Adverse reactions : תופעות לוואי

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