Symbyax (Olanzapine / Fluoxetine Hydrochloride) - Warnings and Precautions

Weight Gain — Potential consequences of weight gain should be considered prior to starting SYMBYAX. Patients receiving SYMBYAX should receive regular monitoring of weight.

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, the mean weight increase for SYMBYAX–treated patients was statistically significantly greater than placebo-treated patients (4 kg vs –0.3 kg). Twenty-two percent of SYMBYAX–treated patients gained at least 7% of their baseline weight, with a median exposure of 6 weeks. This was statistically significantly greater than in placebo-treated patients (1.8%). Approximately three percent of SYMBYAX–treated patients gained at least 15% of their baseline weight, with a median exposure of 8 weeks. This was statistically significantly greater than in placebo–treated patients (0%). Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 2.5% of SYMBYAX–treated patients and zero placebo-treated patients.

Table 6 includes data on weight gain with olanzapine pooled from 68 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use

Amount Gained kg (lb)	6 Weeks (N=2976) (%)	6 Months (N=1536) (%)	12 Months (N=778) (%)	24 Months (N=422) (%)
≤0	27	21	20	22
0–5 (0–11 lb)	57	34	25	22
5–10 (11–22 lb)	15	26	25	22
10–15 (22–33 lb)	2	12	16	18
>15 (>33 lb)	0	6	14	16

During long-term continuation therapy with olanzapine monotherapy (238 median days of exposure), 56% of olanzapine patients met the criterion for having gained greater than 7% of their baseline weight. Average weight gain during long–term therapy was 5.4 kg.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine and olanzapine and fluoxetine in combination have not been established in patients under the age of 18 years. In an analysis of 4 placebo–controlled olanzapine monotherapy studies of adolescent patients (ages 13 to 17 years), including those with schizophrenia (6 weeks) or bipolar disorder (manic or mixed episodes) (3 weeks), olanzapine–treated patients gained an average of 4.6 kg, which was statistically significantly different compared to an average of 0.3 kg in placebo–treated patients, with a median exposure of 3 weeks; 40.6% of olanzapine–treated patients gained at least 7% of their baseline body weight, which was statistically significantly different compared to 9.8% of placebo–treated patients, with a median exposure of 4 weeks; 7.1% of olanzapine–treated patients gained at least 15% of their baseline weight, compared to 2.7% of placebo–treated patients, with a median exposure of 19 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories, but mean changes in weight were greater in adolescents with BMI categories above normal at baseline. Discontinuation due to weight gain occurred in 1% of olanzapine–treated patients, compared to zero placebo–treated patients.

During long–term continuation therapy with olanzapine, 65% of olanzapine–treated patients met the criterion for having gained greater than 7% of their baseline weight. Average weight gain during long–term therapy was 7.4 kg.

Orthostatic Hypotension — SYMBYAX may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and in some patients, syncope, especially during the initial dose–titration period.

In the bipolar depression studies, statistically significantly more orthostatic changes occurred with the SYMBYAX group compared to placebo and olanzapine groups. Orthostatic systolic blood pressure decrease of at least 30 mm Hg occurred in 7.3% (6/82), 1.4% (5/346), and 1.4% (5/352) of the SYMBYAX, olanzapine and placebo groups, respectively. Among the group of controlled clinical studies with SYMBYAX, an orthostatic systolic blood pressure decrease of ≥30 mm Hg occurred in 4% (21/512) of SYMBYAX–treated patients, 5% (10/204) of fluoxetine–treated patients, 2% (16/644) of olanzapine–treated patients, and 2% (8/445) of placebo–treated patients. In this group of studies, the incidence of syncope in SYMBYAX–treated patients was 0.4% (2/571) compared to placebo 0.2% (1/477).

In a clinical pharmacology study of SYMBYAX, three 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 three other healthy subjects treated with various formulations of olanzapine (one oral, two 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 0.4% (2/549) in the SYMBYAX group, 0.2% (1/455) in the placebo group, 0.8% (5/659) in the olanzapine group, and 0% (0/241) 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).

