Ziprasidone Hydrochloride (Page 4 of 9)

6 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 5,700 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 1,831 patient-years. These patients include: (1) 4,331 patients who participated in multiple-dose trials, predominantly in schizophrenia, representing approximately 1698 patient-years of exposure as of February 5,2000. 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.

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) 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 6)

•

Somnolence

•

Respiratory Tract Infection

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 ( ) 5.6

Adverse Reactions Occurring at an Incidence of 2% or More Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled Trials

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 6

Table 6 Treatment-Emergent Adverse Reaction Incidence In Short-Term Oral Placebo-Controlled Trials — Schizophrenia

* Extrapyramidal Symptoms 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 5% in schizophrenia trials. † Dizziness includes the adverse reaction terms dizziness and lightheadedness.
	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

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. Class Effect:

Vital Sign Changes

Ziprasidone is associated with orthostatic hypotension [see WARNINGS AND PRECAUTIONS ( )]. 5.7

ECG Changes

Ziprasidone is associated with an increase in the QTc interval [see ] 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. WARNINGS AND PRECAUTIONS ( ) 5.2.

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 section reported by patients treated with ziprasidone in schizophrenia trials at multiple doses >4 mg/day within the database of 3,834 patients. All reported reactions are included except those already listed in 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 Table 6

Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions:

adverse reactions occurring in at least 1/100 patients (≥1% of patients) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); Frequent –

adverse reactions occurring in 1/100 to 1/1000 patients (in 0.1 to 1% of patients) Infrequent-

adverse reactions occurring in fewer than 1/1000 patients (<0.1% of patients). – Rare

Body as a Whole

abdominal pain, flu syndrome, fever, accidental fall, face edema, chills, photosensitivity reaction, flank pain, hypothermia, motor vehicle accident – Frequent

Cardiovascular System

tachycardia, hypertension, postural hypotension – Frequent

bradycardia, angina pectoris, atrial fibrillation Infrequent –

first degree AV block, bundle branch block, phlebitis, pulmonary embolus, cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, myocarditis, thrombophlebitis Rare –

Digestive System

anorexia, vomiting Frequent –

rectal hemorrhage, dysphagia, tongue edema Infrequent –

gum hemorrhage, jaundice, fecal impaction, gamma glutamyl transpeptidase increased, hematemesis, cholestatic jaundice, hepatitis, hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena – Rare

Endocrine

hypothyroidism, hyperthyroidism, thyroiditis Rare –

Hemic and Lymphatic System

anemia, ecchymosis, leukocytosis, leukopenia, eosinophilia, lymphadenopathy Infrequent –

thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, thrombocythemia – Rare

Metabolic and Nutritional Disorders

thirst, transaminase increased, peripheral edema, hyperglycemia, creatine phosphokinase increased, alkaline phosphatase increased, hypercholesteremia, dehydration, lactic dehydrogenase increased, albuminuria, hypokalemia – Infrequent

BUN increased, creatinine increased, hyperlipemia, hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia, hypoglycemicreaction, hypomagnesemia, ketosis, respiratory alkalosis – Rare

Musculoskeletal System

myalgia – Frequent

tenosynovitis – Infrequent

myopathy Rare –

Nervous System

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 Frequent –

paralysis Infrequent –

myoclonus, nystagmus, torticollis, circumoral paresthesia, opisthotonos, reflexes increased, trismus Rare –

Respiratory System

dyspnea Frequent –

pneumonia, epistaxis Infrequent –

hemoptysis, laryngismus Rare –

Skin and Appendages

maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash – Infrequent

Special Senses

fungal dermatitis Frequent –

conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia Infrequent –

eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis – Rare

Urogenital System

impotence, abnormal ejaculation, amenorrhea, hematuria, menorrhagia, female lactation, polyuria, urinary retention metrorrhagia, male sexual dysfunction, anorgasmia, glycosuria Infrequent –

gynecomastia, vaginal hemorrhage, nocturia, oliguria, female sexual dysfunction, uterine hemorrhage Rare –