Olanzapine and Fluoxetine Capsules

Name: Olanzapine and Fluoxetine Capsules

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)]

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 hydrochloride consisting of 2,547 patients. The conditions and duration of treatment with olanzapine and fluoxetine hydrochloride 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

Overall, 11.3% of the 771 patients in the olanzapine and fluoxetine hydrochloride 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 hydrochloride (incidence of at least 1% for olanzapine and fluoxetine hydrochloride 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

In short term studies, the most commonly observed adverse reactions associated with the use of olanzapine and fluoxetine hydrochloride (incidence ≥5% and at least twice that for placebo in the olanzapine and fluoxetine hydrochloride-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 adverse reactions associated with olanzapine and fluoxetine hydrochloride use were generally similar to those seen in short-term studies. Weight gain, hyperlipidemia, and hyperglycemia were observed in olanzapine and fluoxetine hydrochloride-treated patients throughout the study.

Adverse Reactions Occurring at an Incidence of 2% or More in Short-Term Controlled Studies

Table 16 enumerates the treatment-emergent adverse reactions associated with the use of olanzapine and fluoxetine hydrochloride (incidence of at least 2% for olanzapine and fluoxetine hydrochloride and twice or more than for placebo). The olanzapine and fluoxetine hydrochloride-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 Hydrochloride-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*

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†

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

*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.

†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 younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with the olanzapine and fluoxetine combination.

Additional Findings Observed in Clinical Studies

Sexual Dysfunction

In the pool of controlled olanzapine and fluoxetine hydrochloride studies in patients with bipolar depression, there were higher rates of the treatment-emergent adverse reactions decreased libido, anorgasmia, erectile dysfunction and abnormal ejaculation in the olanzapine and fluoxetine hydrochloride group than in the placebo group. One case of decreased libido led to discontinuation in the olanzapine and fluoxetine hydrochloride group. In the controlled studies that contained a fluoxetine arm, the rates of decreased libido and abnormal ejaculation in the olanzapine and fluoxetine hydrochloride group were less than the rates in the fluoxetine group. None of the differences were statistically significant.

Sexual dysfunction, including priapism, has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

There are no adequate and well-controlled studies examining sexual dysfunction with olanzapine and fluoxetine hydrochloride or fluoxetine treatment. Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment.

Difference Among Dose Levels Observed in Other Olanzapine Clinical Trials

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200), and 40 (N=200) mg/day of olanzapine in patients with Schizophrenia or Schizoaffective Disorder, statistically significant differences among 3 dose groups were observed for the following safety outcomes: weight gain, prolactin elevation, fatigue, and dizziness. Mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs. 40 mg/day. Incidence of treatment-emergent prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) with significant differences between 10 vs. 40 mg/day and 20 vs. 40 mg/day; fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) with significant differences between 10 vs. 40 and 20 vs. 40 mg/day; and dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) with significant differences between 20 vs. 40 mg, was observed.

Other Adverse Reactions Observed in Clinical Studies

Following is a list of treatment-emergent adverse reactions reported by patients treated with olanzapine and fluoxetine hydrochloride in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; and rare reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole Frequent:chills, neck rigidity, photosensitivity reaction; Rare: death1.

Cardiovascular System Frequent: vasodilatation.

Digestive System Frequent:diarrhea; Infrequent: gastritis, gastroenteritis, nausea and vomiting, peptic ulcer; Rare: gastrointestinal hemorrhage, intestinal obstruction, liver fatty deposit, pancreatitis.

Hemic and Lymphatic System Frequent: ecchymosis; Infrequent: anemia, thrombocytopenia; Rare: leukopenia, purpura.

Metabolic and Nutritional Frequent: generalized edema, weight loss; Rare:bilirubinemia, creatinine increased, gout.

Musculoskeletal System Rare: osteoporosis.

Nervous System Frequent: amnesia; Infrequent: ataxia, buccoglossal syndrome, coma, depersonalization, dysarthria, emotional lability, euphoria, hypokinesia, movement disorder, myoclonus; Rare: hyperkinesia, libido increased, withdrawal syndrome.

