Olanzapine And Fluoxetine

Description

11 DESCRIPTION Olanzapine and Fluoxetine Capsules USP combine an atypical antipsychotic and a selective serotonin reuptake inhibitor, olanzapine, USP (the active ingredient in Zyprexa ® , and Zyprexa ® Zydis ® ) and fluoxetine hydrochloride, USP (the active ingredient in Prozac ® , Prozac ® Weekly ™ , and Sarafem ® ). Olanzapine, USP belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10 H -thieno[2,3- b ] [1,5]benzodiazepine. Fluoxetine hydrochloride, USP is a selective serotonin reuptake inhibitor (SSRI). The chemical designation is (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro- p -tolyl)oxy]propylamine hydrochloride. The chemical structures are: C 17 H 20 N 4 S M.W. 312.44 C 17 H 18 F 3 NO

What Is Olanzapine And Fluoxetine Used For?

1 INDICATIONS AND USAGE Olanzapine and fluoxetine capsules are indicated for the treatment of: Acute depressive episodes in Bipolar I Disorder [see Clinical Studies (14.1) ]. Treatment resistant depression (Major Depressive Disorder in patient who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) [see Clinical Studies (14.2) ]. Olanzapine and fluoxetine capsules combine olanzapine, an atypical antipsychotic and fluoxetine, a selective serotonin reuptake inhibitor, indicated for treatment of: Acute Depressive Episodes Associated with Bipolar I Disorder (1) Treatment Resistant Depression (1)

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Adult Starting Dose: 6 mg olanzapine with 25 mg fluoxetine (6 mg/25 mg, once daily in the evening) (2.1 , 2.2 ) Adult Maximum Dose: 12 mg/50 mg once daily (2.1 , 2.2 ). Pediatric Bipolar Depression Starting Dose: 3 mg/25 mg once daily (for ages 10 to 17 years) (2.1) . Pediatric Bipolar Depression Maximum Dose: 12 mg/50 mg (2.1) Starting dose in patients predisposed to hypotensive reactions, hepatic impairment, or with potential for slowed metabolism: 3 mg/25 mg to 6 mg/25 mg. Escalate dose cautiously (2.3) 2.1 Depressive Episodes Associated with Bipolar I Disorder Adults – Administer olanzapine and fluoxetine capsules 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 olanzapine and fluoxetine capsules has not been studied. Make dosage adjustments, if indicated, according to efficacy and tolerability. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine capsules 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 olanzapine and fluoxetine capsules 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; 12/25; 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 olanzapine and fluoxetine capsules 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 olanzapine and fluoxetine capsules has not been studied. Adjust dosage, if indicated, according to efficacy and tolerability. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine capsules 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 olanzapine and fluoxetine capsules 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 olanzapine and fluoxetine capsules...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1) ] Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.2) ] Neuroleptic Malignant syndrome (NMS) [see Warnings and Precautions (5.3) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4) ] Hyperglycemia [see Warnings and Precautions (5.5) ] Dyslipidemia [see Warnings and Precautions (5.5) ] Weight Gain [see Warnings and Precautions (5.5) ] Serotonin Syndrome [see Warnings and Precautions (5.6) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.7) ] Allergic Reactions and Rash [see Warnings and Precautions (5.8) ] Activation of Mania/Hypomania [see Warnings and Precautions (5.9) ] Tardive Dyskinesia [see Warnings and Precautions (5.10) ] Orthostatic Hypotension [see Warnings and Precautions (5.11) ] Falls [see Warnings and Precautions (5.12) ] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.13) ] Dysphagia [see Warnings and Precautions (5.14) ] Seizures [see Warnings and Precautions (5.15) ] Abnormal Bleeding [see Warnings and Precautions (5.16) ] Hyponatremia [see Warnings and Precautions (5.17) ] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.18) ] Body Temperature Dysregulation [see Warnings and Precautions (5.19) ] QT Prolongation [see Warnings and Precautions (5.20) ] Hyperprolactinemia [see Warnings and Precautions (5.22) ] Discontinuation Adverse Reactions [see Warnings and Precautions (5.25) ] Most common adverse reactions (≥5% and at least twice that for placebo) in adults: sedation, weight increased, appetite increased, dry mouth, fatigue, edema, tremor, disturbance in attention, blurred vision. Children and adolescents: sedation, weight increased, appetite increased, tremor, triglyceride increased, hepatic enzymes increased (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 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. Adults — The information below is derived from a clinical study database for olanzapine and fluoxetine capsules 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 olanzapine and fluoxetine capsules 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 Associated with Discontinuation of Treatment in Short-Term, Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression — Overall, 11.3% of the 771 patients in the olanzapine and fluoxetine capsule group discontinued due to adverse reactions compared with 4.4% of the 477 patients for placebo. Adverse reactions leading to discontinuation associated with the use of olanzapine and fluoxetine capsules (incidence of at least 1% for olanzapine and fluoxetine capsules and...

