Premarketing experience
The premarketing development program for oral ziprasidone included approximately
5700 patients and/or normal subjects exposed to one or more doses of ziprasidone.
Of these 5700, over 4800 were patients who participated in multiple-dose effectiveness
trials, and their experience corresponded to approximately 1831 patient-years. These
patients include: (1) 4331 patients who participated in multiple-dose trials, predominantly
in schizophrenia, representing approximately 1698 patient-years of exposure as of
February 5, 2000; and (2) 472 patients who participated in bipolar mania trials
representing approximately 133 patient-years of exposure. The conditions and duration
of treatment with ziprasidone included open-label and double-blind studies, inpatient
and outpatient studies, and short-term and longer-term exposure.
The premarketing development program for intramuscular ziprasidone included 570
patients and/or normal subjects who received one or more injections of ziprasidone.
Over 325 of these subjects participated in trials involving the administration of
multiple doses.
Adverse events during exposure were obtained by collecting voluntarily reported
adverse experiences, as well as results of physical examinations, vital signs, weights,
laboratory analyses, ECGs, and results of ophthalmologic examinations. Adverse experiences
were recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the proportion
of individuals experiencing adverse events without first grouping similar types
of events into a smaller number of standardized event categories. In the tables
and tabulations that follow, standard COSTART dictionary terminology has been used
to classify reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals
who experienced, at least once, a treatment-emergent adverse event of the type listed.
An event was considered treatment emergent if it occurred for the first time or
worsened while receiving therapy following baseline evaluation.
The prescriber should be aware that these figures cannot be used to predict the
incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those which prevailed in the clinical
trials. Similarly, the cited frequencies cannot be compared with figures obtained
from other clinical investigations involving different treatments, uses, and investigators.
The cited figures, however, do provide the prescribing physician with some basis
for estimating the relative contribution of drug and non-drug factors to the side
effect incidence rate in the population studied.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials with Oral Ziprasidone
The following findings are based on the short-term placebo-controlled premarketing
trials for schizophrenia (a pool of two 6-week, and two 4-week fixed-dose trials)
and bipolar mania (a pool of two 3-week flexible-dose trials) in which ziprasidone
was administered in doses ranging from 10 to 200 mg/day.
Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled
Trials of Oral Ziprasidone
Schizophrenia – Approximately 4.1% (29/702) of ziprasidone-treated
patients in short-term, placebo-controlled studies discontinued treatment due to
an adverse event, compared with about 2.2% (6/273) on placebo. The most common event
associated with dropout was rash, including 7 dropouts for rash among ziprasidone
patients (1%) compared to no placebo patients (see PRECAUTIONS).
Bipolar Mania – Approximately 6.5% (18/279) of ziprasidone-treated
patients in short-term, placebo-controlled studies discontinued treatment due to
an adverse event, compared with about 3.7% (5/136) on placebo. The most common events
associated with dropout in the ziprasidone-treated patients were akathisia, anxiety,
depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for each of
these events among ziprasidone patients (1%) compared to one placebo patient each
for dystonia and rash (1%) and no placebo patients for the remaining adverse events.
Commonly Observed Adverse Events in Short-Term, Placebo-Controlled Trials – The
most commonly observed adverse events associated with the use of ziprasidone (incidence
of 5% or greater) and not observed at an equivalent incidence among placebo-treated
patients (ziprasidone incidence at least twice that for placebo) are shown in Tables
1 and 2.
Table 1: Common Treatment-Emergent Adverse Events Associated with the Use of Ziprasidone
in 4- and 6-Week Trials — SCHIZOPHRENIA
Table 2: Common Treatment-Emergent Adverse Events Associated with the Use of Ziprasidone
in 3-Week Trials — BIPOLAR MANIA
Adverse Events Occurring at an Incidence of 2% or More Among Ziprasidone-Treated
Patients in Short-Term, Oral, Placebo-Controlled Trials
Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent
adverse events that occurred during acute therapy (up to 6 weeks) in predominantly
patients with schizophrenia, including only those events that occurred in 2% or
more of patients treated with ziprasidone and for which the incidence in patients
treated with ziprasidone was greater than the incidence in placebo-treated patients.