Respiratory System Infrequent: epistaxis, yawn; Rare: laryngismus.

Skin and Appendages Infrequent: alopecia, dry skin, pruritus; Rare: exfoliative dermatitis.

Special Senses Frequent:taste perversion; Infrequent: abnormality of accommodation, dry eyes.

Urogenital System Frequent: breast pain, menorrhagia2, urinary frequency, urinary incontinence; Infrequent: amenorrhea2, female lactation2, hypomenorrhea2, metrorrhagia2, urinary retention, urinary urgency, urination impaired; Rare: breast engorgement2.

1 This term represents a serious adverse event but does not meet the definition for adverse drug reactions. It is included here because of its seriousness.

2 Adjusted for gender.

Other Adverse Reactions Observed with Olanzapine or Fluoxetine Monotherapy

The following adverse reactions were not observed in olanzapine and fluoxetine hydrochloride-treated patients during premarketing clinical studies but have been reported with olanzapine or fluoxetine monotherapy: aplastic anemia, bruxism, cholestatic jaundice, diabetic coma, dysuria, eosinophilic pneumonia3, erythema multiforme, esophageal ulcer, gynecological bleeding, headache, hypotension, jaundice, neutropenia, restless legs syndrome, sudden unexpected death3, sweating, and violent behaviors3. Random triglyceride levels of ≥1000 mg/dL have been reported.

3 These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

Children and Adolescent Patients (aged 10 to 17 years) with a Diagnosis of Bipolar Depression

The information below is derived from a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine hydrochloride for the treatment of bipolar I depression in patients 10 to 17 years of age.

Adverse Reactions Associated with Discontinuation of Treatment in the Single Pediatric Study

Overall, 14.1% of the 170 patients in the olanzapine and fluoxetine hydrochloride group discontinued due to adverse reactions compared with 5.9% of the 85 patients for placebo. Adverse reactions leading to discontinuation associated with the use of olanzapine and fluoxetine hydrochloride (incidence of at least 1% for olanzapine and fluoxetine hydrochloride and greater than that for placebo) using MedDRA Dictionary coding were weight increased (2.9%), suicidal ideation (1.8%), bipolar disorder (1.2%), and somnolence (1.2%) versus placebo patients which had 0% incidence of weight increased, bipolar disorder, and somnolence, and a 1.2% incidence of suicidal ideation.

Adverse Reactions Occurring at an Incidence of 2% or More and Greater than Placebo

Table 17 enumerates the treatment-emergent adverse reactions associated with the use of olanzapine and fluoxetine hydrochloride (incidence of at least 2% for olanzapine and fluoxetine hydrochloride and twice or more than for placebo).

Table 17: Treatment-Emergent Adverse Reactions: Incidence in a 8-week Randomized, Double-blind, Placebo-Controlled Clinical Trial in Pediatric Bipolar I Depression.

System Organ Class

Adverse Reaction

Percentage of Patients
Reporting Event

Olanzapine and Fluoxetine Hydrochloride
(N=170)

Placebo
(N=85)

Nervous system disorders

Somnolence*

24

2

Tremor

9

1

Investigations

Weight increased

20

1

Blood triglycerides increased

7

2

Blood cholesterol increased

4

0

Hepatic enzyme increased†

9

1

Gastrointestinal disorders

Dyspepsia

3

1

Metabolism and nutrition disorders

Increased appetite

17

1

Psychiatric disorders

Anxiety

3

1

Restlessness

3

1

Suicidal ideation

2

1

Musculoskeletal and connective tissue disorders

Back pain

2

1

Injury, poisoning and procedural complications

Accidental overdose

3

1

Reproductive system and breast disorders

Dysmenorrhea

2

0

*Includes somnolence, sedation, and hypersomnia. No lethargy was reported.

†Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, gamma-glutamyltransferase increased, and transaminases increased.

Vital Signs and Laboratory Studies

Adults

Vital Signs

Tachycardia, bradycardia, and orthostatic hypotension have occurred in olanzapine and fluoxetine hydrochloride-treated patients [see WARNINGS AND PRECAUTIONS (5.11)]. The mean standing pulse rate of olanzapine and fluoxetine hydrochloride-treated patients was reduced by 0.7 beats/min.

