INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo GEODON 20 mg, 40 mg, 60 mg and 80 mg CAPSULES
SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

GEODON 20 mg, 40 mg, 60 mg and 80 mg CAPSULES

Ziprasidone hydrochloride
GEODON 20 mg capsules
GEODON 40 mg capsules
GEODON 60 mg capsules
GEODON 80 mg capsules

COMPOSITION
Each Geodon 20 mg, 40 mg, 60 mg and 80 mg capsule contains ziprasidone hydrochloride monohydrate equivalent to 20 mg, 40 mg, 60 mg and 80 mg ziprasidone respectively.
Geodon capsules contain the following inactive ingredients: lactose, pregelatinised starch, magnesium stearate and gelatin capsules containing titanium dioxide and indigotin (indigo carmine).

PHARMACOLOGICAL CLASSIFICATION
A.2.6.5 Central nervous system depressants: Miscellaneous structures.

PHARMACOLOGICAL ACTION
Ziprasidone has a high affinity for dopamine type 2 (D2) receptors and substantially higher affinity for serotonin type 2A(5HT2A) receptors.
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.
Additional preclinical studies were carried out to identify agonist or antagonist effects at receptors in which ziprasidone binds with high to moderate affinity. 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.
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).
Absorption:
Following oral administration of multiple doses of ziprasidone with food, peak serum concentrations typically occur 6 to 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, while absorption is halved in the fasting state.
There are no clinically significant differences in the pharmacokinetics of ziprasidone in young and elderly, male or female subjects.
Distribution:
Ziprasidone is greater than 99% protein bound. Twice daily dosing generally leads to attainment of steady state after 1 to 3 days. Systemic exposures at steady state are related to dose. Ziprasidone has a volume of distribution of approximately 1.5 L/kg when administered intravenously.
Biotransformation:
Ziprasidone is extensively metabolised after oral administration with only a small amount (<1%) excreted in urine or faeces (<4%) as unchanged drug.
Ziprasidone is primarily cleared via three 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, with approximately 66% being eliminated in faeces. Unchanged ziprasidone represents about 44% of total drug-related material in serum.
In vitro studies indicate that CYP3A4 is the major cytochrome P450 catalysing the oxidative metabolism of ziprasidone. S-methyl-dihydroziprasidone is generated in two steps catalysed by aldehyde oxidase and thiol methyltransferase.
Ziprasidone, S-methyl-dihydroziprasidone, and ziprasidone sulphoxide, when tested in vitro, share properties which may predict a QTc-prolonging effect. S-methyl-dihydroziprasidone is mainly eliminated by faecal excretion and CYP3A4 catalysed metabolism. The sulphoxide is eliminated through renal extraction and by secondary metabolism catalysed by CYP3A4.
In a phase I trial, the CYP3A4 inhibitor ketoconazole (400 mg/day) increased the serum concentrations of ziprasidone by <40%. The serum concentration of S-methyl-dihydroziprasidone, at the expected Tmax of ziprasidone, was increased by 55% during ketoconazole treatment. No additionalQTc prolongation was observed.
Pharmacokinetic evaluation of ziprasidone serum concentrations of patients treated orally has not revealed any significant pharmacokinetic differences between smokers and non-smokers.
Elimination:
The mean terminal phase half life of ziprasidone after multiple dosing of normal volunteers and schizophrenic patients was 6.6 hours and 9.8 hours respectively, in the range 3 to 18 hours.
Mean systemic clearance of ziprasidone administered intravenously is approximately 7,5 mL/min/kg.
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
Geodon is indicated in the treatment of acute exacerbations and in maintaining the clinical improvement during continuation therapy in patients with schizophrenia.

CONTRA-INDICATIONS
Known hypersensitivity to any ingredient of the product.
Known QT-interval prolongation including long QT syndrome. Recent acute myocardial infarction. Uncompensated heart failure. Cardiac arrhythmias requiring treatment with Class I and III antiarrhythmic drugs.
Safety in pregnancy and lactation have not been established.
Use in children, as ziprasidone has not been evaluated in subjects under 18 years of age.

WARNINGS
Lactose
Ziprasidone capsules contain lactose.
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.