Drug Interactions

7 DRUG INTERACTIONS The risks of using olanzapine and fluoxetine capsules 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 olanzapine and fluoxetine capsules. 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 [see Clinical Pharmacology (12.3) ]. Monoamine Oxidase Inhibitor (MAOI) : (2.4 , 2.5 , 4.1 , 5.6 , 7.1 ) Drugs Metabolized by CYP2D6 : Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7) Tricyclic Antidepressants (TCAs) : Monitor TCA levels during coadministration with olanzapine and fluoxetine capsules or when olanzapine and fluoxetine capsules have been recently discontinued (5.6 , 7.7 ) CNS Acting Drugs : Caution is advised if the concomitant administration of olanzapine and fluoxetine capsules and other CNS-active drugs is required (7.2) Antihypertensive Agent : Enhanced antihypertensive effect (7.7) Levodopa and Dopamine Agonists : May antagonize levodopa/dopamine agonists (7.7) Benzodiazepines : May potentiate orthostatic hypotension and sedation (7.6 , 7.7 ) Clozapine : May elevate clozapine levels (7.7) Haloperidol : Elevated haloperidol levels have been observed (7.7) Carbamazepine : Potential for elevated carbamazepine levels and clinical anticonvulsant toxicity (7.7) Phenytoin : Potential for elevated phenytoin levels and clinical anticonvulsant toxicity (7.7) Alcohol : May potentiate sedation and orthostatic hypotension (7.7) Serotonergic Drugs : (2.4 , 2.5 , 4.1 , 5.6 , 7.3 ) Fluvoxamine : May increase olanzapine levels; a lower dose of the olanzapine component of olanzapine and fluoxetine capsules should be considered (7.6) Drugs that Interfere with Hemostasis : (e.g., NSAIDs, Aspirin, Warfarin, etc.): May potentiate the risk of bleeding (7.4) Drugs Tightly Bound to Plasma Proteins : Fluoxetine may cause shift in plasma concentrations (7.7) Drugs that Prolong the QT Interval : Do not use olanzapine and fluoxetine capsules in combination with thioridazine or pimozide. Use olanzapine and fluoxetine capsules with caution in combination with other drugs that prolong the QT interval (4.2 , 5.20 , 7.7 , 7.8 ) 7.1 Monoamine Oxidase Inhibitors (MAOIs) [ See Dosage and Administration ( 2.4 , 2.5 ), Contraindications ( 4.1 ), and Warnings and Precautions ( 5.6 ) ]. 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of olanzapine and fluoxetine capsules 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...

