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 )
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 ) Pimozid e: 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 )
4.1Monoamine 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 )] .
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 capsules can also prolong the QT interval.
Warnings and precautions
Neuroleptic Malignant Syndrome : Manage with immediate discontinuation and close monitoring ( 5.3 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue if DRESS is suspected ( 5.4 ) Metabolic Changes : Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain ( 5.5 ) Hyperglycemia and Diabetes Mellitus : In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death.
Monitor for symptoms of hyperglycemia. Perform fasting blood glucose testing before beginning, and periodically during treatment. ( 5.5 ) Dyslipidemia : Appropriate clinical monitoring is recommended, including fasting blood lipid testing before beginning, and periodically during, treatment ( 5.5 ) Weight gain : Consider potential consequences of weight gain. Monitor weight regularly ( 5.5 ) Serotonin Syndrome : Serotonin syndrome has been reported with SSRIs and SNRIs, including olanzapine and fluoxetine capsules, both when taken alone, but especially when co-administered with other serotonergic agents.
If such symptoms occur, discontinue olanzapine and fluoxetine capsules and serotonergic agents and initiate supportive treatment. If concomitant use of olanzapine and fluoxetine capsules with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 5.6 ) Angle-Closure Glaucoma : Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.7 ) Allergic Reactions and Rash : Discontinue upon appearance of rash or allergic phenomena ( 5.8 ) Activation of Mania/Hypomania : Screen for Bipolar Disorder and monitor for activation of mania/hypomania ( 5.9 ) Tardive Dyskinesia : Discontinue if clinically appropriate ( 5.10 ) Orthostatic Hypotension : Can be associated with bradycardia and syncope.
Risk is increased during initial dose titration. Use caution in patients with cardiovascular disease or cerebrovascular disease, and those conditions that could affect hemodynamic responses ( 5.11 ) Leukopenia, Neutropenia, and Agranulocytosis : Has been reported with antipsychotics, including olanzapine and fluoxetine capsules. Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy.
Consider discontinuing olanzapine and fluoxetine capsules at the first sign of a clinically significant decline in WBC in the absence of other causative factors ( 5.13 ) Seizures : Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.15 ) Increased Risk of Bleeding : SSRIs increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding ( 5.16 ) Hyponatremia : Can occur in association with syndrome of inappropriate antidiuretic hormone (SIADH).
Consider discontinuing olanzapine and fluoxetine capsules if symptomatic hyponatremia occurs (SIADH) ( 5.17 ) Potential for Cognitive and Motor Impairment : Has potential to impair judgment, thinking, and motor skills. Caution patients about operating machinery ( 5.18 ) QT Prolongation : QT prolongation and ventricular arrhythmia including Torsade de Pointes have been reported with fluoxetine. Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure.
Use cautiously in patients with risk factors for QT prolongation ( 4.2 , 5.20 ) Anticholinergic (antimuscarinic) Effects : Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, history of paralytic ileus or related conditions ( 5.21 ) Hyperprolactinemia : May elevate prolactin levels ( 5.22 ) Long Elimination Half-Life of Fluoxetine : Changes in dose will not be fully reflected in plasma for several weeks ( 5.24 ) Sexual Dysfunction: Olanzapine and fluoxetine capsules use may cause symptoms of sexual dysfunction ( 5.26 )
5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults 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 Table 1. Table 1: Suicidality per 1000 Patients Treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases 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.
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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 )
7.1Monoamine Oxidase Inhibitors
(MAOIs) [See Dosage and Administration ( 2.4 , 2.5 ), Contraindications ( 4.1 ), and Warnings and Precautions ( 5.6 )] .
7.2CNS 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 schedules, and monitoring of clinical status [see Clinical Pharmacology ( 12.3 )] .
7.3Other Serotonergic Drugs
The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with olanzapine and fluoxetine capsules increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of olanzapine and fluoxetine capsules and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.6 )] .
7.4 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.
Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin [see Warnings and Precautions ( 5.16 )] . Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics. Single doses of olanzapine did not affect the pharmacokinetics of warfarin. Patients receiving warfarin therapy should be carefully monitored when olanzapine and fluoxetine capsules are initiated or discontinued.
7.5Electroconvulsive 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 Warnings and Precautions ( 5.15 )] .
7.6Potential for Other Drugs to Affect Olanzapine and Fluoxetine Capsules
Benzodiazepines — Co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions ( 7.7 )] . Inducers of 1A2 — 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 [see Drug Interactions ( 7.7 )] .
Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics [see Drug Interactions ( 7.7 )] . Inhibitors of CYP1A2 — Fluvoxamine 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 olanzapine and fluoxetine capsules should be considered in patients receiving concomitant treatment with fluvoxamine.
The Effect of Other Drugs on Olanzapine — Fluoxetine, an inhibitor of CYP2D6, decreases olanzapine clearance a small amount [see Clinical Pharmacology ( 12.3 )]. Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine clearance. The effect of CYP1A2 inhibitors, such as fluvoxamine and some fluoroquinolone antibiotics, on olanzapine and fluoxetine capsules 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.
7.7Potential for Olanzapine and Fluoxetine Capsules to Affect Other Drugs
Pimozide — Concomitant use of olanzapine and fluoxetine capsules and pimozide is contraindicated. Pimozide can prolong the QT interval. Olanzapine and fluoxetine capsules can increase the level of pimozide through inhibition of CYP2D6. Olanzapine and fluoxetine capsules can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT c prolongation.
While a specific study with pimozide and olanzapine and fluoxetine capsules has not been conducted, the potential for drug interactions or QT c prolongation warrants restricting the concurrent use of pimozide and olanzapine and fluoxetine capsules [see Contraindications ( 4.2 ), Warnings and Precautions ( 5.20 ), and Drug Interactions ( 7.8 )] . Carbamazepine — Patients on stable doses of carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.
Alcohol — The coadministration of ethanol with olanzapine and fluoxetine capsules may potentiate sedation and orthostatic hypotensi
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Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.16 ) and Clinical Considerations] . Neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations) .
Overall available data from published epidemiologic studies and postmarketing reports of pregnant women exposed to olanzapine or fluoxetine have not established a drug-associated increased risk of major birth defects or miscarriage (see Data) . Some studies in pregnant women exposed to fluoxetine have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see Data) .
There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension (PPHN) (see Data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, during pregnancy (see Clinical Considerations). Neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations).
In animal studies, administration of the combination of olanzapine and fluoxetine during the period of organogenesis resulted in adverse effects on development (decreased fetal body weights in rats and rabbits and retarded skeletal ossification in rabbits) at maternally toxic doses greater than those used clinically. When administered to rats throughout pregnancy and lactation, an increase in early postnatal mortality was observed at doses similar to those used clinically (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, miscarriage, or another adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants.
This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum. Maternal Adverse Reactions Use of olanzapine and fluoxetine capsules in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.16 )] .
Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.
Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Neonates exposed to fluoxetine, and other SSRIs or 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 findings 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 Warnings and Precautions ( 5.6 )] . Infants exposed to SSRIs, particularly later in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality.
Several recent epidemiologic studies suggest a positive statistical association between SSRI (including fluoxetine) use in pregnancy and PPHN. Other studies do not show a significant statistical association. Data Human Data It has been shown that olanzapine and fluoxetine can cross the placenta. Placental passage of olanzapine has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy.
The clinical relevance of this finding is unknown. Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.
Several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. However, these studies results do not establish a causal relationship. Methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. However, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy.
Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for persistent pulmonary hypertension (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data Olanzapine and fluoxetine capsules — 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) [approximately 2 and 1 times the maximum recommended human dose (MRHD) for olanzapine and fluoxetine capsules: for olanzapine (12 mg) and fluoxetine (50 mg), respectively based on mg/m 2 body surface area], and 4 and 8 mg/kg/day (high-dose) [approximately 3 and 2 times the MRHD based on mg/m 2 body surface area, respectively]. In rabbits, the doses were 4 and 4 mg/kg/day (low-dose) [approximately 6 and 2 times the MRHD based on mg/m 2 body surface area, respectively], and 8 and 8 mg/kg/day (high-dose) [approximately 13 and 3 times the MRHD based on mg/m 2 body surface area, 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 orally
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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 )] Increased Risk of 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 )] Anticholinergic (antimuscarinic) Effects [see Warnings and Precautions ( 5.21 )] Hyperprolactinemia [see Warnings and Precautions ( 5.22 )] Discontinuation Adverse Reactions [see Warnings and Precautions ( 5.25 )] Sexual Dysfunction [see Warnings and Precautions ( 5.26 )] 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 Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 greater than that for placebo) using MedDRA Dictionary coding were weight increased (2%) and sedation (1%) versus placebo patients which had 0% incidence of weight increased and sedation. Commonly Observed Adverse Reactions in Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression — In short-term studies, the most commonly observed adverse reactions associated with the use of olanzapine and fluoxetine capsules (incidence ≥5% and at least twice that for placebo in the olanzapine and fluoxetine capsule-controlled database) using MedDRA Dictionary coding were: disturbance in attention, dry mouth, fatigue, hypersomnia, increased appetite, peripheral edema, sedation, somnolence, tremor, vision blurred, and weight increased.
Adverse reactions reported in clinical trials of olanzapine and fluoxetine in combination are generally consistent with treatment-emergent adverse reactions during olanzapine or fluoxetine monotherapy. In a 47-week maintenance study in adults with treatment resistant depression, adverse reactions associated with olanzapine and fluoxetine capsule use were generally similar to those seen in short-term studies. Weight gain, hyperlipidemia, and hyperglycemia were observed in olanzapine and fluoxetine capsule -treated patients throughout the study.
Adverse Reactions Occurring at an Incidence of 2% or More in Short-Term Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression — Table 16 enumerates the treatment-emergent adverse reactions associated with the use of olanzapine and fluoxetine capsules (incidence of at least 2% for olanzapine and fluoxetine capsules and twice or more than for placebo). The olanzapine and fluoxetine capsule-controlled column includes patients with various diagnoses while the placebo column includes only patients with bipolar depression and major depression with psychotic features.
Table 16: Adverse Reactions: Incidence in the Short-Term Controlled Clinical Studies in Adults System Organ Class Adverse Reaction Percentage of Patients Reporting Event Olanzapine and Fluoxetine Capsule-Controlled (N=771) Placebo (N=477) Eye disorders Vision blurred 5 2 Gastrointestinal disorders Dry mouth 15 6 Flatulence 3 1 Abdominal distension 2 0 General disorders and administration site conditions Fatigue 12 2 Edema a 15 2 Asthenia 3 1 Pain 2 1 Pyrexia 2 1 Infections and infestations Sinusitis 2 1 Investigations Weight increased 25 3 Metabolism and nutrition disorders Increased appetite 20 4 Musculoskeletal and connective tissue disorders Arthralgia 4 1 Pain in extremity 3 1 Musculoskeletal stiffness 2 1 Nervous system disorders Somnolence b 27 11 Tremor 9 3 Disturbance in attention 5 1 Psychiatric disorders Restlessness 4 1 Thinking abnormal 2 1 Nervousness 2 1 Reproductive system and breast disorders Erectile dysfunction 2 1 a Includes edema, edema peripheral, pitting edema, generalized edema, eyelid edema, face edema, gravitational edema, localized edema, periorbital edema, swelling, joint swelling, swelling face, and eye swelling. b Includes somnolence, sedation, hypersomnia, and lethargy.
Extrapyramidal Symptoms Dystonia, Class Effect for Antipsychotics — Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs.
In general, an elevated risk of acute dystonia may be observed in males and youn
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Composition
Active ingredients
FLUOXETINE HYDROCHLORIDE EQ 25MG BASE; OLANZAPINE EQ 3MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
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