Laboratory Changes

In olanzapine and fluoxetine hydrochloride clinical studies, olanzapine and fluoxetine hydrochloride was associated with statistically significantly greater frequencies for the following treatment-emergent findings in laboratory analytes (normal at baseline to abnormal at any time during the trial) compared to placebo: elevated prolactin ( 28% vs. 5%); elevated urea nitrogen (3% vs. 0.8%); elevated uric acid (3% vs. 0.5%); low albumin (3% vs. 0.3%); low bicarbonate (14% vs. 9%); low hemoglobin (3% vs. 0%); low inorganic phosphorus (2% vs. 0.3%); low lymphocytes (2% vs. 0%); and low total bilirubin (15% vs. 4%).

As with olanzapine, asymptomatic elevations of hepatic aminotransferases [ALT, AST, and GGT] and alkaline phosphatase have been observed with olanzapine and fluoxetine hydrochloride. In the olanzapine and fluoxetine hydrochloride-controlled database, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (38/698) of patients exposed to olanzapine and fluoxetine hydrochloride compared with 0.5% (2/378) of placebo-treated patients and 4% (33/751) of olanzapine-treated patients. ALT elevations ≥5 times ULN were observed in 2% (11/701) of olanzapine and fluoxetine hydrochloride-treated patients, compared to 0.3% (1/379) of placebo-treated patients and 1% (11/760) of olanzapine-treated patients. No patient with elevated ALT values experienced jaundice or liver failure, or met the criteria for Hy’s Rule. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine and fluoxetine hydrochloride or discontinued olanzapine and fluoxetine hydrochloride.

Rare postmarketing reports of hepatitis have been received in patients treated with olanzapine. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period in patients treated with olanzapine.

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.

An increase in creatine phosphokinase has been reported very rarely in olanzapine and fluoxetine hydrochloride-treated patients and infrequently in clinical trials of olanzapine-treated patients.

QT Interval Prolongation

In patients treated with olanzapine and fluoxetine hydrochloride QTcF≥450 msec for males and QTcF≥470 msec for females has been reported frequently (≥1%). The incidence of QTcF>500 msec associated with olanzapine and fluoxetine hydrochloride treatment in clinical trials has been rare and was not significantly different from the incidence associated with placebo. The mean increase in QTc interval for olanzapine and fluoxetine hydrochloride-treated patients (5.17 msec) in the one clinical study directly comparing olanzapine and fluoxetine hydrochloride to placebo in adult patients was significantly greater than that for placebo-treated patients (-1.66 msec).

Children and Adolescents (aged 10 to 17 years)

In a single 8-week randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine hydrochloride for treatment of bipolar I depression in patients 10 to 17 years of age, the following was observed:

Vital Signs

In the olanzapine and fluoxetine hydrochloride-treated patients compared with placebo-treated patients, the mean orthostatic blood pressure and standing pulse rate were not significantly different between treatment groups.

Body Weight

An increase in weight greater than or equal to 7% occurred in 52.4% of the olanzapine and fluoxetine hydrochloride group and 3.6% of the placebo group. Weight gain greater than or equal to 15% occurred in 14.1% of the olanzapine and fluoxetine hydrochloride group and none of the placebo group.

Laboratory Changes

Olanzapine and fluoxetine hydrochloride was associated with statistically significantly greater frequencies for the following treatment-emergent findings in laboratory analytes (normal or low at baseline to abnormal at any time during the trial) compared to placebo: elevated ALT (45.9% vs. 2.5%); elevated AST (33.7% vs. 7.6%); high fasting total cholesterol (28.9% vs. 8.2%); high fasting LDL cholesterol (19.7% vs. 6.5%); high fasting triglycerides (52.3% vs. 27.3%), and elevated prolactin (85% vs 36%). No patient with elevated hepatic enzyme values experienced jaundice or liver failure, or met the criteria for Hy's Rule. Five patients experienced an adverse event potentially associated with elevated prolactin; these events included dysmenorrhoea, galactorrhoea, and ovulation disorder.

