Zyprexa
Generic Name: olanzapine
Dosage Form: tablets, orally disintegrating tablets, injection
WARNING:
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. Analyses of seventeen
placebo-controlled trials (modal duration of 10 weeks), largely in patients
taking atypical antipsychotic drugs, revealed a risk of death in drug-treated
patients of between 1.6 to 1.7 times the risk of death in placebo-treated
patients. Over the course of a typical 10-week controlled trial, the rate of
death in drug-treated patients was about 4.5%, compared to a rate of about 2.6%
in the placebo group. Although the causes of death were varied, most of the
deaths appeared to be either cardiovascular (e.g., heart failure, sudden death)
or infectious (e.g., pneumonia) in nature. Observational studies suggest that,
similar to atypical antipsychotic drugs, treatment with conventional
antipsychotic drugs may increase mortality. The extent to which the findings of
increased mortality in observational studies may be attributed to the
antipsychotic drug as opposed to some characteristic(s) of the patients is not
clear. Zyprexa (olanzapine) is not approved for the treatment of patients with
dementia-related psychosis [see Warnings and Precautions (5.1, 5.14) and Patient Counseling
Information (17.2)].
When
using Zyprexa and fluoxetine in combination, also refer to the Boxed Warning
section of the package insert for Symbyax.
Indications and Usage for Zyprexa
Schizophrenia
Oral
Zyprexa is indicated for the treatment of schizophrenia. Efficacy was established
in three clinical trials in adult patients with schizophrenia: two 6-week
trials and one maintenance trial. In adolescent patients with schizophrenia
(ages 13-17), efficacy was established in one 6-week trial [see
Clinical Studies (14.1)].
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 dyslipidemia. 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)].
Bipolar I Disorder (Manic or Mixed Episodes)
Monotherapy — Oral Zyprexa is indicated for the acute treatment of
manic or mixed episodes associated with bipolar I 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 bipolar I
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 dyslipidemia. 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)].
Adjunctive Therapy to Lithium or Valproate — Oral Zyprexa is indicated for the treatment
of manic or mixed episodes associated with bipolar I 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)].
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 I disorder should be part of a total treatment
program that often includes psychological, educational and social
interventions.
Zyprexa IntraMuscular: Agitation Associated with
Schizophrenia and Bipolar I Mania
Zyprexa
IntraMuscular is indicated for the treatment of acute agitation associated with
schizophrenia and bipolar I 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 often 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.
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. 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.
SLIDESHOW
Depression Symptoms To Watch For
Zyprexa Dosage and Administration
Schizophrenia
Adults
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 Populations — 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 ≥65 years of
age), or who may be more pharmacodynamically sensitive to olanzapine [see
Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)]. 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 demonstrated in a
placebo-controlled trial [see Clinical Studies (14.1)]. The physician who elects to use Zyprexa 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 (14.1)].
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.
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 I 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.
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.
Zyprexa IntraMuscular: Agitation Associated with
Schizophrenia and Bipolar I Mania
Dose Selection for Agitated Adult Patients with
Schizophrenia and Bipolar I Mania — 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 (5.7)]. 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.
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 (2.1, 2.2)].
Intramuscular Dosing in Special Populations — 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 for Injection — 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
|
Volume of Injection,
mL
|
|
10
|
Withdraw total contents of vial
|
|
7.5
|
1.5
|
|
5
|
1
|
|
2.5
|
0.5
|
Physical Incompatibility Information — 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.
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.
Adults
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 of co-administration of doses above 18 mg olanzapine
with 75 mg fluoxetine has not been evaluated in clinical studies.
Children and Adolescents (10-17 years of age)
Oral
olanzapine should be administered in combination with fluoxetine once daily in
the evening, without regard to meals, generally beginning with 2.5 mg of
oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated,
can be made according to efficacy and tolerability. Safety of co-administration
of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated
in pediatric clinical studies.
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 Correspondence
Between Symbyaxa and the Combination of Zyprexa and Fluoxetine
|
|
a Symbyax
(olanzapine/fluoxetine HCl) is a fixed-dose combination of Zyprexa and
fluoxetine.
|
|
For
|
Use in Combination
|
|
Symbyax
|
Zyprexa
|
Fluoxetine
|
|
(mg/day)
|
(mg/day)
|
(mg/day)
|
|
3 mg olanzapine/25 mg fluoxetine
|
2.5
|
20
|
|
6 mg olanzapine/25 mg fluoxetine
|
5
|
20
|
|
12 mg olanzapine/25 mg fluoxetine
|
10+2.5
|
20
|
|
6 mg olanzapine/50 mg fluoxetine
|
5
|
40+10
|
|
12 mg olanzapine/50 mg fluoxetine
|
10+2.5
|
40+10
|
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 I disorder, is a chronic illness
requiring chronic treatment. The physician should periodically reexamine the
need for continued pharmacotherapy.
Zyprexa
monotherapy is not indicated for the treatment of depressive episodes
associated with bipolar I disorder.
Zyprexa and Fluoxetine in Combination: Treatment
Resistant Depression
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/25 mg
(olanzapine/fluoxetine) per day and 12 mg/50 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).
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 under 10
years of age [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)].
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
|
|
|
2.5 mg
|
5 mg
|
7.5 mg
|
10 mg
|
15 mg
|
20 mg
|
|
Tablet No.
|
4112
|
4115
|
4116
|
4117
|
4415
|
4420
|
|
Identification
|
LILLY
|
LILLY
|
LILLY
|
LILLY
|
LILLY
|
LILLY
|
|
|
4112
|
4115
|
4116
|
4117
|
4415
|
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:
|
|
TABLET STRENGTH
|
|
Zyprexa ZYDIS Tablets
|
5 mg
|
10 mg
|
15 mg
|
20 mg
|
|
Tablet No.
|
4453
|
4454
|
4455
|
4456
|
|
Debossed
|
5
|
10
|
15
|
20
|
Zyprexa
IntraMuscular is available in 10 mg vial (1s).
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.
Warnings and Precautions
When
using Zyprexa and fluoxetine in combination, also refer to the Warnings and
Precautions section of the package insert for Symbyax.
Elderly Patients with Dementia-Related Psychosis
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
Stroke —
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)].
Suicide
The
possibility of a suicide attempt is inherent in schizophrenia and in
bipolar I 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.
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 (17.3)].
5.4 Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS)
Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with
olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash
or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with
systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis,
and/or pericarditis. DRESS is sometimes fatal. Discontinue olanzapine if DRESS
is suspected [see Patient Counseling Information (17.4)].
Metabolic Changes
Atypical
antipsychotic drugs have been associated with metabolic changes including
hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be
associated with increased cardiovascular/cerebrovascular risk. Olanzapine's
specific metabolic profile is presented below.
Hyperglycemia and Diabetes Mellitus
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 (17.5)].
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 (CATIE). The mean increase of serum glucose
(fasting and nonfasting samples) from 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,
patients treated with anti-diabetic agents, patients with a baseline random
glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL).
Olanzapine-treated patients had a greater mean HbA1c increase
from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c 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: Changes in Fasting Glucose
Levels from Adult Olanzapine Monotherapy Studies
|
|
a Not
Applicable.
|
|
|
|
|
Up to 12 weeks
exposure
|
At least 48 weeks
exposure
|
|
Laboratory Analyte
|
Category Change (at
least once)
from Baseline
|
Treatment Arm
|
N
|
Patients
|
N
|
Patients
|
|
Fasting
Glucose
|
Normal to High
(<100 mg/dL to ≥126 mg/dL)
|
Olanzapine
|
543
|
2.2%
|
345
|
12.8%
|
|
Placebo
|
293
|
3.4%
|
NAa
|
NAa
|
|
Borderline to High
(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)
|
Olanzapine
|
178
|
17.4%
|
127
|
26.0%
|
|
Placebo
|
96
|
11.5%
|
NAa
|
NAa
|
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 Adolescents — 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 Fasting Glucose
Levels from Adolescent Olanzapine Monotherapy Studies
|
|
a Not
Applicable.
|
|
|
|
|
Up to 12 weeks
exposure
|
At least 24 weeks
exposure
|
|
Laboratory Analyte
|
Category Change (at
least once)
from Baseline
|
Treatment Arm
|
N
|
Patients
|
N
|
Patients
|
|
Fasting
Glucose
|
Normal to High
(<100 mg/dL to ≥126 mg/dL)
|
Olanzapine
|
124
|
0%
|
108
|
0.9%
|
|
Placebo
|
53
|
1.9%
|
NAa
|
NAa
|
|
Borderline to High
(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)
|
Olanzapine
|
14
|
14.3%
|
13
|
23.1%
|
|
Placebo
|
13
|
0%
|
NAa
|
NAa
|
Dyslipidemia
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 (17.6)].
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 HDL 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 or borderline to high, or changes
in HDL 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
|
|
a Not
Applicable.
|
|
|
|
|
Up to 12 weeks
exposure
|
At least 48 weeks
exposure
|
|
Laboratory Analyte
|
Category Change (at
least once)
from Baseline
|
Treatment Arm
|
N
|
Patients
|
N
|
Patients
|
|
Fasting
Triglycerides
|
Increase by ≥50 mg/dL
|
Olanzapine
|
745
|
39.6%
|
487
|
61.4%
|
|
Placebo
|
402
|
26.1%
|
NAa
|
NAa
|
|
Normal to High
(<150 mg/dL to ≥200 mg/dL)
|
Olanzapine
|
457
|
9.2%
|
293
|
32.4%
|
|
Placebo
|
251
|
4.4%
|
NAa
|
NAa
|
|
Borderline to High
(≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)
|
Olanzapine
|
135
|
39.3%
|
75
|
70.7%
|
|
Placebo
|
65
|
20.0%
|
NAa
|
NAa
|
|
|
|
|
|
|
|
|
|
Fasting Total
Cholesterol
|
Increase by ≥40 mg/dL
|
Olanzapine
|
745
|
21.6%
|
489
|
32.9%
|
|
Placebo
|
402
|
9.5%
|
NAa
|
NAa
|
|
Normal to High
(<200 mg/dL to ≥240 mg/dL)
|
Olanzapine
|
392
|
2.8%
|
283
|
14.8%
|
|
Placebo
|
207
|
2.4%
|
NAa
|
NAa
|
|
Borderline to High
(≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)
|
Olanzapine
|
222
|
23.0%
|
125
|
55.2%
|
|
Placebo
|
112
|
12.5%
|
NAa
|
NAa
|
|
|
|
|
|
|
|
|
|
Fasting LDL
Cholesterol
|
Increase by ≥30 mg/dL
|
Olanzapine
|
536
|
23.7%
|
483
|
39.8%
|
|
Placebo
|
304
|
14.1%
|
NAa
|
NAa
|
|
Normal to High
(<100 mg/dL to ≥160 mg/dL)
|
Olanzapine
|
154
|
0%
|
123
|
7.3%
|
|
Placebo
|
82
|
1.2%
|
NAa
|
NAa
|
|
Borderline to High
(≥100 mg/dL and <160 mg/dL to ≥160 mg/dL)
|
Olanzapine
|
302
|
10.6%
|
284
|
31.0%
|
|
Placebo
|
173
|
8.1%
|
NAa
|
NAa
|
In phase
1 of the Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE), over a median exposure of 9.2 months, the mean
increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In
phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.
Olanzapine Monotherapy in Adolescents — 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 adolescents, including
those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed
episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline
in mean fasting total cholesterol, LDL cholesterol, and triglycerides of
12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to
increases from baseline in mean fasting total cholesterol and LDL cholesterol
of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of
1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no
clinically meaningful differences were observed between olanzapine-treated
adolescents and placebo-treated adolescents.
In
long-term studies (at least 24 weeks), adolescents had increases from baseline
in mean fasting total cholesterol, LDL cholesterol, and triglycerides of
5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean
decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows
categorical changes in fasting lipids values in adolescents.
Table 5: Changes in Fasting Lipids Values
from Adolescent Olanzapine Monotherapy Studies
|
|
a Not
Applicable.
|
|
|
|
|
Up to 6 weeks
exposure
|
At least 24 weeks
exposure
|
|
Laboratory Analyte
|
Category Change (at
least once)
from Baseline
|
Treatment Arm
|
N
|
Patients
|
N
|
Patients
|
|
Fasting
Triglycerides
|
Increase by ≥50 mg/dL
|
Olanzapine
|
138
|
37.0%
|
122
|
45.9%
|
|
Placebo
|
66
|
15.2%
|
NAa
|
NAa
|
|
Normal to High
(<90 mg/dL to >130 mg/dL)
|
Olanzapine
|
67
|
26.9%
|
66
|
36.4%
|
|
Placebo
|
28
|
10.7%
|
NAa
|
NAa
|
|
Borderline to High
(≥90 mg/dL and ≤130 mg/dL to >130 mg/dL)
|
Olanzapine
|
37
|
59.5%
|
31
|
64.5%
|
|
Placebo
|
17
|
35.3%
|
NAa
|
NAa
|
|
|
|
|
|
|
|
|
|
Fasting Total
Cholesterol
|
Increase by ≥40 mg/dL
|
Olanzapine
|
138
|
14.5%
|
122
|
14.8%
|
|
Placebo
|
66
|
4.5%
|
NAa
|
NAa
|
|
Normal to High
(<170 mg/dL to ≥200 mg/dL)
|
Olanzapine
|
87
|
6.9%
|
78
|
7.7%
|
|
Placebo
|
43
|
2.3%
|
NAa
|
NAa
|
|
Borderline to High
(≥170 mg/dL and <200 mg/dL to ≥200 mg/dL)
|
Olanzapine
|
36
|
38.9%
|
33
|
57.6%
|
|
Placebo
|
13
|
7.7%
|
NAa
|
NAa
|
|
|
|
|
|
|
|
|
|
Fasting LDL
Cholesterol
|
Increase by ≥30 mg/dL
|
Olanzapine
|
137
|
17.5%
|
121
|
22.3%
|
|
Placebo
|
63
|
11.1%
|
NAa
|
NAa
|
|
Normal to High
(<110 mg/dL to ≥130 mg/dL)
|
Olanzapine
|
98
|
5.1%
|
92
|
10.9%
|
|
Placebo
|
44
|
4.5%
|
NAa
|
NAa
|
|
Borderline to High
(≥110 mg/dL and <130 mg/dL to ≥130 mg/dL)
|
Olanzapine
|
29
|
48.3%
|
21
|
47.6%
|
|
Placebo
|
9
|
0%
|
NAa
|
NAa
|
Weight Gain
Potential
consequences of weight gain should be considered prior to starting olanzapine.
Patients receiving olanzapine should receive regular monitoring of weight [see
Patient Counseling Information (17.7)].
