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Logo GEODON IM 20 mg/mL powder for solution for injection
SCHEDULING STATUS:
S5        (GEODON IM 20 mg/mL powder for solution for injection)
S1        (Pfizer Water for injections)

GEODON 20 mg/mL POWDER FOR SOLUTION FOR INJECTION
WATER FOR INJECTION (SOLVENT FOR GEODON 20 mg/mL POWDER FOR SOLUTION FOR INJECTION)

PROPRIETARY NAME
(and dosage form):

GEODON IM 20 mg/mL powder for solution for injection
(vials)
Water for injections (ampoules)

COMPOSITION
Each single-use vial contains a lyophile of ziprasidone mesylate complexed with sulphobutyl ether â-cyclodextrin sodium. After reconstitution with 1.2 mL water for injection, each mL contains ziprasidone mesylate trihydrate equivalent to 20 mg ziprasidone
Excipients: Sulphobutyl ether beta-cyclodextrin sodium.
Each ampoule of Pfizer Water for Injections contains an extractable volume of 1,2 mL sterile water for injections.

PHARMACOLOGICAL CLASSIFICATION:
A 2.6.5: Central Nervous System Depressants: Miscellaneous structures

PHARMACOLOGICAL ACTION:
Pharmacodynamic properties
Ziprasidone has a high affinity for dopamine type 2 (D2) receptors and substantially higher affinity for serotonin type 2A(5HT2A) receptors. Receptor blockade, 12 hours after a single oral dose of 40 mg, was greater than 80% for serotonin type 2A and greater than 50% for D2 using positron emission tomography (PET). Ziprasidone also interacts with serotonin 5HT2c 5HT1D and 5HT1A receptors where its affinities for these sites are equal to or greater than its affinity for the D2 receptor. Ziprasidone has moderate affinity for neuronal serotonin and norepinephrine transporters. Ziprasidone demonstrates moderate affinity at histamine H(1)- and alpha(1)-receptors. Ziprasidone demonstrates negligible affinity for muscarinic M(1)-receptors.
Ziprasidone has been shown to be an antagonist at both serotonin type 2A (5HT2A) and dopamine type 2 (D2) receptors. It is proposed that the antipsychotic activity is mediated, in part, through this combination of antagonist activities. Ziprasidone is also a potent antagonist at 5HT2c and 5HT1D receptors, a potent agonist at the 5HT1A receptor and inhibits neuronal reuptake of norepinephrine and serotonin.
Pharmacokinetic properties
The bioavailability of ziprasidone administered intramuscularly is 100%. After intramuscular administration of single doses, peak serum concentrations typically occur at approximately 30 - 60 minutes post-dose. Exposure increases in a dose-related manner and following 3 days of intramuscular dosing, little accumulation is observed. The mean terminal half-life on the third day ranged from 8 to10 hours.
The mean terminal half-life of ziprasidone after intravenous administration is 6 hours. Mean clearance of ziprasidone administered intravenously is 5 mL/min/kg and the volume of distribution is approximately 1.1 L/kg.
Ziprasidone is more than 99% protein bound in serum.
Ziprasidone is extensively metabolised after oral administration with only a small amount excreted in urine (<1%) or faeces (<4%) as unchanged drug.
Ziprasidone is primarily cleared via three proposed metabolic routes to yield four major circulating metabolites, benzisothiazole piperazine (BITP) sulphoxide, BITP sulphone, ziprasidone sulphoxide and S-methyl-dihydroziprasidone. Approximately 20% of the dose is excreted in urine, and approximately 66% is eliminated in faeces. Unchanged ziprasidone represents about 44% of total drug-related material in serum.
An in vivo study suggests that conversion to S-methyl dihydroziprasidone is the major route of metabolism for ziprasidone. In vitro studies indicate that this metabolite arises via aldehyde oxidase catalysed reduction, with subsequent S-methylation. Oxidative metabolism, principally via CYP3A4 with potential contribution of CYP1A2, is also involved.
Ziprasidone, S-methyl-dihydroziprasidone, and ziprasidone sulphoxide, when tested in vitro, share properties that may predict a QTc-prolonging effect. S-methyl-dihydroziprasidone is mainly eliminated in faeces presumably by biliary excretion with a minor contribution by CYP3A4 catalysed metabolism. Ziprasidone sulphoxide is eliminated through renal excretion and by secondary metabolism catalysed by CYP3A4.
Pharmacokinetic screening of patients treated orally has not revealed any significant pharmacokinetic differences between smokers and non-smokers.
No clinically significant age- or gender-differences in the pharmacokinetics were observed following oral administration.
No marked differences in the pharmacokinetics of oral ziprasidone have been observed in patients with decreased kidney function (creatinine clearance >10 mL/min). It is unknown whether serum concentrations of the metabolites are increased in these patients.
In mild to moderate impairment of liver function (Child Pugh A or B) caused by cirrhoses, the serum concentrations after oral administration were 30% higher and the terminal half-life was about 2 hours longer than in normal patients. The effect of liver impairment on serum concentrations of the metabolites is unknown.

INDICATIONS
Acute control of agitation in psychotic patients for a maximum of 3 consecutive days.

