Olanzapine and Fluoxetine: Package Insert and Label Information (Page 6 of 13)

5.21 Anticholinergic (antimuscarinic) Effects

Anticholinergic (antimuscarinic) Effects

The following precautions for the individual components may be applicable to olanzapine and fluoxetine capsules.

Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical studies, olanzapine and fluoxetine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for study discontinuations; olanzapine and fluoxetine capsules should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, a history of paralytic ileus, or related conditions.

5.22 Hyperprolactinemia

As with other drugs that antagonize dopamine D ₂ receptors, olanzapine and fluoxetine HCl elevates prolactin levels, and the elevation persists during administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds that increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

Adults — In controlled clinical studies of olanzapine and fluoxetine HCl (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 28% of adults treated with olanzapine and fluoxetine HCl as compared to 5% of placebo-treated patients. The elevations persisted throughout administration of olanzapine and fluoxetine HCl. In a pooled analysis from clinical studies including 2929 adults treated with olanzapine and fluoxetine HCl, potentially associated clinical manifestations included menstrual-related events ¹ (1% [20/1946] of females), sexual function-related events² (7% [192/2929] of females and males), and breast-related events³ (0.8% [16/1946] of females, 0.2% [2/983] of males).

Children and Adolescents — In a single, 8 week, randomized, placebo controlled clinical trial investigating olanzapine and fluoxetine for the treatment of bipolar 1 depression in patients 10 to 17 years of age, olanzapine and fluoxetine was associated with a statistically significant greater mean change from baseline in prolactin levels compared to placebo (8.7 mcg/L vs mcg/L, respectively). Although prolactin concentrations were very commonly (>10%) elevated above normal in both the olanzapine and fluoxetine and placebo groups, more than twice as many olanzapine and fluoxetine-treated patients were seen with these elevations compared to placebo treated patients. Five patients experienced an adverse event potentially associated with elevated prolactin; these events included dysmenorrhea, galactorrhea, and ovulation disorder.

The magnitude and frequency of change in prolactin in children and adolescents was larger than observed in adult patients treated with olanzapine and fluoxetine, but was similar to that observed in adolescents treated with olanzapine and fluoxetine.

Olanzapine monotherapy – In placebo controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual related events¹ (2% [40/3240] of females), sexual function related events² (2% [150/8136] of females and males), and breast related events³ (0.7% [23/3240] of females, 0.25 [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events ¹ (1% [2/168] of females), sexual function-related events² (0.7% [3/454] of females and males), and breast-related events³ (2% [3/168] of females, 2% [7/286] of males), [se e Use in Specific Populations (8.4)].

^1. Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

^2. Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

^3. Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed. 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 oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of 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%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

5.23 Concomitant Use of Olanzapine and Fluoxetine Products

Olanzapine and fluoxetine HCl contains the same active ingredients that are in in Zyprexa^® , Zyprexa^® Zydis^® , Zyprexa^® Relprevv^TM (olanzapine), and in Prozac^® , and Sarafem^® (fluoxetine HCl). Caution should be exercised when prescribing these medications concomitantly with olanzapine and fluoxetine [see Overdosage (10)].

5.24 Long Elimination Half-Life of Fluoxetine

Because of the long elimination half-lives of fluoxetine and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see Clinical Pharmacology (12.3)].

5.25 Discontinuation Adverse Reactions

During marketing of fluoxetine, a component of olanzapine and fluoxetine HCl, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug [see Dosage and Administration (2.4)].

5.26 Sexual Dysfunction

​ Use of SSRIs, including fluoxetine a component of olanzapine and fluoxetine, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, olanzapine and fluoxetine use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, olanzapine and fluoxetine use may result in decreased libido and delayed or absent orgasm.

​ It is important for prescribers to inquire about sexual function prior to initiation of olanzapine and fluoxetine and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)]
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions(5.2)]
• Neuroleptic Malignant syndrome (NMS) [see Warnings and Precautions (5.3)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)[see Warnings and Precautions (5.4)]
• Hyperglycemia [see Warnings and Precautions (5.5)]
• Dyslipidemia [see Warnings and Precautions (5.5)]
• Weight Gain [see Warnings and Precautions (5.5)]
• Serotonin Syndrome [see Warnings and Precautions (5.6)]
• Angle-Closure Glaucoma [see Warnings and Precautions (5.7)]
• Allergic Reactions and Rash [see Warnings and Precautions (5.8)]
• Activation of Mania/Hypomania [see Warnings and Precautions (5.9)]
• Tardive Dyskinesia [see Warnings and Precautions (5.10)]
• Orthostatic Hypotension [see Warnings and Precautions (5.11)]
• Falls [see Warnings and Precautions (5.12)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.13)]
• Dysphagia [see Warnings and Precautions (5.14)]
• Seizures [see Warnings and Precautions (5.15)]
• Abnormal Bleeding [see Warnings and Precautions (5.16)]
• Hyponatremia [see Warnings and Precautions (5.17)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.18)]
• Body Temperature Dysregulation [see Warnings and Precautions (5.19)]
• QT Prolongation [see Warnings and Precautions (5.20)]
• 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)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