Olanzapine Monotherapy in Adults — In an analysis of 13 placebo-controlled
olanzapine monotherapy studies, olanzapine-treated patients gained an average
of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb)
weight loss in placebo-treated patients with a median exposure of 6 weeks;
22.2% of olanzapine-treated patients gained at least 7% of their baseline
weight, compared to 3% of placebo-treated patients, with a median exposure to
event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of
their baseline weight, compared to 0.3% of placebo-treated patients, with a
median exposure to event of 12 weeks. Clinically significant weight gain was
observed across all baseline Body Mass Index (BMI) categories.
Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients
and in 0% of placebo-treated patients.
In
long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg
(12.3 lb) (median exposure of 573 days, N=2021). The percentages of
patients who gained at least 7%, 15%, or 25% of their baseline body weight with
long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to
weight gain occurred in 0.4% of olanzapine-treated patients following at least
48 weeks of exposure.
Table
6 includes data
on adult weight gain with olanzapine pooled from 86 clinical trials. The data
in each column represent data for those patients who completed treatment
periods of the durations specified.
Table 6: Weight Gain with Olanzapine Use
in Adults
|
|
Amount Gained
kg (lb)
|
6 Weeks
(N=7465)
(%)
|
6 Months
(N=4162)
(%)
|
12 Months
(N=1345)
(%)
|
24 Months
(N=474)
(%)
|
36 Months
(N=147)
(%)
|
|
≤0
|
26.2
|
24.3
|
20.8
|
23.2
|
17.0
|
|
0 to ≤5 (0-11 lb)
|
57.0
|
36.0
|
26.0
|
23.4
|
25.2
|
|
>5 to ≤10 (11-22 lb)
|
14.9
|
24.6
|
24.2
|
24.1
|
18.4
|
|
>10 to ≤15 (22-33 lb)
|
1.8
|
10.9
|
14.9
|
11.4
|
17.0
|
|
>15 to ≤20 (33-44 lb)
|
0.1
|
3.1
|
8.6
|
9.3
|
11.6
|
|
>20 to ≤25 (44-55 lb)
|
0
|
0.9
|
3.3
|
5.1
|
4.1
|
|
>25 to ≤30 (55-66 lb)
|
0
|
0.2
|
1.4
|
2.3
|
4.8
|
|
>30 (>66 lb)
|
0
|
0.1
|
0.8
|
1.2
|
2
|
Dose
group differences with respect to weight gain 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, 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.
Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have
not been established in patients under the age of 13 years. Mean increase in
weight in adolescents was greater than in adults. In 4 placebo-controlled
trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated
patients, compared to 0% of placebo-treated patients.
Table 7: Weight Gain with Olanzapine Use
in Adolescents from 4 Placebo-Controlled Trials
|
|
|
Olanzapine-treated
patients
|
Placebo-treated
patients
|
|
Mean change in
body weight from baseline (median exposure = 3 weeks)
|
4.6 kg (10.1 lb)
|
0.3 kg (0.7 lb)
|
|
Percentage of
patients who gained at least 7% of baseline body weight
|
40.6%
|
9.8%
|
|
(median exposure to 7% = 4 weeks)
|
(median exposure to 7% = 8 weeks)
|
|
Percentage of
patients who gained at least 15% of baseline body weight
|
7.1%
|
2.7%
|
|
(median exposure to 15% = 19 weeks)
|
(median exposure to 15% = 8 weeks)
|
In
long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg
(24.6 lb); (median exposure of 201 days, N=179). The percentages of adolescents
who gained at least 7%, 15%, or 25% of their baseline body weight with
long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent
patients, mean weight gain by baseline BMI category was 11.5 kg
(25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb),
respectively, for normal (N=106), overweight (N=26) and obese (N=17).
Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated
patients following at least 24 weeks of exposure.
Table
8 shows data on
adolescent weight gain with olanzapine pooled from 6 clinical trials. The data
in each column represent data for those patients who completed treatment
periods of the durations specified. Little clinical trial data is available on
weight gain in adolescents with olanzapine beyond 6 months of treatment.
Table 8: Weight Gain with Olanzapine Use
in Adolescents
|
|
Amount Gained
kg (lb)
|
6 Weeks
(N=243)
(%)
|
6 Months
(N=191)
(%)
|
|
≤0
|
2.9
|
2.1
|
|
0 to ≤5 (0-11 lb)
|
47.3
|
24.6
|
|
>5 to ≤10 (11-22 lb)
|
42.4
|
26.7
|
|
>10 to ≤15 (22-33 lb)
|
5.8
|
22.0
|
|
>15 to ≤20 (33-44 lb)
|
0.8
|
12.6
|
|
>20 to ≤25 (44-55 lb)
|
0.8
|
9.4
|
|
>25 to ≤30 (55-66 lb)
|
0
|
2.1
|
|
>30 to ≤35 (66-77 lb)
|
0
|
0
|
|
>35 to ≤40 (77-88 lb)
|
0
|
0
|
|
>40 (>88 lb)
|
0
|
0.5
|
Tardive Dyskinesia
A
syndrome of potentially irreversible, involuntary, dyskinetic movements may
develop in patients treated with antipsychotic drugs. Although the prevalence
of the syndrome appears to be highest among the elderly, especially elderly
women, it is impossible to rely upon prevalence estimates to predict, at the
inception of antipsychotic treatment, which patients are likely to develop the
syndrome. Whether antipsychotic drug products differ in their potential to
cause tardive dyskinesia is unknown.
The risk
of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the
total cumulative dose of antipsychotic drugs administered to the patient
increase. However, the syndrome can develop, although much less commonly, after
relatively brief treatment periods at low doses or may even arise after
discontinuation of treatment.
There is
no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is
withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially
suppress) the signs and symptoms of the syndrome and thereby may possibly mask
the underlying process. The effect that symptomatic suppression has upon the
long-term course of the syndrome is unknown.
Given
these considerations, olanzapine should be prescribed in a manner that is most
likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients (1) who suffer from a
chronic illness that is known to respond to antipsychotic drugs, and
(2) for whom alternative, equally effective, but potentially less harmful
treatments are not available or appropriate. In patients who do require chronic
treatment, the smallest dose and the shortest duration of treatment producing a
satisfactory clinical response should be sought. The need for continued
treatment should be reassessed periodically.
If signs
and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug
discontinuation should be considered. However, some patients may require
treatment with olanzapine despite the presence of the syndrome.
For
specific information about the warnings of lithium or valproate, refer to the
Warnings section of the package inserts for these other products.
Orthostatic Hypotension
Olanzapine
may induce orthostatic hypotension associated with dizziness, tachycardia,
bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably
reflecting its α1-adrenergic antagonistic properties [see
Patient Counseling Information (17.8)].
From an
analysis of the vital sign data in an integrated database of 41 completed
clinical studies in adult patients treated with oral olanzapine, orthostatic
hypotension was recorded in ≥20% (1277/6030) of patients.
For oral
olanzapine therapy, the risk of orthostatic hypotension and syncope may be
minimized by initiating therapy with 5 mg QD [see
Dosage and Administration (2)]. A more gradual titration to the target dose should
be considered if hypotension occurs.
Hypotension,
bradycardia with or without hypotension, tachycardia, and syncope were also
reported during the clinical trials with intramuscular olanzapine for
injection. In an open-label clinical pharmacology study in nonagitated patients
with schizophrenia in which the safety and tolerability of intramuscular
olanzapine were evaluated under a maximal dosing regimen (three 10 mg
doses administered 4 hours apart), approximately one-third of these patients
experienced a significant orthostatic decrease in systolic blood pressure
(i.e., decrease ≥30 mmHg) [see Dosage and
Administration (2.4)]. Syncope was reported in 0.6% (15/2500) of
olanzapine-treated patients in phase 2-3 oral olanzapine studies and in 0.3%
(2/722) of olanzapine-treated patients with agitation in the intramuscular
olanzapine for injection studies. Three normal volunteers in phase 1 studies
with intramuscular olanzapine experienced hypotension, bradycardia, and sinus
pauses of up to 6 seconds that spontaneously resolved (in 2 cases the reactions
occurred on intramuscular olanzapine, and in 1 case, on oral olanzapine). The
risk for this sequence of hypotension, bradycardia, and sinus pause may be
greater in nonpsychiatric patients compared to psychiatric patients who are
possibly more adapted to certain effects of psychotropic drugs. For
intramuscular olanzapine for injection therapy, patients should remain
recumbent if drowsy or dizzy after injection until examination has indicated
that they are not experiencing postural hypotension, bradycardia, and/or
hypoventilation.
Olanzapine
should be used with particular caution in patients with known cardiovascular
disease (history of myocardial infarction or ischemia, heart failure, or
conduction abnormalities), cerebrovascular disease, and conditions which would
predispose patients to hypotension (dehydration, hypovolemia, and treatment
with antihypertensive medications) where the occurrence of syncope, or
hypotension and/or bradycardia might put the patient at increased medical risk.
Caution
is necessary in patients who receive treatment with other drugs having effects
that can induce hypotension, bradycardia, respiratory or central nervous system
depression [see Drug Interactions (7)].
Concomitant administration of intramuscular olanzapine and parenteral
benzodiazepine is not recommended due to the potential for excessive sedation
and cardiorespiratory depression.
5.8 Falls
Zyprexa
may cause somnolence, postural hypotension, motor and sensory instability,
which may lead to falls and, consequently, fractures or other injuries. For
patients with diseases, conditions, or medications that could exacerbate these
effects, complete fall risk assessments when initiating antipsychotic treatment
and recurrently for patients on long-term antipsychotic therapy.
Leukopenia, Neutropenia, and Agranulocytosis
Class Effect — In clinical trial and/or postmarketing experience,
events of leukopenia/neutropenia have been reported temporally related to
antipsychotic agents, including Zyprexa. Agranulocytosis has also been
reported.
Possible
risk factors for leukopenia/neutropenia include pre-existing low white blood
cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients
with a history of a clinically significant low WBC or drug induced
leukopenia/neutropenia should have their complete blood count (CBC) monitored
frequently during the first few months of therapy and discontinuation of
Zyprexa should be considered at the first sign of a clinically significant
decline in WBC in the absence of other causative factors.
Patients
with clinically significant neutropenia should be carefully monitored for fever
or other symptoms or signs of infection and treated promptly if such symptoms
or signs occur. Patients with severe neutropenia (absolute neutrophil count
<1000/mm3) should discontinue Zyprexa and have their WBC
followed until recovery.
Dysphagia
Esophageal
dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients
with advanced Alzheimer's disease. Olanzapine is not approved for the treatment
of patients with Alzheimer's disease.
Seizures
During
premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated
patients. There were confounding factors that may have contributed to the
occurrence of seizures in many of these cases. Olanzapine should be used
cautiously in patients with a history of seizures or with conditions that
potentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine
is not approved for the treatment of patients with Alzheimer's disease.
Conditions that lower the seizure threshold may be more prevalent in a
population of 65 years or older.
Potential for Cognitive and Motor Impairment
Somnolence
was a commonly reported adverse reaction associated with olanzapine treatment,
occurring at an incidence of 26% in olanzapine patients compared to 15% in
placebo patients. This adverse reaction was also dose related. Somnolence led
to discontinuation in 0.4% (9/2500) of patients in the premarketing database.
Since
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 Patient Counseling Information (17.9)].
Body Temperature Regulation
Disruption
of the body's ability to reduce core body temperature has been attributed to
antipsychotic agents. Appropriate care is advised when prescribing olanzapine
for patients who will be experiencing conditions which may contribute to an
elevation in core body temperature, e.g., exercising strenuously, exposure to
extreme heat, receiving concomitant medication with anticholinergic activity,
or being subject to dehydration [see Patient
Counseling Information (17.10)].
Use in Patients with Concomitant Illness
Clinical
experience with olanzapine in patients with certain concomitant systemic
illnesses is limited [see Clinical Pharmacology (12.3)].
Olanzapine
exhibits in vitro muscarinic receptor affinity. In premarketing clinical
trials with olanzapine, olanzapine 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
discontinuations from olanzapine, but olanzapine should be used with caution in
patients with clinically significant prostatic hypertrophy, narrow angle
glaucoma, or a history of paralytic ileus or related conditions.
In 5
placebo-controlled studies of olanzapine in elderly patients with
dementia-related psychosis (n=1184), the following treatment-emergent adverse
reactions were reported in olanzapine-treated patients at an incidence of at
least 2% and significantly greater than placebo-treated patients: falls,
somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy,
increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual
hallucinations. The rate of discontinuation due to adverse reactions was
greater with olanzapine than placebo (13% vs 7%). Elderly patients with
dementia-related psychosis treated with olanzapine are at an increased risk of
death compared to placebo. Olanzapine is not approved for the treatment of
patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17.2)].
Olanzapine
has not been evaluated or used to any appreciable extent in patients with a
recent history of myocardial infarction or unstable heart disease. Patients
with these diagnoses were excluded from premarketing clinical studies. Because
of the risk of orthostatic hypotension with olanzapine, caution should be
observed in cardiac patients [see Warnings
and Precautions (5.7)].
Hyperprolactinemia
As with
other drugs that antagonize dopamine D2 receptors,
olanzapine elevates prolactin levels, and the elevation persists during chronic
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 impotence 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 which 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.
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% [49/3240] of females), sexual
function-related events2 (2% [150/8136] of females and males), and
breast-related events3 (0.7% [23/3240] of females, 0.2% [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 events1 (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) [see 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.
Use in Combination with Fluoxetine, Lithium, or
Valproate
When
using Zyprexa and fluoxetine in combination, the prescriber should also refer
to the Warnings and Precautions section of the package insert for Symbyax. When
using Zyprexa in combination with lithium or valproate, the prescriber should
refer to the Warnings and Precautions sections of the package inserts for
lithium or valproate [see Drug Interactions (7)].
Laboratory Tests
Fasting
blood glucose testing and lipid profile at the beginning of, and periodically
during, treatment is recommended [see Warnings
and Precautions (5.5) and Patient Counseling
Information (17.5, 17.6)].
Adverse Reactions
When
using Zyprexa and fluoxetine in combination, also refer to the Adverse
Reactions section of the package insert for Symbyax.
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.
Clinical Trials in Adults
The
information below for olanzapine is derived from a clinical trial database for
olanzapine consisting of 10,504 adult patients with approximately 4765
patient-years of exposure to olanzapine plus 722 patients with exposure to
intramuscular olanzapine for injection. This database includes: (1) 2500
patients who participated in multiple-dose oral olanzapine premarketing trials
in schizophrenia and Alzheimer's disease representing approximately 1122
patient-years of exposure as of February 14, 1995; (2) 182 patients
who participated in oral olanzapine premarketing bipolar I disorder (manic
or mixed episodes) trials representing approximately 66 patient-years of
exposure; (3) 191 patients who participated in an oral olanzapine trial of
patients having various psychiatric symptoms in association with Alzheimer's
disease representing approximately 29 patient-years of exposure; (4) 5788
additional patients from 88 oral olanzapine clinical trials as of
December 31, 2001; (5) 1843 additional patients from 41 olanzapine
clinical trials as of October 31, 2011; and (6) 722 patients who
participated in intramuscular olanzapine for injection premarketing trials in
agitated patients with schizophrenia, bipolar I disorder (manic or mixed
episodes), or dementia. Also included below is information from the
premarketing 6-week clinical study database for olanzapine in combination with
lithium or valproate, consisting of 224 patients who participated in bipolar I
disorder (manic or mixed episodes) trials with approximately 22 patient-years
of exposure.