Allergic Events and Rash — In SYMBYAX premarketing controlled clinical studies, the overall incidence of rash or allergic events 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, three patients discontinued (one due to rash, which was moderate in severity, and two due to allergic events, one 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 events 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 events, possibly related to vasculitis, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events.

Anaphylactoid events, including bronchospasm, angioedema, and urticaria alone and in combination, have been reported.

Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom.

Whether these systemic events 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 events 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.

Serotonin Syndrome — The development of a potentially life–threatening serotonin syndrome may occur with SNRIs and SSRIs, including SYMBYAX treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). 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).

The concomitant use of SYMBYAX with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors (MAOI) and PRECAUTIONS, Drug Interactions).

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 (see PRECAUTIONS, Drug Interactions).

The concomitant use of SYMBYAX with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions).

Neuroleptic Malignant Syndrome (NMS) — 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.

Tardive Dyskinesia — 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) 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.

Thioridazine — In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25–mg oral dose of thioridazine produced a 2.4–fold higher C_max and a 4.5–fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs that inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS).

Thioridazine administration produces a dose–related prolongation of the QT_c interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes–type arrhythmias and sudden death. This risk is expected to increase with fluoxetine–induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS, Thioridazine).

PRECAUTIONS

General

Concomitant Use of Olanzapine and Fluoxetine Products  — SYMBYAX contains the same active ingredients that are in Zyprexa and Zyprexa Zydis (olanzapine) and in Prozac, Prozac Weekly, and Sarafem (fluoxetine HCl). Caution should be exercised when prescribing these medications concomitantly with SYMBYAX.

Abnormal Bleeding — SSRIs and SNRIs, including fluoxetine, may increase the risk of bleeding events. 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 events related to SSRIs and SNRIs 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 (see DRUG INTERACTIONS).

Mania/Hypomania — In the two controlled bipolar depression studies there was no statistically significant difference in the incidence of manic events (manic reaction or manic depressive reaction) between SYMBYAX– and placebo–treated patients. In one of the studies, the incidence of manic events 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 events 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 treatment of bipolar depression makes it difficult to interpret these findings until additional data is obtained. Because of this and the cyclical nature of bipolar disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during treatment with SYMBYAX.

Body Temperature Regulation — Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic drugs. Appropriate care is advised when prescribing SYMBYAX for patients who will be experiencing conditions which may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).

Cognitive and Motor Impairment — Somnolence was a commonly reported adverse event associated with SYMBYAX treatment, occurring at an incidence of 22% in SYMBYAX patients compared with 11% in placebo patients. Somnolence led to discontinuation in 2% (10/571) of patients in the premarketing controlled clinical studies.

As with any CNS–active drug, SYMBYAX has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that SYMBYAX therapy does not affect them adversely.

Discontinuation of Treatment with SYMBYAX

During marketing of fluoxetine, a component of SYMBYAX, and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self–limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see DOSAGE AND ADMINISTRATION).

Dysphagia — Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease. Olanzapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Half–Life — Because of the long elimination half–lives of fluoxetine and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination).

Hyperprolactinemia — As with other drugs that antagonize dopamine D₂ receptors, SYMBYAX elevates prolactin levels, and a modest elevation persists during administration; however, possibly associated clinical manifestations (e.g., galactorrhea and breast enlargement) were infrequently observed.

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 of this type. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin–elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. 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 (see Carcinogenesis). However, neither clinical studies nor epidemiologic studies 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.

Hyponatremia — Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including 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 SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). 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.

Seizures — Seizures occurred in 0.2% (4/2066) of SYMBYAX–treated patients during open–label premarketing clinical studies. No seizures occurred in the premarketing controlled SYMBYAX studies. Seizures have also been reported with both olanzapine and fluoxetine monotherapy. Therefore, SYMBYAX should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of ≥65 years of age.

