Symbyax Information
Symbyax () Warning: Suicidality And Antidepressant Drugs And Increased Mortality In Elderly Patients With Dementia-related Psychosis
Suicidality and Antidepressant Drugs
— Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Symbyax () or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Symbyax () is not approved for use in pediatric patients.
[See Warnings and Precautions (), Use in Specific Populations (), and Patient Counseling Information ()].
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
— Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Symbyax () (olanzapine and fluoxetine HCl) is not approved for the treatment of patients with dementia-related psychosis
[see Warnings and Precautions (, ) and Patient Counseling Information ()].
Symbyax () Dosage And Administration
Symbyax () should be administered once daily in the evening, generally beginning with the 6 mg/25 mg capsule. While food has no appreciable effect on the absorption of olanzapine and fluoxetine given individually, the effect of food on the absorption of Symbyax () has not been studied. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Antidepressant efficacy was demonstrated with Symbyax () in a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg . The safety of doses above 18 mg per 75 mg has not been evaluated in clinical studies.
While there is no body of evidence to answer the question of how long a patient treated with Symbyax () should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy.
Symbyax () should be administered once daily in the evening, generally beginning with the 6 mg/25 mg capsule. While food has no appreciable effect on the absorption of olanzapine and fluoxetine given individually, the effect of food on the absorption of Symbyax () has not been studied. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Antidepressant efficacy was demonstrated with Symbyax () in a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg . The safety of doses above 18 mg per 75 mg has not been evaluated in clinical studies.
While there is no body of evidence to answer the question of how long a patient treated with Symbyax () should remain on it, it is generally accepted that treatment resistant depression (Major Depressive Disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy.
Symbyax () Dosage Forms And Strengths
Capsules (mg equivalent olanzapine/mg equivalent fluoxetine):
Symbyax () Contraindications
The use of Symbyax () is contraindicated with the following:
Symbyax () Warnings And Precautions
Patients with Major Depressive Disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with Major Depressive Disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in .
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for Major Depressive Disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms .
Families and caregivers of patients being treated with antidepressants for Major Depressive Disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.
It should be noted that Symbyax () is not approved for use in treating any indications in the pediatric population .
A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
If after recovering from NMS, a patient requires treatment with an antipsychotic, the patient should be carefully monitored, since recurrences of NMS have been reported .
In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.
Table 2
Table 4
Table 5
Table 7
The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of Symbyax () with MAOIs intended to treat depression is contraindicated .
If concomitant treatment of Symbyax () with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases .
The concomitant use of Symbyax () with serotonin precursors (such as tryptophan) is not recommended .
Treatment with Symbyax () and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately, if the above reactions occur, and supportive symptomatic treatment should be initiated .
In Symbyax () premarketing controlled clinical studies, the overall incidence of rash or allergic reactions in Symbyax () -treated patients [4.6% (26/571)] was similar to that of placebo [5.2% (25/477)]. The majority of the cases of rash and/or urticaria were mild; however, 3 patients discontinued (1 due to rash, which was moderate in severity and 2 due to allergic reactions, 1 of which included face edema).
In fluoxetine US clinical studies, 7% of 10,782 fluoxetine-treated patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical studies, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.
In fluoxetine premarketing clinical studies, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but 1 was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.
Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions.
Anaphylactoid reactions, including bronchospasm, angioedema, and urticaria alone and in combination, have been reported.
Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom.
Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possible allergic phenomena for which an alternative etiology cannot be identified, Symbyax () should be discontinued.
A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a manic episode in patients at risk for Bipolar Disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should include a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression. It should be noted that Symbyax () is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder.
In the 2 controlled bipolar depression studies there was no statistically significant difference in the incidence of manic reactions (manic reaction or manic depressive reaction) between Symbyax () - and placebo-treated patients. In 1 of the studies, the incidence of manic reactions was (7% [3/43]) in Symbyax () -treated patients compared to (3% [5/184]) in placebo-treated patients. In the other study, the incidence of manic reactions was (2% [1/43]) in Symbyax () -treated patients compared to (8% [15/193]) in placebo-treated patients. This limited controlled trial experience of Symbyax () in the acute treatment of depressive episodes associated with Bipolar I Disorder makes it difficult to interpret these findings until additional data is obtained. Because of this and the cyclical nature of Bipolar I Disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during treatment with Symbyax () .
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
The incidence of dyskinetic movement in Symbyax () -treated patients was infrequent. The mean score on the Abnormal Involuntary Movement Scale (AIMS) in the Symbyax () -controlled database across clinical studies involving Symbyax () -treated patients decreased from baseline. Nonetheless, Symbyax () should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on Symbyax () , drug discontinuation should be considered. However, some patients may require treatment with Symbyax () despite the presence of the syndrome. The need for continued treatment should be reassessed periodically.
Symbyax () may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period .