CONTRA-INDICATIONS
Known hypersensitivity to ziprasidone or any of the excipients.
Known QT interval prolongation. Congenital long QT syndrome. Recent acute myocardial infarction. Uncompensated heart failure. Arrhythmias treated with Class I and III antiarrythmic drugs. (See Warningsand Side-effects and Special Precautions).
Safety in pregnancy and lactation has not been demonstrated.
The safety and efficacy of ziprasidone intramuscular injectionhas not been evaluated in children and adolescents.

WARNINGS
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.
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 Contraindications)
QT interval
Ziprasidone causes a mild to moderate prolongation of the QT-interval (SeeSide-effects and Special Precautions). Ziprasidone should therefore not be given together with medicinal products that are known to prolong the QT interval. 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 Contraindications).
Seizures
Caution is advised when treating patients with a history of seizures.
Neuroleptic Malignant Syndrome (NMS)
In clinical trials there was one reported case of NMS in patients receiving Geodon. The management of NMS should include immediate discontinuation of all antipsychotic medication, including Geodon.
Tardive Dyskinesia
Although in clinical trials the incidence of treatment emergent tardive dyskinesia was comparable in patients receiving Geodon and placebo, the risk of tardive dyskinesia may increase with long term exposure. 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 temporarily deteriorate or even arise after discontinuation of treatment.
Effects on ability to drive and use machines
Administration of ziprasidone results in somnolence. Patients should be instructed not to drive or operate machines until this effect has resolved.

DOSAGE AND DIRECTIONS FOR USE
FOR INTRAMUSCULAR INJECTION.
Treatment with the intramuscular formulation should only be used in patients where treatment with an oral formulation is considered to be inappropriate.
Adults
The recommended dose is 10 mg administered as required up to a maximum dose of 40 mg per day. Doses of 10 mg may be administered every 2 hours. Some patients may require an initial dose of 20 mg, which can be followed by a further dose of 10 mg after 4 hours. Thereafter, doses of 10 mg may be given every 2 hours up to a maximum daily dose of 40 mg. Intramuscular administration of ziprasidone for more than 3 consecutive days has not been studied.
If long-term therapy is indicated, oral ziprasidone hydrochloride capsules, up to 80 mg twice daily, should replace the intramuscular administration as soon as possible.
Elderly
The clinical experience with intramuscular treatment in elderly patients (>65 years) is limited. Treatment with intramuscular injection is not recommended to these patients. See Warnings and Side-effects and Special Precautions).
Use in renal impairment
Ziprasidone intramuscular injection should be administered with caution in patients with impaired renal function. (See Pharmacokinetic properties).
Use in hepatic impairment
In patients with mild to moderate hepatic insufficiency, lower doses should be considered. There is a lack of experience in patients with severe hepatic insufficiency and ziprasidone should be used with caution in this group. (See Pharmacokinetic properties).

Reconstitution
The contents of the vial should be reconstituted by introduction of 1,2 mL of the supplied Water for Injections, affording a concentration of 20 mg ziprasidone per mL, and shaking until complete dissolution has occurred (approximately one minute). Only clear solutions, free of visible particles, should be used. Only one dose (0,5 mL corresponding to the 10 mg dose, or 1 mL corresponding to the 20 mg dose), should be withdrawn from each vial and the remainder discarded.
This product does not contain an antimicrobial preservative. Chemical and physical in-use stability of the reconstituted product has been demonstrated for 24 hours up to 25°C and 7 days at 2 - 8°C. However, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer that 24 hours at 2 - 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Incompatibilities
This medicinal product must NOT be mixed with other medicinal products or solvents except Water for Injections.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
GEODON intramuscular:
GEODON IM has been administered in clinical trials to over 1000 subjects. The table below contains adverse events with possible, probable or unknown relationship to in flexible dose phase 2/3 trials. The most common reactions were injection site pain, nausea, somnolence and dizziness.

Organ system Very common (>1/10) Common
(>1/100, <1/10)		 Uncommon (>1/1000,
<1/100)		 Rare
(>1/10000,
<1/1000)
Body as a whole   Injection site pain, asthenia, headache Injection site reaction, flu syndrome 
Cardiovascular   Hypertension, postural hypotension Bradycardia, hypotension, vasodilatation, tachycardia 
Digestive   Diarrhoea, nausea Anorexia, dry mouth, vomiting 
Nervous   Somnolence, dizziness, akathisia Extrapyramidal syndrome, agitation, aphasia, cogwheel rigidity, dystonia, insomnia, personality disorder, psychosis, speech disorder, vertigo 
Respiratory     Laryngismus 
Skin and appendages     Sweating 

