A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Zyprexa Side Effects, and Drug Interactions - Olanzapine
Zyprexa Side Effects, and Drug Interactions - Olanzapine
SIDE EFFECTS
The information below is derived from a clinical trial database
for olanzapine consisting of 8661 patients with approximately 4165 patient-years
of exposure. This database includes: (1) 2500 patients who participated in multiple-dose
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 premarketing bipolar mania trials representing approximately
66 patient-years of exposure; (3) 191 patients who participated in a trial of
patients having various psychiatric symptoms in association with Alzheimer’s
disease representing approximately 29 patient-years of exposure; and (4) 5788
patients from 88 additional clinical trials as of December 31, 2001. In addition,
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 mania trials with approximately 22 patient-years of exposure, is
included below.
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 events, 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 events, 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 mania.
However, this information is also generally applicable to bipolar mania.
Adverse events 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 events without first grouping
similar types of events into a smaller number of standardized event categories.
In the tables and tabulations that follow, standard COSTART dictionary terminology
has been used initially to classify reported adverse events.
The stated frequencies of adverse events represent the proportion
of individuals who experienced, at least once, a treatment-emergent adverse
event of the type listed. An event was considered treatment emergent if it occurred
for the first time or worsened while receiving therapy following baseline evaluation.
The reported events do not include those event terms which were so general as
to be uninformative. Events listed elsewhere in labeling may not be repeated
below. It is important to emphasize that, although the events 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 event incidence
in the population studied.
Incidence of Adverse Events in Short-Term, Placebo-Controlled
and Combination Trials
The following findings are based on premarketing trials for
schizophrenia, bipolar mania, a subsequent trial of patients having various
psychiatric symptoms in association with Alzheimer’s disease, and premarketing
combination trials.
Adverse Events 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 events (5% for olanzapine
vs 6% for placebo). However, discontinuations due to increases in SGPT were
considered to be drug related (2% for olanzapine vs 0% for placebo) (see
PRECAUTIONS).
Bipolar Mania Monotherapy — Overall, there was
no difference in the incidence of discontinuation due to adverse events (2%
for olanzapine vs 2%for placebo).
Adverse Events Associated with Discontinuation of Treatment
in Short-Term Combination Trials
Bipolar Mania Combination Therapy — In a study
of patients who were already tolerating either lithium or valproate as monotherapy,
discontinuation rates due to adverse events were 11% for the combination of
olanzapine with lithium or valproate compared to 2% for patients who remained
on lithium or valproate monotherapy. Discontinuations with the combination of
olanzapine and lithium or valproate that occurred in more than 1patient were:
somnolence (3%), weight gain (1%), and peripheral edema (1%).
Commonly Observed Adverse Events in Short-Term, Placebo-Controlled
Trials
The most commonly observed adverse events associated with the
use of olanzapine (incidence of 5% or greater) and not observed at an equivalent
incidence among placebo-treated patients (olanzapine incidence at least twicethat
for placebo) were:
|
Common Treatment-Emergent Adverse Events Associated with
the Use of Olanzapine in 6-Week Trials — SCHIZOPHRENIA
|
| |
Percentage of Patients Reporting Event
|
|
Adverse Event
|
Olanzapine
|
Placebo
|
| |
(N=248)
|
(N=118)
|
|
Postural hypotension
|
5
|
2
|
|
Constipation
|
9
|
3
|
|
Weight gain
|
6
|
1
|
|
Dizziness
|
11
|
4
|
|
Personality disorder1
|
8
|
4
|
|
Akathisia
|
5
|
1
|
|
1 Personality disorder is the COSTART term
for designating non-aggressive objectionable behavior.
|
|
Common Treatment-Emergent Adverse Events Associated with
the Use of Olanzapine in 3-Week and 4-Week Trials — BIPOLAR MANIA
|
| |
Percentage of Patients Reporting Event
|
|
Adverse Event
|
Olanzapine
|
Placebo
|
| |
(N=125)
|
(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
|
Adverse Events Occurring at an Incidence of 2% or More Among
Olanzapine-Treated Patients in Short-Term, Placebo-Controlled Trials
Table 1 enumerates the incidence, rounded to the nearest percent,
of treatment-emergent adverse events that occurred in 2% or more of patients
treated with olanzapine (doses ³2.5mg/day) and with
incidence greater than placebo who participated in the acute phase of placebo-controlled
trials.