Transaminase Elevations — As with olanzapine, asymptomatic elevations of hepatic transaminases [ALT (SGPT), AST (SGOT), and GGT] and alkaline phosphatase have been observed with SYMBYAX. In the SYMBYAX–controlled database, ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 6.3% (31/495) of patients exposed to SYMBYAX compared with 0.5% (2/384) of the placebo patients and 4.5% (25/560) of olanzapine–treated patients. The difference between SYMBYAX and placebo was statistically significant. None of these 31 SYMBYAX–treated patients experienced jaundice and three had transient elevations >200 IU/L.

In olanzapine placebo–controlled studies, clinically significant ALT (SGPT) 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 SGPT ≤90 IU/L, the incidence of SGPT 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. Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Laboratory Tests).

Use in Patients with Concomitant Illness

Clinical experience with SYMBYAX in patients with concomitant systemic illnesses is limited (see CLINICAL PHARMACOLOGY, Renal Impairment and Hepatic Impairment). 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 events possibly related to cholinergic antagonism. Such adverse events 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 five placebo–controlled studies of olanzapine in elderly patients with dementia–related psychosis (n=1184), the following treatment–emergent adverse events 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 events 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. If the prescriber elects to treat elderly patients with dementia–related psychosis, vigilance should be exercised (see BOX WARNING and WARNINGS).

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 (see BOX WARNING and WARNINGS).

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 (see WARNINGS, Orthostatic Hypotension).

In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half–lives of these substances. A lower dose of the fluoxetine–component of SYMBYAX should be used in patients with cirrhosis. Caution is advised when using SYMBYAX in patients with diseases or conditions that could affect its metabolism (see CLINICAL PHARMACOLOGY, Hepatic Impairment and DOSING AND ADMINISTRATION, Special Populations).

Olanzapine and fluoxetine individual pharmacokinetics do not differ significantly in patients with renal impairment. SYMBYAX dosing adjustment based upon renal impairment is not routinely required (see CLINICAL PHARMACOLOGY, Renal Impairment).

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with SYMBYAX and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for SYMBYAX. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking SYMBYAX.

Clinical Worsening and Suicide Risk — Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day–to–day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Hyperglycemia — Patients should be advised of the potential risk of hyperglycemia–related adverse events. Patients should be monitored regularly for worsening of glucose control.

Weight Gain — Patients should be counseled that SYMBYAX is associated with weight gain. Patients should have their weight monitored regularly.

Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SYMBYAX and triptans, tramadol or other serotonergic agents.

Abnormal Bleeding — Patients should be cautioned about the concomitant use of SYMBYAX and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding).

Alcohol — Patients should be advised to avoid alcohol while taking SYMBYAX.

Cognitive and Motor Impairment — As with any CNS–active drug, SYMBYAX has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that SYMBYAX therapy does not affect them adversely.

Concomitant Medication — Patients should be advised to inform their physician if they are taking Prozac^®, Prozac Weekly™, Sarafem^®, fluoxetine, Zyprexa^®, or Zyprexa Zydis^®. Patients should also be advised to inform their physicians if they are taking or plan to take any prescription or over–the–counter drugs, including herbal supplements, since there is a potential for interactions.

Heat Exposure and Dehydration — Patients should be advised regarding appropriate care in avoiding overheating and dehydration.

Nursing — Patients, if taking SYMBYAX, should be advised not to breast–feed.

Orthostatic Hypotension — Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol (see WARNINGS and Drug Interactions).

Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during SYMBYAX therapy.

Rash — Patients should be advised to notify their physician if they develop a rash or hives while taking SYMBYAX.

Treatment Adherence — Patients should be advised to take SYMBYAX exactly as prescribed, and to continue taking SYMBYAX as prescribed even after their mood symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking SYMBYAX, without consulting their physician.

Patient information is printed at the end of this insert. Physicians should discuss this information with their patients and instruct them to read the Medication Guide before starting therapy with SYMBYAX and each time their prescription is refilled.

Laboratory Tests

Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Transaminase Elevations).

Drug Interactions

The risks of using SYMBYAX in combination with other drugs have not been extensively evaluated in systematic studies. The drug–drug interactions of the individual components 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. Caution is advised if the concomitant administration of SYMBYAX and other CNS–active drugs is required. 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 (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination).

