`
`.2
`
`Bipolar I Disorder (Manic or Mixed Episodes)
`Monotherapy — Oral ZYPREXA is indicated for the acute treatment of manic or mixed episodes associated with bipolar 1
`disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic
`or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with
`manic or mixed episodes associated with bipolarl disorder (ages 13-17), efficacy was established in one 3—week trial [see Clinical
`Studies (14.2)].
`When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential
`(in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should consider the potential long-term risks
`when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see
`Warnings and Precautions (5. 5, 5. 6)].
`Adiunctive Therapy to Lithium or Valproat - Oral ZYPREXA is indicated for the treatment of manic or mixed episodes
`associated with bipolarl disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults.
`The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials [see Clinical
`Studies (14.2)].
`
`1.3
`
`Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder
`Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging. For
`pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of
`periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder
`be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with
`medication treatment. Medication treatment for both pediatric schizophrenia and bipolar l disorder should be part of a total treatment
`program that often includes psychological, educational and social interventions.
`1.4
`ZYPREXA IntraMuscuIar: Agitation Associated with Schizophrenia and Bipolar I Mania
`ZYPREXA IntraMuscular is indicated for the treatment of acute agitation associated with schizophrenia and bipolarI mania.
`Efficacy was demonstrated in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients
`with: schizophrenia or bipolar I disorder (manic or mixed episodes) [see Clinical Studies (14.3)].
`“Psychomotor agitation” is defined in DSM—IV as “excessive motor activity associated with a feeling of inner tension.”
`Patients experiencing agitation ofien manifest» behaviors that interfere with their diagnosis and care, e.g., threatening behaviors,
`escalating or urgently distressing behavior, or self-exhausting behavior, leading clinicians to the use of intramuscular antipsychotic
`medications to achieve immediate control of the agitation.
`1.5
`ZYPREXA and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder
`Oral ZYPREXA and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I
`disorder, based on clinical studies in adult patients. When using ZYPREXA and fluoxetine in combination, refer to the Clinical
`Studies section of the package insert for Symbyax.
`ZYPREXA monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.
`ZYPREXA and Fluoxetine in Combination: Treatment Resistant Depression
`Oral ZYPREXA and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major
`depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the
`current episode), based on clinical "studies in adult patients. When using ZYPREXA and fluoxetine in combination, refer to the
`Clinical Studies section of the package insert for Symbyax.
`ZYPREXA monotherapy is not indicated for the treatment of treatment resistant depression.
`
`1.6
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`Adults
`
`Schizophrenia
`
`Dose Selection — Oral olanzapine should be administered on a once—a-day schedule without regard to meals, generally
`beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated,
`should generally occur at intervals of not less than 1 week, since steady state for olanzapine would not be achieved for approximately
`1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.
`Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above
`10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose
`of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. Olanzapine is not indicated for
`use in doses above 20 mg/day.
`Dosing in Special Population — The recommended starting dose is 5 mg in patients who are debilitated, who have a
`predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of
`olanzapine (e.g., nonsmoking female patients 265 years of age), or who may be more pharmacodynamically sensitive to olanzapine
`[see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology {1 2. 3)]. When indicated, dose escalation
`should be performed with caution in these patients.
`Maintenance Treatment —— The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response
`in schizophrenic patients who had been stable on ZYPREXA for approximately 8 weeks and were then followed for relapse has been
`
`
`
`5 d
`
`emonstrated in a placebo-controlled trial [see Clinical Studies (14.1)]. The physician who elects to use ZYFREXA for extended
`periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
`
`Adolescents
`
`Dose Selection — Oral olanzapine should be administered on a once-a—day schedule without regard to meals with a
`recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was
`demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 12.5 mg/day (mean dose
`of 11.1 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.
`The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies (141)].
`Maintenance Treatment — The efficacy of ZYPREXA for the maintenance treatment of schizophrenia in the adolescent
`population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with
`comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that
`responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be
`periodically reassessed to determine the need for maintenance treatment.
`2.2
`Bipolar I Disorder (Manic or Mixed Episodes)
`Adults
`>
`
`Dose Selection for Monotherapy — Oral olanzapine should be administered on a once—a-day schedule without regard to
`meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24
`hours, reflecting the procedures in the placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements
`of 5 mg QD are recommended.
`Short-term (3-4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The
`safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical Studies (14.2)].
`Maintenance Monotherapy — The benefit of maintaining bipolar I patients on monotherapy with oral ZYPREXA at a dose of
`5 to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [see
`Clinical Studies (14.2)]. The physician who elects to use ZYPREXA for extended periods should periodically reevaluate the long-term
`usefulness of the drug for the individual patient.