|
Table 1 Treatment-Emergent Adverse Events: Incidence
in Short-Term, Placebo-Controlled Clinical Trials1
|
| |
Percentage of Patients Reporting Event
|
| |
Olanzapine
|
Placebo
|
|
Body System/Adverse Event
|
(N=532)
|
(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
|
|
1 Events reported by at least 2% of patients
treated with olanzapine, except the following events which had an incidence
equal to or less than placebo: abdominal pain, agitation, anorexia, anxiety,
apathy, confusion, depression, diarrhea, dysmenorrhea2, hallucinations,
headache, hostility, hyperkinesia, myalgia, nausea, nervousness, paranoid
reaction, personality disorder3, rash, thinking abnormal, weight
loss.
|
|
2 Denominator used was for females only (olanzapine,N=201;
placebo,N=114).
|
|
3 Personality disorder is the COSTART term
for designating non-aggressive objectionable behavior.
|
Commonly Observed Adverse Events in Short-Term Combination
Trials
In the bipolar mania combination placebo-controlled trials,
the most commonly observed adverse events associated with the combination of
olanzapine and lithium or valproate (incidence of ³5%
and at least twiceplacebo) were:
|
Common Treatment-Emergent Adverse Events Associated with
the Use of Olanzapine in 6-Week Combination Trials — BIPOLAR MANIA
|
| |
Percentage of Patients Reporting Event
|
|
Adverse Event
|
Olanzapine with
|
Placebo with
|
| |
lithium or valproate
|
lithium or valproate
|
| |
(N=229)
|
(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 Events Occurring at an Incidence of 2% or More Among
Olanzapine-Treated Patients in Short-Term Combination Trials
Table 2 enumerates the incidence, rounded to the nearest percent,
of treatment-emergent adverse events that occurred in 2% or more of patients
treated with the combination of olanzapine (doses ³5
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 2 Treatment-Emergent Adverse Events: Incidence in
Short-Term, Placebo-Controlled Combination Clinical Trials1
|
| |
Percentage of Patients Reporting Event
|
| |
Olanzapine with
|
Placebo with
|
| |
lithium or valproate
|
lithium or valproate
|
|
Body System/Adverse Event
|
(N=229)
|
(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
|
|
Dysmenorrhea2
|
2
|
0
|
|
Vaginitis2
|
2
|
0
|
|
1 Events reported by at least 2% of patients
treated with olanzapine, except the following events which had an incidence
equal to or less than placebo: abdominal pain, abnormal dreams, abnormal
ejaculation, agitation, akathisia, anorexia, anxiety, arthralgia, cough
increased, diarrhea, dyspepsia, emotional lability, fever, flatulence,
flu syndrome, headache, hostility, insomnia, libido decreased, libido
increased, menstrual disorder2, myalgia, nausea, nervousness,
pain, paranoid reaction, personality disorder, rash, rhinitis, sleep disorder,
thinking abnormal, vomiting.
|
|
2 Denominator used was for females only (olanzapine,N=128;
placebo,N=51).
|
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.
Additional Findings Observed in Clinical Trials
The following findings are based on clinical trials.
Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled
Trials
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 olanzapine at 3 fixed
doses with placebo in the treatment of schizophrenia.
|
TREATMENT-EMERGENT EXTRAPYRAMIDAL SYMPTOMS ASSESSED BY
RATING SCALES INCIDENCE IN A FIXED DOSAGE RANGE, PLACEBO-CONTROLLED CLINICAL
TRIAL — ACUTE PHASE*
|
| |
Percentage of Patients Reporting Event
|
| |
|
Olanzapine
|
Olanzapine
|
Olanzapine
|
| |
Placebo
|
5±2.5mg/day
|
10±2.5mg/day
|
15 ± 2.5mg/day
|
|
Parkinsonism1
|
15
|
14
|
12
|
14
|
|
Akathisia2
|
23
|
16
|
19
|
27
|
|
* No statistically significant differences.
|
|
1 Percentage of patients with a Simpson-Angus
Scale total score>3.
|
|
2 Percentage of patients with a Barnes Akathisia
Scale global score ³2.
|
The following table enumerates the percentage of patients with
treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported
adverse events during acute therapy in the same controlled clinical trial comparing
olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia.
