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Geodon (Ziprasidone Hydrochloride) - Side Effects and Adverse Reactions

 
 



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.



REPORTS OF SUSPECTED GEODON SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Geodon. The information is not vetted and should not be considered as verified clinical evidence.

Possible Geodon side effects / adverse reactions in 38 year old female

Reported by a physician from United States on 2011-10-03

Patient: 38 year old female

Reactions: Galactorrhoea, Hyperprolactinaemia, Pituitary Tumour

Suspect drug(s):
Invega Sustenna
    Indication: Schizophrenia
    Start date: 2011-07-01

Geodon
    Indication: Product Used FOR Unknown Indication

Invega
    Administration route: Oral
    Indication: Schizophrenia
    End date: 2011-07-01



Possible Geodon side effects / adverse reactions in 55 year old female

Reported by a physician from United States on 2011-10-07

Patient: 55 year old female

Reactions: Narcolepsy

Adverse event resulted in: life threatening event

Suspect drug(s):
Geodon
    Indication: Mania

Geodon
    Dosage: 80 mg, 2x/day
    Indication: Bipolar Disorder
    Start date: 2010-01-01
    End date: 2011-01-01



Possible Geodon side effects / adverse reactions in 48 year old female

Reported by a physician from United States on 2011-10-07

Patient: 48 year old female

Reactions: Narcolepsy

Adverse event resulted in: life threatening event

Suspect drug(s):
Geodon
    Indication: Mania

Geodon
    Dosage: 80 mg, 2x/day
    Indication: Bipolar Disorder
    Start date: 2010-01-01
    End date: 2011-01-01



See index of all Geodon side effect reports >>

Drug label data at the top of this Page last updated: 2010-12-20

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