Zyprexa (Olanzapine) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

The information below is derived from a clinical trial database for olanzapine consisting of 8661 patients with approximately 4165 patient-years of exposure to oral olanzapine and 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 mania 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 patients from 88 additional oral olanzapine clinical trials as of December 31, 2001; and (5) 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. 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 or agitation. However, this information is also generally applicable to bipolar mania and agitation.

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 that 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 of (1) oral olanzapine for schizophrenia, bipolar mania, 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 mania.

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 oral olanzapine vs 6% for placebo). However, discontinuations due to increases in SGPT were considered to be drug related (2% for oral 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 oral olanzapine vs 2% for placebo).

Agitation -- Overall, there was no difference in the incidence of discontinuation due to adverse events (0.4% for intramuscular olanzapine for injection vs 0% 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 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 Events in Short-Term, Placebo-Controlled Trials

The most commonly observed adverse events 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:

There was one adverse event (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 mania was 6% for intramuscular olanzapine for injection and 3% for placebo.

Adverse Events Occurring at an Incidence of 2% or More Among Oral 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 oral olanzapine (doses >/=2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials.

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 >/=5% and at least twice placebo) were:

Adverse Events Occurring at an Incidence of 2% or More Among Oral 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 >/=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.

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 Events Occurring at an Incidence of 1% or More Among Intramuscular Olanzapine for Injection-Treated Patients in Short-Term, Placebo-Controlled Trials

Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred in 1% or more of patients treated with intramuscular olanzapine for injection (dose range of 2.5-10.0 mg/injection) and with incidence greater than placebo who participated in the short-term, placebo-controlled trials in agitated patients with schizophrenia or bipolar mania.

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 oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia.

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.

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 three injections during the trials (see CLINICAL PHARMACOLOGY). Patient assessments were conducted during the 24 hours following the initial dose of intramuscular olanzapine for injection. There were no statistically significant differences from placebo.

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse events in the same controlled clinical trial comparing fixed doses of intramuscular olanzapine for injection with placebo in agitated patients with schizophrenia. There were no statistically significant differences from placebo.

Other Adverse Events -- The following table addresses dose relatedness for other adverse events using data from a schizophrenia trial involving fixed dosage ranges of oral olanzapine. 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.

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 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 5.4 kg.

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 oral olanzapine (at multiple doses >/=1 mg/day) in clinical trials (8661 patients, 4165 patient-years of exposure). This listing may 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 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

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.

Following is a list of terms that reflect treatment-emergent adverse events reported by patients treated with intramuscular olanzapine for injection (at one or more doses >/=2.5 mg/injection) in clinical trials (722 patients). This listing may 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 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 1/100 to 1/1000 patients.

Body as a Whole -- Frequent: injection site pain; Infrequent: abdominal pain and fever.

Cardiovascular System -- Infrequent: AV block, heart block, and syncope.

Digestive System -- Infrequent: diarrhea and nausea.

Hemic and Lymphatic System -- Infrequent: anemia.

Metabolic and Nutritional Disorders -- Infrequent: creatine phosphokinase increased, dehydration, and hyperkalemia.

Musculoskeletal System -- Infrequent: twitching.

Nervous System -- Infrequent: abnormal gait, akathisia, articulation impairment, confusion, and emotional lability.

Skin and Appendages -- Infrequent: sweating.

REPORTS OF SUSPECTED ZYPREXA SIDE EFFECTS / ADVERSE REACTIONS

Possible Zyprexa side effects / adverse reactions in 77 year old male

Reported by a physician from Switzerland on 2011-10-03

Patient: 77 year old male weighing 65.0 kg (143.0 pounds)

Reactions: Full Blood Count Abnormal, Sinus Tachycardia

Suspect drug(s):
Cymbalta
    Dosage: 30 mg, qd
    Administration route: Oral
    Start date: 2010-10-01
    End date: 2011-04-01

Cymbalta
    Dosage: 60 mg, qd
    Administration route: Oral
    Start date: 2011-04-01
    End date: 2011-08-25

Cymbalta
    Dosage: 15 mg, qd
    Administration route: Oral
    Start date: 2011-08-26

Zyprexa
    Dosage: 2.5 mg, qd
    Administration route: Oral
    End date: 2011-04-01

Other drugs received by patient: Lorazepam; Clozapine

Possible Zyprexa side effects / adverse reactions in 43 year old female

Reported by a consumer/non-health professional from Germany on 2011-10-03

Patient: 43 year old female

Reactions: Weight Decreased, Fear, Bundle Branch Block Right, Sinus Bradycardia, Death, Completed Suicide, Depressed Mood, Lethargy

Adverse event resulted in: death

Suspect drug(s):
Zyprexa

Possible Zyprexa side effects / adverse reactions in 46 year old male

Reported by a physician from Greece on 2011-10-03

Patient: 46 year old male weighing 82.0 kg (180.4 pounds)

Reactions: Confusional State, Dysarthria, Chills, Dizziness, Gait Disturbance

Adverse event resulted in: hospitalization

Suspect drug(s):
Olanzapine
    Dosage: 300 mg, every 4 weeks
    Indication: Bipolar I Disorder
    Start date: 2010-03-01

Zyprexa
    Dosage: 10 mg, qd
    Administration route: Oral
    Indication: Bipolar I Disorder
    Start date: 2010-03-01

Other drugs received by patient: Depakene; Voltaren /sch/; Norgesic /00040301/