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Symbyax (Olanzapine / Fluoxetine Hydrochloride) - Side Effects and Adverse Reactions



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 or predict the rates observed in practice.

Clinical Trials Experience

The information below is derived from a clinical study database for SYMBYAX consisting of 2547 patients with treatment resistant depression, depressive episodes associated with Bipolar I Disorder, Major Depressive Disorder with psychosis, or sexual dysfunction with approximately 1085 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 reactions 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 reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories.

In the tables and tabulations that follow, MedDRA or COSTART Dictionary terminology has been used to classify reported adverse reactions. The data in the tables 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. It is possible that reactions 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 nondrug factors to the side effect incidence rate in the population studied.

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression  â€” Overall, 11.3% of the 771 patients in the SYMBYAX group discontinued due to adverse reactions compared with 4.4% of the 477 patients for placebo. Adverse reactions leading to discontinuation associated with the use of SYMBYAX (incidence of at least 1% for SYMBYAX and greater than that for placebo) using MedDRA Dictionary coding were weight increased (2%) and sedation (1%) versus placebo patients which had 0% incidence of weight increased and sedation.

Commonly Observed Adverse Reactions in Short-Term, Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression  — The most commonly observed adverse reactions associated with the use of SYMBYAX (incidence ≥5% and at least twice that for placebo in the SYMBYAX-controlled database) using MedDRA Dictionary coding were: disturbance in attention, dry mouth, fatigue, hypersomnia, increased appetite, peripheral edema, sedation, somnolence, tremor, vision blurred, and weight increased. Adverse reactions reported in clinical trials of olanzapine and fluoxetine in combination are generally consistent with treatment-emergent adverse reactions during olanzapine or fluoxetine monotherapy.

Adverse Reactions Occurring at an Incidence of 2% or More in Short-Term Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression  â€” Table 10 enumerates the treatment-emergent adverse reactions associated with the use of SYMBYAX (incidence of at least 2% for SYMBYAX and twice or more than for placebo). The SYMBYAX-controlled column includes patients with various diagnoses while the placebo column includes only patients with bipolar depression and major depression with psychotic features.

Table 10: Treatment-Emergent Adverse Reactions: Incidence in Controlled Clinical Studies
System Organ Class Adverse Reaction Percentage of Patients Reporting Event

Eye disorders Vision blurred 5 2
Gastrointestinal disorders Dry mouth 15 6
Flatulence 3 1
Abdominal distension 2 0
General disorders and administration site conditions Fatigue 12 2
Edema peripheral 9 0
Edema 3 0
Asthenia 3 1
Pain 2 1
Pyrexia 2 1
Infections and infestations Sinusitis 2 1
Investigations Weight increased 25 3
Metabolism and nutrition disorders Increased appetite 20 4
Musculoskeletal and connective tissue disorders Arthralgia 4 1
Pain in extremity 3 1
Musculoskeletal stiffness 2 1
Nervous system disorders Somnolence 14 6
Tremor 9 3
Sedation 8 4
Hypersomnia 5 1
Disturbance in attention 5 1
Lethargy 3 1
Psychiatric disorders Restlessness 4 1
Thinking abnormal 2 1
Nervousness 2 1
Reproductive system and breast disorders Erectile dysfunction 2 1

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

Sexual Dysfunction — In the pool of controlled SYMBYAX studies in patients with bipolar depression, there were higher rates of the treatment-emergent adverse reactions 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.

Difference Among Dose Levels Observed in Other Olanzapine Clinical Trials

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 Adverse Reactions Observed in Clinical Studies

Following is a list of treatment-emergent adverse reactions reported by patients treated with SYMBYAX in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; and rare reactions are those occurring in fewer than 1/1000 patients.