|
TREATMENT-EMERGENT EXTRAPYRAMIDAL SYMPTOMS ASSESSED BY
ADVERSE EVENTS INCIDENCE IN A FIXED DOSAGE RANGE, PLACEBO-CONTROLLED CLINICAL
TRIAL — ACUTE PHASE
|
| |
Percentage of Patients Reporting Event
|
|
|
|
Olanzapine
|
Olanzapine
|
Olanzapine
|
| |
Placebo
|
5 ± 2.5 mg/day
|
10 ± 2.5 mg/day
|
15 ± 2.5 mg/day
|
| |
(N=68)
|
(N=65)
|
(N=64)
|
(N=69)
|
|
Dystonic events1
|
1
|
3
|
2
|
3
|
|
Parkinsonism events2
|
10
|
8
|
14
|
20
|
|
Akathisia events3
|
1
|
5
|
11*
|
10*
|
|
Dyskinetic events4
|
4
|
0
|
2
|
1
|
|
Residual events5
|
1
|
2
|
5
|
1
|
|
Any extrapyramidal event
|
16
|
15
|
25
|
32*
|
|
* Statistically significantly different from placebo.
|
|
1 Patients with the following COSTART terms
were counted in this category: dystonia, generalized spasm, neck rigidity,
oculogyric crisis, opisthotonos, torticollis.
|
|
2 Patients with the following COSTART terms
were counted in this category: akinesia, cogwheel rigidity, extrapyramidal
syndrome, hypertonia, hypokinesia, masked facies, tremor.
|
|
3 Patients with the following COSTART terms
were counted in this category: akathisia, hyperkinesia.
|
|
4 Patients with the following COSTART terms
were counted in this category: buccoglossal syndrome, choreoathetosis,
dyskinesia, tardive dyskinesia.
|
|
5 Patients with the following COSTART terms
were counted in this category: movement disorder, myoclonus, twitching.
|
Other Adverse Events — The following table addresses
dose relatedness for other adverse events using data from a schizophrenia trial
involving fixed dosage ranges. It enumerates the percentage of patients with
treatment-emergent adverse events for the three 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 events for which there
was a statistically significant trend.
| |
Percentage of Patients Reporting Event
|
| |
|
Olanzapine
|
Olanzapine
|
Olanzapine
|
|
Adverse Event
|
Placebo
|
5 ± 2.5 mg/day
|
10 ± 2.5 mg/day
|
15 ± 2.5 mg/day
|
| |
(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
|
Vital Sign Changes — Olanzapine is associated
with orthostatic hypotension and tachycardia (see PRECAUTIONS).
Weight Gain — In placebo-controlled, 6-week studies,
weight gain was reported in 5.6% of olanzapine patients compared to 0.8% of
placebo patients. Olanzapine patients gained an average of 2.8 kg, compared
to an average 0.4 kg weight loss in placebo patients; 29% of olanzapine patients
gained greater than 7% of their baseline weight, compared to 3% of placebo patients.
A categorization of patients at baseline on the basis of body mass index (BMI)
revealed a significantly greater effect in patients with low BMI compared to
normal or overweight patients; nevertheless, weight gain was greater in all
3 olanzapine groups compared to the placebo group. During long-term continuation
therapy with olanzapine (238 median days of exposure), 56% of olanzapine patients
met the criterion for having gained greater than 7% of their baseline weight.
Average weight gain during long-term therapy was 5.4kg.
Laboratory Changes — An assessment of the premarketing
experience for olanzapine revealed an association with asymptomatic increases
in SGPT, SGOT, and GGT (see PRECAUTIONS).
Olanzapine administration was also associated with increases in serum prolactin
(see PRECAUTIONS), with an asymptomatic
elevation of the eosinophil count in 0.3%of patients, and with an increase in
CPK.
Given the concern about neutropenia associated with other psychotropic
compounds and the finding of leukopenia associated with the administration of
olanzapine in several animal models (see ANIMAL TOXICOLOGY), careful
attention was given to examination of hematologic parameters in premarketing
studies with olanzapine. There was no indication of a risk of clinically significant
neutropenia associated with olanzapine treatment in the premarketing database
for this drug.
