Ziprasidone hydrochloride monohydrate Capsules
1. NAME(S) OF THE MEDICINAL PRODUCT
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
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.
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
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
Use in the Elderly
Generally, no dosage adjustment is required in elderly patients (65 years
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.
Ziprasidone is contraindicated in patients with:
Known hypersensitivity to ziprasidone or any of the excipients;
Known QT interval prolongation including congenital long QT Syndrome;
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
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
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
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:
• 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.)
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.
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, 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.
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.
As with other antipsychotics, caution is recommended when treating patients
with a history of seizures.
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.