`Dose Selection for Adjunctive Treatment — When administered as adjunctive treatment to lithium or valproate, oral
`olanzapine dosing should generally begin with 10 mg once-a—day without regard to meals.
`Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical Studies (14.2)]. The
`safety of doses above 20 mg/day has not been evaluated in clinical trials.
`
`Adolescents
`
`Dose Selection — Oral olanzapine should be administered on a once—a—day schedule without regard to meals with a
`recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar l disorder (manic or
`mixed episodes) was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of
`10.7 mg/day (mean dose of 8.9 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are
`recommended.
`
`The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies (14.2)].
`Maintenance Treatment — The efficacy of ZYPREXA for the maintenance treatment of bipolar I disorder in the adolescent
`population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of
`olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients
`be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically
`reassessed to determine the need for maintenance treatment.
`
`2.3
`
`Administration of ZYPREXA ZYDIS (olanzapine orally disintegrating tablets)
`After opening sachet, peel back foil on blister. Do not push tablet through foil. Immediately upon opening the blister, using
`dry hands, remove tablet and place entire ZYPREXA ZYDIS in the mouth. Tablet disintegration occurs rapidly in saliva so it can be
`easily swallowed with or without liquid.
`2.4
`ZYPREXA IntraMuscular: Agitation Associated with Schizophrenia and Bipolar I Mania
`Dose Selection for Agitated Adult Patients with Schizophrenia and Bipolar l Mani — The efficacy of intramuscular
`olanzapine for injection in controlling agitation in these disorders was demonstrated in a dose range of 2.5 mg to 10 mg. The
`recommended dose in these patients is 10 mg. A lower dose of 5 or 7.5 mg may be considered when clinical factors warrant [see
`Clinical Studies (14.3)]. If agitation warranting additional intramuscular doses persists following the initial dose, subsequent doses up
`to 10 mg may be given. However, the efficacy of repeated doses of intramuscular olanzapine for injection in agitated patients has not
`been systematically evaluated in controlled clinical trials. Also, the safety of total daily doses greater than 30 mg, or 10 mg injections
`given more frequently than 2 hours after the initial dose, and 4 hours after the second dose have not been evaluated in clinical trials.
`Maximal dosing of intramuscular olanzapine (e.g., 3 doses of 10 mg administered 2-4 hours apart) may be associated with a
`substantial occurrence of significant orthostatic hypotension [see Warnings and Precautions (5.8)]. Thus, it is recommended that
`patients requiring subsequent intramuscular injections be assessed for orthostatic hypotension prior to the administration of any
`subsequent doses of intramuscular olanzapine for injection. The administration of an additional dose to a patient with a clinically
`significant postural change in systolic blood pressure is not recommended.
`
`
`
`6
`
`If ongoing olanzapine therapy is clinically indicated, oral olanzapine may be initiated in a range of 5-20 mg/day as soon as
`clinically appropriate [see Dosage and Administration (2.], 2. 2)].
`Intramuscular Dosing in Special Population —— A dose of 5 mg/injection should be considered for geriatric patients or when
`other clinical factors warrant. A lower dose of 2.5 mg/injection should be considered for patients who otherwise might be debilitated,
`be predisposed to hypotensive reactions, or be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions
`(5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)].
`Administration of ZYPREXA IntraMuscular —— ZYPREXA IntraMuscular is intended for intramuscular use only. Do not
`administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass.
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
`whenever solution and container permit.
`
`Directions for Preparation of ZYPREXA IntraMuscular with Sterile Water foriijection — Dissolve the contents of the vial
`using 2.1 mL of Sterile Water for Injection to provide a solution containing approximately 5 mg/mL of olanzapine. The resulting
`solution should appear clear and yellow. ZYPREXA IntraMuscular reconstituted with Sterile Water for Injection should be used
`immediately (within 1 hour) after reconstitution. Discard any unused portion.
`The following table provides injection volumes for delivering various doses of intramuscular olanzapine for injection
`reconstituted with Sterile Water for Injection.
`
`Dose, mg Olanzapine
`10
`7.5
`5
`2.5
`
`Volume of Injection, mL
`Withdraw total contents of vial
`1.5
`I
`0.5
`
`Physical Incompatibilifl Informatio — ZYPREXA IntraMuscular should be reconstituted only with Sterile Water for
`Injection. ZYPREXA IntraMuscular should not be combined in a syringe with diazepam injection because precipitation occurs when
`these products are mixed. Lorazepam injection should not be used to reconstitute ZYPREXA IntraMuscular as this combination
`results in a delayed reconstitution time. ZYPREXA IntraMuscular should not be combined in a syringe with haloperidol injection
`because the resulting low pH has been shown to degrade olanzapine over time.
