Zyprexa® (olanzapine): Undesirable effects

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, glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia, dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases, 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 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 syndrome12 Discontinuation symptoms7, 12
Cardiac disorders
		Bradycardia QTc prolongation	Ventricular tachycardia/ fibrillation, sudden death11
Vascular disorders
Orthostatic hypotension10		Thromboembolism (including pulmonary embolism and deep vein thrombosis)
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		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
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. 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).

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.