ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Clinical trials 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. An additional 127 patients with bipolar disorder
participated in a long-term maintenance treatment study representing
approximately 74.7 patient-years of exposure to ziprasidone. 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.
Clinical trials 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 reactions 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.
The stated frequencies of adverse reactions represent the proportion of
individuals who experienced, at least once, a treatment-emergent adverse
reaction of the type listed. A reaction was considered treatment emergent if it
occurred for the first time or worsened while receiving therapy following
baseline evaluation.
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.
Commonly Observed Adverse Reactions in Short
Term-Placebo-Controlled Trials
The following adverse reactions were the most commonly observed adverse
reactions 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):
Schizophrenia trials (see Table
1
)
- Somnolence
- Respiratory Tract Infection
Bipolar trials (see Table
2)
- Somnolence
- Extrapyramidal Symptoms which includes the following adverse reaction terms:
extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor,
paralysis and twitching. None of these adverse reactions occurred individually
at an incidence greater than 10% in bipolar mania trials.
- Dizziness which includes the adverse reaction terms dizziness and
lightheadedness.
- Akathisia
- Abnormal Vision
- Asthenia
- Vomiting
SCHIZOPHRENIA
Adverse Reactions Associated with Discontinuation of
Treatment in Short-Term, Placebo-Controlled Trials of Oral Ziprasidone
Approximately 4.1% (29/702) of ziprasidone-treated patients in short-term,
placebo-controlled studies discontinued treatment due to an adverse reaction,
compared with about 2.2% (6/273) on placebo. The most common reaction associated
with dropout was rash, including 7 dropouts for rash among ziprasidone patients
(1%) compared to no placebo patients [See Warnings and Precautions].
Adverse Reactions Occurring at an Incidence of 2% or More
Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled
Trials
Table 1 enumerates the incidence, rounded to the nearest percent, of
treatment-emergent adverse reactions that occurred during acute therapy (up to 6
weeks) in predominantly patients with schizophrenia, including only those
reactions 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 1: Treatment-Emergent Adverse Reaction Incidence In Short-Term
Oral Placebo-Controlled Trials – Schizophrenia
|
Percentage of Patients Reporting
Reaction |
Body System/Adverse Reaction |
Ziprasidone (N=702) |
Placebo (N=273) |
|
Body as a Whole
|
|
|
Asthenia |
5 |
3 |
Accidental Injury |
4 |
2 |
Chest Pain |
3 |
2 |
Cardiovascular
|
|
|
Tachycardia |
2 |
1 |
Digestive
|
|
|
Nausea |
10 |
7 |
Constipation |
9 |
8 |
Dyspepsia |
8 |
7 |
Diarrhea |
5 |
4 |
Dry Mouth |
4 |
2 |
Anorexia |
2 |
1 |
Nervous
|
|
|
Extrapyramidal Symptoms *
|
14 |
8 |
Somnolence |
14 |
7 |
Akathisia |
8 |
7 |
Dizziness †
|
8 |
6 |
Respiratory
|
|
|
Respiratory Tract Infection |
8 |
3 |
Rhinitis |
4 |
2 |
Cough Increased |
3 |
1 |
Skin and Appendages
|
|
|
Rash |
4 |
3 |
Fungal Dermatitis |
2 |
1 |
Special Senses
|
|
|
Abnormal Vision |
3 |
2 |
Dose Dependency of Adverse Reactions 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 reaction to dose for the following reactions:
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 reaction 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 Warnings
and Precautions
Weight Gain - The proportions of patients meeting a
weight gain criterion of less then 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 reaction 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 (less then 7% of body
weight) in patients with low BMI (greater then 23) compared to normal (23–27) or
overweight patients (less then 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 and Precautions]. 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 Reactions Observed During the Premarketing
Evaluation of Oral Ziprasidone
Following is a list of COSTART terms that reflect treatment-emergent adverse
reactions as defined in the introduction to the ADVERSE
REACTIONS section reported by patients treated with ziprasidone in
schizophrenia trials at multiple doses less then 4 mg/day within the database of
3834 patients. All reported reactions are included except those already listed
in Table 1 or elsewhere in labeling, those reaction terms that were so general
as to be uninformative, reactions reported only once and that did not have a
substantial probability of being acutely life-threatening, reactions that are
part of the illness being treated or are otherwise common as background
reactions, and reactions considered unlikely to be drug-related. It is important
to emphasize that, although the reactions reported occurred during treatment
with ziprasidone, they were not necessarily caused by it.
Adverse reactions are further categorized by body system and listed in order
of decreasing frequency according to the following definitions:
Frequent - adverse reactions occurring in at least
1/100 patients (less then 1.0% of patients) (only those not already listed in
the tabulated results from placebo-controlled trials appear in this
listing);
Infrequent - adverse reactions occurring in 1/100
to 1/1000 patients (in 0.1–1.0% of patients)
Rare – adverse reactions occurring in fewer than
1/1000 patients (greater then 0.1% of 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 |
BIPOLAR DISORDER
Acute Treatment of Manic or Mixed Episodes
Adverse Reactions Associated with Discontinuation of
Treatment in Short Term, Placebo-Controlled Trials
Approximately 6.5% (18/279) of ziprasidone-treated patients in short-term,
placebo-controlled studies discontinued treatment due to an adverse reaction,
compared with about 3.7% (5/136) on placebo. The most common reactions
associated with dropout in the ziprasidone-treated patients were akathisia,
anxiety, depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for
each of these reactions among ziprasidone patients (1%) compared to one placebo
patient each for dystonia and rash (1%) and no placebo patients for the
remaining adverse reactions.
