ADVERSE REACTIONS
The information below is derived from a premarketing clinical study database for SYMBYAX consisting of 2066 patients with various diagnoses with approximately 1061 patient–years of exposure. The conditions and duration of treatment with SYMBYAX varied greatly and included (in overlapping categories) open–label and double–blind phases of studies, inpatients and outpatients, fixed–dose and dose–titration studies, and short–term or long–term exposure.
Adverse events were recorded by clinical investigators using descriptive 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 limited (i.e., reduced) number of standardized event categories.
In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The data in the tables 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. It is possible that events reported during therapy were not necessarily related to drug exposure.
The prescriber should be aware that the figures in the tables and tabulations 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 that prevailed in the clinical studies. 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 clinician with some basis for estimating the relative contribution of drug and non–drug factors to the side effect incidence rate in the population studied.
Incidence in Controlled Clinical Studies
The following findings are based on the short–term, controlled premarketing studies in various diagnoses including bipolar depression.
Adverse events associated with discontinuation of treatment — Overall, 10% of the patients in the SYMBYAX group discontinued due to adverse events compared with 4.6% for placebo. Table 7 enumerates the adverse events leading to discontinuation associated with the use of SYMBYAX (incidence of at least 1% for SYMBYAX and greater than that for placebo). The bipolar depression column shows the incidence of adverse events with SYMBYAX in the bipolar depression studies and the “SYMBYAX–Controlled” column shows the incidence in the controlled SYMBYAX studies; the placebo column shows the incidence in the pooled controlled studies that included a placebo arm.
Table 7: Adverse Events Associated with Discontinuation
|
Adverse Event
|
Percentage of Patients Reporting Event
|
|
SYMBYAX
|
Placebo
|
|
Bipolar Depression
(N=86)
|
SYMBYAX-Controlled
(N=571)
|
(N=477)
|
|
Asthenia
|
0
|
1
|
0
|
|
Somnolence
|
0
|
2
|
0
|
|
Weight gain
|
0
|
2
|
0
|
|
Chest pain
|
1
|
0
|
0
|
Commonly observed adverse events in controlled clinical studies — The most commonly observed adverse events associated with the use of SYMBYAX (incidence of ≥5% and at least twice that for placebo in the SYMBYAX–controlled database) were: asthenia, edema, increased appetite, peripheral edema, pharyngitis, somnolence, thinking abnormal, tremor, and weight gain.
Adverse events occurring at an incidence of 2% or more in controlled clinical studies — Table 8 enumerates the treatment–emergent adverse events associated with the use of SYMBYAX (incidence of at least 2% for SYMBYAX and twice or more that for placebo).
Table 8: Treatment-Emergent Adverse Events: Incidence in Controlled Clinical Studies |
Body System/Adverse Event
|
Percentage of Patients Reporting Event
|
|
SYMBYAX
|
Placebo
|
|
Bipolar Depression
(N=86)
|
SYMBYAX-Controlled
(N=571)
|
(N=477)
|
|
Body as a Whole
|
|
|
|
|
Asthenia
|
13
|
15
|
3
|
|
Accidental injury
|
5
|
3
|
2
|
|
Fever
|
4
|
3
|
1
|
|
Cardiovascular System
|
|
|
|
|
Hypertension
|
2
|
2
|
1
|
|
Tachycardia
|
2
|
2
|
0
|
|
Digestive System
|
|
|
|
|
Diarrhea
|
19
|
8
|
7
|
|
Dry mouth
|
16
|
11
|
6
|
|
Increased appetite
|
13
|
16
|
4
|
|
Tooth disorder
|
1
|
2
|
1
|
|
Metabolic and Nutritional Disorders
|
|
|
|
|
Weight gain
|
17
|
21
|
3
|
|
Peripheral edema
|
4
|
8
|
1
|
|
Edema
|
0
|
5
|
0
|
|
Musculoskeletal System
|
|
|
|
|
Joint disorder
|
1
|
2
|
1
|
|
Twitching
|
6
|
2
|
1
|
|
Arthralgia
|
5
|
3
|
1
|
|
Nervous System
|
|
|
|
|
Somnolence
|
21
|
22
|
11
|
|
Tremor
|
9
|
8
|
3
|
|
Thinking abnormal
|
6
|
6
|
3
|
|
Libido decreased
|
4
|
2
|
1
|
|
Hyperkinesia
|
2
|
1
|
1
|
|
Personality disorder
|
2
|
1
|
1
|
|
Sleep disorder
|
2
|
1
|
1
|
|
Amnesia
|
1
|
3
|
0
|
|
Respiratory System
|
|
|
|
|
Pharyngitis
|
4
|
6
|
3
|
|
Dyspnea
|
1
|
2
|
1
|
|
Special Senses
|
|
|
|
|
Amblyopia
|
5
|
4
|
2
|
|
Ear pain
|
2
|
1
|
1
|
|
Otitis media
|
2
|
0
|
0
|
|
Speech disorder
|
0
|
2
|
0
|
|
Urogenital System
|
|
|
|
|
Abnormal ejaculation
|
7
|
2
|
1
|
|
Impotence
|
4
|
2
|
1
|
|
Anorgasmia
|
3
|
1
|
0
|
Extrapyramidal Symptoms
Dystonia, Class Effect for Antipsychotics — 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, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with the olanzapine and fluoxetine combination.
