or CGI-S from Baseline to Day 14.
The efficacy of ziprasidone when used in combination with mood stabilizers such as lithium, carbamazepine, sodium valproate or lamotrigine has not been established in the treatment of acute mania.
There are no long term clinical studies investigating the efficacy of ziprasidone in the prevention of recurrence of manic/depressive symptoms.

Results of a large post-marketing safety study (Zodiac study).

A randomized post-approval study of 18,239 patients with observational follow-up for one year was conducted to determine whether ziprasidone is associated with an increased risk of non-suicide mortality, compared to olanzapine, in patients with schizophrenia. This study, which was conducted in naturalistic clinical practice settings, showed no significant difference in its primary endpoint of the rate of non-suicide mortality between ziprasidone and olanzapine treatments (risk ratio 1.02; 95% CI 0.76-1.39). All-cause mortality also did not differ between the two treatment groups (risk ratio 1.01; 95% CI 0.77-1.33).

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of multiple doses of ziprasidone with food, peak serum concentrations typically occur 6-8 hours post-dose. Ziprasidone demonstrates linear kinetics over the therapeutic dose range of 40-80 mg twice daily in fed subjects. The absolute bioavailability of a 20 mg dose is 60% in the fed state.
Pharmacokinetic studies have demonstrated that the bioavailability of ziprasidone is significantly increased by up to 100% in the presence of food. Therefore, ziprasidone must be taken with food.

Distribution.

Ziprasidone is greater than 99% protein bound, binding primarily to albumin and α1-acid glycoprotein. Twice daily dosing generally leads to attainment of steady state within 1-3 days. Systemic exposures at steady state are related to dose. Ziprasidone has a volume of distribution of approximately 1.1 L/kg when administered intravenously.

Metabolism.

Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (< 1%) or faeces (< 4%) as unchanged drug. Ziprasidone is primarily cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole piperazine (BITP) sulfoxide, BITP sulfone, ziprasidone sulfoxide and S-methyl-dihydroziprasidone. Approximately 20% of the dose is excreted in the urine, with approximately 66% being eliminated in the faeces. Unchanged ziprasidone represents about 44% of total drug-related concentration in serum.
In vitro studies indicate that CYP3A4 is the major cytochrome catalysing the oxidative metabolism of ziprasidone with some potential contribution from CYP1A2. S-methyl-dihydroziprasidone is generated in two steps catalysed by aldehyde oxidase and thiol methyltransferase.
Ziprasidone, S-methyl-dihydroziprasidone and ziprasidone sulfoxide, when tested in vitro, share properties which may predict a QTc-prolonging effect. S-methyl-dihydroziprasidone is mainly eliminated by biliary excretion and CYP3A4 catalysed metabolism. Ziprasidone sulfoxide is eliminated through renal excretion and by secondary metabolism catalysed by CYP3A4 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

The mean terminal phase half-life after multiple dosing in normal volunteers and schizophrenic patients is between 6-10 hours, with a range of individual values from 3 to 18 hours.
Mean systemic clearance of ziprasidone administered intravenously is approximately 5 mL/min/kg.

Special populations.

Elderly (> 65 years).

There are no clinically significant differences in the pharmacokinetics of ziprasidone in young adults and elderly.
In a multiple-dose (8 days of treatment) study involving 32 subjects, there was no difference in the pharmacokinetics of ziprasidone between elderly (> 65 years) and young (18-45 years) adult subjects. Additionally, population pharmacokinetic evaluation of patients in controlled trials has revealed no evidence of clinically significant age-related differences in the pharmacokinetics of ziprasidone. Dosage modifications for age are, therefore, not recommended.

Children and adolescents.

Ziprasidone is not approved for use in paediatric patients and should not be used in children and adolescents younger than 18 years of age.

Gender.

In a multiple-dose (8 days of treatment) study involving 32 subjects, there was no difference in the pharmacokinetics of ziprasidone between men and women. Additionally, population pharmacokinetic evaluation of patients in controlled trials has revealed no evidence of clinically significant gender-related differences in the pharmacokinetics of ziprasidone. Dosage modifications for gender are, therefore, not recommended.

Race.

No specific pharmacokinetic study was conducted to investigate the effects of race. Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-related differences in the pharmacokinetics of ziprasidone. Dosage modifications for race are, therefore, not recommended.

