Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Adverse reactions seen with olanzapine pamoate
Post-injection syndrome reactions have occurred with ZYPADHERA leading to symptoms consistent with olanzapine overdose (see sections 4.2 and 4.4). Clinical signs and symptoms included symptoms of sedation (ranging from mild in severity up to coma) and/or delirium (including confusion, disorientation, agitation, anxiety and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension and convulsion.


Other adverse reactions observed in patients treated with ZYPADHERA were similar to those seen with oral olanzapine. In clinical trials with ZYPADHERA, the only adverse reaction reported at a statistically significantly higher rate in the ZYPADHERA group than in the placebo group was sedation (ZYPADHERA 8.2%, placebo 2.0%). Among all ZYPADHERA treated patients, sedation was reported by 4.7% of patients.


In clinical trials with ZYPADHERA the incidence of injection site related adverse reactions was approximately 8%. The most commonly reported injection site related adverse reaction was pain (5%); some other injection site adverse reactions reported were (in decreasing frequency): nodule type reactions, erythema type reactions, non-specific injection site reactions, irritation, oedema type reactions, bruising, haemorrhage, and anaesthesia. These events occurred in about 0.1 to 1.1% of patients.

In a review of safety data from clinical trials and spontaneous postmarketing reports, injection site abscess was rarely (≥ 1/10,000 to < 1/1,000) reported.

Adverse reactions seen with olanzapine
The undesirable effects listed below have been observed following administration of olanzapine.

Adults
The most frequently (seen in ≥ 1% of patients ) reported adverse reactions associated with the use of olanzapine in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin, cholesterol, glucose and triglyceride levels (see section 4.4), glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section          4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.

Tabulated list of adverse reactions

The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the data available).

Very common            Common                       Uncommon                   Rare                       Not known Blood and the lymphatic system disorders
Eosinophilia                                            Thrombocytopenia11 Leukopenia10
Neutropenia10
Immune system disorders
Hypersensitivity11
Metabolism and nutrition disorders
Weight gain1           Elevated cholesterol         Development or             Hypothermia12 levels2,3                    exacerbation of
Elevated glucose             diabetes occasionally levels4                      associated with
Elevated triglyceride        ketoacidosis or coma,
levels2,5                    including some fatal
Glucosuria                   cases (see section
Increased appetite           4.4)11

Nervous system disorders
Somnolence             Dizziness                    Seizures where in most     Neuroleptic malignant 
Akathisia6            cases a history of         syndrome (see section Parkinsonism6         seizures or risk factors   4.4)12
Dyskinesia6           for seizures were          Discontinuation reported11                 symptoms7,12


Dystonia (including oculogyration)11
Tardive dyskinesia11


Amnesia 9
Dysarthria
Restless Legs
Syndrome
Cardiac disorder
Ventricular
Bradycardia                tachycardia/fibrillation,
QTc prolongation (see      sudden death (see section section 4.4)               4.4) 11
Vascular disorder
Orthostatic hypotension10                         Thromboembolism
(including pulmonary embolism and deep vein thrombosis) (see section
4.4)

Respiratory, thoracic and mediastinal disorders
Epistaxis9

Gastrointestinal disorders
Mild, transient           Abdominal distension9      Pancreatitis11 anticholinergic effects including constipation and dry mouth
Hepatobiliary disorders
Transient,                                           Hepatitis (including asymptomatic                                         hepatocellular,
elevations of hepatic                                cholestatic or mixed aminotransferases                                    liver injury)11
(ALT, AST),
especially in early treatment (see section
4.4)
Skin and subcutaneous tissue disorders
Rash                      Photosensitivity                                       Drug Reaction with reaction                                               Eosinophilia and Alopecia                                               Systemic Symptoms (DRESS)
Musculoskeletal and connective tissue disorders
Arthralgia9                                           Rhabdomyolysis11 Renal and urinary disorders
Urinary incontinence
Urinary retention


Urinary hesitation11
Pregnancy, puerperium and perinatal conditions
Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders
Erectile dysfunction in    Amenorrhea                                      Priapism12 males                      Breast enlargement
Decreased libido in        Galactorrhea in males and females          females
Gynaecomastia/breast enlargement in males
General disorders and administration site conditions
Asthenia                                                                  Injection site abscess Fatigue
Oedema
Pyrexia10
Injection site pain
Investigations
Elevated plasma                 Increased alkaline              Increased total prolactin levels8               phosphatase10                   bilirubin High creatine phosphokinase11
High Gamma
Glutamyltransferase 10
High uric acid 10

1
Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain ≥ 7% of baseline body weight was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon (0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25% of their baseline body weight with long-term exposure (at least 48 weeks) were very common (64.4 %, 31.7 % and 12.3 %, respectively).

2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high (≥ 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 - < 6.2 mmol/l) to high (≥ 6.2 mmol/l) were very common.

4 Observed    for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l). Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were very common.

5 Observed    for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high (≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l - < 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.

6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it cannot be concluded at present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.

7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly.
8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal range in approximately 30% of olanzapine treated patients with normal baseline prolactin value. In the majority of these patients the elevations were generally mild, and remained below two times the upper limit of normal range.

9   Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10   As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

11   Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.

12   Adverse event identified from spontaneous post-marketing reporting with frequency estimated at the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.


Long-term exposure (at least 48 weeks)
The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.

Additional information on special populations
In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions compared to placebo (see also section 4.4).
Very common adverse reactions associated with the use of olanzapine in this patient group were abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were observed commonly.

In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson’s disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo.

In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (10%) of tremor, dry mouth, increased appetite, and weight gain. Speech disorder was also reported commonly. During treatment with olanzapine in combination with lithium or divalproex, an increase of  7% from baseline body weight occurred in 17.4% of patients during acute treatment (up to 6 weeks). Long-term olanzapine treatment (up to 12 months) for recurrence prevention in patients with bipolar disorder was associated with an increase of 7% from baseline body weight in 39.9% of patients.

Paediatric population
Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years.
Although no clinical studies designed to compare adolescents to adults have been conducted, data from the adolescent trials were compared to those of the adult trials.

The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain (≥ 7%) appears to occur more frequently in the adolescent population compared to adults with comparable exposures. The magnitude of weight gain and the proportion of adolescent patients who had clinically significant weight gain were greater with long-term exposure (at least 24 weeks) than with short-term exposure.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10).

Metabolism and nutrition disorders
Very common: Weight gain13, elevated triglyceride levels14, increased appetite.
Common: Elevated cholesterol levels15
Nervous system disorders
Very common: Sedation (including: hypersomnia, lethargy, somnolence).
Gastrointestinal disorders

Common: Dry mouth
Hepato-biliary disorders
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).
Investigations
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16.
13Following short term treatment (median duration 22 days), weight gain ≥ 7% of baseline body weight (kg) was very common (40.6 %), ≥ 15% of baseline body weight was common (7.1 %) and ≥ 25 % was common (2.5 %). With long-term exposure (at least 24 weeks), 89.4 % gained ≥ 7 %, 55.3 % gained ≥ 15 % and 29.1 % gained ≥ 25% of their baseline body weight.

14 Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high (≥ 1.467 mmol/l) and changes in fasting triglycerides from borderline at baseline (≥ 1.016 mmol/l - < 1.467 mmol/l) to high (≥ 1.467 mmol/l).
15 Changesin total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high (≥ 5.17 mmol/l) were observed commonly. Changes in total fasting cholesterol levels from borderline at baseline (≥ 4.39 - < 5.17 mmol/l) to high (≥ 5.17 mmol/l) were very common.
16   Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.

Reporting suspected adverse reactions after authorisation 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 http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.go v.il