Symbyax Side Effects

Please note - some side effects for Symbyax may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Symbyax - for the Consumer

Symbyax

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Symbyax:

Blurred vision; constipation; decreased sexual desire or ability; diarrhea; dizziness; drowsiness; dry mouth; increased appetite; sore throat; tiredness; weakness; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur when using Symbyax:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); abnormal thoughts; black or bloody stools; chest pain; confusion; decreased coordination; fainting; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; hallucinations; joint pain; memory loss; new or worsening mental or mood changes (eg, agitation, anxiety, depression, panic attacks, aggressiveness, impulsiveness, irritability, hostility, exaggerated feeling of well being, restlessness, inability to sit still); red, swollen, blistered, or peeling skin; seizures; severe or persistent dizziness, headache, or trouble sleeping; suicidal thoughts or attempts; swelling of the hands, ankles, or feet; symptoms of dehydration (eg, decreased sweating or urination, severe or persistent dry mouth, feeling very hot or thirsty); symptoms of high prolactin levels (eg, enlarged breast size, decreased sexual ability, missed menstrual period, nipple discharge); symptoms of stroke (eg, one-sided weakness, slurred speech); tremor; trouble concentrating, speaking, swallowing, or walking; trouble urinating; uncontrolled muscle movements (eg, arm or leg movements, twitching of the face or tongue, jerking or twisting); unusual bruising or bleeding; unusual swelling or sweating; unusual weakness; vision changes; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Symbyax Side Effects - for the Professional

Symbyax

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 — 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 — 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
		Symbyax-Controlled	Placebo
		(N=771)	(N=477)
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, erectile dysfunction 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.

There are no adequate and well-controlled studies examining sexual dysfunction with Symbyax or fluoxetine treatment. Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment.

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, depersonalization, 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, bruxism, cholestatic jaundice, diabetic coma, dysuria, eosinophilic pneumonia3, erythema multiforme, esophageal ulcer, gynecological bleeding, headache, hypotension, jaundice, neutropenia, sudden unexpected death3, sweating, 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 (5.11)]. 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 (28% vs 5%); elevated urea nitrogen (3% vs 0.8%); elevated uric acid (3% vs 0.5%); low albumin (3% vs 0.3%); low bicarbonate (14% vs 9%); low hemoglobin (3% vs 0%); low inorganic phosphorus (2% vs 0.3%); low lymphocytes (2% vs 0%); and low total bilirubin (15% vs 4%).

As with olanzapine, asymptomatic elevations of hepatic aminotransferases [ALT, AST, and GGT] and alkaline phosphatase have been observed with Symbyax. In the Symbyax-controlled database, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (38/698) of patients exposed to Symbyax compared with 0.5% (2/378) of placebo-treated patients and 4% (33/751) of olanzapine-treated patients. ALT elevations ≥5 times ULN were observed in 2% (11/701) of Symbyax-treated patients, compared to 0.3% (1/379) of placebo-treated patients and 1% (11/760) of olanzapine-treated patients. No patient with elevated ALT values experienced jaundice or liver failure, or met the criteria for Hy's Rule. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with Symbyax or discontinued Symbyax.

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

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.

An increase in creatine phosphokinase has been reported very rarely in Symbyax-treated patients and infrequently in clinical trials of olanzapine-treated patients.

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).

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Side Effects by Body System - for Healthcare Professionals

Nervous system

Nervous system side effects have frequently included somnolence (up to 22%), tremor (up to 9%), abnormal thinking (6%), decreased libido (up to 4%), amnesia (up to 3%), hyperkinesia (up to 2%), personality disorder (up to 2%), and sleep disorder (up to 2%). Seizures, 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, acute brain syndrome, aphasia, dystonia, increased libido, subarachnoid hemorrhage, and withdrawal syndrome have also been reported. Bruxism and headache have been reported.

Metabolic

Fourteen percent of fluoxetine-olanzapine treated patients met criteria for having gained greater than 10% of their baseline weight.

Metabolic side effects have frequently included weight gain (up to 21%), peripheral edema (up to 8%), edema (up to 5%), and weight loss. Alcohol intolerance, dehydration, glycosuria, hyperlipemia, hypoglycemia, hypokalemia, obesity, acidosis, bilirubinemia, increased creatinine, gout, hyperkalemia, and hypoglycemic reaction have also been reported. Diabetic coma has been reported.

Gastrointestinal

Gastrointestinal side effects have frequently included diarrhea (up to 19%), dry mouth (up to 16%), increased appetite (up to 16%), tooth disorder (up to 2%), increased salivation, and thirst. Cholelithiasis, colitis, eructation, esophagitis, gastritis, gastroenteritis, gingivitis, nausea, vomiting, peptic ulcer, periodontal abscess, stomatitis, tooth caries, aphthous stomatitis, fecal incontinence, gastrointestinal hemorrhage, taste perversion, intestinal obstruction, and pancreatitis have also been reported. Dysphagia has been reported infrequently. Esophageal ulcer has also been reported.

Genitourinary

Genitourinary side effects have frequently included abnormal ejaculation (up to 7%), impotence (up to 4%), anorgasmia (up to 3%), breast pain, menorrhagia, urinary frequency, urinary incontinence, and urinary tract infection. Amenorrhea, breast enlargement, breast neoplasm, cystitis, dysuria, female lactation, fibrocystic breast, hematuria, hypomenorrhea, leukorrhea, menopause, metrorrhagia, oliguria, ovarian disorder, polyuria, urinary retention, urinary urgency, impaired urination, vaginal hemorrhage, vaginal moniliasis, and vaginitis have been reported infrequently. Breast carcinoma, breast engorgement, endometrial disorder, gynecomastia, kidney calculus, and enlarged uterine fibroids have also been reported. Gynecological bleeding has been reported. Additional findings observed in clinical studies have included decreased libido, anorgasmia, erectile dysfunction and abnormal ejaculation.