ECG Changes — Between-group comparisons for pooled
placebo-controlled trials revealed no statistically significant olanzapine/placebo
differences in the proportions of patients experiencing potentially important
changes in ECG parameters, including QT, QTc, and PR intervals. Olanzapine use
was associated with a mean increase in heart rate of 2.4 beats per minute compared
to no change among placebo patients. This slight tendency to tachycardia may
be related to olanzapine’s potential for inducing orthostatic changes (see
PRECAUTIONS).
Other Adverse Events Observed During the Clinical Trial Evaluation
of Olanzapine
Following is a list of terms that reflect treatment-emergent
adverse events reported by patients treated with olanzapine (at multiple doses
³1 mg/day) in clinical trials (8661 patients, 4165
patient-years of exposure). This listing does not include those events already
listed in previous tables or elsewhere in labeling, those events for which a
drug cause was remote, those event terms which were so general as to be uninformative,
and those events reported only once or twice which did not have a substantial
probability of being acutely life-threatening.
Events are further categorized by body system and listed in
order of decreasing frequency according to the following definitions: frequent
adverse events are those occurring in at least 1/100 patients (only those not
already listed in the tabulated results from placebo-controlled trials appear
in this listing); infrequent adverse events are those occurring in 1/100to 1/1000patients;
rare events are those occurring in fewer than 1/1000patients.
Body as a Whole — Frequent: dental pain and flu
syndrome; Infrequent: abdomen enlarged, chills, face edema, intentional
injury, malaise, moniliasis, neck pain, neck rigidity, pelvic pain, photosensitivity
reaction, and suicide attempt; Rare: chills and fever, hangover effect,
and sudden death.
Cardiovascular System — Frequent: hypotension;
Infrequent: atrial fibrillation, bradycardia, cerebrovascular accident,
congestive heart failure, heart arrest, hemorrhage, migraine, pallor, palpitation,
vasodilatation, and ventricular extrasystoles; Rare: arteritis, heart
failure, and pulmonary embolus.
Digestive System — Frequent: flatulence, increased
salivation, and thirst; Infrequent: dysphagia, esophagitis, fecal impaction,
fecal incontinence, gastritis, gastroenteritis, gingivitis, hepatitis, melena,
mouth ulceration, nausea and vomiting, oral moniliasis, periodontal abscess,
rectal hemorrhage, stomatitis, tongue edema, and tooth caries; Rare: aphthous
stomatitis, enteritis, eructation, esophageal ulcer, glossitis, ileus, intestinal
obstruction, liver fatty deposit, and tongue discoloration.
Endocrine System — Infrequent: diabetes mellitus;
Rare: diabetic acidosis and goiter.
Hemic and Lymphatic System — Infrequent: anemia,
cyanosis, leukocytosis, leukopenia, lymphadenopathy, and thrombocytopenia; Rare:
normocytic anemia and thrombocythemia.
Metabolic and Nutritional Disorders — Infrequent:
acidosis, alkaline phosphatase increased, bilirubinemia, dehydration, hypercholesteremia,
hyperglycemia, hyperlipemia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia,
lower extremity edema, and upper extremity edema; Rare: gout, hyperkalemia,
hypernatremia, hypoproteinemia, ketosis, and water intoxication.
Musculoskeletal System — Frequent: joint stiffness
and twitching; Infrequent: arthritis, arthrosis, leg cramps, and myasthenia;
Rare: bone pain, bursitis, myopathy, osteoporosis, and rheumatoid arthritis.
Nervous System — Frequent: abnormal dreams, amnesia,
delusions, emotional lability, euphoria, manic reaction, paresthesia, and schizophrenic
reaction; Infrequent: akinesia, alcohol misuse, antisocial reaction,
ataxia, CNS stimulation, cogwheel rigidity, delirium, dementia, depersonalization,
dysarthria, facial paralysis, hypesthesia, hypokinesia, hypotonia, incoordination,
libido decreased, libido increased, obsessive compulsive symptoms, phobias,
somatization, stimulant misuse, stupor, stuttering, tardive dyskinesia, vertigo,
and withdrawal syndrome; Rare: circumoral paresthesia, coma, encephalopathy,
neuralgia, neuropathy, nystagmus, paralysis, subarachnoid hemorrhage, and tobacco
misuse.