The
conditions and duration of treatment with olanzapine 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 longer-term exposure. Adverse reactions were assessed by
collecting adverse reactions, results of physical examinations, vital signs,
weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic
examinations.
Certain
portions of the discussion below relating to objective or numeric safety
parameters, namely, dose-dependent adverse reactions, vital sign changes,
weight gain, laboratory changes, and ECG changes are derived from studies in
patients with schizophrenia and have not been duplicated for bipolar I
disorder (manic or mixed episodes) or agitation. However, this information is
also generally applicable to bipolar I disorder (manic or mixed episodes)
and agitation.
Adverse
reactions during exposure were obtained by spontaneous report and recorded by
clinical investigators using terminology of their own choosing. Consequently,
it is not possible to provide a meaningful estimate of the proportion of individuals
experiencing adverse reactions without first grouping similar types of
reactions into a smaller number of standardized reaction categories. In the
tables and tabulations that follow, MedDRA and COSTART Dictionary terminology
has been used to classify reported adverse reactions.
The stated frequencies of adverse reactions
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. The reported reactions
do not include those reaction terms that were so general as to be
uninformative. Reactions listed elsewhere in labeling may not be repeated
below. It is important to emphasize that, although the reactions occurred
during treatment with olanzapine, they were not necessarily caused by it. The
entire label should be read to gain a complete understanding of the safety
profile of olanzapine.
The prescriber should be aware that the figures in
the tables and tabulations cannot be used to predict the incidence of side
effects in the course of usual medical practice where patient characteristics
and other factors differ from those that prevailed in the clinical trials.
Similarly, the cited frequencies cannot be compared with figures obtained from
other clinical investigations involving different treatments, uses, and
investigators. The cited figures, however, do provide the prescribing physician
with some basis for estimating the relative contribution of drug and nondrug
factors to the adverse reactions incidence in the population studied.
Incidence of Adverse Reactions in
Short-Term, Placebo-Controlled and Combination Trials
The following findings are based on premarketing
trials of (1) oral olanzapine for schizophrenia, bipolar I disorder
(manic or mixed episodes), a subsequent trial of patients having various
psychiatric symptoms in association with Alzheimer's disease, and premarketing
combination trials, and (2) intramuscular olanzapine for injection in
agitated patients with schizophrenia or bipolar I mania.
Adverse Reactions Associated with
Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials
Schizophrenia — Overall, there was
no difference in the incidence of discontinuation due to adverse reactions (5%
for oral olanzapine vs 6% for placebo). However, discontinuations due to
increases in ALT were considered to be drug related (2% for oral olanzapine vs
0% for placebo).
Bipolar I Disorder (Manic or Mixed
Episodes) Monotherapy — Overall, there was no difference in the
incidence of discontinuation due to adverse reactions (2% for oral olanzapine
vs 2% for placebo).
Agitation — Overall, there was no
difference in the incidence of discontinuation due to adverse reactions (0.4%
for intramuscular olanzapine for injection vs 0% for placebo).
Adverse Reactions Associated with
Discontinuation of Treatment in Short-Term Combination Trials
Bipolar I Disorder (Manic or Mixed
Episodes), Olanzapine as Adjunct to Lithium or Valproate — In a study of
patients who were already tolerating either lithium or valproate as
monotherapy, discontinuation rates due to adverse reactions were 11% for the
combination of oral olanzapine with lithium or valproate compared to 2% for
patients who remained on lithium or valproate monotherapy. Discontinuations
with the combination of oral olanzapine and lithium or valproate that occurred
in more than 1 patient were: somnolence (3%), weight gain (1%), and peripheral
edema (1%).
Commonly Observed Adverse Reactions
in Short-Term, Placebo-Controlled Trials
The most commonly observed adverse reactions
associated with the use of oral olanzapine (incidence of 5% or greater) and not
observed at an equivalent incidence among placebo-treated patients (olanzapine
incidence at least twice that for placebo) were:
Table 9: Common Treatment-Emergent Adverse Reactions Associated with
the Use of Oral Olanzapine in 6-Week Trials — SCHIZOPHRENIA
|
|
|
a Personality
disorder is the COSTART term for designating nonaggressive objectionable
behavior.
|
|
|
Adverse Reaction
|
Percentage of Patients
Reporting Event
|
|
|
Olanzapine
(N=248)
|
Placebo
(N=118)
|
|
|
Postural
hypotension
|
5
|
2
|
|
|
Constipation
|
9
|
3
|
|
|
Weight
gain
|
6
|
1
|
|
|
Dizziness
|
11
|
4
|
|
|
Personality
disordera
|
8
|
4
|
|
|
Akathisia
|
5
|
1
|
|
Table 10: Common Treatment-Emergent Adverse Reactions Associated with
the Use of Oral Olanzapine in 3-Week and 4-Week Trials — Bipolar I Disorder
(Manic or Mixed Episodes)
|
|
|
Adverse Reaction
|
Percentage of Patients
Reporting Event
|
|
|
Olanzapine
(N=125)
|
Placebo
(N=129)
|
|
|
Asthenia
|
15
|
6
|
|
|
Dry
mouth
|
22
|
7
|
|
|
Constipation
|
11
|
5
|
|
|
Dyspepsia
|
11
|
5
|
|
|
Increased
appetite
|
6
|
3
|
|
|
Somnolence
|
35
|
13
|
|
|
Dizziness
|
18
|
6
|
|
|
Tremor
|
6
|
3
|
|
Olanzapine Intramuscular — There was 1 adverse reaction (somnolence)
observed at an incidence of 5% or greater among intramuscular olanzapine for
injection-treated patients and not observed at an equivalent incidence among
placebo-treated patients (olanzapine incidence at least twice that for placebo)
during the placebo-controlled premarketing studies. The incidence of somnolence
during the 24 hour IM treatment period in clinical trials in agitated patients
with schizophrenia or bipolar I mania was 6% for intramuscular olanzapine
for injection and 3% for placebo.
Adverse Reactions Occurring at an Incidence of 2% or
More among Oral Olanzapine-Treated Patients in Short-Term, Placebo-Controlled
Trials
Table
11 enumerates the
incidence, rounded to the nearest percent, of treatment-emergent adverse
reactions that occurred in 2% or more of patients treated with oral olanzapine
(doses ≥2.5 mg/day) and with incidence greater than placebo who
participated in the acute phase of placebo-controlled trials.
Table 11: Treatment-Emergent Adverse
Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with
Oral Olanzapine
|
|
|
Body System/Adverse Reaction
|
Percentage of Patients Reporting Event
|
|
|
Olanzapine
(N=532)
|
Placebo
(N=294)
|
|
|
Body as a Whole
|
|
|
|
|
Accidental
injury
|
12
|
8
|
|
|
Asthenia
|
10
|
9
|
|
|
Fever
|
6
|
2
|
|
|
Back pain
|
5
|
2
|
|
|
Chest pain
|
3
|
1
|
|
|
Cardiovascular System
|
|
|
|
|
Postural
hypotension
|
3
|
1
|
|
|
Tachycardia
|
3
|
1
|
|
|
Hypertension
|
2
|
1
|
|
|
Digestive System
|
|
|
|
|
Dry mouth
|
9
|
5
|
|
|
Constipation
|
9
|
4
|
|
|
Dyspepsia
|
7
|
5
|
|
|
Vomiting
|
4
|
3
|
|
|
Increased
appetite
|
3
|
2
|
|
|
Hemic and Lymphatic System
|
|
|
|
|
Ecchymosis
|
5
|
3
|
|
|
Metabolic and Nutritional Disorders
|
|
|
|
|
Weight gain
|
5
|
3
|
|
|
Peripheral edema
|
3
|
1
|
|
|
Musculoskeletal System
|
|
|
|
|
Extremity pain
(other than joint)
|
5
|
3
|
|
|
Joint pain
|
5
|
3
|
|
|
Nervous System
|
|
|
|
|
Somnolence
|
29
|
13
|
|
|
Insomnia
|
12
|
11
|
|
|
Dizziness
|
11
|
4
|
|
|
Abnormal gait
|
6
|
1
|
|
|
Tremor
|
4
|
3
|
|
|
Akathisia
|
3
|
2
|
|
|
Hypertonia
|
3
|
2
|
|
|
Articulation
impairment
|
2
|
1
|
|
|
Respiratory System
|
|
|
|
|
Rhinitis
|
7
|
6
|
|
|
Cough increased
|
6
|
3
|
|
|
Pharyngitis
|
4
|
3
|
|
|
Special Senses
|
|
|
|
|
Amblyopia
|
3
|
2
|
|
|
Urogenital System
|
|
|
|
|
Urinary
incontinence
|
2
|
1
|
|
|
Urinary tract
infection
|
2
|
1
|
|
Dose Dependency of Adverse Reactions
A dose
group difference has been observed for fatigue, dizziness, weight gain and
prolactin elevation. 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 fatigue (10 mg/day:
1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant
differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of
dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%)
was observed with significant differences between 20 vs 40 mg. Dose group
differences were also noted for weight gain and prolactin elevation [see
Warnings and Precautions (5.5, 5.15)].
The
following table addresses dose relatedness for other adverse reactions using
data from a schizophrenia trial involving fixed dosage ranges of oral
olanzapine. It enumerates the percentage of patients with treatment-emergent
adverse reactions for the 3 fixed-dose range groups and placebo. The data were
analyzed using the Cochran-Armitage test, excluding the placebo group, and the
table includes only those adverse reactions for which there was a trend.
Table 12: Percentage of Patients from a
Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the 3DoseRangeGroups and Placebo
|
|
|
Percentage of
Patients Reporting Event
|
|
|
|
Olanzapine
|
Olanzapine
|
Olanzapine
|
|
|
Placebo
|
5 ± 2.5 mg/day
|
10 ± 2.5 mg/day
|
15 ± 2.5 mg/day
|
|
Adverse Reaction
|
(N=68)
|
(N=65)
|
(N=64)
|
(N=69)
|
|
Asthenia
|
15
|
8
|
9
|
20
|
|
Dry mouth
|
4
|
3
|
5
|
13
|
|
Nausea
|
9
|
0
|
2
|
9
|
|
Somnolence
|
16
|
20
|
30
|
39
|
|
Tremor
|
3
|
0
|
5
|
7
|
Commonly Observed Adverse Reactions in Short-Term
Trials of Oral Olanzapine as Adjunct to Lithium or Valproate
In the
bipolar I disorder (manic or mixed episodes) adjunct placebo-controlled
trials, the most commonly observed adverse reactions associated with the
combination of olanzapine and lithium or valproate (incidence of ≥5% and at
least twice placebo) were:
Table 13: Common Treatment-Emergent
Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week
Adjunct to Lithium or Valproate Trials — Bipolar I Disorder (Manic or Mixed
Episodes)
|
|
|
Adverse Reaction
|
Percentage of
Patients Reporting Event
|
|
|
Olanzapine with lithium
or valproate
(N=229)
|
Placebo with lithium
or valproate
(N=115)
|
|
|
Dry mouth
|
32
|
9
|
|
|
Weight gain
|
26
|
7
|
|
|
Increased
appetite
|
24
|
8
|
|
|
Dizziness
|
14
|
7
|
|
|
Back pain
|
8
|
4
|
|
|
Constipation
|
8
|
4
|
|
|
Speech disorder
|
7
|
1
|
|
|
Increased
salivation
|
6
|
2
|
|
|
Amnesia
|
5
|
2
|
|
|
Paresthesia
|
5
|
2
|
|
Adverse Reactions Occurring at an Incidence of 2% or
More among Oral Olanzapine-Treated Patients in Short-Term Trials of Olanzapine
as Adjunct to Lithium or Valproate
Table
14 enumerates the incidence,
rounded to the nearest percent, of treatment-emergent adverse reactions that
occurred in 2% or more of patients treated with the combination of olanzapine
(doses ≥5 mg/day) and lithium or valproate and with incidence greater than
lithium or valproate alone who participated in the acute phase of
placebo-controlled combination trials.
Table 14: Treatment-Emergent Adverse
Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of
Oral Olanzapine as Adjunct to Lithium or Valproate
|
|
a Denominator
used was for females only (olanzapine, N=128; placebo, N=51).
|
|
Body System/Adverse Reaction
|
Percentage of
Patients Reporting Event
|
|
Olanzapine with
lithium or valproate
(N=229)
|
Placebo with lithium
or valproate
(N=115)
|
|
Body as a Whole
|
|
|
|
Asthenia
|
18
|
13
|
|
Back pain
|
8
|
4
|
|
Accidental
injury
|
4
|
2
|
|
Chest pain
|
3
|
2
|
|
Cardiovascular System
|
|
|
|
Hypertension
|
2
|
1
|
|
Digestive System
|
|
|
|
Dry mouth
|
32
|
9
|
|
Increased
appetite
|
24
|
8
|
|
Thirst
|
10
|
6
|
|
Constipation
|
8
|
4
|
|
Increased
salivation
|
6
|
2
|
|
Metabolic and Nutritional Disorders
|
|
|
|
Weight gain
|
26
|
7
|
|
Peripheral edema
|
6
|
4
|
|
Edema
|
2
|
1
|
|
Nervous System
|
|
|
|
Somnolence
|
52
|
27
|
|
Tremor
|
23
|
13
|
|
Depression
|
18
|
17
|
|
Dizziness
|
14
|
7
|
|
Speech disorder
|
7
|
1
|
|
Amnesia
|
5
|
2
|
|
Paresthesia
|
5
|
2
|
|
Apathy
|
4
|
3
|
|
Confusion
|
4
|
1
|
|
Euphoria
|
3
|
2
|
|
Incoordination
|
2
|
0
|
|
Respiratory System
|
|
|
|
Pharyngitis
|
4
|
1
|
|
Dyspnea
|
3
|
1
|
|
Skin and Appendages
|
|
|
|
Sweating
|
3
|
1
|
|
Acne
|
2
|
0
|
|
Dry skin
|
2
|
0
|
|
Special Senses
|
|
|
|
Amblyopia
|
9
|
5
|
|
Abnormal vision
|
2
|
0
|
|
Urogenital System
|
|
|
|
Dysmenorrheaa
|
2
|
0
|
|
Vaginitisa
|
2
|
0
|
For
specific information about the adverse reactions observed with lithium or
valproate, refer to the Adverse Reactions section of the package inserts for
these other products.
