Chemical formula: C₁₇H₂₀N₄S Molecular mass: 312.432 g/mol PubChem compound: 4585
Olanzapine interacts in the following cases:
Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval.
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary.
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108% respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson’s disease and dementia is not recommended.
A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh Class A or B), the starting dose should be 5 mg and only increased with caution.
Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.
Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly.
In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.
The starting dose and dose range need not be routinely altered for non-smokers relative to smokers. The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary.
Neuroleptic Malignant Syndrome (NMS) is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.
Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly.
Olanzapine is not recommended for use in patients with dementia-related psychosis and/or behavioural disturbances because of an increase in mortality and the risk of cerebrovascular accident. In placebocontrolled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementiarelated psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age >65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g. pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g. stroke, transient ischemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age >75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.
Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (≥0.1% and <1%). A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients with schizophrenia often present with acquired risk factors for venous thromboembolism all possible risk factors of VTE e.g. immobilisation of patients, should be identified and preventive measures undertaken.
While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.
The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson’s disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo, and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of antiParkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.
Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported uncommonly, including some fatal cases. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic medicines, including olanzapine, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.
Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur uncommonly in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.
There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.
New born infant exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast feed an infant if they are taking olanzapine.
Effects on fertility are unknown.
No studies on the effects on the ability to drive and use machines have been performed. Because olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.
A common (≥1/100 to <1/10) undesirable effect associated with the use of intramuscular olanzapine in clinical trials was somnolence.
In post marketing reports, temporal association of treatment with IM olanzapine with cases of respiratory depression, hypotension or bradycardia and death have been very rarely reported, mostly in patients who concomitantly received benzodiazepines, and/or other antipsychotic medicinal products or who were treated in excess of olanzapine recommended daily doses.
The following list is based on the undesirable effects and laboratory investigations from clinical trials with olanzapine powder for solution for injection rather than oral olanzapine.
Common (≥1/100 to <1/10): Bradycardia with or without hypotension or syncope, tachycardia.
Uncommon (≥1/1,000 to <1/100): Sinus pause.
__Common (≥1/100 to <1/10): __Postural hypotension, hypotension.
Uncommon (≥1/1,000 to <1/100): Hypoventilation.
Common (≥1/100 to <1/10): Injection site discomfort.
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.
Adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials are listed below. 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).
Common: Eosinophilia, Leukopenia10, Neutropenia10
Rare: Thrombocytopenia11
Uncommon: Hypersensitivity11
Very common: Weight gain1
Common: Elevated cholesterol levels2,3, Elevated glucose levels4, Elevated triglyceride levels2,5, Glucosuria, Increased appetite
Uncommon: Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases11
Rare: Hypothermia12
Very common: Somnolence
Common: Dizziness, Akathisia6, Parkinsonism6, Dyskinesia6
Uncommon: Seizures where in most cases a history of seizures or risk factors for seizures were reported11, Dystonia (including oculogyration)11, Tardive dyskinesia11, Amnesia9, Dysarthria, Stuttering11,13, Restless Legs Syndrome
Rare: Neuroleptic malignant syndrome12, Discontinuation symptoms7,12
Uncommon: Bradycardia QTc prolongation
Rare: Ventricular tachycardia/fibrillation, sudden death11
Very common: Orthostatic hypotension10
Uncommon: Thromboembolism (including pulmonary embolism and deep vein thrombosis)
Uncommon: Epistaxis9
Common: Mild, transient anticholinergic effects including constipation and dry mouth
Uncommon: Abdominal distension9
Rare: Pancreatitis11
Common: Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment
Rare: Hepatitis (including hepatocellular, cholestatic or mixed liver injury)11
Common: Rash
Uncommon: Photosensitivity reaction, Alopecia
Not known: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Common: Arthralgia9
Rare: Rhabdomyolysis11
Uncommon: Urinary incontinence, urinary retention, Urinary hesitation11
Not known: Drug withdrawal syndrome neonatal
Common: Erectile dysfunction in males, Decreased libido in males and females
Uncommon: Amenorrhea, Breast enlargement, Galactorrhea in females, Gynaecomastia/breast enlargement in males
Rare: Priapism12
Common: Asthenia, Fatigue, Oedema, Pyrexia10
Very common: Elevated plasma prolactin levels8
Common: Increased alkaline phosphatase10, High creatine phosphokinase11, High Gamma Glutamyltransferase10, High uric acid10
Uncommon: Increased total bilirubin
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).
2 Mean 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.
13 Undesirable effects listed and observed following administration of oral and LAIM olanzapine, which may also occur following administration of RAIM olanzapine.
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.
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.
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).
Very common: Weight gain15, elevated triglyceride levels14, increased appetite.
Common: Elevated cholesterol levels16
Very common: Sedation (including: hypersomnia, lethargy, somnolence).
Common: Dry mouth
Very common: Elevations of hepatic aminotransferases (ALT/AST).
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels17.
14 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.
15 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).
16 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.
17 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.
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