Contraindications

4 CONTRAINDICATIONS Monoamine Oxidase Inhibitors (MAOI) : Because of the risk of serotonin syndrome, do not use MAOIs intended to treat psychiatric disorders with olanzapine and fluoxetine capsules or within 5 weeks of stopping treatment with olanzapine and fluoxetine capsules. Do not use olanzapine and fluoxetine capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start olanzapine and fluoxetine capsules in a patient who is being treated with linezolid or intravenous methylene blue. (4.1) Pimozide : Do not use. Risk of QT interval prolongation (4.2 , 5.20 , 7.7 , 7.8 ) Thioridazine : Do not use. Risk of QT interval prolongation. Do not use thioridazine within 5 weeks of discontinuing olanzapine and fluoxetine capsules (4.2 , 5.20 , 7.7 , 7.8 ) 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with olanzapine and fluoxetine capsules or within 5 weeks of stopping treatment with olanzapine and fluoxetine capsules is contraindicated because of an increased risk of serotonin syndrome. The use of olanzapine and fluoxetine capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.4) and Warnings and Precautions (5.6) ]. Starting olanzapine and fluoxetine capsules in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.5) and Warnings and Precautions (5.6) ]. 4.2 Other Contraindications Pimozide [see Warnings and Precautions (5.20) and Drug Interactions (7.7 , 7.8) ] Thioridazine [see Warnings and Precautions (5.20) and Drug Interactions (7.7 , 7.8) ] Pimozide and thioridazine prolong the QT interval. Olanzapine and fluoxetine capsules can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Olanzapine and fluoxetine...

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled clinical studies with olanzapine and fluoxetine capsules or their components (olanzapine and fluoxetine) in pregnant women. A number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. Neonates exposed to fluoxetine, a component of olanzapine and fluoxetine capsules, and other SSRIs and SNRIs late in the third trimester have developed complications arising immediately upon delivery (respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying) requiring prolonged hospitalization, respiratory support, and tube feeding. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture is consistent with serotonin syndrome. Neonates exposed to olanzapine, a component of olanzapine and fluoxetine capsules, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). Olanzapine and fluoxetine capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, taking into account the risk of untreated Bipolar I Depression or Treatment Resistant Depression. Human Data There are no adequate and well-controlled...

8.3 Nursing Mothers Olanzapine and fluoxetine capsules — Studies evaluating the individual components of olanzapine and fluoxetine capsules (olanzapine and fluoxetine) in nursing mothers are described below. Because of the potential for serious adverse reactions in nursing infants from olanzapine and fluoxetine capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is recommended that women not breast-feed when receiving olanzapine and fluoxetine capsules. 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. It is recommended that women receiving olanzapine should not breast-feed. Fluoxetine — Fluoxetine is excreted in human breast milk. In 1 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.

Overdosage

10 OVERDOSAGE Olanzapine and fluoxetine capsules — 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 olanzapine and fluoxetine capsules, have been reported. 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. Reports of fatality in association with overdose of olanzapine alone have been received. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral...

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Olanzapine and fluoxetine capsules USP are supplied as follows: 3 mg/25 mg strength: Capsules with opaque buff body and cap with "TEVA" imprinted on the cap and "5503" imprinted on the body, in bottles of 30. (NDC 42291-652-30) 6 mg/25 mg strength: Capsules with opaque orange body and cap with "TEVA" imprinted on the cap and "5504" imprinted on the body, in bottles of 30. (NDC 42291-653-30) 6 mg/50 mg strength: Capsules with opaque white body and cap with "TEVA" imprinted on the cap and "5505" imprinted on the body, in bottles of 30. (NDC 42291-654-30) 12 mg/25 mg strength: Capsules with opaque yellow body and cap with "TEVA" imprinted on the cap and "5506" imprinted on the body, in bottles of 30. (NDC 42291-655-30) 12 mg/50 mg strength: Capsules with opaque maroon body and cap with "TEVA" imprinted on the cap and "5507" imprinted on the body, in bottles of 30. (NDC 42291-656-30) 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F) with excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture. Keep container tightly closed. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). 16.1 How Supplied Olanzapine and fluoxetine capsules USP are supplied as follows: 3 mg/25 mg strength: Capsules with opaque buff body and cap with "TEVA" imprinted on the cap and "5503" imprinted on the body, in bottles of 30. (NDC 42291-652-30) 6 mg/25 mg strength: Capsules with opaque orange body and cap with "TEVA" imprinted on the cap and "5504" imprinted on the body, in bottles of 30. (NDC 42291-653-30) 6 mg/50 mg strength: Capsules with opaque white body and cap with "TEVA" imprinted on the cap and "5505" imprinted on the body, in bottles of 30. (NDC 42291-654-30) 12 mg/25 mg strength: Capsules with opaque yellow body and cap with "TEVA" imprinted on the cap and "5506" imprinted on the body, in...