The data in the tables represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adults – The information below is derived from a clinical study database for olanzapine and fluoxetine consisting of 2547 patients with treatment resistant depression, depression episodes associated with Bipolar 1 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 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 1 Disorder and Treatment Resistant Depression— Overall, 11.3% of the 771 patients in the olanzapine and fluoxetine HCl 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 HCl (incidence of at least 1% for olanzapine and fluoxetine HCl 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 , Controlled Studies Depressive Episodes Associated with Bipolar 1 Disorder and Treatment Resistant Depression— In short-term studies, the most commonly observed adverse reactions associated with the use of olanzapine and fluoxetine HCl (incidence ≥5% and at least twice that for placebo in the olanzapine and fluoxetine HCl -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 use were generally similar to those seen in short-term studies. Weight gain, hyperlipidemia, and hyperglycemia were observed in olanzapine and fluoxetine-treated patients throughout the study.

Adverse Reactions Occurring at an Incidence of 2% or More in Short-Term Controlled Studies Depressive Episodes Associated with Bipolar 1 Disorder and Treatment Resistant Depression— Table 16 enumerates the treatment-emergent adverse reactions associated with the use of olanzapine and fluoxetine HCl (incidence of at least 2% for olanzapine and fluoxetine HCl and twice or more than for placebo). The olanzapine and fluoxetine HCl -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-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 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 HCl 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 HCl group than in the placebo group. One case of decreased libido led to discontinuation in the olanzapine and fluoxetine HCl group. In the controlled studies that contained a fluoxetine arm, the rates of decreased libido and abnormal ejaculation in the olanzapine and fluoxetine HCl 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, healthcare providers should routinely inquire about such possible side effects.

There are no adequate and well-controlled studies examining dysfunction with olanzapine and fluoxetine 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 HCl 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-treated patients during premarketing clinical studies but have been reported with olanzapine or fluoxetine monotherapy: Bruxism, dysuria, esophageal ulcer, gynecological bleeding, headache, hypotension, neutropenia, sudden unexpected death³ and sweating.

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.

⁴ Stuttering was only studied in oral and long acting injection (LAI) olanzapine formulations

Children andAdolescent Patients(aged10to 17years)witha Diagnosis of Bipolar Depression

The information below is derived from asingle, 8-week, randomized, placebo-controlledclinical trial investigating olanzapine and fluoxetine for thetreatment of bipolarI depression in patients 10 to 17 years of age.

Adverse Reactions Associated with Discontinuation of Treatment in the single pediatric study – Overall, 14% of the 170 patients in the olanzapine and fluoxetine group discontinued to adverse reactions compared to 5.9% of the 85 patients for placebo. Adverse reactions leading to discontinuation associated with the use of olanzapine and fluoxetine ( incidence of a least 1% for olanzapine and fluoxetine 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 (incidence of at least 2% for olanzapine and fluoxetine 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 (N=170)	Placebo (N=85)
Nervous system disorders	Somnolence a	24	2
	Tremor	9	1
Investigations	Weight increased	20	1
	Blood triglycerides increased	7	2
	Blood cholesterol increased	4	0
	Hepatic enzyme increased b	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

^a Includes somnolence, sedation, and hypersomnia. No lethargy was reported.

^b 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-treated patients [see Warnings and Precautions ( 5.11)]. The mean standing pulse rate of olanzapine and fluoxetine treated patients was reduced by 0.7 beats/min.

Laboratory Changes — In olanzapine and fluoxetine clinical studies, (including treatment resistant depression, depressive episodes associated with Bipolar I Disorder, Major Depressive Disorder with psychosis, or sexual dysfunction), olanzapine and fluoxetine 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 HCl. In the olanzapine and fluoxetine HCl -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 HCl 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 HCl-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 or discontinued olanzapine and fluoxetine.

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 HCl-treated patients and infrequently in clinical trials of olanzapine-treated patients.

QT Interval Prolongation – In patients treated with olanzapine and fluoxetine QT_C F≥450 msec for males and QTcF≥470 msec for females has been reported frequently (≥1%). The incidence of QT_C F>500 msec associated with olanzapine and fluoxetine treatment in clinical trials has been rare and was not significantly different from the incidence associated with placebo. The mean increase in QT_C interval for olanzapine and fluoxetine-treated patients (5.17 msec) in the one clinical study directly comparing olanzapine and fluoxetine 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 for treatment of bipolar 1 depression in patients 10 to 17 years of age, the following was observed:

Vital Signs – In the olanzapine and fluoxetine 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 or equal to 7% occurred in 52.4% of the olanzapine and fluoxetine 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 group and none of the placebo group.

Laboratory Changes — Olanzapine and Fluoxetine was accociated 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 7.7%) 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 and adverse event potentially associated with elevated prolactin; these events included dysmenorrhea, galactorrhea, and ovulation disorder.

QT Interval Prolongation – Olanzapine and Fluoxetine was associated with a statistically significant greater mean increase in QT_c F interval (8.2 msec [95% CI 6.2, 10.2]) compared with placebo. No patients developed QT_c increases ≥60 msec or QT_c ≥480 msec [see Warnings and Precautions ( 5.20)].