  •   Body as a Whole — Frequent: chills, neck rigidity, photosensitivity reaction; Rare: death1.
  •   Cardiovascular System — Frequent: vasodilatation; Infrequent: QT-interval prolonged.
  •   Digestive System — Frequent: diarrhea; Infrequent: gastritis, gastroenteritis, nausea and vomiting, peptic ulcer; Rare: gastrointestinal hemorrhage, intestinal obstruction, liver fatty deposit, pancreatitis.
  •   Hemic and Lymphatic System — Frequent: ecchymosis; Infrequent: anemia, thrombocytopenia; Rare: leukopenia, purpura.
  •   Metabolic and Nutritional — Frequent: generalized edema, weight loss; Rare: bilirubinemia, creatinine increased, gout.
  •   Musculoskeletal System — Rare: osteoporosis.
  •   Nervous System — Frequent: amnesia; Infrequent: ataxia, buccoglossal syndrome, coma, dysarthria, emotional lability, euphoria, hypokinesia, movement disorder, myoclonus; Rare: hyperkinesia, libido increased, withdrawal syndrome.
  •   Respiratory System — Infrequent: epistaxis, yawn; Rare: laryngismus.
  •   Skin and Appendages — Infrequent: alopecia, dry skin, pruritis; Rare: exfoliative dermatitis.
  •   Special Senses — Frequent: taste perversion; Infrequent: abnormality of accommodation, dry eyes.
  •   Urogenital System — Frequent: breast pain, menorrhagia2, urinary frequency, urinary incontinence; Infrequent: amenorrhea2, female lactation2, hypomenorrhea2, metrorrhagia2, urinary retention, urinary urgency, urination impaired; Rare: breast engorgement2.

1 This term represents a serious adverse event but does not meet the definition for adverse drug reactions. It is included here because of its seriousness.

2 Adjusted for gender.

Other Adverse Reactions Observed with Olanzapine or Fluoxetine Monotherapy

The following adverse reactions 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 pneumonia3, erythema multiforme, jaundice, neutropenia, sudden unexpected death3, and violent behaviors3. Random triglyceride levels of ≥1000 mg/dL have been reported.

3 These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

Vital Signs and Laboratory Studies

Vital Signs — Tachycardia, bradycardia, and orthostatic hypotension have occurred in SYMBYAX-treated patients [see Warnings and Precautions ]. The mean standing pulse rate of SYMBYAX-treated patients was reduced by 0.7 beats/min.

Laboratory Changes — In SYMBYAX clinical studies, (including treatment resistant depression, depressive episodes associated with Bipolar I Disorder, Major Depressive Disorder with psychosis, or sexual dysfunction) SYMBYAX was associated with statistically significantly greater frequencies for the following treatment-emergent findings in laboratory analytes (normal at baseline to abnormal at any time during the trial) compared to placebo: elevated prolactin (27.6% vs 4.8%); elevated urea nitrogen (2.8% vs 0.8%); elevated uric acid (2.9% vs 0.5%); low albumin (2.7% vs 0.3%); low bicarbonate (14.1% vs 8.8%); low hemoglobin (2.6% vs 0%); low inorganic phosphorus (1.9% vs 0.3%); low lymphocytes (1.9% vs 0%); and low total bilirubin (15.3% vs 3.9%).

As with olanzapine, asymptomatic elevations of hepatic transaminases [ALT, AST, and GGT] and alkaline phosphatase have been observed with SYMBYAX. In the SYMBYAX-controlled database, ALT elevations (normal baseline and ≥3 times the upper limit of the normal range post-baseline) were observed in 3.4% (20/586) of patients exposed to SYMBYAX compared with none of the 342 placebo patients and 3.5% (23/665) of olanzapine-treated patients. The difference between SYMBYAX and placebo was statistically significant. Of the SYMBYAX patients who started normal at baseline and had increases in ALT ≥5 times the upper limit of normal range, none experienced jaundice and 4 had transient elevations >200 IU/L [see Adverse Reactions].

In olanzapine placebo-controlled studies, clinically significant ALT elevations (≥3 times the upper limit of the normal range) were observed in 2% (6/243) of patients exposed to olanzapine compared with 0% (0/115) of the placebo patients. None of these patients experienced jaundice. In 2 of these patients, liver enzymes decreased toward normal despite continued treatment and, in 2 others, enzymes decreased upon discontinuation of olanzapine. In the remaining 2 patients, 1, seropositive for hepatitis C, had persistent enzyme elevations for 4 months after discontinuation, and the other had insufficient follow-up to determine if enzymes normalized.

