Special Warning : אזהרת שימוש

5       WARNINGS AND PRECAUTIONS
5.1     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,Use in Specific Populations (8.5)].
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].



5.2     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.
5.3     Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

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.

5.5      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 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 Up to 12 weeks        At least 48 exposure        weeks exposure
Laboratory           Category Change (at least once)           Treatment Analyte                      from Baseline                       Arm           N      Patient      N      Patient s                   s
Normal to High                   Olanzapine      543      2.2%       345     12.8% Fasting               (<100 mg/dL to 126 mg/dL)              Placebo        293      3.4%      NAa        NAa Glucose                     Borderline to High                Olanzapine      178     17.4%       127     26.0% (100 mg/dL and <126 mg/dL to 126 mg/dL)       Placebo         96     11.5%      NAa        NAa a     Not Applicable.

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

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.
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 3 shows categorical changes in fasting lipids values.

Table 3: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies Up to 12 weeks        At least 48 exposure        weeks exposure
Laboratory            Category Change (at least once)            Treatment Analyte                        from Baseline                        Arm          N      Patient     N       Patient s                   s
Increase by 50 mg/dL                Olanzapine      745     39.6%      487      61.4% Placebo        402     26.1%      NAa        NAa
Fasting                      Normal to High                   Olanzapine      457      9.2%      293      32.4% Triglycerides            (<150 mg/dL to 200 mg/dL)               Placebo        251      4.4%      NAa        NAa Borderline to High                 Olanzapine      135     39.3%       75      70.7% (150 mg/dL and <200 mg/dL to 200 mg/dL)        Placebo         65     20.0%      NAa        NAa 
Increase by 40 mg/dL                Olanzapine      745       21.6%      489         32.9% Placebo        402        9.5%      NAa          NAa
Fasting Total                 Normal to High                    Olanzapine      392        2.8%      283         14.8% Cholesterol           (<200 mg/dL to 240 mg/dL)                Placebo        207        2.4%      NAa          NAa Borderline to High                  Olanzapine      222       23.0%      125         55.2% (200 mg/dL and <240 mg/dL to 240 mg/dL)        Placebo        112       12.5%      NAa          NAa 
Increase by 30 mg/dL                Olanzapine      536       23.7%      483         39.8% Placebo        304       14.1%      NAa          NAa
Fasting LDL                   Normal to High                    Olanzapine      154         0%       123          7.3% Cholesterol            (<100 mg/dL to 160 mg/dL)                Placebo         82        1.2%      NAa          NAa Borderline to High                  Olanzapine      302       10.6%      284         31.0% (100 mg/dL and <160 mg/dL to 160 mg/dL)        Placebo        173        8.1%      NAa          NAa a     Not Applicable.

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.

Weight Gain
Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight.



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 4 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 4: Weight Gain with Olanzapine Use in Adults
6 Weeks          6 Months          12 Months         24 Months                   36 Months Amount Gained              (N=7465)         (N=4162)           (N=1345)          (N=474)                     (N=147) kg (lb)                 (%)               (%)               (%)               (%)                         (%) 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.

5.6     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.
Tardive dyskinesia, 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.
5.7     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 1-adrenergic antagonistic properties.
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. 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)].

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.
5.9     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.
5.10 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.
5.11 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.
5.12 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.
5.13 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.
5.14      Anticholinergic (antimuscarinic) Effects
Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2].. In premarketing clinical trials, Zyprexa 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, but Zyprexa should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1)].
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 and Warnings and Precautions (5.1)].
5.15 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.


5.16 Use in Combination with Lithium or Valproate
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)].
5.17 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)].
6        ADVERSE REACTIONS
6.1      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).
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 5: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Trials — SCHIZOPHRENIA
Percentage of Patients Reporting Event
Olanzapine                              Placebo
Adverse Reaction                                        (N=248)                                (N=118) Postural hypotension                                        5                                     2 Constipation                                                9                                     3 Weight gain                                                 6                                     1 Dizziness                                                  11                                     4 Personality disordera                                       8                                     4 Akathisia                                                   5                                     1 a Personality disorder is the COSTART term for designating nonaggressive objectionable behavior.


Table 6: 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) Percentage of Patients Reporting Event
Olanzapine                               Placebo
Adverse Reaction                                   (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 Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short- Term, Placebo-Controlled Trials


Table 6 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 6: Treatment-Emergent Adverse Reactions:
Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine Percentage of Patients Reporting Event
Olanzapine                               Placebo
Body System/Adverse Reaction                          (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 
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 7: Percentage of Patients from a Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the 3 Dose Range Groups and Placebo
Percentage of Patients Reporting Event
Olanzapine              Olanzapine          Olanzapine
Adverse Reaction             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 
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 8: 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)
Percentage of Patients Reporting Event
Olanzapine with                         Placebo with lithium or valproate                   lithium or valproate
Adverse Reaction                                     (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 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 9 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 9: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine as Adjunct to Lithium or Valproate
Percentage of Patients Reporting Event
Olanzapine with                        Placebo with lithium or valproate                  lithium or valproate
Body System/Adverse Reaction                           (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
Dysmenorrheaa                                             2                                     0 Vaginitisa                                                2                                     0 a 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.

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 10: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — 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 Parkinsonisma                      15                      14                    12                  14 Akathisiab                         23                      16                    19                  27 a Percentage of patients with a Simpson-Angus Scale total score >3.
 b Percentage of patients with a Barnes Akathisia Scale global score 2.


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 11: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — 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 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 12: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar I Disorder — Adolescents 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 
a   Categories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined in MedDRA version 12.0.

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.



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.

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)].
6.2     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, salivary hypersecretion stuttering1 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.
1
Stuttering was only studied in oral and long acting injection (LAI) formulations.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il

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