Antihypertensive agents — Because of the potential for olanzapine to induce hypotension, SYMBYAX may enhance the effects of certain antihypertensive agents (see WARNINGS, Orthostatic Hypotension).

Anti–Parkinsonian — The olanzapine component of SYMBYAX may antagonize the effects of levodopa and dopamine agonists.

Benzodiazepines — Multiple doses of olanzapine did not influence the pharmacokinetics of diazepam and its active metabolite N–desmethyldiazepam. However, the coadministration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine.

When concurrently administered with fluoxetine, the half–life of diazepam may be prolonged in some patients (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Biperiden — Multiple doses of olanzapine did not influence the pharmacokinetics of biperiden.

Carbamazepine — Carbamazepine therapy (200 mg BID) causes an approximate 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance.

Patients on stable doses of carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.

Clozapine — Elevation of blood levels of clozapine has been observed in patients receiving concomitant fluoxetine.

Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment (see Seizures).

Ethanol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The coadministration of ethanol with SYMBYAX may potentiate sedation and orthostatic hypotension.

Fluvoxamine — Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine C_max following fluvoxamine administration of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of the olanzapine component of SYMBYAX should be considered in patients receiving concomitant treatment with fluvoxamine.

Haloperidol — Elevation of blood levels of haloperidol has been observed in patients receiving concomitant fluoxetine.

Lithium — Multiple doses of olanzapine did not influence the pharmacokinetics of lithium.

There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored in patients taking SYMBYAX concomitantly with lithium.

Monoamine oxidase inhibitors — See CONTRAINDICATIONS.

Phenytoin — Patients on stable doses of phenytoin have developed elevated plasma levels of phenytoin with clinical phenytoin toxicity following initiation of concomitant fluoxetine.

Pimozide — Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT_c prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT_c prolongation warrants restricting the concurrent use of pimozide and fluoxetine. Concomitant use of fluoxetine and pimozide is contraindicated (see CONTRAINDICATIONS).

Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including SYMBYAX, and the potential for serotonin syndrome, caution is advised when SYMBYAX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non–selective MAOI), lithium, tramadol, or St. John’s Wort (see WARNINGS, Serotonin Syndrome). The concomitant use of SYMBYAX with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan).

Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

Thioridazine — See CONTRAINDICATIONS and WARNINGS, Thioridazine.

Tricyclic antidepressants (TCAs) — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

In two fluoxetine studies, previously stable plasma levels of imipramine and desipramine have increased >2– to 10–fold when fluoxetine has been administered in combination. This influence may persist for three weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when SYMBYAX is coadministered or has been recently discontinued (see Drugs metabolized by CYP2D6 and CLINICAL PHARMACOLOGY, Accumulation and slow elimination).

Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of SYMBYAX with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).

Tryptophan — Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress.

Valproate — In vitro studies using human liver microsomes determined that olanzapine has little potential to inhibit the major metabolic pathway, glucuronidation, of valproate. Further, valproate has little effect on the metabolism of olanzapine in vitro. Thus, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely.

Warfarin — Warfarin (20–mg single dose) did not affect olanzapine pharmacokinetics. Single doses of olanzapine did not affect the pharmacokinetics of warfarin.

Drugs that interfere with hemostasis (e.g., NSAIDs, Aspirin, Warfarin) — Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case–control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin (see PRECAUTIONS, Abnormal Bleeding). Patients receiving warfarin therapy should be carefully monitored when SYMBYAX is initiated or discontinued.

Drugs metabolized by CYP2D6 — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP2D6. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by this enzyme.

Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous five weeks. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for a decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (including but not limited to, flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated thioridazine plasma levels, thioridazine should not be administered with fluoxetine or within a minimum of five weeks after fluoxetine has been discontinued (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors (MAOI) and WARNINGS, Thioridazine).

Drugs metabolized by CYP3A — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

In an in vivo interaction study involving the coadministration of fluoxetine with single doses of terfenadine (a CYP3A substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A activity is not likely to be of clinical significance.

