SYMBYAX Capsule Ref.[50742] Active ingredients: Fluoxetine Olanzapine

2.1 Depressive Episodes Associated with Bipolar I Disorder

Adults

Administer SYMBYAX once daily in the evening, generally beginning with the 6 mg/25 mg (mg olanzapine/mg equivalent fluoxetine) 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. Make dosage adjustments, if indicated, according to efficacy and tolerability. Antidepressant efficacy was demonstrated with SYMBYAX in a dose range of olanzapine 6 mg to 12 mg and fluoxetine 25 mg to 50 mg [see Clinical Studies (14.1)]. The safety of doses above 18 mg of olanzapine and 75 mg of fluoxetine has not been evaluated in adult clinical studies. Periodically reexamine the need for continued pharmacotherapy.

Children and Adolescents (10 to 17 years of age)

Administer SYMBYAX once daily in the evening, generally beginning with the 3 mg/25 mg capsule, without regard to meals, with a recommended target dose within the approved dosing range (6/25; 6/50; 12/50 mg) [see Clinical Studies (14.1)]. The safety of doses above 12 mg of olanzapine and 50 mg of fluoxetine has not been evaluated in pediatric clinical studies. Periodically reexamine the need for continued pharmacotherapy.

2.2 Treatment Resistant Depression

Administer SYMBYAX 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. Adjust dosage, if indicated, according to efficacy and tolerability. Antidepressant efficacy was demonstrated with SYMBYAX in a dose range of olanzapine 6 mg to 18 mg and fluoxetine 25 mg to 50 mg [see Clinical Studies (14.2)]. The safety of doses above 18 mg/75 mg has not been evaluated in clinical studies. Periodically reexamine the need for continued pharmacotherapy.

2.3 Specific Populations

Start SYMBYAX at 3 mg/25 mg or 6 mg/25 mg in patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of SYMBYAX (female gender, geriatric age, nonsmoking status) or those patients who may be pharmacodynamically sensitive to olanzapine. Titrate slowly and adjust dosage as needed in patients who exhibit a combination of factors that may slow metabolism. SYMBYAX has not been systematically studied in patients >65 years of age or in patients <10 years of age [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3, 12.4)].

2.4 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with SYMBYAX. Conversely, at least 5 weeks should be allowed after stopping SYMBYAX before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

2.5 Use of SYMBYAX with Other MAOIs such as Linezolid or Methylene Blue

Do not start SYMBYAX in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].

In some cases, a patient already receiving SYMBYAX therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue are judged to outweigh the risks of serotonin syndrome in a particular patient, SYMBYAX should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with SYMBYAX may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.6)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with SYMBYAX is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.6)].

2.6 Discontinuation of Treatment with SYMBYAX

Symptoms associated with discontinuation of fluoxetine, a component of SYMBYAX, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.25)].

SYMBYAX

During premarketing clinical studies of olanzapine and fluoxetine in combination, overdose of both fluoxetine and olanzapine were reported in 5 study subjects. Four of the 5 subjects experienced loss of consciousness (3) or coma (1). No fatalities occurred.

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

In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia as well as a patient that experienced sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and Company has received reports of fatality in association with overdose of olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.

Fluoxetine

The following have been reported with fluoxetine overdosage:

• Seizures, which may be delayed, and altered mental status including coma.
• Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, Torsade de Pointes, and cardiac arrest. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.
• Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk).

10.1 Management of Overdose

For current information on the management of SYMBYAX (olanzapine and fluoxetine) overdose, consider contacting a Certified Poison Control Center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. In managing overdose, consider the possibility of multiple drug involvement. Establish and maintain an airway and ensure adequate ventilation. Commence cardiovascular monitoring immediately and 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 increases the possibility of serious sequelae and extends 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.

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.