`2.5
`ZYPREXA and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder
`When using ZYPREXA and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for
`Symbyax.
`Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals,
`generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to
`efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was
`demonstrated with ZYPREXA and fluoxetine in combination in adult patients with a dose range of-olanzapine 6 to 12 mg and
`fluoxetine 25 to 50 mg.
`Safety and efficacy of ZYPREXA and fluoxetine in combination was determined in clinical trials supporting approval of
`Symbyax (fixed dose combination of ZYPREXA and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per
`day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses
`of ZYPREXA and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components
`according to efficacy and tolerability.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Table 1: Approximate Dose Corres - ondence Between_Symb_ygx“ and the Combination of ZYPREXA and Fluoxetine
`For
`Use in Combination
`
`
`
`
`
`
`3 mg olanzapine/ZS mg fluoxetine
`
`6 mg olanzapine/25 mg fluoxetine
`
`12 mg olanzapine/ZS mg fluoxetine
`
`6 mg olanzapine/SO mg fluoxetine
`
`
`l_21n_g olanzapige/SO mg fluoxetine
`,
`a Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of ZYPREXA and fluoxetine.
`
`While there is no body of evidence to answer the question of how long a patient treated with ZYPREXA and fluoxetine in
`combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with
`bipolar l disorder, is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued
`pharmacotherapy.
`.
`Safety of co—administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.
`ZYPREXA monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.
`ZYPREXA and Fluoxetine in Combination: Treatment Resistant Depression
`
`2.6
`
`
`
`
`
`I
`
`
`
`7
`
`When using ZYPREXA and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for
`Symbyax.
`Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals,
`generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to
`efficacy and tolerability within dose ranges of oral olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was
`demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18 mg and
`fluoxetine 25 to 50 mg.
`'
`Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of
`Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/ZS mg (olanzapine/fluoxetine) per
`day and 12 mg/SO mg (olanzapine/fluoxetine) per day. Table 1 above demonstrates the appropriate individual component doses of
`ZYPREXA and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components
`according to efficacy and tolerability.
`While there is no body of evidence to answer the question of how long a patient treated with ZYPREXA and fluoxetine in
`combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult
`patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a
`chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy.
`Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.
`ZYPREXA monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients
`who do not respond to 2 antidepressants of adequate dose and duration in the current episode).
`2.7
`ZYPREXA and Fluoxetine in Combination: Dosing in Special Populations
`The starting dose of oral olanzapine 2.5-5 mg with fluoxetine 20 mg should be used for patients with a predisposition to
`hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the
`metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may
`be pharmacodynamically sensitive to olanzapine. Dosing modification may be necessary in patients who exhibit a combination of
`factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. ZYPREXA
`and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients <18 years of age [see
`Warnings and Precautions (5. I 4), Drug Interactions (7), and Clinical Pharmacology (12. 3)].
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`The ZYPREXA 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets are white, round, and imprinted in blue ink with LILLY and tablet
`number. The 15 mg tablets are elliptical, blue, and debossed with LILLY and tablet number. The 20 mg tablets are elliptical, pink, and
`debossed with LILLY and tablet number. Tablets are not scored. The tablets are available as follows:
`
`TABLET STRENGTH
`.
`10 mg
`.
`
`4112
`4116
`4117
`4115
`Tablet No.
`LILLY
`LILLY
`LILLY
`LILLY
`Identification
`4112
`4115
`4116
`4117
`
`
`
`
`4415
`LILLY
`4415
`
`4420
`LILLY
`4420
`
`ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) are yellow, round, and debossed with the tablet strength. Tablets
`are not scored. The tablets are available as follows:
`
`
`
`ZYPREXA ZYDIS Tablets
`Tablet No.
`Debossed
`
`4453
`5
`
`TABLET STRENGTH
`10 m
`15 m
`4454
`4455
`10
`15
`
`4456
`20
`
`ZYPREXA IntraMuscula'r is available in 10 mg vial (Is).
`
`4
`
`CONTRAINDICATIONS
`
`None with ZYPREXA monotherapy.
`-
`- When using ZYPREXA and fluoxetine in combination, also refer to the Contraindications section of the package insert
`for Symbyax.
`For specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the
`package inserts for these other products.
`
`-
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`When using ZYPREXA and fluoxetine in combination, also refer to the Warnings and Precautions section of the package
`insert for Symbyax.
`5.]
`Elderly Patients with Dementia-Related Psychosis
`
`
`
`8
`
`Increased Mortality -— Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
`increased risk of death. ZYPREXA is not approved for the treatment of patients with dementia-related psychosis [see Boxed
`Warning, Warnings and Precautions (5.14), and Patient Counseling Information (17.2)].