Effect of olanzapine on drugs metabolized by other CYP enzymes — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, and CYP2C19. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

The effect of other drugs on olanzapine — Fluoxetine, an inhibitor of CYP2D6, decreases olanzapine clearance a small amount (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine clearance. Fluvoxamine, an inhibitor of CYP1A2, decreases olanzapine clearance (see Drug Interactions, Fluvoxamine). The effect of CYP1A2 inhibitors, such as fluvoxamine and some fluoroquinolone antibiotics, on SYMBYAX has not been evaluated. Although olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter olanzapine clearance. Therefore, a dosage increase (for induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs.

Drugs tightly bound to plasma proteins — The in vitro binding of SYMBYAX to human plasma proteins is similar to the individual components. The interaction between SYMBYAX and other highly protein–bound drugs has not been fully evaluated. Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein–bound fluoxetine by other tightly bound drugs (see CLINICAL PHARMACOLOGY, Distribution and PRECAUTIONS, Drug Interactions).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies were conducted with SYMBYAX. The following data are based on findings in studies performed with the individual components.

Carcinogenesis

Olanzapine — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78–week studies at doses of 3, 10, and 30/20 mg/kg/day [equivalent to 0.8 to 5 times the maximum recommended human daily dose (MRHD) on a mg/m² basis] and 0.25, 2, and 8 mg/kg/day (equivalent to 0.06 to 2 times the MRHD on a mg/m² basis). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, and 4 mg/kg/day (males) and 0.25, 1, 4, and 8 mg/kg/day (females) (equivalent to 0.1 to 2 and 0.1 to 4 times the MRHD on a mg/m² basis, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in one mouse study in females dosed at 8 mg/kg/day (2 times the MRHD on a mg/m² basis). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2 to 5 times the MRHD on a mg/m² basis); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (0.5 and 2 times the MRHD on a mg/m² basis, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4–fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin–mediated. The relevance for human risk of the finding of prolactin–mediated endocrine tumors in rodents is unknown (see PRECAUTIONS, Hyperprolactinemia).

Fluoxetine — The dietary administration of fluoxetine to rats and mice for two years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and 0.7 times, respectively, the MRHD on a mg/m² basis), produced no evidence of carcinogenicity.

Mutagenesis

Olanzapine — No evidence of mutagenic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.

Fluoxetine — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.

Impairment of Fertility

SYMBYAX — Fertility studies were not conducted with SYMBYAX. However, in a repeat–dose rat toxicology study of three months duration, ovary weight was decreased in females treated with the low–dose [2 and 4 mg/kg/day (1 and 0.5 times the MRHD on a mg/m² basis), respectively] and high–dose [4 and 8 mg/kg/day (2 and 1 times the MRHD on a mg/m² basis), respectively] combinations of olanzapine and fluoxetine. Decreased ovary weight, and corpora luteal depletion and uterine atrophy were observed to a greater extent in the females receiving the high–dose combination than in females receiving either olanzapine or fluoxetine alone. In a 3–month repeat–dose dog toxicology study, reduced epididymal sperm and reduced testicular and prostate weights were observed with the high–dose combination of olanzapine and fluoxetine [5 and 5 mg/kg/day (9 and 2 times the MRHD on a mg/m² basis), respectively] and with olanzapine alone (5 mg/kg/day or 9 times the MRHD on a mg/m² basis).

Olanzapine — In a fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the MRHD on a mg/m² basis, respectively). Discontinuance of olanzapine treatment reversed the effects on male–mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the MRHD on a mg/m² basis). Diestrous was prolonged and estrous was delayed at 1.1 mg/kg/day (0.6 times the MRHD on a mg/m² basis); therefore, olanzapine may produce a delay in ovulation.

Fluoxetine — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m² basis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use).