Smoking.

Based on in vitro studies utilizing human liver enzymes, ziprasidone is not a substrate for CYP1A2; smoking should therefore not have an effect on the pharmacokinetics of ziprasidone. Consistent with these in vitro results, population pharmacokinetic evaluation has not revealed any significant pharmacokinetic differences between smokers and non-smokers.

Renal impairment.

Because ziprasidone is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a major impact on the pharmacokinetics of ziprasidone. The pharmacokinetics of ziprasidone following 8 days of 20 mg twice daily dosing were similar among subjects with varying degrees of renal impairment (n = 27) and subjects with normal renal function, indicating that dosage adjustment based upon the degree of renal impairment is not required. Ziprasidone is not removed by haemodialysis.
No marked differences in the pharmacokinetics of ziprasidone have been observed in patients with decreased kidney function (creatinine clearance > 10 mL/min).

Hepatic impairment.

As ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would be expected to increase the AUC of ziprasidone; a multiple-dose study at 20 mg twice daily for 5 days in subjects (n = 13) with clinically significant (Child Pugh Class A and B) cirrhosis revealed an increase in AUC0-12 of 13% and 34% in Child Pugh Class A and B, respectively, compared to a matched control group (n = 14). A half-life of 7.1 hours was observed in subjects with cirrhosis compared to 4.8 hours in the control group.

5.3 Preclinical Safety Data

Genotoxicity.

Ziprasidone was tested for genotoxic potential in assays for gene mutation and chromosomal damage. There was a reproducible response in the Ames assay in one strain of S. typhimurium in the absence of metabolic activation. Equivocal results were obtained in both the in vitro mammalian cell gene mutation assay and the in vitro chromosomal aberration assay in human lymphocytes. Ziprasidone was negative in the in vivo chromosomal aberration assay in mouse bone marrow.

Carcinogenicity.

Lifetime carcinogenicity studies were conducted with ziprasidone administered in the diet to rats and mice. In rats, there was no evidence of increased tumour incidences at doses up to 12 mg/kg/day, corresponding to systemic exposure (plasma AUC0-24 h) similar to that in humans at the maximum recommended dose. In male mice, there was no increase in tumour incidences at doses up to 200 mg/kg/day, corresponding to systemic exposure about 2.5 x than that in humans. In female mice, dose-related increases in the incidence of hyperplasia and neoplasia in the pituitary (shown immunohistochemically to be prolactin-producing) and mammary gland were seen at 50-200 mg/kg/day, corresponding to systemic exposure about 1-4 x greater than that in humans; a no-effect dose level for these effects was not established. Proliferative changes in the pituitary and mammary glands of rodents have been observed following chronic administration of other antipsychotic agents and are associated with increased prolactin concentrations. Although clinical and epidemiological studies have not shown an association between chronic administration of this class of drugs and tumourigenesis in humans, the use of ziprasidone in patients with familial history or previously detected breast cancer should be avoided. Caution should be exercised when considering ziprasidone treatment in patients with pituitary tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each capsule contains the following inactive ingredients: sodium starch glycollate (type B), macrogol 6000, lactose monohydrate, sucrose, ammonium chloride, sodium lauryl sulfate, gelatin, titanium dioxide, indigo carmine (20 mg, 40 mg and 80 mg capsules only), TekPrint SW-9008 black ink (ARTG # 2328) and purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

20 mg/40 mg/60 mg/80 mg.

Blister pack (PA/Al/PVC/Al) of 60 capsules.

Titration pack.

Contains 2 x 40 mg capsules, 2 x 60 mg capsules and 2 x 80 mg capsules available in PA/Al/PVC/Al blister packs.
Not all strengths may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Chemical Name: 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydro-2H- indol-2-one hydrochloride monohydrate.
Molecular Formula: C21H21ClN4OS.HCl.H2O.
Molecular Weight: 467.41.
Ziprasidone is a white to slightly pink powder, practically insoluble in water and slightly soluble in methanol and methylene chloride. It is an antipsychotic agent for oral administration and is chemically unrelated to phenothiazine or butyrophenone antipsychotic agents.

CAS number.

138982-67-9.

7 Medicine Schedule (Poisons Standard)

S4: Prescription Only Medicine.

Summary Table of Changes