Olanzapine: Package Insert and Label Information (Page 6 of 7)

14.2 Bipolar I Disorder (Manic or Mixed Episodes)

Adults
Monotherapy — The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in adult patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course.The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow:
(1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome.
(2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score.
(3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having a decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse.
Adjunct to Lithium or Valproate — The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in 2 controlled trials in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The results of the trials follow:
(1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score
(2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.
Adolescents
Acute Monotherapy — The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) was established in a 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) according to the DSM-IV-TR (n=161). Diagnosis was confirmed by the K-SADS-PL.
The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) total score.
In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 10.7 mg/day, mean dose of 8.9 mg/day) was more effective than placebo in the treatment of adolescents with manic or mixed episodes associated with bipolar I disorder, as supported by the statistically significantly greater mean reduction in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group. While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Olanzapine tablets, USP 2.5 mg, are white to off white coloured, round shaped, biconvex, film coated tablets debossed ‘CL’ on one side, and ‘39’ on other side, 5 mg, are white to off white coloured, round shaped, biconvex, film coated tablets debossed ‘CL 40’ on one side and plain on other side 7.5 mg are white to off white coloured, round shaped, biconvex, film coated tablets debossed ‘CL 41’ on one side and plain on other side, 10 mg are white to off white coloured, round shaped, biconvex, film coated tablets debossed ‘CL 42’ on one side and plain on other side. The 15 mg tablets are blue coloured, oval shaped biconvex film coated tablets having ‘CL 43’ debossed on one side and plain on other side. The 20 mg tablets are pink coloured, oval shaped biconvex film coated tablets having ‘CL 44’ debossed on one side and plain on other side.

The tablets are available as follows:

	TABLET STRENGTH
	2.5 mg	5 mg	7.5 mg	10 mg	15 mg	20 mg
Identification	CL 39	CL 40	CL 41	CL 42	CL 43	CL 44
NDC Codes:
Blisters – 100s	NDC 33342-067-12	NDC 33342-068-12	NDC 33342-069-12	NDC 33342-070-12	NDC 33342-071-12	NDC 33342-072-12
Bottles 1000s	NDC 33342-067-44	NDC 33342-068-44	NDC 33342-069-44	NDC 33342-070-44	NDC 33342-071-44	NDC 33342-072-44
Bottles 500s	—	—	—	NDC 33342-070-15	NDC 33342-071-15	NDC 33342-072-15
Bottles 100s	NDC 33342-067-11	NDC 33342-068-11	NDC 33342-069-11	NDC 33342-070-11	NDC 33342-071-11	NDC 33342-072-11
Bottles 30s	NDC 33342-067-07	NDC 33342-068-07	NDC 33342-069-07	NDC 33342-070-07	NDC 33342-071-07	NDC 33342-072-07

16.2 Storage and Handling

Store olanzapine tablets, USP at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide) for the oral formulations.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking olanzapine as monotherapy or in combination with fluoxetine. If you do not think you are getting better or have any concerns about your condition while taking olanzapine tablets, call your doctor. When using olanzapine and fluoxetine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

Neuroleptic Malignant Syndrome (NMS)

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Patients should be advised to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4) ]

Hyperglycemia and Diabetes Mellitus

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor’s instructions about how often to check their blood sugar while taking olanzapine tablets [see Warnings and Precautions (5.5)].

Dyslipidemia

Patients should be counseled that dyslipidemia has occurred during treatment with olanzapine. Patients should have their lipid profile monitored regularly [see Warnings and Precautions (5.5)].

Weight Gain

Patients should be counseled that weight gain has occurred during treatment with olanzapine. Patients should have their weight monitored regularly [see Warnings and Precautions (5.5)].

Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heart beat, or fainting.

Potential for Cognitive and Motor Impairment

Because olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Warnings and Precautions (5.12)].

Body Temperature Regulation

Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they 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 [see Warnings and Precautions (5.13)].

Concomitant Medication

Patients should be advised to inform their healthcare providers if they are taking, or plan to take, Symbyax. Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see Drug Interactions (7)].

Alcohol

Patients should be advised to avoid alcohol while taking olanzapine tablets [see Drug Interactions (7)].

Use in Specific Populations

Pregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with olanzapine tablets. Advise patients that olanzapine tablets may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to olanzapine tablets during pregnancy [see Use in Specific Populations (8.1)].

Lactation — Advise breastfeeding women using olanzapine tablets to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs. [see Use in Specific Populations (8.3)].

Infertility — Advise females of reproductive potential that olanzapine tablets may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

Pediatric Use — Olanzapine tablets are indicated for treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adolescents 13 to 17 years of age. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic aminotransferase levels. Patients should be counseled about the potential long-term risks associated with olanzapine tablets and advised that these risks may lead them to consider other drugs first [see Indications and Usage (1.1, 1.2)]. Safety and effectiveness of olanzapine tablets in patients under 13 years of age have not been established. Safety and efficacy of olanzapine tablets and fluoxetine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with bipolar I disorder. Safety and effectiveness of olanzapine tablets and fluoxetine in combination in patients <10 years of age have not been established [see Warnings and Precautions (5.5) and Use in Specific Populations (8.4)].

Need for Comprehensive Treatment Program in Pediatric Patients

Olanzapine is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures (psychological, educational, social) for patients with the disorder. Effectiveness and safety of olanzapine have not been established in pediatric patients less than 13 years of age. Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the healthcare provider’s assessment of the chronicity and severity of the patient’s symptoms [see Indications and Usage ( 1.3)].

All other trademarks are the properties of their respective owners.

Revised : September 2022

Manufactured for:

Macleods Pharma USA, Inc.

Princeton, NJ 08540

Manufactured by:

Macleods Pharmaceuticals Ltd.

Baddi, Himachal Pradesh, INDIA

Medication Guide available at: www.macleodspharma.com/usa

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