QT Interval Prolongation

Olanzapine and fluoxetine hydrochloride was associated with a statistically significantly greater mean increase in QTcF interval (8.2 msec [95% CI 6.2, 10.2]) compared with placebo. No patients developed QTc increases ≥60 msec or QTc ≥480 msec [see WARNINGS AND PRECAUTIONS (5.20)].

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of olanzapine and fluoxetine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine and fluoxetine hydrochloride therapy include the following: rhabdomyolysis and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis).

Drug Interactions

The risks of using olanzapine and fluoxetine hydrochloride 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 hydrochloride. 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 Inhibitors (MAOIs)

[See DOSAGE AND ADMINISTRATION (2.4, 2.5), CONTRAINDICATIONS (4.1), and WARNINGS AND PRECAUTIONS (5.6)]

CNS Acting Drugs

Caution is advised if the concomitant administration of olanzapine and fluoxetine hydrochloride 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 )].

Serotonergic Drugs

[See DOSAGE AND ADMINISTRATION (2.4, 2.5), CONTRAINDICATIONS (4.1), and WARNINGS AND PRECAUTIONS(5.6)]

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 hydrochloride is initiated or discontinued.

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 WARNINGS AND PRECAUTIONS (5.15)].

Potential for Other Drugs to Affect Olanzapine and Fluoxetine Hydrochloride

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 Cmax 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 hydrochloride 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 hydrochloride 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.

Potential for Olanzapine and Fluoxetine Hydrochloride to Affect Other Drugs

Pimozide

Concomitant use of olanzapine and fluoxetine hydrochloride and pimozide is contraindicated. Pimozide can prolong the QT interval. Olanzapine and fluoxetine hydrochloride can increase the level of pimozide through inhibition of CYP2D6. Olanzapine and fluoxetine hydrochloride can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and olanzapine and fluoxetine hydrochloride has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and olanzapine and fluoxetine hydrochloride [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 co-administration of ethanol with olanzapine and fluoxetine hydrochloride may potentiate sedation and orthostatic hypotension [see DRUG INTERACTIONS (7.6)].

Thioridazine

Thioridazine should not be administered with olanzapine and fluoxetine hydrochloride or administered within a minimum of 5 weeks after discontinuation of olanzapine and fluoxetine hydrochloride because of the risk of QT prolongation [see CONTRAINDICATIONS (4.2), WARNINGS AND PRECAUTIONS (5.20), and DRUG INTERACTIONS (7.8)].

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 Cmax 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 CONTRAINDICATIONS (4.2)].

Thioridazine administration produces a dose-related prolongation of the QTc 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 (4.2)].

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 5 weeks after fluoxetine has been discontinued [see CONTRAINDICATIONS (4.2)].

Tricyclic Antidepressants (TCAs)

Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

In 2 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 3 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 olanzapine and fluoxetine hydrochloride is coadministered or has been recently discontinued [see WARNINGS AND PRECAUTIONS (5.6) and CLINICAL PHARMACOLOGY (12.3)].

Antihypertensive Agents

Because of the potential for olanzapine to induce hypotension, olanzapine and fluoxetine hydrochloride may enhance the effects of certain antihypertensive agents [see WARNINGS AND PRECAUTIONS (5.11)].

Levodopa and Dopamine Agonists

The olanzapine component of olanzapine and fluoxetine hydrochloride 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.

When concurrently administered with fluoxetine, the half-life of diazepam may be prolonged in some patients [see CLINICAL PHARMACOLOGY (12.3)]. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Clozapine

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

Haloperidol

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

Phenytoin

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

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 5 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).

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.

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 olanzapine and fluoxetine hydrochloride concomitantly with lithium [see WARNINGS AND PRECAUTIONS (5.5)].

Drugs Tightly Bound to Plasma Proteins

The in vitro binding of olanzapine and fluoxetine hydrochloride to human plasma proteins is similar to the individual components. The interaction between olanzapine and fluoxetine hydrochloride 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 (12.3)].

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.

