Zyprexa ® (olanzapine)

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Zyprexa® (olanzapine): Undesirable effects

Summary of the safety profile of Zyprexa coated tablets (olanzapine).

ZYPREXA t




Summary of the safety profile


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

Leukopenia10

Neutropenia10


Thrombocytopenia11


Immune system disorders




Hypersensitivity11



Metabolism and nutrition disorders


Weight gain1

Elevated cholesterol levels2,3

Elevated glucose levels4

Elevated triglyceride levels2,5

Glucosuria

Increased appetite

Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4) 11

Hypothermia12


Nervous system disorders


Somnolence

Dizziness

Akathisia6

Parkinsonism6

Dyskinesia6

Seizures where in most cases a history of seizures or risk factors for seizures were reported 11

Dystonia (including oculogyration) 11

Tardive dyskinesia11

Amnesia 9

Dysarthria

Stuttering11

Restless Legs Syndrome11


Neuroleptic malignant syndrome (see section 4.4) 12

Discontinuation symptoms7, 12


Cardiac disorders




Bradycardia

QTc prolongation (see section 4.4)

Ventricular tachycardia/ fibrillation, sudden death (see section 4.4) 11


Vascular disorders


Orthostatic hypotension10


Thromboembolism (including pulmonary embolism and deep vein thrombosis) (see section 4.4)



Respiratory, thoracic and mediastinal disorders



Epistaxis9



Gastrointestinal disorders



Mild, transient anticholinergic effects including constipation and dry mouth

Abdominal distension9

Salivary

hypersecretion11

Pancreatitis11


Hepatobiliary disorders



Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment (see section 4.4)


Hepatitis (including hepatocellular, cholestatic or mixed liver injury) 11


Skin and subcutaneous tissue disorders



Rash

Photosensitivity reaction

Alopecia


Drug Reaction with Eosinophilia and 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 males

Decreased libido in males and females

Amenorrhea

Breast enlargement

Galactorrhea in females Gynaecomastia/breast enlargement in males

Priapism12


General disorders and administration site conditions



Asthenia

Fatigue

Oedema

Pyrexia10




Investigations


Elevated plasma prolactin levels8

Increased alkaline phosphatase10

High creatine phosphokinase11

High Gamma Glutamyltransferase10

High uric acid 10

Increased total bilirubin



1Clinically 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.


3Observed 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.


4Observed 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.


5Observed 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.


6In 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.


7Acute 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 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.

Hepatobiliary 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.


14Observed 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).


15Changes in 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.


16Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.


REFERENCE


Zyprexa [Summary of Product Characteristics]. Utrecht, The Netherlands: Eli Lilly Nederland B.V.


Date of Last Review: March 09, 2020

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