Within the larger olanzapine premarketing database of about 2400 patients with baseline ALT ≤90 IU/L, the incidence of ALT elevation to >200 IU/L was 2% (50/2381). Again, none of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.

Among all 2500 patients in olanzapine clinical studies, approximately 1% (23/2500) discontinued treatment due to transaminase increases.

Rare postmarketing reports of hepatitis have been received. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

Effect on Cardiac Repolarization — The mean increase in QTc interval for SYMBYAX-treated patients (4.4 msec) in clinical studies was significantly greater than that for placebo-treated (-0.8 msec), olanzapine-treated (-0.3 msec) patients, and fluoxetine-treated (1.7 msec) patients. There were no significant differences between patients treated with SYMBYAX, placebo, olanzapine, or fluoxetine in the incidence of QTc outliers (>500 msec).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of SYMBYAX. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to SYMBYAX therapy include the following: rhabdomyolysis and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis).


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

Possible Symbyax side effects / adverse reactions in 7 year old male

Reported by a physician from United States on 2011-10-06

Patient: 7 year old male weighing 30.4 kg (66.9 pounds)

Reactions: Completed Suicide, Abnormal Behaviour, Impulsive Behaviour, Aggression

Adverse event resulted in: death

Suspect drug(s):
    Dosage: 3mg/25mg (1 in 1 d),
    Indication: Aggression
    Start date: 2009-03-18
    End date: 2009-04-16

    Dosage: 3mg/25mg (1 in 1 d),
    Indication: Impulsive Behaviour
    Start date: 2009-03-18
    End date: 2009-04-16

    Dosage: 5 mg (5 mg, 1 in 1 d), oral
    Administration route: Oral
    Indication: Anxiety
    Start date: 2009-02-03
    End date: 2009-03-18

    Dosage: 30 mg (30 mg, 1 in 1 d), oral; 50 mg (50 mg, 1 in 1 d), oral
    Administration route: Oral
    Indication: Affective Disorder
    Start date: 2009-03-31
    End date: 2009-04-16

    Dosage: 30 mg (30 mg, 1 in 1 d), oral; 50 mg (50 mg, 1 in 1 d), oral
    Administration route: Oral
    Indication: Attention Deficit/hyperactivity Disorder
    Start date: 2009-03-31
    End date: 2009-04-16

    Dosage: 30 mg (30 mg, 1 in 1 d), oral; 50 mg (50 mg, 1 in 1 d), oral
    Administration route: Oral
    Indication: Affective Disorder
    Start date: 2008-12-09
    End date: 2009-03-30

    Dosage: 30 mg (30 mg, 1 in 1 d), oral; 50 mg (50 mg, 1 in 1 d), oral
    Administration route: Oral
    Indication: Attention Deficit/hyperactivity Disorder
    Start date: 2008-12-09
    End date: 2009-03-30

Possible Symbyax side effects / adverse reactions in 40 year old female

Reported by a consumer/non-health professional from Mexico on 2011-10-10

Patient: 40 year old female weighing 100.0 kg (220.0 pounds)

Reactions: OFF Label USE, Dyspnoea, Aspiration Bronchial, Vomiting, Intentional Overdose, Suicide Attempt, Acute Lung Injury, Mobility Decreased

Adverse event resulted in: hospitalization

Suspect drug(s):

Other drugs received by patient: Levothyroxine Sodium

Possible Symbyax side effects / adverse reactions in 23 year old female

Reported by a physician from United States on 2011-10-18

Patient: 23 year old female

Reactions: Road Traffic Accident, Intentional Drug Misuse, Somnolence

Suspect drug(s):

See index of all Symbyax side effect reports >>

Drug label data at the top of this Page last updated: 2009-03-19

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