ZELDOX^®
Ziprasidone hydrochloride monohydrate Capsules

1. NAME(S) OF THE MEDICINAL PRODUCT
ZELDOX

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Capsules containing ziprasidone hydrochloride monohydrate equivalent to 20, 40, 60 or 80 mg ziprasidone.

3. PHARMACEUTICAL FORM
Ziprasidone is available as capsules for oral administration:
20 mg - No. 4 blue/white capsules, marked "Pfizer" and "ZDX 20"
40 mg - No. 4 blue capsules, marked "Pfizer" and "ZDX 40"
60 mg - No. 3 white capsules, marked "Pfizer" and "ZDX 60"
80 mg - No. 2 blue/white capsules, marked "Pfizer" and "ZDX 80"

4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Schizophrenia
Ziprasidone is indicated for the management of schizophrenia and other psychotic disorders, and for maintenance of clinical improvement and prevention of relapse during continuation therapy. The efficacy of ziprasidone in the treatment of the positive and negative symptoms of schizophrenia was established in four- and six-week placebo- and active-controlled clinical trials of hospitalized patients experiencing an acute exacerbation of the illness.

In a 52-week placebo-controlled clinical trial of chronic stable inpatients, ziprasidone demonstrated continuing improvement in primary negative symptoms and in global (psychological, social and occupational) functioning in this study of inpatient population over a 52-week period.

An analysis of the effect of ziprasidone on patients with clinically significant depressive symptoms, defined as ≥14 on the Montgomery-Asberg Depression Rating Scale (MADRS), was conducted in two multicenter placebo-controlled studies in acute schizophrenia. A statistically significant improvement versus placebo (p<0.05) in the MADRS was observed in these two studies in patients receiving 60 mg and 80 mg twice daily.

Bipolar Mania
Ziprasidone is indicated for the treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features.
 

Treatment of mania with ziprasidone for more than 3 weeks and prophylactic use in bipolar disorder have not been systematically evaluated in controlled clinical trials.

4.2 Posology and Method of Administration
Ziprasidone capsules for oral use.

Use in Adults
Schizophrenia and Bipolar Mania

The recommended initial dose is 40 mg twice daily, to be taken with food (see Section 5.2 Pharmacokinetic Properties). Daily dosage may subsequently be adjusters on the basis of individual clinical status up to a maximum of 80 mg twice daily. If indicated, the maximum recommended dose may be reached as early as Day 3 of treatment.

Use in Children
Safety and effectiveness in children under 18 years have not been established.

Use in the Elderly
Generally, no dosage adjustment is required in elderly patients (65 years and over).

Use in Renal Impairment
No dosage adjustment is required in patients with renal impairment.

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 Section 5.2 Pharmacokinetic Properties.)

Use in Smokers
No dosage adjustment is required in patients who smoke.

4.3 Contraindications
Ziprasidone is contraindicated in patients with:
Known hypersensitivity to ziprasidone or any of the excipients;
Known QT interval prolongation including congenital long QT Syndrome;

Recent myocardial infarction;
Uncompensated heart failure;
Cardiac arrhythmias requiring treatment with Class IA and III antiarrhythmic drugs. (See Section 4.4 Special Warnings and Precautions for Use.)

Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have riot been performed. An additive effect of ziprasidone and other drugs that prolong the OT interval cannot be excluded. Therefore, ziprasidone should not be given with dofetilide, sotalol, quinidine, other Class IA and III antiarrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquin, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. Ziprasidone is also contraindicated with drugs that have demonstrated QT prolongation as one of the pharmacodynamic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bolded warning.

4.4 Special Warnings and Precautions for Use

QT Interval
Ziprasidone causes a mild to moderate prolongation of the QT interval.

In the premarketing clinical trials database for the oral formulation, the incidence of QTc prolongation above 500 msec was 3 in a total of 3266 (0.1 %) in ziprasidone-treated patients and 1 in a total of 538 (0.2%) in placebo-treated patients.

Some drugs including Class IA and III antiarrhythmics that prolong the QT interval greater than 500 msec have been associated with the rare occurrence of torsade de polntes, a Iife-threatening arrhythmia (see Section 4.3 Contraindications).

There have been rare post-marketing reports of torsade de pointes in patients with multiple confounding risk factors taking ziprasidone. A causal relationship with ziprasidone has not been established.

Ziprasidone should be used with caution in patients with the following risk factors, which can increase the risk for occurrence of this arrhythmia:
• bradycardia;
• electrolyte imbalance;
• concomitant use with other drugs that prolong QT.

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. (See Section 4.3 Contraindications.)

Ziprasidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Neroleptic Malignant Syndrome (NMS)
Neuroleptic Malignant Syndrome (NMS), a potentially fatal complex, has been reported in association with antipsychotic drugs, including ziprasidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (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 must be discontinued.

Tardive Dyskinesia
As with other antipsychotics, there is a potential for ziprasidone to cause tardive dyskinesia and other tardive extrapyramidal syndromes after long-term treatment. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of ziprasidone should be considered.

Hyperglycemia/Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. 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. However, epidemiological studies, which did not include ziprasidone, suggest an increased risk of treatment-emergent hyperglycemiarelated adverse events in patients treated with the atypical antipsychotics included in these studies. There have been few reports of hyperglycemia or diabetes in patients treated with ziprasidone.

Patients with an established diagnosis of diabetes mellitus should be monitored for worsening of glucose control. Appropriate clinical monitoring is advised for patients with risk factors for diabetes (e.g., obesity, family history of diabetes) and those who develop symptoms of hyperglycemia during treatment with atypical antipsychotics. Patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia and weakness.

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

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.

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

Increased Risk o Cerebrovascular Accidents in The Dementia Population

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

Increased Mortality ink Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis have been shown to be at an increased risk of death compared with placebo when treated with some atypical antipsychotic drugs. Study data with ziprasidone in the treatment of elderly patients with dementia are insufficient to conclude whether or not there is an increased risk of death with ziprasidone versus placebo in this patient population. Ziprasidone is not approved for the treatment of elderly patients with dementia-related psychosis.

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