Table 3: Treatment-Emergent Adverse Event Incidence In Short-Term Oral Placebo-Controlled
Trials — SCHIZOPHRENIA
Table 4 enumerates the incidence, rounded to the nearest percent, of treatment-emergent
adverse events that occurred during acute therapy (up to 3 weeks) in patients with
bipolar mania, including only those events that occurred in 2% or more of patients
treated with ziprasidone and for which the incidence in patients treated with ziprasidone
was greater than the incidence in placebo-treated patients.
Table 4: Treatment-Emergent Adverse Event Incidence In Short-Term Oral Placebo-Controlled
Trials — BIPOLAR MANIA
Explorations for interactions on the basis of gender did not reveal any clinically
meaningful differences in the adverse event occurrence on the basis of this demographic
factor.
Dose Dependency of Adverse Events in Short-Term, Fixed-Dose, Placebo-Controlled Trials
An analysis for dose response in the schizophrenia 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.
Extrapyramidal Symptoms (EPS) – The incidence of reported EPS (which
included the adverse event terms extrapyramidal syndrome, hypertonia, dystonia,
dyskinesia, hypokinesia, tremor, paralysis and twitching) for ziprasidone-treated
patients in the short-term, placebo-controlled schizophrenia trials was 14% vs.
8% for placebo. Objectively collected data from those trials on the Simpson-Angus
Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally
show a difference between ziprasidone and placebo.
Dystonia –
Class Effect: Symptoms of dystonia, prolonged
abnormal contractions of muscle groups, may occur in susceptible individuals during
the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles,
sometimes progressing to tightness of the throat, swallowing difficulty, difficulty
breathing, and/or protrusion of the tongue. While these symptoms can occur at low
doses, they occur more frequently and with greater severity with high potency and
at higher doses of first generation antipsychotic drugs. An elevated risk of acute
dystonia is observed in males and younger age groups.
Vital Sign Changes – Ziprasidone is associated with orthostatic
hypotension (see PRECAUTIONS).
Weight Gain – The proportions of patients meeting a weight gain
criterion of ≥7% of body weight were compared in a pool of four 4- and 6-week placebo-controlled
schizophrenia clinical trials, revealing a statistically significantly greater incidence
of weight gain for ziprasidone (10%) compared to placebo (4%). A median weight gain
of 0.5 kg was observed in ziprasidone patients compared to no median weight change
in placebo patients. In this set of clinical trials, weight gain was reported as
an adverse event in 0.4% and 0.4% of ziprasidone and placebo patients, respectively.
During long-term therapy with ziprasidone, a categorization of patients at baseline
on the basis of body mass index (BMI) revealed the greatest mean weight gain and
highest incidence of clinically significant weight gain (>7% of body weight)
in patients with low BMI (<23) compared to normal (23-27) or overweight patients
(>27). There was a mean weight gain of 1.4 kg for those patients with a "low"
baseline BMI, no mean change for patients with a "normal" BMI, and a 1.3 kg mean
weight loss for patients who entered the program with a "high" BMI.
ECG Changes – Ziprasidone is associated with an increase in the
QTc interval (see WARNINGS). In the schizophrenia trials, ziprasidone was
associated with a mean increase in heart rate of 1.4 beats per minute compared to
a 0.2 beats per minute decrease among placebo patients.
Other Adverse Events Observed During the Premarketing Evaluation of Oral Ziprasidone
Following is a list of COSTART terms that reflect treatment-emergent adverse events
as defined in the introduction to the ADVERSE REACTIONS section reported
by patients treated with ziprasidone in schizophrenia trials at multiple doses >4
mg/day within the database of 3834 patients. All reported events are included except
those already listed in Table 3 or elsewhere in labeling, those event terms that
were so general as to be uninformative, events reported only once and that did not
have a substantial probability of being acutely life-threatening, events that are
part of the illness being treated or are otherwise common as background events,
and events considered unlikely to be drug-related. It is important to emphasize
that, although the events reported occurred during treatment with ziprasidone, they
were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency according to the following definitions: frequent adverse events are those
occurring in at least 1/100 patients (only those not already listed in the tabulated
results from placebo-controlled trials appear in this listing); infrequent adverse
events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring
in fewer than 1/1000 patients.
Body as a Whole: Frequent: abdominal pain, flu syndrome, fever,
accidental fall, face edema, chills, photosensitivity reaction, flank pain, hypothermia,
motor vehicle accident.