Special Precautions
Central Nervous System Medication/Alcohol
Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting medication and alcohol. As it exhibits in vitro dopamine antagonism, ziprasidone may antagonise the effects of direct and indirect dopamine agonists.
QT Interval
Geodon may cause a prolongation of the QTc-interval.
In the premarketing clinical trials database for the oral formulation, the incidence of QTc 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.
Medicines that prolong the QT interval have been associated with the rare occurrence of torsade de pointes, a life-threatening arrhythmia. Bradycardia, electrolyte imbalance or concomitant use with other medicines that prolong QT can increase the risk of occurrence of this arrhythmia. Therefore, Geodon should be used with caution in patients with these risk factors. If cardiac symptoms suggestive of arrhythmias are observed or reported during treatment, then appropriate cardiac diagnostics should be performed. If the QTc interval is greater than 500 msec, it is recommended that treatment be stopped.
Effects on Ability to Drive and Use Machines
Ziprasidone may cause somnolence. Patients likely to drive or operate other machines should therefore be cautioned appropriately.

DOSAGE AND DIRECTION FOR USE
Use in Adults:
The recommended dose 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. If indicated, the maximum recommended dose of 80 mg twice daily may be reached as early as day 3 of treatment. Some patients may be adequately managed on 20 mg twice daily.
Use in the elderly:
There is only limited clinical information in the elderly. Caution should be exercised when Geodon is administered in the elderly.
Use in Renal Impairment:
No dosage adjustment is required in patients with impaired renal function.
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.
Seizures: Caution is advised when administering Geodon to patients with seizures.
Effects of Smoking:
No dosage adjustment is required in patients who smoke (see Pharmacological Action).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Geodon capsules have been administered in clinical trials to over 5500 subjects. The most common adverse event was somnolence. The table below contains adverse events with possible, probable or unknown relationship to ziprasidone which 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 dehydrogenase 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 mild to moderate prolongation of the QT interval. In clinical trials, a mean QTc 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.
Other Findings
In long-term maintenance treatment in clinical trials, prolactin levels in patients treated with ziprasidone were elevated (in 12%) compared with 3% in the placebo group. Gynecomastia and breast enlargement have been observed. In most patients, levels returned to normal ranges without cessation of treatment.

Interactions with Other Drugs and Other Forms of Interaction
Effect of Ziprasidone on Other Medicines
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-fold higher than the free concentration that can be expected in vivo. Ziprasidone is unlikely to cause clinically important drug interactions mediated by these enzymes.
Dextromethorphan - the pharmacokinetics and metabolism of dextromethorphan, a CYP2D6 substrate, was unaffected by ziprasidone.
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 has no effect on the steady state or renal clearance of lithium.
Effect of Other Medicines on Ziprasidone:
Ziprasidone is metabolised by aldehyde oxidase and to a lesser extent by CYP3A4. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase. Ketoconazole (400 mg/day), a potent inhibitor of CYP3A4, produced an increase of approximately 35% in ziprasidone exposure (AUC and Cmax). Carbamazepine 200 mg twice daily, an inducer of CYP3A4, produced a decrease of 36% in ziprasidone exposure. These changes produced by ketoconazole or carbamazepine are unlikely to be clinically relevant. Cimetidine, a nonspecific CYP inhibitor, did not significantly alter the pharmacokinetics of ziprasidone.
Antacid - multiple doses of aluminium- and magnesium-containing antacid did not affect the pharmacokinetics of ziprasidone.
In addition, pharmacokinetic screening of patients in clinical trials has not revealed any evidence of clinically significant interactions with benztropine, propranolol or lorazepam.
Pharmacokinetic studies have demonstrated that the bioavailability of ziprasidone is significantly increased in the presence of food. It is therefore recommended that ziprasidone should be taken with food.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In cases of suspected overdose, the possibility of multiple medication involvement should be considered. Gastric lavage, (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose 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: No. 4, blue/white, opaque capsules, marked “Pfizer”and ZDX 20”
GEODON 40 mg: No. 4, blue, opaque capsules, marked “Pfizer”and ZDX 40”
GEODON 60 mg: No. 3 white, opaque capsules, marked “Pfizer”and ZDX 60”
GEODON 80 mg: No. 2 blue/white, opaque capsules, marked “Pfizer”and ZDX 80”

PRESENTATION
GEODON capsules are available in the following containers:
Blister strips (PVC/foil) containing 14, 20, 30, 50, 56, 60 or 100 capsules
HDPE bottles containing 100 capsules

STORAGE INSTRUCTIONS
Store below 30°C. Keep out of reach of children.

REGISTRATION NUMBERS
GEODON 20 mg capsules: 32/2.6.5/0584
GEODON 40 mg capsules: 32/2.6.5/0585
GEODON 60 mg capsules: 32/2.6.5/0586
GEODON 80 mg capsules: 32/2.6.5/0587

NAME AND BUSINESS ADDRESS OF APPLICANT
Pfizer Laboratories (Pty) Ltd
102 Rivonia Road
Sandton 2196
SOUTH AFRICA

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
31 October 2003

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

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