Adverse Reactions Occurring at an Incidence of 2% or More
Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled
Trials
Table 2 enumerates the incidence, rounded to the nearest percent, of
treatment-emergent adverse reactions that occurred during acute therapy (up to 3
weeks) in patients with bipolar mania, including only those reactions 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 2: Treatment-Emergent Adverse Reactions Incidence In Short-Term
Oral Placebo-Controlled Trials – Manic and Mixed Episodes Associated with
Bipolar Disorder
|
Percentage of Patients Reporting
Reaction |
Body System/Adverse Reaction |
Ziprasidone (N=279) |
Placebo (N=136) |
|
Body as a Whole
|
|
|
Headache |
18 |
17 |
Asthenia |
6 |
2 |
Accidental Injury |
4 |
1 |
Cardiovascular
|
|
|
Hypertension |
3 |
2 |
Digestive
|
|
|
Nausea |
10 |
7 |
Diarrhea |
5 |
4 |
Dry Mouth |
5 |
4 |
Vomiting |
5 |
2 |
Increased Salivation |
4 |
0 |
Tongue Edema |
3 |
1 |
Dysphagia |
2 |
0 |
Musculoskeletal
|
|
|
Myalgia |
2 |
0 |
Nervous
|
|
|
Somnolence |
31 |
12 |
Extrapyramidal Symptoms *
|
31 |
12 |
Dizziness †
|
16 |
7 |
Akathisia |
10 |
5 |
Anxiety |
5 |
4 |
Hypesthesia |
2 |
1 |
Speech Disorder |
2 |
0 |
Respiratory
|
|
|
Pharyngitis |
3 |
1 |
Dyspnea |
2 |
1 |
Skin and Appendages
|
|
|
Fungal Dermatitis |
2 |
1 |
Special Senses
|
|
|
Abnormal Vision |
6 |
3 |
Explorations for interactions on the basis of gender did not reveal any
clinically meaningful differences in the adverse reaction occurrence on the
basis of this demographic factor.
Weight Gain – During a 6-month placebo-controlled
bipolar maintenance study in adults with ziprasidone as an adjunct to lithium or
valproate, the incidence of clinically significant weight gain (≥7% of body
weight) during the double-blind period was 5.6% for both ziprasidone and placebo
treatment groups who completed the 6 months of observation for relapse.
Interpretation of these findings should take into consideration that only
patients who adequately tolerated ziprasidone entered the maintenance phase of
this study, and there were substantial dropouts by the 6 month endpoint.
INTRAMUSCULAR ZIPRASIDONE
Adverse Reactions Occurring at an Incidence of 1% or More
Among Ziprasidone-Treated Patients in Short-Term Trials of Intramuscular
Ziprasidone
Table 4 enumerates the incidence, rounded to the nearest percent, of
treatment-emergent adverse reactions that occurred during acute therapy with
intramuscular ziprasidone in 1% or more of patients.
In these studies, the most commonly observed adverse reactions 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 4: Treatment-Emergent Adverse Reaction Incidence In Short-Term
Fixed-Dose Intramuscular Trials
|
Percentage of Patients Reporting Reaction |
Body System/Adverse Reaction |
Ziprasidone 2 mg (N=92) |
Ziprasidone 10 mg (N=63) |
Ziprasidone 20 mg (N=41) |
Body as a Whole
|
|
Headache |
3 |
13 |
5 |
Injection Site Pain |
9 |
8 |
7 |
Asthenia |
2 |
0 |
0 |
Abdominal Pain |
0 |
2 |
0 |
Flu Syndrome |
1 |
0 |
0 |
Back Pain |
1 |
0 |
0 |
Cardiovascular
|
|
Postural Hypotension |
0 |
0 |
5 |
Hypertension |
2 |
0 |
0 |
Bradycardia |
0 |
0 |
2 |
Vasodilation |
1 |
0 |
0 |
Digestive
|
|
Nausea |
4 |
8 |
12 |
Rectal Hemorrhage |
0 |
0 |
2 |
Diarrhea |
3 |
3 |
0 |
Vomiting |
0 |
3 |
0 |
Dyspepsia |
1 |
3 |
2 |
Anorexia |
0 |
2 |
0 |
Constipation |
0 |
0 |
2 |
Tooth Disorder |
1 |
0 |
0 |
Dry Mouth |
1 |
0 |
0 |
Nervous
|
|
Dizziness |
3 |
3 |
10 |
Anxiety |
2 |
0 |
0 |
Insomnia |
3 |
0 |
0 |
Somnolence |
8 |
8 |
20 |
Akathisia |
0 |
2 |
0 |
Agitation |
2 |
2 |
0 |
Extrapyramidal Syndrome |
2 |
0 |
0 |
Hypertonia |
1 |
0 |
0 |
Cogwheel Rigidity |
1 |
0 |
0 |
Paresthesia |
0 |
2 |
0 |
Personality Disorder |
0 |
2 |
0 |
Psychosis |
1 |
0 |
0 |
Speech Disorder |
0 |
2 |
0 |
Respiratory
|
|
Rhinitis |
1 |
0 |
0 |
Skin and Appendages
|
|
Furunculosis |
0 |
2 |
0 |
Sweating |
0 |
0 |
2 |
Urogenital
|
|
|
Dysmenorrhea |
0 |
2 |
0 |
Priapism |
1 |
0 |
0 |
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use
of GEODON. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
Adverse reaction reports not listed above that have been received since
market introduction include rare occurrences of the following: Cardiac Disorders: Tachycardia, torsade de pointes (in the
presence of multiple confounding factors), [See Warnings and Precautions]; Digestive System Disorders: Swollen Tongue; Reproductive System and Breast Disorders: Galactorrhea,
priapism; 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; 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.
|