Respiratory System — Frequent: dyspnea; Infrequent:
apnea, asthma, epistaxis, hemoptysis, hyperventilation, hypoxia, laryngitis,
and voice alteration; Rare: atelectasis, hiccup, hypoventilation, lung
edema, and stridor.
Skin and Appendages — Frequent: sweating; Infrequent:
alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, pruritus,
seborrhea, skin discoloration, skin ulcer, urticaria, and vesiculobullous rash;
Rare: hirsutism and pustular rash.
Special Senses — Frequent: conjunctivitis; Infrequent:
abnormality of accommodation, blepharitis, cataract, deafness, diplopia,
dry eyes, ear pain, eye hemorrhage, eye inflammation, eye pain, ocular muscle
abnormality, taste perversion, and tinnitus; Rare: corneal lesion, glaucoma,
keratoconjunctivitis, macular hypopigmentation, miosis, mydriasis, and pigment
deposits lens.
Urogenital System — Frequent: vaginitis*; Infrequent:
abnormal ejaculation*, amenorrhea*, breast pain, cystitis, decreased menstruation*,
dysuria, female lactation*, glycosuria, gynecomastia, hematuria, impotence*,
increased menstruation*, menorrhagia*, metrorrhagia*, polyuria, premenstrual
syndrome*, pyuria, urinary frequency, urinary retention, urinary urgency, urination
impaired, uterine fibroids enlarged*, and vaginal hemorrhage*; Rare: albuminuria,
breast enlargement, mastitis, and oliguria.
*Adjusted for gender.
Postintroduction Reports
Adverse events reported since market introduction which were
temporally (but not necessarily causally) related to ZYPREXA therapy include
the following: allergic reaction (e.g.,anaphylactoid reaction, angioedema, pruritus
or urticaria), diabetic coma, pancreatitis, and priapism.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Olanzapine is not a controlled substance.
Physical and Psychological 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 dose (20mg) and rhesus monkeys
administered oral doses up to 8times the maximum recommended human daily 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).
DRUG INTERACTIONS
The risks of using olanzapine in combination with other drugs
have not been extensively evaluated in systematic studies. Given the primary
CNS effects of olanzapine, caution should be used when olanzapine is taken in
combination with other centrally acting drugs and alcohol.
Because of its potential for inducing hypotension, olanzapine
may enhance the effects of certain antihypertensive agents. Olanzapine may antagonize
the effects of levodopa and dopamine agonists.
The Effect of Other Drugs on Olanzapine — Agents
that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and
rifampin, may cause an increase in olanzapine clearance. Inhibitors of CYP1A2
could potentially inhibit olanzapine clearance. Although olanzapine is metabolized
by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably
alter olanzapine clearance. Therefore, a dosage increase (for induction) or
a dosage decrease (for inhibition) may need to be considered with specific drugs.
Charcoal — The administration of activated charcoal
(1 g) reduced the Cmax and AUC of olanzapine by about 60%. As peak olanzapine
levels are not typically obtained until about 6hours after dosing, charcoal
may be a useful treatment for olanzapine overdose.
Cimetidine and Antacids — Single doses of cimetidine
(800 mg) or aluminum- and magnesium-containing antacids did not affect the oral
bioavailability of olanzapine.
Carbamazepine — 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.
Ethanol — Ethanol (45mg/70kg singledose) did
not have an effect on olanzapine pharmacokinetics.
Fluoxetine — Fluoxetine (60 mg single dose or
60 mg daily 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.
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.
Warfarin — Warfarin (20mg singledose) did not
affect olanzapine pharmacokinetics.
Effect of Olanzapine on Other Drugs — 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.
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.
Valproate — Studies in vitro using human liver
microsomes determined that olanzapine has little potential to inhibit the major
metabolic pathway, glucuronidation, of valproate. Further, valproate has little
effect on the metabolism of olanzapine in vitro. In vivo administration of 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.
Single doses of olanzapine did not affect the pharmacokinetics
of imipramine or its active metabolite desipramine, and warfarin. Multiple doses
of olanzapine did not influence the kinetics of diazepam and its active metabolite
N-desmethyldiazepam, ethanol, or biperiden. However, the co-administration of
either diazepam or ethanol with olanzapine potentiated the orthostatic hypotension
observed with olanzapine. Multiple doses of olanzapine did not affect the pharmacokinetics
of theophylline or its metabolites.
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