Additional Findings Observed in Clinical Studies
The following findings are based on clinical studies.
Effect on cardiac repolarization — The mean increase in QTc interval for SYMBYAX–treated patients (4.9 msec) in clinical studies was significantly greater than that for placebo–treated (–0.9 msec) and olanzapine–treated (0.6 msec) patients, but was not significantly different from fluoxetine–treated (3.7 msec) patients. There were no differences between patients treated with SYMBYAX, placebo, olanzapine, or fluoxetine in the incidence of QTc outliers (>500 msec).
Laboratory changes — In SYMBYAX clinical studies, SYMBYAX was associated with asymptomatic mean increases in alkaline phosphatase, cholesterol, GGT, and uric acid compared with placebo (see PRECAUTIONS, Transaminase Elevations).
SYMBYAX was associated with a slight decrease in hemoglobin that was statistically significantly greater than that seen with placebo, olanzapine, and fluoxetine.
An elevation in serum prolactin was observed with SYMBYAX. This elevation was not statistically different than that seen with olanzapine (see PRECAUTIONS, Hyperprolactinemia).
Sexual dysfunction — In the pool of controlled SYMBYAX studies, there were higher rates of the treatment–emergent adverse events decreased libido, anorgasmia, impotence and abnormal ejaculation in the SYMBYAX group than in the placebo group. One case of decreased libido led to discontinuation in the SYMBYAX group. In the controlled studies that contained a fluoxetine arm, the rates of decreased libido and abnormal ejaculation in the SYMBYAX group were less than the rates in the fluoxetine group. None of the differences were statistically significant.
Sexual dysfunction, including priapism, has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
Vital signs — Tachycardia, bradycardia, and orthostatic hypotension have occurred in SYMBYAX–treated patients (see WARNINGS, Orthostatic Hypotension). The mean pulse of SYMBYAX–treated patients was reduced by 1.6 beats/min.
Additional findings — In a single 8–week randomized, double–blind, fixed–dose, study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of olanzapine in patients with schizophrenia or schizoaffective disorder, statistically significant differences among 3 dose groups were observed for the following safety outcomes: weight gain, prolactin elevation, fatigue and dizziness. Mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day. Incidence of treatment–emergent prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) with significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day; fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) with significant differences between 10 vs 40 and 20 vs 40 mg/day; and dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) with significant differences between 20 vs 40 mg, was observed.
Other Events Observed in Clinical Studies
Following is a list of all treatment–emergent adverse events reported at anytime by individuals taking SYMBYAX in clinical studies except (1) those listed in the body or footnotes of Tables 7 and 8 above or elsewhere in labeling, (2) those for which the COSTART terms were uninformative or misleading, (3) those events for which a causal relationship to SYMBYAX use was considered remote, and (4) events occurring in only 1 patient treated with SYMBYAX and which did not have a substantial probability of being acutely life–threatening.
Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on 1 or more occasions in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1000 patients, and rare events are those occurring in <1/1000 patients.
Body as a Whole — Frequent: chills, infection, neck pain, neck rigidity, photosensitivity reaction; Infrequent: cellulitis, cyst, hernia, intentional injury, intentional overdose, malaise, moniliasis, overdose, pelvic pain, suicide attempt; Rare: death, tolerance decreased.