In the Symbyax () -controlled clinical trials across all indications, there were no significant differences between Symbyax () -treated patients and olanzapine, fluoxetine- or placebo-treated patients in exposure-adjusted rates of orthostatic systolic blood pressure decreases of at least 30 mm Hg. Orthostatic systolic blood pressure decreases of at least 30 mm Hg occurred in 4.0% (28/705), 2.3% (19/831), 4.5% (18/399), and 1.8% (8/442) of the Symbyax () , olanzapine, fluoxetine, and placebo groups, respectively. In this group of studies, the incidence of syncope-related adverse reactions (i.e., syncope and/or loss of consciousness) in Symbyax () -treated patients was 0.4% (3/771) compared to placebo 0.2% (1/477).
In a clinical pharmacology study of Symbyax () , 3 healthy subjects were discontinued from the trial after experiencing severe, but self-limited, hypotension and bradycardia that occurred 2 to 9 hours following a single 12-mg/50-mg dose of Symbyax () . Reactions consisting of this combination of hypotension and bradycardia (and also accompanied by sinus pause) have been observed in at least 3 other healthy subjects treated with various formulations of olanzapine (1 oral, 2 intramuscular). In controlled clinical studies, the incidence of patients with a ≥20 bpm decrease in orthostatic pulse concomitantly with a ≥20 mm Hg decrease in orthostatic systolic blood pressure was 0.3% (2/706) in the Symbyax () group, 0.2% (1/445) in the placebo group, 0.7% (6/837) in the olanzapine group, and 0% (0/404) in the fluoxetine group.
Symbyax () should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).
Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count
SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of Symbyax () and NSAIDs, aspirin, or other drugs that affect coagulation .
Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine and Symbyax () . In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Symbyax () was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk . Discontinuation of Symbyax () should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. .
Clinical experience with Symbyax () in patients with concomitant systemic illnesses is limited . The following precautions for the individual components may be applicable to Symbyax () .
Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical studies, Symbyax () was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for study discontinuations; Symbyax () should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, a history of paralytic ileus, or related conditions.
In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following treatment-emergent adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations. The rate of discontinuation due to adverse reactions was significantly greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis .
As with other CNS-active drugs, Symbyax () should be used with caution in elderly patients with dementia. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis, vigilance should be exercised .
Symbyax () has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the premarket testing.
Caution is advised when using Symbyax () in cardiac patients and in patients with diseases or conditions that could affect hemodynamic responses .
2
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds that increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.
In controlled clinical studies of Symbyax () (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 28% of adults treated with Symbyax () as compared to 5% of placebo-treated patients. The elevations persisted throughout administration of Symbyax () . In a pooled analysis from clinical studies including 2929 adults treated with Symbyax () , potentially associated clinical manifestations included menstrual-related events (1% [20/1946] of females), sexual function-related events (7% [192/2929] of females and males), and breast-related events (0.8% [16/1946] of females, 0.2% [2/983] of males).
In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events (2% [49/3240] of females), sexual function-related events (2% [150/8136] of females and males), and breast-related events (0.7% [23/3240] of females, 0.2% [9/4896] of males).
In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events (1% [2/168] of females), sexual function-related events (0.7% [3/454] of females and males), and breast-related events (2% [3/168] of females, 2% [7/286] of males), .
Symbyax () 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.
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.
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).
Symbyax () Drug Interactions
The risks of using Symbyax () in combination with other drugs have not been extensively evaluated in systematic studies. The drug-drug interactions sections of fluoxetine and olanzapine are applicable to Symbyax () . As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status .
Symbyax () Overdosage
Symbyax ()
Adverse reactions involving overdose of fluoxetine and olanzapine in combination, and Symbyax () , have been reported spontaneously to Eli Lilly and Company. An overdose of combination therapy is defined as confirmed or suspected ingestion of a dose of >20 mg olanzapine in combination with a dose of >80 mg fluoxetine. Adverse reactions associated with these reports included somnolence (sedation), impaired consciousness (coma), impaired neurologic function (ataxia, confusion, convulsions, dysarthria), arrhythmias, lethargy, essential tremor, agitation, acute psychosis, hypotension, hypertension, and aggression. Fatalities have been confounded by exposure to additional substances including alcohol, thioridazine, oxycodone, and propoxyphene.
Olanzapine
Fluoxetine
Among 633 adult patients who overdosed on fluoxetine alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdose, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, erectile dysfunction, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdose were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established.
Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the 6 fatalities was a 9-year-old boy who had a history of OCD, Tourette's Syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams, which was non-lethal.
Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) included coma, delirium, ECG abnormalities (such as QT-interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope.
In managing overdose, the possibility of multiple drug involvement should be considered. In case of acute overdose, establish and maintain an airway and ensure adequate ventilation, which may include intubation. Induction of emesis is not recommended as the possibility of obtundation, seizures, or dystonic reactions of the head and neck following overdose may create a risk for aspiration. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
A specific precaution involves patients who are taking or have recently taken Symbyax () and may have ingested excessive quantities of a TCA (tricyclic antidepressant). In such cases, accumulation of the parent TCA and/or an active metabolite may increase the possibility of serious sequelae and extend the time needed for close medical observation.