Adverse Reactions Occurring at an Incidence of 1% or
More among Intramuscular Olanzapine for Injection-Treated Patients in
Short-Term, Placebo-Controlled Trials
Table
15 enumerates the
incidence, rounded to the nearest percent, of treatment-emergent adverse
reactions that occurred in 1% or more of patients treated with intramuscular
olanzapine for injection (dose range of 2.5-10 mg/injection) and with
incidence greater than placebo who participated in the short-term,
placebo-controlled trials in agitated patients with schizophrenia or bipolar I
mania.
Table 15: Treatment-Emergent Adverse
Reactions: Incidence in Short-Term (24 Hour), Placebo-Controlled Clinical
Trials with Intramuscular Olanzapine for Injection in Agitated Patients with
Schizophrenia or Bipolar I Mania
|
|
|
Body System/Adverse Reaction
|
Percentage of
Patients Reporting Event
|
|
|
Olanzapine
(N=415)
|
Placebo
(N=150)
|
|
|
Body as a Whole
|
|
|
|
|
Asthenia
|
2
|
1
|
|
|
Cardiovascular System
|
|
|
|
|
Hypotension
|
2
|
0
|
|
|
Postural
hypotension
|
1
|
0
|
|
|
Nervous System
|
|
|
|
|
Somnolence
|
6
|
3
|
|
|
Dizziness
|
4
|
2
|
|
|
Tremor
|
1
|
0
|
|
Extrapyramidal Symptoms
The
following table enumerates the percentage of patients with treatment-emergent
extrapyramidal symptoms as assessed by categorical analyses of formal rating
scales during acute therapy in a controlled clinical trial comparing oral
olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a
6-week trial.
Table 16: Treatment-Emergent
Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a FixedDosageRange, Placebo-Controlled Clinical
Trial of Oral Olanzapine in Schizophrenia — Acute Phase
|
|
a Percentage
of patients with a Simpson-Angus Scale total score >3.
|
|
b Percentage
of patients with a Barnes Akathisia Scale global score ≥2.
|
|
|
Percentage of
Patients Reporting Event
|
|
Placebo
|
Olanzapine
5 ± 2.5 mg/day
|
Olanzapine
10 ± 2.5 mg/day
|
Olanzapine
15 ± 2.5 mg/day
|
|
Parkinsonisma
|
15
|
14
|
12
|
14
|
|
Akathisiab
|
23
|
16
|
19
|
27
|
The
following table enumerates the percentage of patients with treatment-emergent
extrapyramidal symptoms as assessed by spontaneously reported adverse reactions
during acute therapy in the same controlled clinical trial comparing olanzapine
at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week
trial.
Table 17: Treatment-Emergent
Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a FixedDosageRange, Placebo-Controlled Clinical
Trial of Oral Olanzapine in Schizophrenia — Acute Phase
|
|
a Patients
with the following COSTART terms were counted in this category: dystonia,
generalized spasm, neck rigidity, oculogyric crisis, opisthotonos,
torticollis.
|
|
b Patients
with the following COSTART terms were counted in this category: akinesia,
cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked
facies, tremor.
|
|
c Patients
with the following COSTART terms were counted in this category: akathisia,
hyperkinesia.
|
|
d Patients
with the following COSTART terms were counted in this category: buccoglossal
syndrome, choreoathetosis, dyskinesia, tardive dyskinesia.
|
|
e Patients
with the following COSTART terms were counted in this category: movement
disorder, myoclonus, twitching.
|
|
|
Percentage of
Patients Reporting Event
|
|
Placebo
(N=68)
|
Olanzapine
5 ± 2.5 mg/day
(N=65)
|
Olanzapine
10 ± 2.5 mg/day
(N=64)
|
Olanzapine
15 ± 2.5 mg/day
(N=69)
|
|
Dystonic eventsa
|
1
|
3
|
2
|
3
|
|
Parkinsonism
eventsb
|
10
|
8
|
14
|
20
|
|
Akathisia eventsc
|
1
|
5
|
11
|
10
|
|
Dyskinetic
eventsd
|
4
|
0
|
2
|
1
|
|
Residual eventse
|
1
|
2
|
5
|
1
|
|
Any
extrapyramidal event
|
16
|
15
|
25
|
32
|
a Patients with the following COSTART
terms were counted in this category: dystonia, generalized spasm, neck
rigidity, oculogyric crisis, opisthotonos, torticollis.
b Patients with the following COSTART
terms were counted in this category: akinesia, cogwheel rigidity,
extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.
c Patients with the following COSTART
terms were counted in this category: akathisia, hyperkinesia.
d Patients with the following COSTART
terms were counted in this category: buccoglossal syndrome, choreoathetosis,
dyskinesia, tardive dyskinesia.
e Patients with the following COSTART
terms were counted in this category: movement disorder, myoclonus, twitching.
The
following table enumerates the percentage of adolescent patients with
treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported
adverse reactions during acute therapy (dose range: 2.5 to 20 mg/day).
Table 18: Treatment-Emergent
Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in
Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar
I Disorder — Adolescents
|
|
a Categories
are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as
defined in MedDRA version 12.0.
|
|
|
Percentage of
Patients Reporting Event
|
|
|
Placebo
|
Olanzapine
|
|
Categoriesa
|
(N=89)
|
(N=179)
|
|
Dystonic events
|
0
|
1
|
|
Parkinsonism
events
|
2
|
1
|
|
Akathisia events
|
4
|
6
|
|
Dyskinetic
events
|
0
|
1
|
|
Nonspecific
events
|
0
|
4
|
|
Any
extrapyramidal event
|
6
|
10
|
The
following table enumerates the percentage of patients with treatment-emergent
extrapyramidal symptoms as assessed by categorical analyses of formal rating
scales during controlled clinical trials comparing fixed doses of intramuscular
olanzapine for injection with placebo in agitation. Patients in each dose group
could receive up to 3 injections during the trials [see Clinical
Studies (14.3)]. Patient assessments were conducted during the 24
hours following the initial dose of intramuscular olanzapine for injection.
Table 19: Treatment-Emergent Extrapyramidal Symptoms Assessed by
Rating Scales Incidence in a Fixed Dose, Placebo-Controlled Clinical Trial of
Intramuscular Olanzapine for Injection in Agitated Patients with
Schizophrenia
|
|
a Percentage
of patients with a Simpson-Angus Scale total score >3.
|
|
b Percentage
of patients with a Barnes Akathisia Scale global score ≥2.
|
|
|
Percentage of Patients
Reporting Event
|
|
Placebo
|
Olanzapine
IM
2.5
mg
|
Olanzapine
IM
5
mg
|
Olanzapine
IM
7.5
mg
|
Olanzapine
IM
10
mg
|
|
Parkinsonisma
|
0
|
0
|
0
|
0
|
3
|
|
Akathisiab
|
0
|
0
|
5
|
0
|
0
|
The following table enumerates the percentage of
patients with treatment-emergent extrapyramidal symptoms as assessed by
spontaneously reported adverse reactions in the same controlled clinical trial
comparing fixed doses of intramuscular olanzapine for injection with placebo in
agitated patients with schizophrenia.
Table 20: Treatment-Emergent Extrapyramidal Symptoms Assessed by
Adverse Reactions Incidence in a Fixed Dose, Placebo-Controlled Clinical
Trial of Intramuscular Olanzapine for Injection in Agitated Patients with
Schizophrenia
|
|
a Patients
with the following COSTART terms were counted in this category: dystonia,
generalized spasm, neck rigidity, oculogyric crisis, opisthotonos,
torticollis.
|
|
b Patients
with the following COSTART terms were counted in this category: akinesia,
cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked
facies, tremor.
|
|
c Patients
with the following COSTART terms were counted in this category: akathisia,
hyperkinesia.
|
|
d Patients
with the following COSTART terms were counted in this category: buccoglossal
syndrome, choreoathetosis, dyskinesia, tardive dyskinesia.
|
|
e Patients
with the following COSTART terms were counted in this category: movement
disorder, myoclonus, twitching.
|
|
|
Percentage of Patients
Reporting Event
|
|
Placebo
(N=45)
|
Olanzapine
IM
2.5
mg
(N=48)
|
Olanzapine
IM
5
mg
(N=45)
|
Olanzapine
IM
7.5
mg
(N=46)
|
Olanzapine
IM
10
mg
(N=46)
|
|
Dystonic
eventsa
|
0
|
0
|
0
|
0
|
0
|
|
Parkinsonism
eventsb
|
0
|
4
|
2
|
0
|
0
|
|
Akathisia
eventsc
|
0
|
2
|
0
|
0
|
0
|
|
Dyskinetic
eventsd
|
0
|
0
|
0
|
0
|
0
|
|
Residual
eventse
|
0
|
0
|
0
|
0
|
0
|
|
Any
extrapyramidal events
|
0
|
4
|
2
|
0
|
0
|
Dystonia, Class Effect: 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 olanzapine use.
Other Adverse Reactions
Other Adverse Reactions Observed During the Clinical
Trial Evaluation of Oral Olanzapine
Following
is a list of treatment-emergent adverse reactions reported by patients treated
with oral olanzapine (at multiple doses ≥1 mg/day) 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; rare reactions are
those occurring in fewer than 1/1000 patients.
Body
as a Whole — Infrequent: chills, face edema,
photosensitivity reaction, suicide attempt1; Rare: chills and fever,
hangover effect, sudden death1.
Cardiovascular
System — Infrequent: cerebrovascular
accident, vasodilatation.
Digestive
System — Infrequent: abdominal
distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal
obstruction, liver fatty deposit.
Hemic
and Lymphatic System — Infrequent: thrombocytopenia.
Metabolic
and Nutritional Disorders — Frequent: alkaline phosphatase
increased; Infrequent:bilirubinemia, hypoproteinemia.
Musculoskeletal
System — Rare: osteoporosis.
Nervous
System — Infrequent: ataxia, dysarthria,
libido decreased, stupor; Rare: coma.
Respiratory
System — Infrequent: epistaxis; Rare: lung edema.
Skin
and Appendages — Infrequent: alopecia.
Special
Senses — Infrequent: abnormality of
accommodation, dry eyes; Rare: mydriasis.
Urogenital
System — Infrequent: amenorrhea2, breast pain, decreased
menstruation, impotence2, increased menstruation2, menorrhagia2, metrorrhagia2, polyuria2, urinary frequency,
urinary retention, urinary urgency, urination impaired.
1 These terms represent serious adverse events
but do not meet the definition for adverse drug reactions. They are included
here because of their seriousness.
2 Adjusted for gender.
Other Adverse Reactions Observed During the Clinical
Trial Evaluation of Intramuscular Olanzapine for Injection
Following
is a list of treatment-emergent adverse reactions reported by patients treated
with intramuscular olanzapine for injection (at 1 or more doses ≥2.5 mg/injection)
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) for 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.
Body
as a Whole — Frequent: injection site pain.
Cardiovascular
System — Infrequent: syncope.
Digestive
System — Infrequent: nausea.
Metabolic
and Nutritional Disorders — Infrequent: creatine
phosphokinase increased.
Clinical
Trials in Adolescent Patients (age 13 to 17 years)
Commonly Observed Adverse Reactions in Oral
Olanzapine Short-Term, Placebo-Controlled Trials
Adverse
reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg)
reported with an incidence of 5% or more and reported at least twice as
frequently as placebo-treated patients are listed in Table 21.
Table 21: Treatment-Emergent Adverse Reactions of ≥5% Incidence among Adolescents (13-17 Years Old)
with Schizophrenia or Bipolar I Disorder (Manic or Mixed Episodes)
|
|
a Patients
with the following MedDRA terms were counted in this category: hypersomnia,
lethargy, sedation, somnolence.
|
|
b Patients
with the following MedDRA terms were counted in this category: abdominal
pain, abdominal pain lower, abdominal pain upper.
|
|
Adverse Reactions
|
Percentage of Patients
Reporting Event
|
|
6 Week Trial
%
Schizophrenia Patients
|
3 Week Trial
%
Bipolar Patients
|
|
Olanzapine
(N=72)
|
Placebo
(N=35)
|
Olanzapine
(N=107)
|
Placebo
(N=54)
|
|
Sedationa
|
39
|
9
|
48
|
9
|
|
Weight
increased
|
31
|
9
|
29
|
4
|
|
Headache
|
17
|
6
|
17
|
17
|
|
Increased
appetite
|
17
|
9
|
29
|
4
|
|
Dizziness
|
8
|
3
|
7
|
2
|
|
Abdominal
painb
|
6
|
3
|
6
|
7
|
|
Pain
in extremity
|
6
|
3
|
5
|
0
|
|
Fatigue
|
3
|
3
|
14
|
6
|
|
Dry
mouth
|
4
|
0
|
7
|
0
|
Adverse Reactions Occurring at an Incidence of 2% or
More among Oral Olanzapine-Treated Patients in Short-Term (3-6 weeks),
Placebo-Controlled Trials
Adverse
reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg)
reported with an incidence of 2% or more and greater than placebo are listed
in Table
22.
Table 22: Treatment-Emergent Adverse Reactions of ≥2% Incidence among Adolescents (13-17 Years Old)
(Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of
Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes])
|
|
a Patients
with the following MedDRA terms were counted in this category: hypersomnia,
lethargy, sedation, somnolence.
|
|
b The
terms alanine aminotransferase (ALT), aspartate aminotransferase (AST), and
hepatic enzyme were combined under liver enzymes.
|
|
c Patients
with the following MedDRA terms were counted in this category: lower
respiratory tract infection, respiratory tract infection, respiratory tract
infection viral, upper respiratory tract infection, viral upper respiratory
tract infection.
|
|
Adverse Reaction
|
Percentage of Patients
Reporting Event
|
|
Olanzapine
(N=179)
|
Placebo
(N=89)
|
|
Sedationa
|
44
|
9
|
|
Weight
increased
|
30
|
6
|
|
Increased
appetite
|
24
|
6
|
|
Headache
|
17
|
12
|
|
Fatigue
|
9
|
4
|
|
Dizziness
|
7
|
2
|
|
Dry
mouth
|
6
|
0
|
|
Pain
in extremity
|
5
|
1
|
|
Constipation
|
4
|
0
|
|
Nasopharyngitis
|
4
|
2
|
|
Diarrhea
|
3
|
0
|
|
Restlessness
|
3
|
2
|
|
Liver
enzymes increasedb
|
8
|
1
|
|
Dyspepsia
|
3
|
1
|
|
Epistaxis
|
3
|
0
|
|
Respiratory
tract infectionc
|
3
|
2
|
|
Sinusitis
|
3
|
0
|
|
Arthralgia
|
2
|
0
|
|
Musculoskeletal
stiffness
|
2
|
0
|
Vital Signs and Laboratory Studies
Vital Sign Changes — Oral olanzapine was associated with orthostatic
hypotension and tachycardia in clinical trials. Intramuscular olanzapine for injection
was associated with bradycardia, hypotension, and tachycardia in clinical
trials [see Warnings and Precautions (5)].