Biperiden

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

Theophylline

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

Drugs that Prolong the QT Interval

Do not use olanzapine and fluoxetine hydrochloride in combination with thioridazine or pimozide. Use olanzapine and fluoxetine hydrochloride with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine [see CONTRAINDICATIONS (4.2), WARNINGS AND PRECAUTIONS (5.20), DRUG INTERACTIONS (7.7), and CLINICAL PHARMACOLOGY (12.3)].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies were conducted with olanzapine and fluoxetine hydrochloride. The following data are based on findings in studies performed with the individual components, therefore all dose multiples (based on body surface area) reflect the maximum recommended human dose (MRHD) of 20 mg olanzapine, or 80 mg fluoxetine, when each drug is administered separately.

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 1 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 WARNINGS AND PRECAUTIONS (5.22)].

Fluoxetine

The dietary administration of fluoxetine to rats and mice for 2 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 genotoxic 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

Olanzapine and Fluoxetine Hydrochloride

Fertility studies were not conducted with olanzapine and fluoxetine hydrochloride. However, in a repeat-dose rat toxicology study of 3 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 an oral 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. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine at a high dose (30 mg/kg) associated with significant toxicity [see USE IN SPECIFIC POPULATIONS (8.4)].

How Supplied/Storage and Handling

How Supplied

Olanzapine and Fluoxetine Capsules, USP are available as follows:

3 mg/25 mg, is yellow ivory opaque body and peach opaque cap hard gelatin capsule imprinted with ‘ SANDOZ’ ‘651’ in black ink on both cap and body filled with yellow colored powder.

NDC 0781-2195-31, bottles of 30 capsules

6 mg/25 mg, is yellow ivory opaque body and orange opaque cap hard gelatin capsule imprinted with ‘SANDOZ’ ‘664’ in black ink on both cap and body filled with yellow colored powder.

NDC 0781-2191-31, bottle of 30 capsules

6 mg/50 mg, is light gray opaque body and orange opaque cap hard gelatin capsule imprinted with ‘SANDOZ’ ‘666’ in black ink on both cap and body filled with yellow colored powder.

NDC 0781-2193-31, bottle of 30 capsules

12 mg/25 mg, is yellow ivory opaque body and red opaque cap hard gelatin capsule imprinted with ‘SANDOZ’ ‘665’ in black ink on both cap and body filled with yellow colored powder.

NDC 0781-2192-31, bottle of 30 capsules

12 mg/50 mg, is light grey opaque body and red opaque cap hard gelatin capsule imprinted with ‘SANDOZ’ ‘667’ in black ink on both cap and body filled with yellow colored powder.

NDC 0781-2194-31, bottle of 30 capsules

Storage and Handling

Store at 68° to 77°F (20° to 25°C) [see USP Controlled Room Temperature]. Keep tightly closed and protect from light and moisture.

Medication guide

Olanzapine and Fluoxetine Capsules, USP

(oh-LAN-zah-peen and floo-OX-eh-teen)

Read the Medication Guide that comes with Olanzapine and Fluoxetine Capsules before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about Olanzapine and Fluoxetine Capsules.

What is the most important information I should know about Olanzapine and Fluoxetine Capsules?

Olanzapine and Fluoxetine Capsules may cause serious side effects, including:

1. Suicidal thoughts or actions. 2. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). 3. High blood sugar (hyperglycemia). 4. High fat levels in your blood (increased cholesterol and triglycerides), especially in children and adolescents age 10 to 17. 5. Weight gain, especially in children and adolescents age 10 to 17.

These serious side effects are described below.

1. Suicidal thoughts or actions.

Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions:

Talk to your, or your family member's, healthcare provider about:

  ∘ all risks and benefits of treatment with antidepressant medicines. ∘ all treatment choices for depression or other serious mental illness. • Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. • Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. • How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • or other unusual changes in behavior or mood.

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information. 2. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). Olanzapine and Fluoxetine Capsules are not approved for treating psychosis in elderly people with dementia. 3. High blood sugar (hyperglycemia): High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to: • build up of acid in your blood due to ketones (ketoacidosis) • coma • death

Your doctor should do tests to check your blood sugar before you start taking Olanzapine and Fluoxetine Capsules and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when Olanzapine and Fluoxetine Capsules are stopped. People with diabetes and some people who did not have diabetes before taking Olanzapine and Fluoxetine Capsules need to take medicine for high blood sugar even after they stop taking Olanzapine and Fluoxetine Capsules.