Cardiovascular System — Frequent: migraine, vasodilatation; Infrequent: arrhythmia, bradycardia, cerebral ischemia, electrocardiogram abnormal, hypotension, QT–interval prolonged; Rare: angina pectoris, atrial arrhythmia, atrial fibrillation, bundle branch block, congestive heart failure, myocardial infarct, peripheral vascular disorder, T–wave inverted.
Digestive System — Frequent: increased salivation, thirst; Infrequent: cholelithiasis, colitis, eructation, esophagitis, gastritis, gastroenteritis, gingivitis, hepatomegaly, nausea and vomiting, peptic ulcer, periodontal abscess, stomatitis, tooth caries; Rare: aphthous stomatitis, fecal incontinence, gastrointestinal hemorrhage, gum hemorrhage, intestinal obstruction, liver fatty deposit, pancreatitis.
Endocrine System — Infrequent: hypothyroidism.
Hemic and Lymphatic System — Frequent: ecchymosis; Infrequent: anemia, leukocytosis, lymphadenopathy; Rare: coagulation disorder, leukopenia, purpura, thrombocythemia.
Metabolic and Nutritional — Frequent: generalized edema, weight loss; Infrequent: alcohol intolerance, dehydration, glycosuria, hyperlipemia, hypoglycemia, hypokalemia, obesity; Rare: acidosis, bilirubinemia, creatinine increased, gout, hyperkalemia, hypoglycemic reaction.
Musculoskeletal System — Infrequent: arthritis, bone disorder, generalized spasm, leg cramps, tendinous contracture, tenosynovitis; Rare: arthrosis, bursitis, myasthenia, myopathy, osteoporosis, rheumatoid arthritis.
Nervous System — Infrequent: abnormal gait, ataxia, buccoglossal syndrome, cogwheel rigidity, coma, confusion, depersonalization, dysarthria, emotional lability, euphoria, extrapyramidal syndrome, hostility, hypesthesia, hypokinesia, incoordination, movement disorder, myoclonus, neuralgia, neurosis, vertigo; Rare: acute brain syndrome, aphasia, dystonia, libido increased, subarachnoid hemorrhage, withdrawal syndrome.
Respiratory System — Frequent: bronchitis, lung disorder; Infrequent: apnea, asthma, epistaxis, hiccup, hyperventilation, laryngitis, pneumonia, voice alteration, yawn; Rare: emphysema, hemoptysis, laryngismus.
Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, pruritis, psoriasis, skin discoloration, vesiculobullous rash; Rare: exfoliative dermatitis, maculopapular rash, seborrhea, skin ulcer.
Special Senses — Frequent: abnormal vision, taste perversion, tinnitus; Infrequent: abnormality of accommodation, conjunctivitis, deafness, diplopia, dry eyes, eye pain, miosis; Rare: eye hemorrhage.
Urogenital System — Frequent: breast pain, menorrhagia, urinary frequency, urinary incontinence, urinary tract infection; Infrequent: amenorrhea, breast enlargement, breast neoplasm, cystitis, dysuria, female lactation, fibrocystic breast, hematuria, hypomenorrhea, leukorrhea, menopause, metrorrhagia, oliguria, ovarian disorder, polyuria, urinary retention, urinary urgency, urination impaired, vaginal hemorrhage, vaginal moniliasis, vaginitis; Rare: breast carcinoma, breast engorgement, endometrial disorder, gynecomastia, kidney calculus, uterine fibroids enlarged.
Other Events Observed with Olanzapine or Fluoxetine Monotherapy
The following adverse events were not observed in SYMBYAX–treated patients during premarketing clinical studies but have been reported with olanzapine or fluoxetine monotherapy: aplastic anemia, cholestatic jaundice, diabetic coma, dyskinesia, eosinophilic pneumonia, erythema multiforme, hepatitis, idiosyncratic hepatitis, jaundice, neutropenia, priapism, pulmonary embolism, rhabdomyolysis, serotonin syndrome, serum sickness–like reaction, sudden unexpected death, suicidal ideation, vasculitis, venous thromboembolic events (including pulmonary embolism and deep venous thrombosis), violent behaviors. Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported.
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