Due to the large volume of distribution of olanzapine and fluoxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidote for either fluoxetine or olanzapine overdose is known. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. Do not use epinephrine, dopamine, or other sympathomimetics with β-agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade.
The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the .
Symbyax () Description
Symbyax () (olanzapine and fluoxetine HCl capsules) combines an atypical antipsychotic and a selective serotonin reuptake inhibitor, olanzapine (the active ingredient in Zyprexa, and Zyprexa Zydis) and fluoxetine hydrochloride (the active ingredient in Prozac, Prozac Weekly, and Sarafem).
Olanzapine belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10-thieno[2,3-] [1,5]benzodiazepine. The molecular formula is CHNS, which corresponds to a molecular weight of 312.44.
Fluoxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI). The chemical designation is (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro--tolyl)oxy]propylamine hydrochloride. The molecular formula is CHFNO•HCl, which corresponds to a molecular weight of 345.79.
The chemical structures are:
Olanzapine is a yellow crystalline solid, which is practically insoluble in water.
Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water.
Symbyax () capsules are available for oral administration in the following strength combinations:
Each capsule also contains pregelatinized starch, gelatin, dimethicone, titanium dioxide, sodium lauryl sulfate, edible black ink, red iron oxide, yellow iron oxide, and/or black iron oxide.
Symbyax () Clinical Pharmacology
Olanzapine binds with high affinity to the following receptors: serotonin 5HT, 5HT (K=4, 11, and 5 nM, respectively), dopamine D (K=11 to 31 nM), histamine H (K=7 nM), and adrenergic α receptors (K=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT (K=57 nM) and muscarinic M (K=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABA, BZD, and β-adrenergic receptors (K>10 μM). Fluoxetine is an inhibitor of the serotonin transporter and is a weak inhibitor of the norepinephrine and dopamine transporters.
Antagonism at receptors other than dopamine and 5HT may explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of muscarinic M receptors may explain its anticholinergic-like effects. The antagonism of histamine H receptors by olanzapine may explain the somnolence observed with this drug. The antagonism of α-adrenergic receptors by olanzapine may explain the orthostatic hypotension observed with this drug. Fluoxetine has relatively low affinity for muscarinic, α-adrenergic, and histamine H receptors.
Symbyax () Clinical Studies
The efficacy of Symbyax () for the acute treatment of depressive episodes associated with Bipolar I Disorder was established in 2 identically designed, 8-week, randomized, double-blind, controlled studies of patients who met Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for Bipolar I Disorder, Depressed utilizing flexible dosing of Symbyax () (6/25, 6/50, or 12/50 mg/day), olanzapine (5 to 20 mg/day), and placebo. These studies included patients (≥18 years of age [n=788]) with or without psychotic symptoms and with or without a rapid cycling course.
The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 to 60. The primary outcome measure of these studies was the change from baseline to endpoint in the MADRS total score. In both studies, Symbyax () was statistically significantly superior to both olanzapine monotherapy and placebo in reduction of the MADRS total score.
The efficacy of Symbyax () in acute treatment resistant depression was demonstrated with data from 3 clinical studies (n=579). Doses evaluated in these studies ranged from 6 to 18 mg for olanzapine and 25 to 50 mg for fluoxetine.
An 8-week randomized, double-blind controlled study was conducted to evaluate the efficacy of Symbyax () in patients (n=300) who met DSM-IV criteria for Major Depressive Disorder and did not respond to 2 antidepressants of adequate dose and duration in their current episode. Patients who were not responding to an antidepressant in their current episode entered an 8-week open-label fluoxetine lead-in; non-responders were randomized (1:1:1) to receive Symbyax () , olanzapine, or fluoxetine, and were treated for 8 weeks. Symbyax () was flexibly dosed between 6/50 mg, 12/50 mg, and 18/50 mg. Results from this study yielded statistically significant greater reduction in mean total MADRS scores from baseline to endpoint for Symbyax () versus fluoxetine and olanzapine. A second study with the same treatment-resistant patient population (n=28), when analyzed with change in MADRS as the outcome measure, demonstrated statistically significantly greater reduction in MADRS scores for Symbyax () versus fluoxetine and olanzapine. A third study demonstrated statistically significantly greater reduction in total MADRS scores for Symbyax () versus fluoxetine or olanzapine alone, when analyzed in a subpopulation of depressed patients (n=251) who met the definition of treatment resistance (patients who had not responded to 2 antidepressants of adequate dose and duration in the current episode).
Symbyax () How Supplied/storage And Handling
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Keep tightly closed and protect from moisture.
Symbyax () Patient Counseling Information
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Symbyax () .
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