`In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-
`treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).
`Cerebrovascular Adverse Events (CVAE), Including Strok —— Cerebrovascular adverse events (e.g., stroke, transient
`ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related
`psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated
`with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-
`related psychosis [see Boxed Warning and Patient Counseling Information (17.2)].
`5.2
`Suicide
`
`The possibility of a suicide attempt is inherent in schizophrenia and in bipolar l disorder, and close supervision of high—risk
`patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent
`with good patient management, in order to reduce the risk of overdose.
`5.3
`Neuroleptic Malignant Syndrome (NMS)
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in
`association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia,
`muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis
`and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and
`acute renal failure.
`
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude
`cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or
`inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include
`central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
`The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to
`concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical
`problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment.
`regimens for NMS.
`.
`If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should
`be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient
`Counseling Information (1 7.3)].
`5.4
`Hyperglycemia
`Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of
`diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140—200 mg/dL). Patients
`taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should
`undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with
`atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and
`weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting
`blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some
`patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see Patient Counseling
`Information (17.4)].
`'
`Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in
`patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use
`and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with
`schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an
`increased risk of treatment—emergent hyperglycemia—related adverse reactions in patients treated with the atypical antipsychotics.
`While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears
`to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.
`Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in
`phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIEI). The mean increase of serum glucose (fasting and
`nonfasting samples) fiom baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.
`In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to
`baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose
`compared to baseline of 0.34 mg/dL.
`.
`Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a
`median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels
`compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in
`patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions,
`I patients treated with anti-diabetic agents, patients with a baseline random glucose level 2200 mg/dL, and/or a baseline fasting glucose
`
`
`
`9
`
`I
`
`level 2126 mg/dL). Olanzapine-treated patients had a greater mean HbAlc increase from baseline of0.04% (median exposure 21
`
`days), compared to a mean HbAlc decrease of 0.06% in placebo-treated subjects (median exposure 17 days).
`In an analysis of 8 placebo~controlled studies (median treatment exposure 4—5 weeks), 6.1% of olanzapine-treated subjects
`(N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and
`long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.
`
`Table 2: Chan- es in Fastin Glucose Levels from Adult Olanza tine Monothera 0 Studies
`
`Up to 12 weeks
`ex . osure
`
`At least 48 weeks
`ex unsure
`
`
`
`Laboratory
`
`from Baseline
`
`Arm
`
`N
`
`543
`
`Patients
`
`2.2%
`
`N
`
`345
`
`Patients
`
`12.8%
`
`
`
`
`
`
`
`
`
`
`
`Category Change (at least once)
`‘ Treatment
`
`
`
`
`Normal to High
`Olanza-ine
`
`
`
`
`
`Fasting
`g<1oo mg/d_Lto 2126 mg/dL)
`
`Olanza- inc
`Glucose
`Borderline to High
`
`
`
`
`
`2100 m/dL and <126 mg/dL to 2126 mg/dL)
`Placebo “—
`
`
`
`
`
`
`a Not Applicable.
`
`
`
`The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients
`who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over
`time.
`
`Olanzapine Monotherapy in Adolescent — The safety and efficacy of olanzapine have not been established in patients under
`the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with
`schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean
`change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting
`glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting
`blood glucose from adolescent olanzapine monotherapy studies.
`
`
`
`
`
`
`Table 3: Changes in Fastingglucose Levels from Adolescent Olanz
`
`a-ine Monothera Studies
`
`
`
`
`
`
`
`Category Change (at least once)
`Laboratory
`from Baseline
`Anal to
`
`
`
`Normal to High
`124 _-E_
`Olanzaine
`
`
`53
`1.9%
`NA”
`NA3
`
`14
`14.3%
`13
`23.1%
`Olanzaine
`
`1
`0%
` /dL
`
`
`“ Not Applicable.
`
`
`
`ex - osure
`
`ex - osure
`
`
`
`
`
`
`
`
`,
`
`5.5
`
`Hyperlipidemia
`Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic
`follow-up lipid evaluations in patients using olanzapine, is recommended [see Patient Counseling Information (17.5)].
`Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with
`olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.
`Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment
`duration up to 12 weeks, olanzapine—treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol,
`and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total
`cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting
`HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated
`patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and‘triglycerides) were greater in patients without
`evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related
`adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.
`In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL
`cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting I-IDL cholesterol
`of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase
`further after approximately 4-6 months.
`The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal
`2 or borderline to high, or changes in I-IDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48
`weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.
`
`Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies
`
`
`
`10
`
`from Baseline
`
`Normal to High
`<150 m-ldL to 2200 m - /dL
`
`ex - osure
`
`ex