Musculoskeletal

Musculoskeletal side effects have frequently included twitching (up to 6%), arthralgia (up to 5%), and joint disorder (up to 2%). Arthritis, bone disorder, generalized spasm, leg cramps, tendinous contracture, tenosynovitis, arthrosis, bursitis, myasthenia, myopathy, osteoporosis, and rheumatoid arthritis have also been reported.

Respiratory

Collective data gathered from 17 placebo-controlled clinical studies (n=5106) involving the use of atypical antipsychotic agents for the treatment of behavioral disorders in the elderly patient with dementia showed a risk of death 1.6 to 1.7 times greater in the drug treated patient than in the placebo treated patient. The average length of duration for the trials was 10 weeks with the cause of death in the majority of cases, though not all, reported as either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Although fluoxetine-olanzapine was not included in these studies, the consistent findings across all three relevant chemical classes support the opinion that these findings are likely to be applicable to all atypical antipsychotic agents. Fluoxetine-olanzapine is not approved by the FDA for use in the treatment of behavioral disorders in elderly patients with dementia.

Respiratory side effects have frequently included pharyngitis (up to 6%), dyspnea (up to 2%), bronchitis, and lung disorder. Apnea, asthma, epistaxis, hiccup, hyperventilation, laryngitis, pneumonia, voice alteration, yawn, emphysema, hemoptysis, and laryngismus have also been reported. An increased risk of mortality, possibly due to an infection, such as pneumonia, has been reported with the use of atypical antipsychotic agents in the treatment of behavioral disorders in the elderly patient with dementia. Eosinophilic pneumonia has been reported.

Ocular

Ocular side effects have frequently included amblyopia (up to 5%) and abnormal vision. Abnormality of accommodation, conjunctivitis, diplopia, dry eyes, eye pain, miosis, and eye hemorrhage have also been reported.

Cardiovascular

Cardiovascular side effects have frequently included hypertension (2%), tachycardia (2%), bradycardia, orthostatic hypotension, and vasodilatation. Arrhythmia, cerebral ischemia, abnormal electrocardiogram, hypotension, prolongation of QT interval, anginal pectoris, atrial arrhythmia, atrial fibrillation, bundle branch block, congestive heart failure, myocardial infarction, peripheral vascular disorder, and inverted T-wave have also been reported. An increased risk of mortality, possibly due to heart failure or sudden death, has been reported with the use of atypical antipsychotic agents in the treatment of behavioral disorders in the elderly patient with dementia.

Collective data gathered from 17 placebo-controlled clinical studies (n=5106) involving the use of atypical antipsychotic agents for the treatment of behavioral disorders in the elderly patient with dementia showed a risk of death 1.6 to 1.7 times greater in the drug treated patient than in the placebo treated patient. The average length of duration for the trials was 10 weeks with the cause of death in the majority of cases, though not all, reported as either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Although fluoxetine-olanzapine was not included in these studies, the consistent findings across all three relevant chemical classes support the opinion that these findings are likely to be applicable to all atypical antipsychotic agents. Fluoxetine-olanzapine is not approved by the FDA for use in the treatment of behavioral disorders in elderly patients with dementia.

The mean increase in QTc interval for fluoxetine-olanzapine treated patients was significantly greater than that for placebo treated patients or patients treated with olanzapine alone. It was not significantly different from patients treated with fluoxetine alone.

The mean pulse of fluoxetine-olanzapine treated patients has been reported to have been reduced by 1.6 beats per minute.

Other

Other side effects have frequently included asthenia (up to 15%), accidental injury (up to 5%), fever (up to 4 %), ear pain (up to 2%), otitis media (2%), speech disorder (up to 2%), tinnitus, chills, infection, neck pain, neck rigidity, and photosensitivity reaction. Deafness, cellulitis, cyst, hernia, intentional injury, intentional overdose, malaise, moniliasis, overdose, pelvic pain, suicide attempt, death, and decreased tolerance have also been reported. Discontinuation of treatment has been associated with somnolence (up to 2%), weight gain (up to 2%), asthenia (up to 1%), and chest pain (up to 1%). Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic drugs.

Hematologic

Hematologic side effects have frequently included ecchymosis. Anemia, leukocytosis, lymphadenopathy, coagulation disorder, leukopenia, purpura, thrombocythemia, neutropenia, and agranulocytosis have been reported infrequently. Bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake have also been reported. Aplastic anemia has been reported.

Endocrine

Endocrine side effects have rarely included hypothyroidism and hyperprolactinemia.

Hepatic

Hepatic side effects have included hepatomegaly, liver fatty deposit, asymptomatic elevations of hepatic transaminases ALT (SGPT), AST (SGOT), and GGT, and asymptomatic elevations in alkaline phosphatase. Cholestatic jaundice has also been reported.

Dermatologic

Dermatologic side effects have included acne, alopecia, contact dermatitis, dry skin, eczema, pruritus, psoriasis, skin discoloration, vesiculobullous rash, exfoliative dermatitis, maculopapular rash, seborrhea, and skin ulcer. Erythema multiforme and sweating have also been reported.

Psychiatric

Psychiatric side effects have included intentional overdose, suicide attempt, abnormal thinking, and personality disorder. Violent behaviors have also been reported.

General

General side effects have included sudden unexpected death.

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