Laboratory Changes
Olanzapine Monotherapy in Adults: An assessment of the premarketing experience
for olanzapine revealed an association with asymptomatic increases in ALT, AST,
and GGT. Within the original premarketing database of about 2400 adult patients
with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L
was 2% (50/2381). None of these patients experienced jaundice or other symptoms
attributable to liver impairment and most had transient changes that tended to
normalize while olanzapine treatment was continued.
In
placebo-controlled olanzapine monotherapy studies in adults, clinically
significant ALT elevations (change from <3 times the upper limit of normal
[ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients
exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo.
ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated
patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values
returned to normal, or were decreasing, at last follow-up in the majority of
patients who either continued treatment with olanzapine or discontinued
olanzapine. No patient with elevated ALT values experienced jaundice, liver
failure, or met the criteria for Hy's Rule.
From an
analysis of the laboratory data in an integrated database of 41 completed
clinical studies in adult patients treated with oral olanzapine, high GGT
levels were recorded in ≥1% (88/5245) of patients.
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.
Olanzapine
administration was also associated with increases in serum prolactin [see
Warnings and Precautions (5.15)], with an asymptomatic elevation of the eosinophil
count in 0.3% of patients, and with an increase in CPK.
From an
analysis of the laboratory data in an integrated database of 41 completed
clinical studies in adult patients treated with oral olanzapine, elevated uric
acid was recorded in ≥3% (171/4641) of patients.
Olanzapine Monotherapy in Adolescents: In placebo-controlled clinical trials of
adolescent patients with schizophrenia or bipolar I disorder (manic or
mixed episodes), greater frequencies for the following treatment-emergent
findings, at anytime, were observed in laboratory analytes compared to placebo:
elevated ALT (≥3X ULN in patients with ALT at baseline <3X ULN), (12% vs
2%); elevated AST (28% vs 4%); low total bilirubin (22% vs 7%); elevated GGT
(10% vs 1%); and elevated prolactin (47% vs 7%).
In
placebo-controlled olanzapine monotherapy studies in adolescents, clinically
significant ALT elevations (change from <3 times ULN at baseline to ≥3 times
ULN) were observed in 12% (22/192) of patients exposed to olanzapine compared
to 2% (2/109) of patients exposed to placebo. ALT elevations ≥5 times ULN were
observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109)
of placebo-treated patients. ALT values returned to normal, or were decreasing,
at last follow-up in the majority of patients who either continued treatment
with olanzapine or discontinued olanzapine. No adolescent patient with elevated
ALT values experienced jaundice, liver failure, or met the criteria for Hy's
Rule.
ECG Changes — In pooled studies of adults as well as pooled studies of
adolescents, there were no significant differences between olanzapine and
placebo in the proportions of patients experiencing potentially important
changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR
intervals. Olanzapine use was associated with a mean increase in heart rate
compared to placebo (adults: +2.4 beats per minute vs no change with placebo;
adolescents: +6.3 beats per minute vs -5.1 beats per minute with placebo). This
increase in heart rate may be related to olanzapine's potential for inducing
orthostatic changes [see Warnings and Precautions (5.7)].
Postmarketing Experience
The
following adverse reactions have been identified during post-approval use of
Zyprexa. 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 Zyprexa therapy include the following:
allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or
urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic
ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS), hepatitis, jaundice,
neutropenia, pancreatitis, priapism, rash, restless legs syndrome,
rhabdomyolysis, and venous thromboembolic events (including pulmonary embolism
and deep venous thrombosis). Random cholesterol levels of ≥240 mg/dL and
random triglyceride levels of ≥1000 mg/dL have been reported.
Drug Interactions
The risks
of using olanzapine in combination with other drugs have not been extensively
evaluated in systematic studies.
Potential for Other Drugs to Affect Olanzapine
Diazepam — The co-administration of diazepam with olanzapine
potentiated the orthostatic hypotension observed with olanzapine [see
Drug Interactions (7.2)].
Cimetidine and Antacids — Single doses of cimetidine (800 mg) or
aluminum- and magnesium-containing antacids did not affect the oral
bioavailability of olanzapine.
Inducers of CYP1A2 — Carbamazepine therapy (200 mg bid) causes an
approximately 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.
Alcohol — Ethanol (45 mg/70 kg single dose) did not have
an effect on olanzapine pharmacokinetics. The co-administration of alcohol
(i.e., ethanol) with olanzapine potentiated the orthostatic hypotension
observed with olanzapine [see Drug Interactions (7.2)].
Inhibitors of CYP1A2
Fluvoxamine: Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance
of olanzapine. This results in a mean increase in olanzapine Cmax following
fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean
increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of
olanzapine should be considered in patients receiving concomitant treatment
with fluvoxamine.
Inhibitors of CYP2D6
Fluoxetine: Fluoxetine (60 mg single dose or 60 mg daily
dose for 8 days) causes a small (mean 16%) increase in the maximum
concentration of olanzapine and a small (mean 16%) decrease in olanzapine
clearance. The magnitude of the impact of this factor is small in comparison to
the overall variability between individuals, and therefore dose modification is
not routinely recommended. When using Zyprexa and fluoxetine in combination,
also refer to the Drug Interactions section of the package insert for Symbyax.
Warfarin — Warfarin (20 mg single dose) did not affect
olanzapine pharmacokinetics [see Drug Interactions (7.2)].
Inducers of CYP1A2 or Glucuronyl Transferase — Omeprazole and rifampin may cause an increase
in olanzapine clearance.
Charcoal — The administration of activated charcoal (1 g)
reduced the Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine
levels are not typically obtained until about 6 hours after dosing, charcoal
may be a useful treatment for olanzapine overdose.
Potential for Olanzapine to Affect Other Drugs
CNS Acting Drugs — Given the primary CNS effects of olanzapine, caution
should be used when olanzapine is taken in combination with other centrally
acting drugs and alcohol.
Antihypertensive Agents — Olanzapine, because of its potential for
inducing hypotension, may enhance the effects of certain antihypertensive
agents.
Levodopa and Dopamine Agonists — Olanzapine may antagonize the effects of
levodopa and dopamine agonists.
Lorazepam (IM) — Administration of intramuscular lorazepam (2 mg) 1
hour after intramuscular olanzapine for injection (5 mg) did not
significantly affect the pharmacokinetics of olanzapine, unconjugated
lorazepam, or total lorazepam. However, this co-administration of intramuscular
lorazepam and intramuscular olanzapine for injection added to the somnolence
observed with either drug alone [see Warnings
and Precautions (5.7)].
Lithium — Multiple doses of olanzapine (10 mg for 8 days) did
not influence the kinetics of lithium. Therefore, concomitant olanzapine
administration does not require dosage adjustment of lithium [see
Warnings and Precautions (5.16)].
Valproate — Olanzapine (10 mg daily for 2 weeks) did not affect
the steady state plasma concentrations of valproate. Therefore, concomitant
olanzapine administration does not require dosage adjustment of valproate [see
Warnings and Precautions (5.16)].
Effect of Olanzapine on Drug Metabolizing Enzymes — In vitro studies utilizing human liver
microsomes suggest that olanzapine has little potential to inhibit CYP1A2,
CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause
clinically important drug interactions mediated by these enzymes.
Imipramine — Single doses of olanzapine did not affect the
pharmacokinetics of imipramine or its active metabolite desipramine.
Warfarin — Single doses of olanzapine did not affect the
pharmacokinetics of warfarin [see Drug
Interactions (7.1)].
Diazepam — Olanzapine did not influence the pharmacokinetics of
diazepam or its active metabolite N-desmethyldiazepam. However, diazepam
co-administered with olanzapine increased the orthostatic hypotension observed
with either drug given alone [see Drug
Interactions (7.1)].
Alcohol — Multiple doses of olanzapine did not influence the
kinetics of ethanol [see Drug Interactions (7.1)].
Biperiden — Multiple doses of olanzapine did not influence the
kinetics of biperiden.
Theophylline — Multiple doses of olanzapine did not affect the
pharmacokinetics of theophylline or its metabolites.
USE IN SPECIFIC POPULATIONS
When
using Zyprexa and fluoxetine in combination, also refer to the Use in Specific
Populations section of the package insert for Symbyax.
Pregnancy
Teratogenic Effects, Pregnancy Category C — In oral reproduction studies in rats at doses
up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and
30 times the maximum recommended human daily oral dose on a mg/m2 basis,
respectively) no evidence of teratogenicity was observed. In an oral rat
teratology study, early resorptions and increased numbers of nonviable fetuses
were observed at a dose of 18 mg/kg/day (9 times the maximum recommended
human daily oral dose on a mg/m2 basis). Gestation was prolonged at
10 mg/kg/day (5 times the maximum recommended human daily oral dose on a
mg/m2 basis). In an oral rabbit teratology study, fetal toxicity
(manifested as increased resorptions and decreased fetal weight) occurred at a
maternally toxic dose of 30 mg/kg/day (30 times the maximum recommended
human daily oral dose on a mg/m2 basis). Because animal reproduction studies are
not always predictive of human response, this drug should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Placental
transfer of olanzapine occurs in rat pups.
There are
no adequate and well-controlled trials with olanzapine in pregnant females.
Seven pregnancies were observed during clinical trials with olanzapine,
including 2 resulting in normal births, 1 resulting in neonatal death due to a
cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous abortion.
Nonteratogenic Effects — Neonates exposed to antipsychotic drugs
(including Zyprexa), during the third trimester of pregnancy are at risk for
extrapyramidal and/or withdrawal symptoms following delivery. There have been
reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory
distress and feeding disorder in these neonates. These complications have
varied in severity; while in some cases symptoms have been self-limited, in
other cases neonates have required intensive care unit support and prolonged
hospitalization.
Zyprexa
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Labor and Delivery
The
effect of olanzapine on labor and delivery in humans is unknown. Parturition in
rats was not affected by olanzapine.
Nursing Mothers
In a
study in lactating, healthy women, olanzapine was excreted in breast milk. Mean
infant dose at steady state was estimated to be 1.8% of the maternal olanzapine
dose. It is recommended that women receiving olanzapine should not breast-feed.
Pediatric Use
The
safety and effectiveness of oral Zyprexa in the treatment of schizophrenia and
manic or mixed episodes associated with bipolar I disorder were
established in short-term studies in adolescents (ages 13 to 17 years). Use of
Zyprexa in adolescents is supported by evidence from adequate and well-controlled
studies of Zyprexa in which 268 adolescents received Zyprexa in a range of 2.5
to 20 mg/day [see Clinical Studies (14.1, 14.2)]. Recommended starting dose for adolescents is lower
than that for adults [see Dosage and Administration (2.1, 2.2)]. 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 [see Warnings
and Precautions (5.5, 5.15, 5.17) and Adverse Reactions (6.3)]. 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 dyslipidemia. 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 Indications and Usage (1.1, 1.2)].
Safety
and effectiveness of olanzapine in children <13 years of age have not been
established [see Patient Counseling Information (17.14)].
Safety
and efficacy of Zyprexa and fluoxetine in combination in children and
adolescents (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 Zyprexa and fluoxetine in combination in children <10
years of age have not been established.
Geriatric Use
Of the
2500 patients in premarketing clinical studies with oral olanzapine, 11% (263)
were 65 years of age or over. In patients with schizophrenia, there was no
indication of any different tolerability of olanzapine in the elderly compared
to younger patients. Studies in elderly patients with dementia-related
psychosis have suggested that there may be a different tolerability profile in
this population compared to younger patients with schizophrenia. Elderly
patients with dementia-related psychosis treated with olanzapine are at an
increased risk of death compared to placebo. In placebo-controlled studies of
olanzapine in elderly patients with dementia-related psychosis, there was a
higher incidence of cerebrovascular adverse events (e.g., stroke, transient
ischemic attack) in patients treated with olanzapine compared to patients
treated with placebo. Olanzapine is not approved for the treatment of patients
with dementia-related psychosis. Also, the presence of factors that might
decrease pharmacokinetic clearance or increase the pharmacodynamic response to
olanzapine should lead to consideration of a lower starting dose for any
geriatric patient [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.1)].
Clinical
studies of Zyprexa and fluoxetine in combination did not include sufficient
numbers of patients ≥65 years of age to determine whether they respond
differently from younger patients.
Drug Abuse and Dependence
Dependence
In
studies prospectively designed to assess abuse and dependence potential,
olanzapine was shown to have acute depressive CNS effects but little or no
potential of abuse or physical dependence in rats administered oral doses up to
15 times the maximum recommended human daily oral dose (20 mg) and rhesus
monkeys administered oral doses up to 8 times the maximum recommended human
daily oral dose on a mg/m2 basis.
Olanzapine
has not been systematically studied in humans for its potential for abuse,
tolerance, or physical dependence. While the clinical trials did not reveal any
tendency for any drug-seeking behavior, these observations were not systematic,
and it is not possible to predict on the basis of this limited experience the
extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of
drug abuse, and such patients should be observed closely for signs of misuse or
abuse of olanzapine (e.g., development of tolerance, increases in dose,
drug-seeking behavior).
Overdosage
Human Experience
In
premarketing trials involving more than 3100 patients and/or normal subjects,
accidental or intentional acute overdosage of olanzapine was identified in 67
patients. In the patient taking the largest identified amount, 300 mg, the
only symptoms reported were drowsiness and slurred speech. In the limited
number of patients who were evaluated in hospitals, including the patient
taking 300 mg, there were no observations indicating an adverse change in
laboratory analytes or ECG. Vital signs were usually within normal limits
following overdoses.
In
postmarketing reports of overdose with olanzapine alone, symptoms have been
reported in the majority of cases. In symptomatic patients, symptoms with ≥10%
incidence included agitation/aggressiveness, dysarthria, tachycardia, various
extrapyramidal symptoms, and reduced level of consciousness ranging from
sedation to coma. Among less commonly reported symptoms were the following
potentially medically serious reactions: aspiration, cardiopulmonary arrest,
cardiac arrhythmias (such as supraventricular tachycardia and 1 patient
experiencing sinus pause with spontaneous resumption of normal rhythm),
delirium, possible neuroleptic malignant syndrome, respiratory
depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and
Company has received reports of fatality in association with overdose of
olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine
was reported to be possibly as low as 450 mg of oral olanzapine; however,
in another case, a patient was reported to survive an acute olanzapine
ingestion of approximately 2 g of oral olanzapine.
Management of Overdose
For
current information on the management of Zyprexa (olanzapine) overdose, contact
a certified poison control center (1-800-222-1222 or www.poison.org). The
possibility of multiple drug involvement should be considered. In case of acute
overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation, which may include intubation. Gastric lavage (after
intubation, if patient is unconscious) and administration of activated charcoal
together with a laxative should be considered. The administration of activated
charcoal (1 g) reduced the Cmax and AUC of oral olanzapine by about 60%.
As peak olanzapine levels are not typically obtained until about 6 hours after
dosing, charcoal may be a useful treatment for olanzapine overdose.