If you have diabetes, follow your doctor’s instructions about how often to check your blood sugar while taking Olanzapine and Fluoxetine Capsules.

Call your doctor if you have any of these symptoms of high blood sugar (hyperglycemia) while taking Olanzapine and Fluoxetine Capsules:

• feel very thirsty • need to urinate more than usual • feel very hungry • feel weak or tired • feel sick to your stomach • feel confused, or your breath smells fruity.

4. High fat levels in your blood (increased cholesterol and triglycerides). High fat levels may happen in people treated with Olanzapine and Fluoxetine Capsules, especially in children and adolescents (10 to 17 years old). You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking Olanzapine and Fluoxetine Capsules and during treatment.

5. Increase in weight (weight gain): Weight gain is common in people who take Olanzapine and Fluoxetine Capsules. Children and adolescents (10 to 17 years old) who received Olanzapine and Fluoxetine Capsules, were more likely to gain weight and to gain more weight than adults. Some people may gain a lot of weight while taking Olanzapine and Fluoxetine Capsules, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising

What are Olanzapine and Fluoxetine Capsules?

Olanzapine and Fluoxetine Capsules are a prescription medicine used for:

• short-term treatment of episodes of depression that happen with Bipolar I Disorder.

Olanzapine and Fluoxetine Capsules contain two medicines, olanzapine and fluoxetine hydrochloride.

It is not known if Olanzapine and Fluoxetine Capsules are safe and effective in children under the age of 10.

The symptoms of Bipolar I Disorder include alternating periods of depression and high or irritable mood, increased activity and restlessness, racing thoughts, talking fast, impulsive behavior, and a decreased need for sleep. With treatment, some of your symptoms of Bipolar I Disorder may improve.

If you do not think you are getting better, call your doctor.

Who should not take Olanzapine and Fluoxetine Capsules?

• Do not take Olanzapine and Fluoxetine Capsules if you take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. • Do not take an MAOI within 5 weeks of stopping Olanzapine and Fluoxetine Capsules. unless directed to do so by your physician. • Do not start Olanzapine and Fluoxetine Capsules. if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

People who take Olanzapine and Fluoxetine Capsules close in time to an MAOI can have serious and life-threatening side effects, with symptoms including:

• high fever • continued muscle spasms that you cannot control • rigid muscles • changes in heart rate and blood pressure that happen fast • confusion • unconsciousness. • Do not take Olanzapine and Fluoxetine Capsules if you take Mellaril® (thioridazine). Do not take Mellaril®within 5 weeks of stopping Olanzapine and Fluoxetine Capsules. Mellaril can cause serious heart rhythm problems and you could die suddenly. • Do not take Olanzapine and Fluoxetine Capsules if you take the antipsychotic medicine pimozide (Orap®). Do not take pimozide (Orap®) within 5 weeks of stopping Olanzapine and Fluoxetine Capsules.

What should I tell my doctor before taking Olanzapine and Fluoxetine Capsules?

Olanzapine and Fluoxetine Capsules may not be right for you. Before starting Olanzapine and Fluoxetine Capsules, tell your doctor about all your medical conditions, including if you have or had any of the following:

• heart problems • seizures (convulsions) • diabetes or high blood sugar levels (hyperglycemia) • high cholesterol or triglyceride levels in your blood • liver problems • low or high blood pressure • strokes or “mini-strokes” also called transient ischemic attacks (TIAs) • bleeding problems • Alzheimer's disease • angle-closure glaucoma • enlarged prostate in men • bowel obstruction • breast cancer • are pregnant or plan to become pregnant. It is not known if Olanzapine and Fluoxetine Capsules will harm your unborn baby. • are breast-feeding or plan to breast-feed. Olanzapine and fluoxetine can pass into your breast milk and may harm your baby. You should not breast-feed while taking Olanzapine and Fluoxetine Capsules. Talk to your doctor about the best way to feed your baby if you take Olanzapine and Fluoxetine Capsules.