Pregnancy — Pregnancy Category C

SYMBYAX

Embryo fetal development studies were conducted in rats and rabbits with olanzapine and fluoxetine in low–dose and high–dose combinations. In rats, the doses were: 2 and 4 mg/kg/day (low–dose) [1 and 0.5 times the MRHD on a mg/m² basis, respectively], and 4 and 8 mg/kg/day (high–dose) [2 and 1 times the MRHD on a mg/m² basis, respectively]. In rabbits, the doses were 4 and 4 mg/kg/day (low–dose) [4 and 1 times the MRHD on a mg/m² basis, respectively], and 8 and 8 mg/kg/day (high–dose) [9 and 2 times the MRHD on a mg/m² basis, respectively]. In these studies, olanzapine and fluoxetine were also administered alone at the high–doses (4 and 8 mg/kg/day, respectively, in the rat; 8 and 8 mg/kg/day, respectively, in the rabbit). In the rabbit, there was no evidence of teratogenicity; however, the high–dose combination produced decreases in fetal weight and retarded skeletal ossification in conjunction with maternal toxicity. Similarly, in the rat there was no evidence of teratogenicity; however, a decrease in fetal weight was observed with the high–dose combination.

In a pre– and postnatal study conducted in rats, olanzapine and fluoxetine were administered during pregnancy and throughout lactation in combination (low–dose: 2 and 4 mg/kg/day [1 and 0.5 times the MRHD on a mg/m² basis], respectively, high–dose: 4 and 8 mg/kg/day [2 and 1 times the MRHD on a mg/m² basis], respectively, and alone: 4 and 8 mg/kg/day [2 and 1 times the MRHD on a mg/m² basis], respectively). Administration of the high–dose combination resulted in a marked elevation in offspring mortality and growth retardation in comparison to the same doses of olanzapine and fluoxetine administered alone. These effects were not observed with the low–dose combination; however, there were a few cases of testicular degeneration and atrophy, depletion of epididymal sperm and infertility in the male progeny. The effects of the high–dose combination on postnatal endpoints could not be assessed due to high progeny mortality.

There are no adequate and well–controlled studies with SYMBYAX in pregnant women.

SYMBYAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Olanzapine

In reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the MRHD on a mg/m² basis, respectively), no evidence of teratogenicity was observed. In a rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the MRHD on a mg/m² basis). Gestation was prolonged at 10 mg/kg/day (5 times the MRHD on a mg/m² basis). In a rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the MRHD on a mg/m² basis).

Placental transfer of olanzapine occurs in rat pups.

There are no adequate and well–controlled clinical studies with olanzapine in pregnant women. Seven pregnancies were observed during premarketing clinical studies with olanzapine, including two resulting in normal births, one resulting in neonatal death due to a cardiovascular defect, three therapeutic abortions, and one spontaneous abortion.

Fluoxetine

In embryo fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times the MRHD on a mg/m² basis, respectively) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m² basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m² basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no–effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m² basis).

Nonteratogenic Effects — Neonates exposed to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors).

Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1–2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six–fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.

When treating a pregnant woman with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Labor and Delivery

SYMBYAX

The effect of SYMBYAX on labor and delivery in humans is unknown. Parturition in rats was not affected by SYMBYAX. SYMBYAX should be used during labor and delivery only if the potential benefit justifies the potential risk.

Olanzapine

Parturition in rats was not affected by olanzapine. The effect of olanzapine on labor and delivery in humans is unknown.

Fluoxetine

The effect of fluoxetine on labor and delivery in humans is unknown. Fluoxetine crosses the placenta; therefore, there is a possibility that fluoxetine may have adverse effects on the newborn.

Nursing Mothers

SYMBYAX

There are no adequate and well–controlled studies with SYMBYAX in nursing mothers or infants. No studies have been conducted to examine the excretion of olanzapine or fluoxetine in breast milk following SYMBYAX treatment. It is recommended that women not breast–feed when receiving SYMBYAX.

Olanzapine

In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant dose at steady state was estimated to be 1.8% of the maternal olanzapine dose.

Fluoxetine

Fluoxetine is excreted in human breast milk. In one breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the 2nd day of feeding.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of SYMBYAX in a child or adolescent must balance the potential risks with the clinical need.

Fluoxetine

Significant toxicity, including myotoxicity, long–term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures.

In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine–induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1–0.2, 1–2, and 5