Cardiovascular System: Frequent: tachycardia, hypertension, postural
hypotension; Infrequent: bradycardia, angina pectoris, atrial fibrillation;
Rare: first degree AV block, bundle branch block, phlebitis, pulmonary embolus,
cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis,
myocarditis, thrombophlebitis.
Digestive System: Frequent: anorexia, vomiting; Infrequent:
rectal hemorrhage, dysphagia, tongue edema; Rare: gum hemorrhage, jaundice,
fecal impaction, gamma glutamyl transpeptidase increased, hematemesis, cholestatic
jaundice, hepatitis, hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena.
Endocrine: Rare: hypothyroidism, hyperthyroidism, thyroiditis.
Hemic and Lymphatic System: Infrequent: anemia, ecchymosis, leukocytosis,
leukopenia, eosinophilia, lymphadenopathy; Rare: thrombocytopenia, hypochromic
anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, thrombocythemia.
Metabolic and Nutritional Disorders: Infrequent: thirst, transaminase
increased, peripheral edema, hyperglycemia, creatine phosphokinase increased, alkaline
phosphatase increased, hypercholesteremia, dehydration, lactic dehydrogenase increased,
albuminuria, hypokalemia; Rare: BUN increased, creatinine increased, hyperlipemia,
hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia,
glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia,
hypoglycemic reaction, hypomagnesemia, ketosis, respiratory alkalosis.
Musculoskeletal System: Frequent: myalgia; Infrequent:
tenosynovitis; Rare: myopathy.
Nervous System: Frequent: agitation, extrapyramidal syndrome,
tremor, dystonia, hypertonia, dyskinesia, hostility, twitching, paresthesia, confusion,
vertigo, hypokinesia, hyperkinesia, abnormal gait, oculogyric crisis, hypesthesia,
ataxia, amnesia, cogwheel rigidity, delirium, hypotonia, akinesia, dysarthria, withdrawal
syndrome, buccoglossal syndrome, choreoathetosis, diplopia, incoordination, neuropathy;
Infrequent: paralysis; Rare: myoclonus, nystagmus, torticollis, circumoral
paresthesia, opisthotonos, reflexes increased, trismus.
Respiratory System: Frequent: dyspnea; Infrequent: pneumonia,
epistaxis; Rare: hemoptysis, laryngismus.
Skin and Appendages: Infrequent: maculopapular rash, urticaria,
alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash.
Special Senses: Frequent: fungal dermatitis; Infrequent:
conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia; Rare:
eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis.
Urogenital System: Infrequent: impotence, abnormal ejaculation,
amenorrhea, hematuria, menorrhagia, female lactation, polyuria, urinary retention,
metrorrhagia, male sexual dysfunction, anorgasmia, glycosuria; Rare: gynecomastia,
vaginal hemorrhage, nocturia, oliguria, female sexual dysfunction, uterine hemorrhage.
Adverse Findings Observed in Trials of Intramuscular Ziprasidone
Adverse Events Occurring at an Incidence of 1% or More Among Ziprasidone-Treated
Patients in Short-Term Trials of Intramuscular Ziprasidone
Table 5 enumerates the incidence, rounded to the nearest percent, of treatment-emergent
adverse events that occurred during acute therapy with intramuscular ziprasidone
in 1% or more of patients.
In these studies, the most commonly observed adverse events associated with the
use of intramuscular ziprasidone (incidence of 5% or greater) and observed at a
rate on intramuscular ziprasidone (in the higher dose groups) at least twice that
of the lowest intramuscular ziprasidone group were headache (13%), nausea (12%),
and somnolence (20%).
Table 5: Treatment-Emergent Adverse Event Incidence In Short-Term Fixed-Dose Intramuscular
Trials
Other Events Observed During Post-marketing Use
Adverse event reports not listed above that have been received since market introduction
include rare occurrences of the following (no causal relationship with ziprasidone
has been established): Cardiac Disorders: Tachycardia, torsade de pointes
(in the presence of multiple confounding factors - see WARNINGS);
Digestive System Disorders: Swollen tongue; Nervous System Disorders:
Facial droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination
with serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders:
Insomnia, mania/hypomania; Reproductive System and Breast Disorders: Galactorrhea,
priapism; Skin and subcutaneous Tissue Disorders: Allergic reaction (such
as allergic dermatitis, angioedema, orofacial edema, urticaria), rash; Urogenital
System Disorders: Enuresis, urinary incontinence; Vascular Disorders:
Postural hypotension, syncope.