Before starting Olanzapine and Fluoxetine Capsules, tell your doctor about all the medicines that you take, including:

• Prescription and non-prescription medicines • Vitamins, and herbal supplements. • Triptans used to treat migraine headache • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs, MAOIs, or antipsychotics • Tramadol and fentanyl • Amphetamines • Over-the-counter supplements such as tryptophan or St. John’s Wort • Electroconvulsive therapy (ECT)

Olanzapine and Fluoxetine Capsules and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take Olanzapine and Fluoxetine Capsules with your other medicines. Do not start or stop any medicine while taking Olanzapine and Fluoxetine Capsules without talking to your doctor first.

If you take Olanzapine and Fluoxetine Capsules, you should not take any other medicines that contain:

• olanzapine (the active ingredient in Zyprexa® and Zyprexa® Zydis®) or • fluoxetine hydrochloride (the active ingredient in Prozac®, Prozac® Weekly™, and Sarafem®).

You could take too much medicine (overdose).

How should I take Olanzapine and Fluoxetine Capsules?

• Take Olanzapine and Fluoxetine Capsules exactly as prescribed. Your doctor may need to change (adjust) the dose of Olanzapine and Fluoxetine Capsules until it is right for you. • If you miss a dose of Olanzapine and Fluoxetine Capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Olanzapine and Fluoxetine Capsules at the same time. • To prevent serious side effects, do not stop taking Olanzapine and Fluoxetine Capsules suddenly. If you need to stop taking Olanzapine and Fluoxetine Capsules, your doctor can tell you how to safely stop taking it. • If you take too many Olanzapine and Fluoxetine Capsules, call your doctor or poison control center right away, or get emergency treatment. • Olanzapine and Fluoxetine Capsules can be taken with or without food. • Olanzapine and Fluoxetine Capsules are usually taken one time each day, in the evening. • If you do not think you are getting better or have any concerns about your condition while taking Olanzapine and Fluoxetine Capsules, call your doctor.

What should I avoid while taking Olanzapine and Fluoxetine Capsules?

• Olanzapine and Fluoxetine Capsules can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how Olanzapine and Fluoxetine Capsules affects you. • Avoid drinking alcohol while taking Olanzapine and Fluoxetine Capsules. Drinking alcohol while you take Olanzapine and Fluoxetine Capsules may make you sleepier than if you take Olanzapine and Fluoxetine Capsules alone.

What are the possible side effects of Olanzapine and Fluoxetine Capsules?

Other possible serious risks:

• Increased risk of death and increased incidence of stroke or “mini-strokes” called transient ischemic attacks (TIAs) in elderly people with psychosis related to dementia (a brain disorder that lessens the ability to remember, think, and reason). Olanzapine and Fluoxetine Capsules are not approved for these patients. • Severe allergic reactions: Tell your doctor right away if you get red itchy welts (hives) or, a rash alone or with fever and joint pain, while taking Olanzapine and Fluoxetine Capsules. Call your doctor right away if you become severely ill and have some or all of these symptoms: ∘ swelling of your face, eyes, or mouth ∘ trouble breathing • Neuroleptic malignant syndrome (NMS): NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including Olanzapine and Fluoxetine Capsules. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have some or all of these symptoms: ∘ high fever ∘ excessive sweating ∘ rigid muscles ∘ confusion ∘ changes in your breathing, heartbeat, and blood pressure • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs. • Tardive Dyskinesia: This condition causes body movements that keep happening and that you cannot control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking Olanzapine and Fluoxetine Capsules. It may also start after you stop taking Olanzapine and Fluoxetine Capsules. Tell your doctor if you get any body movements that you cannot control. • Serotonin Syndrome: This is a condition that can be life threatening. Call your doctor right away if you become severely ill and have some or all of these symptoms: ∘ agitation, hallucinations, coma or other changes in mental status ∘ coordination problems or muscle twitching (overactive reflexes) ∘ racing heartbeat, high or low blood pressure ∘ sweating or fever ∘ nausea, vomiting, and diarrhea ∘ muscle rigidity ∘ dizziness ∘ flushing ∘ tremor ∘ seizures • Visual problems: ∘ eye pain ∘ changes in vision ∘ swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