The
possibility of obtundation, seizures, or dystonic reaction of the head and neck
following overdose may create a risk of aspiration with induced emesis.
Cardiovascular monitoring should commence immediately and should include
continuous electrocardiographic monitoring to detect possible arrhythmias.
There is
no specific antidote to olanzapine. Therefore, appropriate supportive measures
should be initiated. Hypotension and circulatory collapse should be treated
with appropriate measures such as intravenous fluids and/or sympathomimetic
agents. (Do not use epinephrine, dopamine, or other sympathomimetics with
beta-agonist activity, since beta stimulation may worsen hypotension in the
setting of olanzapine-induced alpha blockade.) Close medical supervision and
monitoring should continue until the patient recovers.
For
specific information about overdosage with lithium or valproate, refer to the
Overdosage section of the package inserts for these products. For specific
information about overdosage with olanzapine and fluoxetine in combination,
refer to the Overdosage section of the Symbyax package insert.
Zyprexa Description
Zyprexa
(olanzapine) is an atypical antipsychotic that belongs to the
thienobenzodiazepine class. The chemical designation is
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b]
[1,5]benzodiazepine. The molecular formula is C17H20N4S, which
corresponds to a molecular weight of 312.44. The chemical structure is:
Olanzapine
is a yellow crystalline solid, which is practically insoluble in water.
Zyprexa
tablets are intended for oral administration only.
Each
tablet contains olanzapine equivalent to 2.5 mg (8 μmol), 5 mg
(16 μmol), 7.5 mg (24 μmol), 10 mg (32 μmol),
15 mg (48 μmol), or 20 mg (64 μmol). Inactive ingredients
are carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate,
microcrystalline cellulose, and other inactive ingredients. The color coating
contains Titanium Dioxide (all strengths), FD&C Blue No. 2 Aluminum
Lake (15 mg), or Synthetic Red Iron Oxide (20 mg). The 2.5, 5, 7.5,
and 10 mg tablets are imprinted with edible ink which contains FD&C
Blue No. 2 Aluminum Lake.
Zyprexa
ZYDIS (olanzapine orally disintegrating tablets) is intended for oral
administration only.
Each
orally disintegrating tablet contains olanzapine equivalent to 5 mg (16 μmol), 10 mg
(32 μmol), 15 mg (48 μmol) or 20 mg (64 μmol). It
begins disintegrating in the mouth within seconds, allowing its contents to be
subsequently swallowed with or without liquid. Zyprexa ZYDIS (olanzapine orally
disintegrating tablets) also contains the
following inactive ingredients: gelatin, mannitol, aspartame, sodium methyl
paraben, and sodium propyl paraben.
Zyprexa
IntraMuscular (olanzapine for injection) is intended for intramuscular use
only.
Each vial
provides for the administration of
10 mg (32 μmol) olanzapine with inactive ingredients 50 mg
lactose monohydrate and 3.5 mg tartaric acid. Hydrochloric acid and/or
sodium hydroxide may have been added during manufacturing to adjust pH.
Zyprexa - Clinical Pharmacology
Mechanism of Action
The
mechanism of action of olanzapine, as with other drugs having efficacy in
schizophrenia, is unknown. However, it has been proposed that this drug's
efficacy in schizophrenia is mediated through a combination of dopamine and
serotonin type 2 (5HT2) antagonism.
The mechanism of action of olanzapine in the treatment of acute manic or mixed
episodes associated with bipolar I disorder is unknown.
Pharmacodynamics
Olanzapine
binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6 (Ki=4, 11, and 5 nM, respectively), dopamine D1-4 (Ki=11-31 nM),
histamine H1 (Ki=7 nM),
and adrenergic α1 receptors (Ki=19 nM).
Olanzapine is an antagonist with moderate affinity binding for
serotonin 5HT3 (Ki=57 nM)
and muscarinic M1-5 (Ki=73, 96,
132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABAA, BZD, and β-adrenergic receptors (Ki>10 μM).
Antagonism
at receptors other than dopamine and 5HT2 may
explain some of the other therapeutic and side effects of olanzapine.
Olanzapine's antagonism of muscarinic M1-5 receptors
may explain its anticholinergic-like effects. Olanzapine's antagonism of
histamine H1 receptors may explain the somnolence
observed with this drug. Olanzapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed
with this drug.
Pharmacokinetics
Oral Administration, Monotherapy — Olanzapine is well absorbed and reaches peak
concentrations in approximately 6 hours following an oral dose. It is
eliminated extensively by first pass metabolism, with approximately 40% of the
dose metabolized before reaching the systemic circulation. Food does not affect
the rate or extent of olanzapine absorption. Pharmacokinetic studies showed
that Zyprexa tablets and Zyprexa ZYDIS (olanzapine orally disintegrating
tablets) dosage forms of olanzapine are bioequivalent.
Olanzapine
displays linear kinetics over the clinical dosing range. Its half-life ranges
from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent
plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean
of 25 L/hr).
Administration
of olanzapine once daily leads to steady-state concentrations in about 1 week
that are approximately twice the concentrations after single doses. Plasma
concentrations, half-life, and clearance of olanzapine may vary between
individuals on the basis of smoking status, gender, and age.
Olanzapine
is extensively distributed throughout the body, with a volume of distribution
of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to
1100 ng/mL, binding primarily to albumin and α1-acid
glycoprotein.
Metabolism and Elimination — Following a single oral dose of 14C labeled
olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged
drug, indicating that olanzapine is highly metabolized. Approximately 57% and
30% of the dose was recovered in the urine and feces, respectively. In the
plasma, olanzapine accounted for only 12% of the AUC for total radioactivity,
indicating significant exposure to metabolites. After multiple dosing, the
major circulating metabolites were the 10-N-glucuronide, present at steady
state at 44% of the concentration of olanzapine, and 4′-N-desmethyl olanzapine,
present at steady state at 31% of the concentration of olanzapine. Both
metabolites lack pharmacological activity at the concentrations observed.
Direct
glucuronidation and cytochrome P450 (CYP) mediated oxidation are the
primary metabolic pathways for olanzapine. In vitro studies suggest that
CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are
involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a
minor metabolic pathway in vivo, because the clearance of olanzapine is
not reduced in subjects who are deficient in this enzyme.
Intramuscular Administration — Zyprexa IntraMuscular results in rapid
absorption with peak plasma concentrations occurring within 15 to 45 minutes.
Based upon a pharmacokinetic study in healthy volunteers, a 5 mg dose of
intramuscular olanzapine for injection produces, on average, a maximum plasma
concentration approximately 5 times higher than the maximum plasma
concentration produced by a 5 mg dose of oral olanzapine. Area under the
curve achieved after an intramuscular dose is similar to that achieved after
oral administration of the same dose. The half-life observed after
intramuscular administration is similar to that observed after oral dosing. The
pharmacokinetics are linear over the clinical dosing range. Metabolic profiles
after intramuscular administration are qualitatively similar to metabolic
profiles after oral administration.
Specific Populations
Renal Impairment — Because olanzapine is highly metabolized before
excretion and only 7% of the drug is excreted unchanged, renal dysfunction
alone is unlikely to have a major impact on the pharmacokinetics of olanzapine.
The pharmacokinetic characteristics of olanzapine were similar in patients with
severe renal impairment and normal subjects, indicating that dosage adjustment
based upon the degree of renal impairment is not required. In addition,
olanzapine is not removed by dialysis. The effect of renal impairment on
metabolite elimination has not been studied.
Hepatic Impairment — Although the presence of hepatic impairment may be
expected to reduce the clearance of olanzapine, a study of the effect of
impaired liver function in subjects (n=6) with clinically significant (Childs
Pugh Classification A and B) cirrhosis revealed little effect on the
pharmacokinetics of olanzapine.
Geriatric — In a study involving 24 healthy subjects, the mean
elimination half-life of olanzapine was about 1.5 times greater in elderly (≥65
years) than in nonelderly subjects (<65 years). Caution should be used in
dosing the elderly, especially if there are other factors that might additively
influence drug metabolism and/or pharmacodynamic sensitivity [see
Dosage and Administration (2)].
Gender — Clearance of olanzapine is approximately 30% lower in
women than in men. There were, however, no apparent differences between men and
women in effectiveness or adverse effects. Dosage modifications based on gender
should not be needed.
Smoking Status — Olanzapine clearance is about 40% higher in smokers than
in nonsmokers, although dosage modifications are not routinely recommended.
Race — In vivo studies have shown that exposures are
similar among Japanese, Chinese and Caucasians, especially after normalization
for body weight differences. Dosage modifications for race are, therefore, not
recommended.
Combined Effects — The combined effects of age, smoking, and gender could
lead to substantial pharmacokinetic differences in populations. The clearance
in young smoking males, for example, may be 3 times higher than that in elderly
nonsmoking females. Dosing modification may be necessary in patients who
exhibit a combination of factors that may result in slower metabolism of
olanzapine [see Dosage and Administration (2)].
Adolescents (ages 13 to 17 years) — In clinical studies, most adolescents were
nonsmokers and this population had a lower average body weight, which resulted
in higher average olanzapine exposure compared to adults.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis — Oral carcinogenicity studies were conducted in mice and
rats. Olanzapine was administered to mice in two 78-week studies at doses of 3,
10, 30/20 mg/kg/day (equivalent to 0.8-5 times the maximum
recommended human daily oral dose on a mg/m2 basis)
and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the maximum
recommended human daily oral dose on a mg/m2 basis).
Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males)
and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4
times the maximum recommended human daily oral dose on a mg/m2 basis,
respectively). The incidence of liver hemangiomas and hemangiosarcomas was
significantly increased in 1 mouse study in female mice dosed at
8 mg/kg/day (2 times the maximum recommended human daily oral dose 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 (2-5 times the maximum
recommended human daily oral dose 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 maximum
recommended human daily oral dose 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 (5.15)].
Mutagenesis — 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.
Impairment of Fertility — 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 maximum recommended human
daily oral dose 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 maximum recommended human daily oral dose on a
mg/m2basis). Diestrous was prolonged and estrous delayed at
1.1 mg/kg/day (0.6 times the maximum recommended human daily oral dose on
a mg/m2 basis); therefore olanzapine may produce a delay in
ovulation.
Animal Toxicology and/or Pharmacology
In animal
studies with olanzapine, the principal hematologic findings were reversible
peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the
maximum recommended human daily oral dose on a mg/m2 basis),
dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia
in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia
and/or reversible hemolytic anemia between 1 and 10 months of treatment.
Dose-related decreases in lymphocytes and neutrophils were seen in mice given
doses of 10 mg/kg (equal to 2 times the maximum recommended human daily
oral dose on a mg/m2 basis) in studies of 3 months' duration.
Nonspecific lymphopenia, consistent with decreased body weight gain, occurred
in rats receiving 22.5 mg/kg (11 times the maximum recommended human daily
oral dose on a mg/m2 basis) for 3 months or 16 mg/kg (8 times
the maximum recommended human daily oral dose on a mg/m2 basis)
for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any of
the species examined. Bone marrows were normocellular or hypercellular,
indicating that the reductions in circulating blood cells were probably due to
peripheral (non-marrow) factors.
Clinical Studies
When
using Zyprexa and fluoxetine in combination, also refer to the Clinical Studies
section of the package insert for Symbyax.
Schizophrenia
Adults
The
efficacy of oral olanzapine in the treatment of schizophrenia was established
in 2 short-term (6-week) controlled trials of adult inpatients who met
DSM III-R criteria for schizophrenia. A single haloperidol arm was
included as a comparative treatment in 1 of the 2 trials, but this trial did
not compare these 2 drugs on the full range of clinically relevant doses for
both.
Several
instruments were used for assessing psychiatric signs and symptoms in these
studies, among them the Brief Psychiatric Rating Scale (BPRS), a
multi-item inventory of general psychopathology traditionally used to evaluate
the effects of drug treatment in schizophrenia. The BPRS psychosis cluster
(conceptual disorganization, hallucinatory behavior, suspiciousness, and
unusual thought content) is considered a particularly useful subset for
assessing actively psychotic schizophrenic patients. A second traditional
assessment, the Clinical Global Impression (CGI), reflects the impression
of a skilled observer, fully familiar with the manifestations of schizophrenia,
about the overall clinical state of the patient. In addition, 2 more recently
developed scales were employed; these included the 30-item Positive and
Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the
BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial
summaries below focus on the following outcomes: PANSS total and/or BPRS total;
BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The
results of the trials follow:
(1) In a
6-week, placebo-controlled trial (n=149) involving 2 fixed olanzapine doses of
1 and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but
not at 1 mg/day), was superior to placebo on the PANSS total score (also
on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS
Negative subscale, and on CGI Severity.
(2) In a
6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of
olanzapine (5 ± 2.5 mg/day, 10 ± 2.5 mg/day, and
15 ± 2.5 mg/day) on a once daily schedule, the 2 highest
olanzapine dose groups (actual mean doses of 12 and 16 mg/day,
respectively) were superior to placebo on BPRS total score, BPRS psychosis
cluster, and CGI severity score; the highest olanzapine dose group was superior
to placebo on the SANS. There was no clear advantage for the high-dose group
over the medium-dose group.
(3) In a
longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV
criteria for schizophrenia and who remained stable on olanzapine during
open-label treatment for at least 8 weeks were randomized to continuation on
their current olanzapine doses (ranging from 10 to 20 mg/day) or to
placebo. The follow-up period to observe patients for relapse, defined in terms
of increases in BPRS positive symptoms or hospitalization, was planned for 12
months, however, criteria were met for stopping the trial early due to an
excess of placebo relapses compared to olanzapine relapses, and olanzapine was
superior to placebo on time to relapse, the primary outcome for this study.
Thus, olanzapine was more effective than placebo at maintaining efficacy in
patients stabilized for approximately 8 weeks and followed for an observation
period of up to 8 months.
Examination
of population subsets (race and gender) did not reveal any differential
responsiveness on the basis of these subgroupings.
Adolescents
The
efficacy of oral olanzapine in the acute treatment of schizophrenia in
adolescents (ages 13 to 17 years) was established in a 6-week double-blind,
placebo-controlled, randomized trial of inpatients and outpatients with
schizophrenia (n=107) who met diagnostic criteria according to DSM-IV-TR
and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia
for School Aged Children-Present and Lifetime Version (K-SADS-PL).
The
primary rating instrument used for assessing psychiatric signs and symptoms in
this trial was the Anchored Version of the Brief Psychiatric Rating Scale for
Children (BPRS-C) total score.
In this
flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose
12.5 mg/day, mean dose of 11.1 mg/day) was more effective than
placebo in the treatment of adolescents diagnosed with schizophrenia, as
supported by the statistically significantly greater mean reduction in BPRS-C
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 Zyprexa 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.
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 Zyprexa 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.