Some of the symptoms reported as adverse events may be associated symptoms of underlying disease.
The most common cardiovascular adverse events reported from fixed doseclinical trials with intramuscular ziprasidone were: dizziness (10 mg - 11%, 20 mg - 12%), tachycardia (10 mg - 4%, 20 mg - 4%) and postural hypotension (10 mg - 2%, 20 mg - 5%).
In premarketing fixed dose clinical trials with ziprasidone intramuscular injection,
hypertension was observed in 2.2% of patients receiving 10 mg and 2.8% of patients receiving 20 mg.
GEODON capsules:
Geodon capsules have been administered in clinical trials to over 5500 subjects. The most common adverse reaction was somnolence. The table below contains adverse events with possible, probable or unknown relationship to ziprasidone that occur at an incidence greater than placebo in short term (4 - 6 week) fixed dose studies.
Organ system Very common (>1/10) Common
(>1/100, <1/10)		 Uncommon (>1/1000,
<1/100)		 Rare
(>1/10000,
<1/1000)
Body as a whole   Asthenia, headache Pain Allergic reaction, fever
Cardiovascular     Postural hypotension, tachycardia Migraine
Digestive   Constipation, dry mouth, dyspepsia, increased salivation, nausea, vomiting Flatulence Tongue oedema
Haemic and lymphatic       Eosinophilia
Metabolic and nutritional     Thirst Lactic dehydro-genase increase
Musculoskeletal     Joint disorder, leg cramps Myalgia, myasthenia
Nervous Somnolence Agitation, akathisia, dizziness, dystonia, extrapyramidal syndrome, hypertonia, tremor Cogwheel rigidity, paresthesia, speech disorder, tardive dyskinesia Abnormal dreams, abnormal gait, akinesia, ataxia, hallucination, neuropathy, paralysis, vertigo
Respiratory     Rhinitis 
Skin and appendages     Maculopapular rash, rash, urticaria Psoriasis, skin disorder
Special senses   Abnormal vision   Amblyopia, conjunctivitis, dry eyes
Urogenital       Dysuria, gynaecomastia, impotence, urinary incontinence

Some of the symptoms reported as adverse events may be associated symptoms of underlying disease.
In short-term and long-term ziprasidone clinical trials, the incidence of seizures and hypotension was uncommon, occurring in less than 1% of ziprasidone treated patients.
Ziprasidone causes a mild to mild to moderate prolongation of the QT interval. In clinical trials, a mean QTc interval increase from screening of 3.3 msec was measured. An increase of 30 to 60 msec was seen in 12.0% (874/7303) of ECG tracings from ziprasidone-treated and 7.6% (61/799) ECG tracings from placebo-treated patients. A prolongation of >60 msec was seen in 1.3% (95/7303) and 0.9% (7/799) of tracings from ziprasidone and placebo-treated patients, respectively. The incidence of QTc interval prolongation above 500 msec was 2 in a total of 3095 (0.06%) in ziprasidone-treated patients and 1 in a total of 440 (0.23%) in placebo-treated patients.
In long term maintenance treatment in 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 manifestation (e.g. gynaecomastia and breast enlargement) was rare.
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.

Interaction with other medicinal products and other forms of interaction
Ziprasidone should not be given together with medicinal products that are known to prolong the QT-interval.
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.
Effect of ziprasidone on other drugs
All interaction studies have been conducted with oral ziprasidone.
An in vivo study with dextromethorphan showed no marked inhibition with 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 drugs 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 drugs on ziprasidone
The CYP3A4 inhibitor ketoconazole (400 mg/day) increased the serum concentrations of ziprasidone by <40%. The serum concentrations of S-methyl-dihydroziprasidone and ziprasidone sulphoxide, at the expected Tmax 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.
Carbamazepine therapy, 200 mg b.i.d for 21 days, resulted in a decrease of approximately 35% in the exposure to ziprasidone.
Antacid –multiple doses of aluminium and magnesium containing antacid did not affect the pharmacokinetics of ziprasidone.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Experience with ziprasidone overdosage is limited. With oral dosing at the largest confirmed amount, 3240 mg, the only symptoms reported were mild sedation, slurred speech and transitory hypertension (200/95 mmHg). No significant QTc prolongation occurred.
The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdosage may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. There is no specific antidote to ziprasidone.

IDENTIFICATION
GEODON 20 mg/mL powder for solution for injection: A vial containing a white to off-white lyophile. The reconstituted product is a clear and practically particle-free solution.
Water for Injections: A clear colourless solvent.

PRESENTATION
A carton containing 1 clear glass vial of GEODON IM 20 mg/mL powder for solution for injection, and 1 clear glass ampoule of Water for Injections.

STORAGE INSTRUCTIONS
Store below 30°C. Protect from light. Keep the container in the outer carton. Do not freeze.
This product does not contain an antimicrobial preservative. Chemical and physical in-use stability of the reconstituted product has been demonstrated for 24 hours up to 25°C and 7 days at 2 - 8°C. However, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer that 24 hours at 2 - 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. The reconstituted solution should be protected from light.
Keep out of reach of children.

REGISTRATION NUMBER (OR REFERENCE NUMBER)
Geodon IM 20 mg/mL: 36/2.6.5/0478
Pfizer Water for Injections: 36/34/0479

NAME AND ADDRESS OF APPLICANT
Pfizer Laboratories (Pty) Ltd
102 Rivonia Rd
Sandton 2146
SOUTH AFRICA

DATE OF PUBLICATION
31 October 2003

New addition to this site: February 2005
Source: Pharmaceutical Industry

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