• Abnormal bleeding: Tell your doctor if you notice any increased or unusual bruising or bleeding while taking Olanzapine and Fluoxetine Capsules, especially if you take one of these medicines: ∘ the blood thinner warfarin (Coumadin, Jantoven) ∘ a non-steroidal anti-inflammatory drug (NSAID) ∘ aspirin • Low salt (sodium) levels in the blood (hyponatremia): Call your doctor right away if you become severely ill and have some or all of these symptoms: ∘ headache ∘ feel weak ∘ confusion ∘ problems concentrating ∘ memory problems ∘ feel unsteady • Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsade de Pointes). This condition can be life threatening. The symptoms may include: ∘ fast, slow, or irregular heartbeat ∘ shortness of breath ∘ dizziness or fainting • Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heart beat, or fainting • Difficulty swallowing • Seizures • Problems with control of body temperature: You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have some or all of these symptoms of dehydration: ∘ sweating too much or not at all ∘ dry mouth ∘ feeling very hot ∘ feeling thirsty ∘ not able to produce urine

Common possible side effects of Olanzapine and Fluoxetine Capsules include: dry mouth, tiredness, sleeping for long period of time, increased appetite, swelling of your hands and feet, drowsiness, tremors (shakes), or blurred vision.

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects with Olanzapine and Fluoxetine Capsules. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088.

How should I store Olanzapine and Fluoxetine Capsules?

• Store Olanzapine and Fluoxetine Capsules at 68° to 77°F (20° to 25°C). • Keep Olanzapine and Fluoxetine Capsules away from light. • Keep Olanzapine and Fluoxetine Capsules dry and away from moisture. Keep the bottle closed tightly.

Keep Olanzapine and Fluoxetine Capsules and all medicines out of the reach of children.

General information about Olanzapine and Fluoxetine Capsules

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Olanzapine and Fluoxetine Capsules for a condition for which it was not prescribed. Do not give Olanzapine and Fluoxetine Capsules to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about Olanzapine and Fluoxetine Capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Olanzapine and Fluoxetine Capsules that was written for healthcare professionals. For more information about Olanzapine and Fluoxetine Capsules, call Sandoz Inc. at 1-800-525-8747.

What are the ingredients in Olanzapine and Fluoxetine Capsules?

Active ingredients: Olanzapine and fluoxetine hydrochloride

Inactive ingredients: Each capsule contains pregelatinized starch.

The capsule shell for the 3 mg/25 mg strength consists of gelatin, FDA/E172 yellow iron oxide, FDA/E172 red iron oxide, titanium dioxide. The black ink is comprised of black iron oxide, potassium hydroxide, propylene glycol, shellac.

The capsule shell for the 6 mg/25 mg strength consists of D&C red # 28, D&C yellow # 10, FDA/E172 yellow iron oxide, gelatin, titanium dioxide. The black ink is comprised of black iron oxide, potassium hydroxide, propylene glycol, shellac.

The capsule shell for the 6 mg/50 mg strength consists of D&C red # 28, D&C yellow # 10, gelatin, FDA/E172 black iron oxide, titanium dioxide. The black ink is comprised of black iron oxide, potassium hydroxide, propylene glycol, shellac.

The capsule shell for the 12 mg/25 mg strength consists of FDA/E172 yellow iron oxide, FD&C Red # 3, red iron oxide, gelatin, titanium dioxide. The black ink is comprised of black iron oxide, potassium hydroxide, propylene glycol, shellac.

The capsule shell for the 12 mg/50 mg strength consists of FDA/E172 black iron oxide, FD&C Red # 3, red iron oxide, gelatin, titanium dioxide. The black ink is comprised of black iron oxide, potassium hydroxide, propylene glycol, shellac.

The brands listed are trademarks of their respective owners and are not trademarks of Sandoz Inc.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured in India by Sandoz Private Ltd.

for Sandoz Inc., Princeton, NJ 08540

Rev. April 2017

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