Zilano 5 ODT/Zilano 10 ODT Adverse Reactions

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, dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases, rash, asthenia, fatigue and edema. 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 (10%), common (1% and <10%), uncommon (0.1% and < 1%), rare (0.01% and < 0.1%), very rare (<0.01%), not known (cannot be estimated from the data available).
Blood and the lymphatic system disorders: Eosinophilia, leucopenia, neutropenia, thrombocytopenia.
Immune system disorders: Allergic reactions.
Metabolism and nutrition disorders: Weight gain, elevated cholesterol levels, elevated glucose level, elevated triglyceride, development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases, hypothermia, glucosuria, increased appetite.
Nervous system disorders: Somnolence, dizziness, akathisia, parkinsonism, dyskinesia, seizures where in most cases a history of seizures or risk factors for seizures were reported, neuroleptic malignant syndrome, dystonia (including oculogyration), tardive dyskinesia, discontinuation symptoms.
Cardiac disorders: Bradycardia, QTc prolongation, ventricular tachycardia/fibrillation, sudden death.
Vascular disorders: Orthostatic hypotension, thromboembolism (including pulmonary embolism and deep vein thrombosis).
Gastrointestinal disorders: Mild, transient anticholinergic effects including constipation and dry mouth, pancreatitis.
Hepatobiliary disorders: Transient hepatitis (including asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment, hepatocellular cholestatic or mixed liver injury.
Skin and subcutaneous tissue disorders: Rash, photosensitivity reactions, alopecia.
Musculoskeletal and connective tissue disorders: Rhabdomyolysis.
Renal and urinary disorders: Urinary incontinence, urinary hesitation.
Reproductive system and breast disorders: Priapism.
General disorders and administration site conditions: Asthenia, fatigue, edema.
Investigations: Elevated plasma prolactin levels, high creatine phosphokinase, increased total bilirubin, increased alkaline phosphatase.
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).
Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.
Observed for fasting normal levels at baseline (<5.17 mmol/L) which increased to high ( 6.2mmol/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.
Observed for fasting normal levels at baseline (<5.56 mmol/L) which increased to high ( 7mmol/L). Changes in fasting glucose from borderline at baseline ( 5.56 - <7 mmol/L) to high ( 7 mmol/L) were very common.
Observed for fasting normal levels at baseline (<1.69 mmol/L) which increased to high ( 2.26mmol/L). Changes in fasting triglycerides from borderline at baseline ( 1.69mmol/L - < 2.26 mmol/L) to high ( 2.26 mmol/L) were very common.
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. Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly. 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. Generally in olanzapine-treated patients, potentially associated breast- and menstrual related clinical manifestations (e.g. amenorrhea, breast enlargement, galactorrhea in females, and gynecomastia/breast enlargement in males) were uncommon. Potentially associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased libido in both genders) were commonly observed.
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. 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 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.
Pediatric 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.
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 (10%), common (1% and < 10%).
Metabolism and nutrition disorders: Very common: Weight gain, elevated triglyceride levels, increased appetite.
Common: Elevated cholesterol levels.
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 levels.
Following 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.
Observed for fasting normal levels at baseline (< 1.016 mmol/L) which increased to high (1.467mmol/L) and changes in fasting triglycerides from borderline at baseline (1.016mmol/L - < 1.467 mmol/L) to high (1.467mmol/L).
Changes 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. Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.