Agitation Associated with Schizophrenia and Bipolar I
Mania
The
efficacy of intramuscular olanzapine for injection for the treatment of
agitation was established in 3 short-term (24 hours of IM treatment)
placebo-controlled trials in agitated adult inpatients from 2 diagnostic
groups: schizophrenia and bipolar I disorder (manic or mixed episodes).
Each of the trials included a single active comparator treatment arm of either
haloperidol injection (schizophrenia studies) or lorazepam injection
(bipolar I mania study). Patients enrolled in the trials needed to be:
(1) judged by the clinical investigators as clinically agitated and
clinically appropriate candidates for treatment with intramuscular medication,
and (2) exhibiting a level of agitation that met or exceeded a threshold
score of ≥14 on the 5 items comprising the Positive and Negative Syndrome
Scale (PANSS) Excited Component (i.e., poor impulse control, tension,
hostility, uncooperativeness and excitement items) with at least 1 individual
item score ≥4 using a 1-7 scoring system (1=absent, 4=moderate, 7=extreme). In
the studies, the mean baseline PANSS Excited Component score was 18.4, with
scores ranging from 13 to 32 (out of a maximum score of 35), thus suggesting
predominantly moderate levels of agitation with some patients experiencing mild
or severe levels of agitation. The primary efficacy measure used for assessing
agitation signs and symptoms in these trials was the change from baseline in
the PANSS Excited Component at 2 hours post-injection. Patients could receive
up to 3 injections during the 24 hour IM treatment periods; however, patients
could not receive the second injection until after the initial 2 hour period
when the primary efficacy measure was assessed. The results of the trials
follow:
(1) In a
placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for
schizophrenia (n=270), 4 fixed intramuscular olanzapine for injection doses of
2.5 mg, 5 mg, 7.5 mg and 10 mg were evaluated. All doses
were statistically superior to placebo on the PANSS Excited Component at 2
hours post-injection. However, the effect was larger and more consistent for
the 3 highest doses. There were no significant pairwise differences for the 7.5
and 10 mg doses over the 5 mg dose.
(2) In a
second placebo-controlled trial in agitated inpatients meeting DSM-IV criteria
for schizophrenia (n=311), 1 fixed intramuscular olanzapine for injection dose
of 10 mg was evaluated. Olanzapine for injection was statistically
superior to placebo on the PANSS Excited Component at 2 hours post-injection.
(3) In a
placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for
bipolar I disorder (and currently displaying an acute manic or mixed
episode with or without psychotic features) (n=201), 1 fixed intramuscular
olanzapine for injection dose of 10 mg was evaluated. Olanzapine for
injection was statistically superior to placebo on the PANSS Excited Component
at 2 hours post-injection.
Examination
of population subsets (age, race, and gender) did not reveal any differential
responsiveness on the basis of these subgroupings.
How Supplied/Storage and Handling
How Supplied
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. The tablets are available as follows:
|
|
TABLET STRENGTH
|
|
|
2.5 mg
|
5 mg
|
7.5 mg
|
10 mg
|
15 mg
|
20 mg
|
|
Tablet No.
|
4112
|
4115
|
4116
|
4117
|
4415
|
4420
|
|
Identification
|
LILLY
|
LILLY
|
LILLY
|
LILLY
|
LILLY
|
LILLY
|
|
|
4112
|
4115
|
4116
|
4117
|
4415
|
4420
|
|
NDC Codes:
|
|
|
|
|
|
|
|
Bottles 30
|
NDC 0002-4112-30
|
NDC 0002-4115-30
|
NDC 0002-4116-30
|
NDC 0002-4117-30
|
NDC 0002-4415-30
|
NDC 0002-4420-30
|
Zyprexa
ZYDIS (olanzapine orally disintegrating tablets) are yellow, round, and
debossed with the tablet strength. The tablets are available as follows:
|
Zyprexa is a registered trademark of Eli
Lilly and Company.
|
|
ZYDIS is a registered trademark of
Catalent Pharma Solutions.
|
|
|
|
|
TABLET STRENGTH
|
|
Zyprexa ZYDIS
Tablets
|
5 mg
|
10 mg
|
15 mg
|
20 mg
|
|
Tablet No.
|
4453
|
4454
|
4455
|
4456
|
|
Debossed
|
5
|
10
|
15
|
20
|
|
NDC Codes:
|
|
|
|
|
|
Dose Pack 30
(Child Resistant)
|
NDC 0002-4453-85
|
NDC 0002-4454-85
|
NDC 0002-4455-85
|
NDC 0002-4456-85
|
Zyprexa IntraMuscular
is available in:
NDC
0002-7597-01 (No. VL7597) – 10 mg vial (1s)
Storage and Handling
Store Zyprexa tablets, Zyprexa ZYDIS, and Zyprexa IntraMuscular
vials (before reconstitution) at controlled room temperature, 20° to 25°C (68°
to 77°F) [see USP]. Reconstituted
Zyprexa IntraMuscular may be stored at controlled room temperature, 20° to 25°C
(68° to 77°F) [see USP] for up to 1
hour if necessary. Discard any unused portion of reconstituted
Zyprexa IntraMuscular. 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.
Protect Zyprexa tablets and Zyprexa ZYDIS from light and
moisture. Protect Zyprexa IntraMuscular from light, do not freeze.
Patient Counseling Information
See FDA-approved 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 Zyprexa 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 Zyprexa, call your doctor. When using Zyprexa
and fluoxetine in combination, also refer to the Patient Counseling Information
section of the package insert for Symbyax.
Information on Medication Guide
Prescribers
or other health professionals should inform patients, their families, and their
caregivers about the potential benefits and potential risks associated with
treatment with Zyprexa, and should counsel them in its appropriate use. A
patient Medication Guide is available for Zyprexa. Prescribers or other health
professionals should instruct patients, their families, and their caregivers to
read the Medication Guide and should assist them in understanding its contents.
Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. When
using Zyprexa and fluoxetine in combination, also refer to the Medication Guide
for Symbyax.
Elderly Patients with Dementia-Related Psychosis:
Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke
Patients
and caregivers should be advised that elderly patients with dementia-related
psychosis treated with antipsychotic drugs are at an increased risk of death.
Patients and caregivers should be advised that elderly patients with
dementia-related psychosis treated with Zyprexa had a significantly higher
incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic
attack) compared with placebo.
Zyprexa
is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].
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 Zyprexa. 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 Zyprexa [see
Warnings and Precautions (5.5)].
Dyslipidemia
Patients
should be counseled that dyslipidemia has occurred during treatment with
Zyprexa. 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
Zyprexa. 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 Zyprexa, 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 heartbeat, or fainting.
Potential for Cognitive and Motor Impairment
Because
Zyprexa 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 Zyprexa 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 physicians if they are taking, or plan to
take, Symbyax. Patients should also be advised to inform their physicians 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 Zyprexa [see
Drug Interactions (7)].
Phenylketonurics
Zyprexa
ZYDIS (olanzapine orally disintegrating tablets) contains phenylalanine (0.34,
0.45, 0.67, or 0.90 mg per 5, 10, 15, or 20 mg tablet,
respectively) [see Description (11)].
Use in Specific Populations
Pregnancy — Patients should be advised to notify their physician if
they become pregnant or intend to become pregnant during therapy with Zyprexa [see
Use in Specific Populations (8.1)].
Nursing Mothers — Patients should be advised not to breast-feed an infant
if they are taking Zyprexa [see Use in Specific Populations (8.3)].
Pediatric Use — Zyprexa is 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 Zyprexa 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 Zyprexa in patients under 13 years
of age have not been established. Safety and efficacy of Zyprexa 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 Zyprexa 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
Zyprexa
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 Zyprexa 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 physician's assessment of the chronicity and severity of the
patient's symptoms [see Indications and Usage (1.3)].
Literature
revised January 23, 2017
Marketed by: LillyUSA,
LLC,Indianapolis,IN46285,USA
Copyright
© 1997, 2017, Eli Lilly and Company. All rights reserved.
ZYP-0005-USPI-20170123
Medication Guide
Zyprexa® (zy-PREX-a)
(olanzapine)
Tablet
Zyprexa® ZYDIS® (zy-PREX-a ZY-dis)
(olanzapine)
Tablet, Orally Disintegrating
Read the
Medication Guide that comes with Zyprexa 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 Zyprexa.
What is the most important information I should know about
Zyprexa?
Zyprexa may cause serious side effects, including:
1. Increased risk of death in
elderly people who are confused, have memory loss and have lost touch with
reality (dementia-related psychosis).
2. High blood sugar
(hyperglycemia).
3. High fat levels in your blood
(increased cholesterol and triglycerides), especially in teenagers age 13 to 17
or when used in combination with fluoxetine in children age 10 to 17.
4. Weight gain, especially in
teenagers age 13 to 17 or when used in combination with fluoxetine in children
age 10 to 17.
These serious side effects are
described below.
1. Increased
risk of death in elderly people who are confused, have memory loss and have
lost touch with reality (dementia-related psychosis). Zyprexa is not approved for
treating psychosis in elderly people with dementia.
2. 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:
o a build up of acid in your
blood due to ketones (ketoacidosis)
o coma
o death
Your doctor should do tests to check your blood sugar before you start taking
Zyprexa and during treatment. In people who do not have diabetes, sometimes
high blood sugar goes away when Zyprexa is stopped. People with diabetes and
some people who did not have diabetes before taking Zyprexa need to take
medicine for high blood sugar even after they stop taking Zyprexa.
If you have diabetes, follow your doctor's instructions about how often to
check your blood sugar while taking Zyprexa.
Call your doctor if you have any of these
symptoms of high blood sugar (hyperglycemia) while taking Zyprexa:
o feel very thirsty
o need to urinate more than
usual
o feel very hungry
o feel weak or tired
o feel sick to your stomach
o feel confused or your
breath smells fruity
3. High
fat levels in your blood (cholesterol and triglycerides). High fat levels may
happen in people treated with Zyprexa, especially in teenagers (13 to 17 years
old), or when used in combination with fluoxetine in children (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 Zyprexa and
during treatment.
4. Weight
gain. Weight
gain is very common in people who take Zyprexa. Teenagers (13 to 17 years old)
are more likely to gain weight and to gain more weight than adults. Children
(10 to 17 years old) are also more likely to gain weight and to gain more
weight than adults when Zyprexa is used in combination with fluoxetine. Some
people may gain a lot of weight while taking Zyprexa, 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 is Zyprexa?
Zyprexa is a prescription medicine
used to treat:
· schizophrenia in people
age 13 or older.
· bipolar disorder,
including:
o
manic or mixed episodes that happen with
bipolar I disorder in people age 13 or older.
o
manic or mixed episodes that happen with
bipolar I disorder, when used with the medicine lithium or valproate, in
adults.
o
long-term treatment of bipolar I disorder in
adults.
· episodes of depression
that happen with bipolar I disorder, when used with the medicine
fluoxetine (Prozac®) in people age 10 or older.
· episodes of depression
that do not get better after 2 other medicines, also called treatment resistant
depression, when used with the medicine fluoxetine (Prozac), in adults.
Zyprexa has not been approved for use in children
under 13 years of age. Zyprexa in combination with fluoxetine has not been
approved for use in children under 10 years of age.
The symptoms of schizophrenia include hearing
voices, seeing things that are not there, having beliefs that are not true, and
being suspicious or withdrawn.
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.
The symptoms of treatment resistant depression
include decreased mood, decreased interest, increased guilty feelings,
decreased energy, decreased concentration, changes in appetite, and suicidal
thoughts or behavior.
Some of your symptoms may improve with treatment.
If you do not think you are getting better, call your doctor.
What should I tell my doctor before
taking Zyprexa?
Zyprexa may not be right for you. Before starting
Zyprexa, tell your doctor if you have or had:
· heart problems
· seizures
· 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)
· Alzheimer's disease
· narrow-angle glaucoma
· enlarged prostate in men
· bowel obstruction
· phenylketonuria, because
Zyprexa ZYDIS contains phenylalanine
· breast cancer
· thoughts of suicide or
hurting yourself
· any other medical
condition
· are pregnant or plan to
become pregnant. It is not known if Zyprexa will harm your unborn baby.
· are breast-feeding or plan
to breast-feed. Zyprexa can pass into your breast milk and may harm your baby.
You should not breast-feed while taking Zyprexa. Talk to your doctor about the
best way to feed your baby if you take Zyprexa.
Tell your doctor if you exercise a lot or are in
hot places often.
The symptoms of bipolar I disorder, treatment
resistant depression, or schizophrenia may include thoughts
of suicide or
of hurting yourself or others. If you have these thoughts at any time, tell
your doctor or go to an emergency room right away.
Tell your doctor about all the
medicines that you take, including prescription and nonprescription
medicines, vitamins, and herbal supplements. Zyprexa 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 Zyprexa with your
other medicines. Do not start or stop any medicine while taking Zyprexa without
talking to your doctor first.
How should I take Zyprexa?
· Take Zyprexa exactly as
prescribed. Your doctor may need to change (adjust) the dose of Zyprexa until
it is right for you.
· If you miss a dose of
Zyprexa, take the missed dose as soon as you remember. If it is almost time for
the next dose, just skip the missed dose and take your next dose at the regular
time. Do not take two doses of Zyprexa at the same time.
· To prevent
serious side effects, do not stop taking Zyprexa suddenly. If you need to stop
taking Zyprexa, your doctor can tell you how to safely stop taking it.
· If
you take too much Zyprexa, call your doctor or poison control center at
1-800-222-1222 right away, or get emergency treatment.
· Zyprexa can be taken with
or without food.
· Zyprexa is usually taken
one time each day.
· Take Zyprexa ZYDIS as
follows:
o
Be sure that your hands are dry.
o
Open the sachet and peel back the foil on the
blister. Do not push the tablet through the foil.
o
As soon as you open the blister, remove the tablet
and put it into your mouth.
o
The tablet will disintegrate quickly in your saliva
so that you can easily swallow it with or without drinking liquid.
· Call your doctor if you do
not think you are getting better or have any concerns about your condition
while taking Zyprexa.
What should I avoid while taking
Zyprexa?
· Zyprexa 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 Zyprexa affects you.
· Avoid drinking alcohol
while taking Zyprexa. Drinking alcohol while you take Zyprexa may make you
sleepier than if you take Zyprexa alone.
What are the possible side effects of
Zyprexa?
Serious side effects may happen when
you take Zyprexa, including:
· See
“What is the most important information I should know about Zyprexa?”, which
describes the increased risk of death in elderly people with dementia-related
psychosis and the risks of high blood sugar, high cholesterol and triglyceride
levels, and weight gain.
· Increased
incidence of stroke or “mini-strokes” called transient ischemic attacks (TIAs)
in elderly people with dementia-related psychosis (elderly people who have lost
touch with reality due to confusion and memory loss). Zyprexa is not approved
for these patients.
· Neuroleptic
Malignant Syndrome (NMS): NMS is a rare but very serious condition that
can happen in people who take antipsychotic medicines, including Zyprexa. NMS
can cause death and must be treated in a hospital. Call your doctor right away
if you become severely ill and have any of these symptoms:
o
high fever
o
excessive sweating
o
rigid muscles
o
confusion
o
changes in your breathing, heartbeat, and blood
pressure.
· Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur with
Zyprexa. 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 can not
control. These movements usually affect the face and tongue. Tardive dyskinesia
may not go away, even if you stop taking Zyprexa. It may also start after you
stop taking Zyprexa. Tell your doctor if you get any body movements that you
can not control.
· Decreased
blood pressure when you change positions, with symptoms of dizziness, fast or
slow heartbeat, or fainting.
· Difficulty
swallowing, that can cause food or liquid to get into your lungs.
· Seizures:
Tell your doctor if you have a seizure during treatment with Zyprexa.
· 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 any of these symptoms of dehydration:
o
sweating too much or not at all
o
dry mouth
o
feeling very hot
o
feeling thirsty
o
not able to produce urine.
Common side effects of Zyprexa
include: lack
of energy, dry mouth, increased appetite, sleepiness, tremor (shakes), having
hard or infrequent stools, dizziness, changes in behavior, or restlessness.
Other common side effects in
teenagers (13-17 years old) include: headache, stomach-area
(abdominal) pain, pain in your arms or legs, or tiredness. Teenagers
experienced greater increases in prolactin, liver enzymes, and sleepiness, as
compared with adults.
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
Zyprexa. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Zyprexa?
· Store Zyprexa at room
temperature, between 68°F to 77°F (20°C to 25°C).
· Keep Zyprexa away from
light.
· Keep Zyprexa dry and away
from moisture.
Keep Zyprexa and all medicines out of
the reach of children.
General information about Zyprexa
Medicines are sometimes prescribed for purposes
other than those listed in a Medication Guide. Do not use Zyprexa for a
condition for which it was not prescribed. Do not give Zyprexa to other people,
even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important
information about Zyprexa. If you would like more information, talk with your
doctor. You can ask your doctor or pharmacist for information about Zyprexa
that was written for healthcare professionals. For more information about
Zyprexa call 1-800-Lilly-Rx (1-800-545-5979).
What are the ingredients in Zyprexa?
Active ingredient: olanzapine
Inactive ingredients:
Tablets — carnauba wax, crospovidone,
hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate,
microcrystalline cellulose, and other inactive ingredients. The color coating
contains: Titanium Dioxide, FD&C Blue No. 2 Aluminum Lake, or Synthetic Red
Iron Oxide.
ZYDIS — gelatin, mannitol, aspartame,
sodium methyl paraben, and sodium propyl paraben.
This Medication Guide has been
approved by theU.S.Food and Drug Administration.
Medication Guide revised October 6, 2016
Marketed by: LillyUSA, LLC
Indianapolis,IN46285,USA
Copyright © 2009, 2016, Eli Lilly and Company. All
rights reserved.
ZYP-0001-MG-20161006
PACKAGE LABEL - Zyprexa 2.5 mg
tablet, bottle of 30
NDC 0002-4112-30
30 Tablets
No. 4112
Zyprexa
Olanzapine Tablets
2.5 mg
Rx only
Medication Guide is to be dispensed to patients.
Lilly
PACKAGE LABEL - Zyprexa 5 mg tablet,
bottle of 30
NDC 0002-4115-30
30 Tablets
No. 4115
Zyprexa
Olanzapine Tablets
5 mg
Rx only
Medication Guide is to be dispensed to patients.
Lilly
PACKAGE LABEL - Zyprexa 7.5 mg
tablet, bottle of 30
NDC 0002-4116-30
30 Tablets
No. 4116
Zyprexa
Olanzapine Tablets
7.5 mg
Rx only
Medication Guide is to be dispensed to patients.
Lilly
PACKAGE LABEL - Zyprexa 10 mg tablet,
bottle of 30
NDC 0002-4117-30
30 Tablets
No. 4117
Zyprexa
Olanzapine Tablets
10 mg
Rx only
Medication Guide is to be dispensed to patients.
Lilly
PACKAGE LABEL - Zyprexa 15 mg tablet,
bottle of 30
NDC 0002-4415-30
30 Tablets
No. 4415
Zyprexa
Olanzapine Tablets
15 mg
Rx only
Medication Guide is to be dispensed to patients.
Lilly
PACKAGE LABEL - Zyprexa 20 mg tablet,
bottle of 30
NDC 0002-4420-30
30 Tablets
No. 4420
Zyprexa
Olanzapine Tablets
20 mg
Rx only
Medication Guide is to be dispensed to patients.
Lilly
PACKAGE LABEL - Zyprexa ZYDIS 5 mg
tablet, 30 sachets
5 mg orally disintegrating tablets
30 Sachets, No. 4453
NDC 0002-4453-85
Rx only
Medication Guide is to be dispensed to patients.
Zyprexa® ZYDIS®
Olanzapine Orally Disintegrating Tablets
5 mg
Phenylketonurics: Contains phenylalanine 0.34 mg
per tablet.
DO NOT OPEN POUCH UNTIL IMMEDIATELY PRIOR TO USE.
Lilly
PACKAGE LABEL - Zyprexa ZYDIS 10 mg
tablet, 30 sachets
10 mg orally disintegrating tablets
30 Sachets, No. 4454
NDC 0002-4454-85
Rx only
Medication Guide is to be dispensed to patients.
Zyprexa® ZYDIS®
Olanzapine Orally Disintegrating Tablets
10 mg
Phenylketonurics: Contains phenylalanine 0.45 mg
per tablet.
DO NOT OPEN POUCH UNTIL IMMEDIATELY PRIOR TO USE.
Lilly
PACKAGE LABEL - Zyprexa ZYDIS 15 mg
tablet, 30 sachets
15 mg orally disintegrating tablets
30 Sachets, No. 4455
NDC 0002-4455-85
Rx only
Medication Guide is to be dispensed to patients.
Zyprexa® ZYDIS®
Olanzapine Orally Disintegrating Tablets
15 mg
Phenylketonurics: Contains phenylalanine 0.67 mg
per tablet.
DO NOT OPEN POUCH UNTIL IMMEDIATELY PRIOR TO USE.
Lilly
PACKAGE LABEL - Zyprexa ZYDIS 20 mg
tablet, 30 sachets
20 mg orally disintegrating tablets
30 Sachets, No. 4456
NDC 0002-4456-85
Rx only
Medication Guide is to be dispensed to patients.
Zyprexa® ZYDIS®
Olanzapine Orally Disintegrating Tablets
20 mg
Phenylketonurics: Contains phenylalanine 0.90 mg
per tablet.
DO NOT OPEN POUCH UNTIL IMMEDIATELY PRIOR TO USE.
Lilly
PACKAGE LABEL - Zyprexa INTRAMUSCULAR
10 mg/vial
NDC 0002-7597-01
1 Vial
No. VL7597
Zyprexa® IntraMuscular
Olanzapine for Injection
Sterile Single Use Vial
Rx only
For intramuscular use only.
10 mg/vial
Lilly
|
Zyprexa olanzapine
tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4112
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
2.5 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Carnauba wax
|
|
|
Crospovidone
|
|
|
HYDROXYPROPYL CELLULOSE (TYPE H)
|
|
|
HYPROMELLOSES
|
|
|
Lactose
|
|
|
Magnesium stearate
|
|
|
Cellulose, Microcrystalline
|
|
|
Titanium dioxide
|
|
|
POLYETHYLENE GLYCOLS
|
|
|
POLYSORBATE 80
|
|
|
|
Product Characteristics
|
|
Color
|
white
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
7mm
|
|
Flavor
|
|
Imprint Code
|
LILLY;4112
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4112-30
|
30 TABLET in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA020592
|
06/23/1997
|
|
|
|
Zyprexa olanzapine
tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4115
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
5 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Carnauba wax
|
|
|
Crospovidone
|
|
|
HYDROXYPROPYL CELLULOSE (TYPE H)
|
|
|
HYPROMELLOSES
|
|
|
Lactose
|
|
|
Magnesium stearate
|
|
|
Cellulose, Microcrystalline
|
|
|
Titanium dioxide
|
|
|
POLYETHYLENE GLYCOLS
|
|
|
POLYSORBATE 80
|
|
|
|
Product Characteristics
|
|
Color
|
white
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
8mm
|
|
Flavor
|
|
Imprint Code
|
LILLY;4115
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4115-30
|
30 TABLET in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA020592
|
10/01/1996
|
|
|
|
Zyprexa olanzapine
tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4116
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
7.5 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Carnauba wax
|
|
|
Crospovidone
|
|
|
HYDROXYPROPYL CELLULOSE (TYPE H)
|
|
|
HYPROMELLOSES
|
|
|
Lactose
|
|
|
Magnesium stearate
|
|
|
Cellulose, Microcrystalline
|
|
|
Titanium dioxide
|
|
|
POLYETHYLENE GLYCOLS
|
|
|
POLYSORBATE 80
|
|
|
|
Product Characteristics
|
|
Color
|
white
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
9mm
|
|
Flavor
|
|
Imprint Code
|
LILLY;4116
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4116-30
|
30 TABLET in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA020592
|
10/01/1996
|
|
|
|
Zyprexa olanzapine
tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4117
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
10 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Carnauba wax
|
|
|
Crospovidone
|
|
|
HYDROXYPROPYL CELLULOSE (TYPE H)
|
|
|
HYPROMELLOSES
|
|
|
Lactose
|
|
|
Magnesium stearate
|
|
|
Cellulose, Microcrystalline
|
|
|
Titanium dioxide
|
|
|
POLYETHYLENE GLYCOLS
|
|
|
POLYSORBATE 80
|
|
|
|
Product Characteristics
|
|
Color
|
white
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
10mm
|
|
Flavor
|
|
Imprint Code
|
LILLY;4117
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4117-30
|
30 TABLET in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA020592
|
10/01/1996
|
|
|
|
Zyprexa olanzapine
tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4415
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
15 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Carnauba wax
|
|
|
Crospovidone
|
|
|
HYDROXYPROPYL CELLULOSE (TYPE H)
|
|
|
HYPROMELLOSES
|
|
|
Lactose
|
|
|
Magnesium stearate
|
|
|
Cellulose, Microcrystalline
|
|
|
Titanium dioxide
|
|
|
Triacetin
|
|
|
|
Product Characteristics
|
|
Color
|
blue
|
Score
|
no score
|
|
Shape
|
OVAL (elliptical)
|
Size
|
12mm
|
|
Flavor
|
|
Imprint Code
|
LILLY;4415
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4415-30
|
30 TABLET in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA020592
|
01/10/2000
|
|
|
|
Zyprexa olanzapine
tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4420
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
20 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Carnauba wax
|
|
|
Crospovidone
|
|
|
HYDROXYPROPYL CELLULOSE (TYPE H)
|
|
|
HYPROMELLOSES
|
|
|
Lactose
|
|
|
Magnesium stearate
|
|
|
Cellulose, Microcrystalline
|
|
|
Titanium dioxide
|
|
|
Ferric Oxide Red
|
|
|
Polyethylene glycol 4000
|
|
|
|
Product Characteristics
|
|
Color
|
pink
|
Score
|
no score
|
|
Shape
|
OVAL (elliptical)
|
Size
|
13mm
|
|
Flavor
|
|
Imprint Code
|
LILLY;4420
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4420-30
|
30 TABLET in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA020592
|
03/01/2001
|
|
|
|
Zyprexa ZYDISolanzapine
tablet, orally disintegrating
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4453
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
5 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Gelatin
|
|
|
Mannitol
|
|
|
Methylparaben Sodium
|
|
|
Propylparaben Sodium
|
|
|
Aspartame
|
|
|
|
Product Characteristics
|
|
Color
|
yellow
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
9mm
|
|
Flavor
|
|
Imprint Code
|
5
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4453-85
|
30 DOSE PACK in 1 CARTON
|
|
|
1
|
NDC:0002-4453-01
|
1 BLISTER PACK in 1 DOSE PACK
|
|
|
1
|
|
1 TABLET, ORALLY DISINTEGRATING in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021086
|
06/01/2000
|
|
|
|
Zyprexa ZYDISolanzapine
tablet, orally disintegrating
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4454
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
10 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Gelatin
|
|
|
Mannitol
|
|
|
Methylparaben Sodium
|
|
|
Propylparaben Sodium
|
|
|
Aspartame
|
|
|
|
Product Characteristics
|
|
Color
|
yellow
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
9mm
|
|
Flavor
|
|
Imprint Code
|
10
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4454-85
|
30 DOSE PACK in 1 CARTON
|
|
|
1
|
NDC:0002-4454-01
|
1 BLISTER PACK in 1 DOSE PACK
|
|
|
1
|
|
1 TABLET, ORALLY DISINTEGRATING in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021086
|
06/01/2000
|
|
|
|
Zyprexa ZYDISolanzapine
tablet, orally disintegrating
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4455
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
15 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Gelatin
|
|
|
Mannitol
|
|
|
Methylparaben Sodium
|
|
|
Propylparaben Sodium
|
|
|
Aspartame
|
|
|
|
Product Characteristics
|
|
Color
|
yellow
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
9mm
|
|
Flavor
|
|
Imprint Code
|
15
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4455-85
|
30 DOSE PACK in 1 CARTON
|
|
|
1
|
NDC:0002-4455-01
|
1 BLISTER PACK in 1 DOSE PACK
|
|
|
1
|
|
1 TABLET, ORALLY DISINTEGRATING in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021086
|
09/01/2001
|
|
|
|
Zyprexa ZYDISolanzapine
tablet, orally disintegrating
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-4456
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
20 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Gelatin
|
|
|
Mannitol
|
|
|
Methylparaben Sodium
|
|
|
Propylparaben Sodium
|
|
|
Aspartame
|
|
|
|
Product Characteristics
|
|
Color
|
yellow
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
9mm
|
|
Flavor
|
|
Imprint Code
|
20
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-4456-85
|
30 DOSE PACK in 1 CARTON
|
|
|
1
|
NDC:0002-4456-01
|
1 BLISTER PACK in 1 DOSE PACK
|
|
|
1
|
|
1 TABLET, ORALLY DISINTEGRATING in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021086
|
09/01/2001
|
|
|
|
Zyprexa INTRAMUSCULARolanzapine
injection, powder, for solution
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0002-7597
|
|
Route of Administration
|
INTRAMUSCULAR
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Olanzapine (Olanzapine)
|
Olanzapine
|
10 mg in 2 mL
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
Lactose monohydrate
|
50 mg in 2 mL
|
|
Tartaric acid
|
3.5 mg in 2 mL
|
|
Hydrochloric acid
|
|
|
Sodium hydroxide
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0002-7597-01
|
1 VIAL in 1 CARTON
|
|
|
1
|
|
2 mL in 1 VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021253
|
04/01/2004
|
|
|
|
Labeler - Eli Lilly
and Company (006421325)
|
Revised:
09/2017
Eli Lilly and Company
