Approval Date.
Olanzapine Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
instruction
Words
Treatment of elderly patients with dementia-related psychotic disorders with atypical antipsychotics is associated with an increased risk of death. An analysis of 17 placebo-controlled clinical trials (mean duration of treatment 10 weeks) in elderly patients with dementia-related psychotic disorders found that the risk of death was 1.6-1.7 times greater in the drug-treated group than in the placebo-controlled group. In a typical 10-week controlled clinical trial, the mortality rate was approximately 4.5% in the drug-treated group and 2.6% in the placebo-controlled group. Although the causes of death varied, most deaths were due to cardiovascular disease (e.g., heart failure, sudden death) or infection (e.g., pneumonia). Observational studies have shown that, similar to atypical antipsychotics, the use of typical antipsychotics increases mortality. The results of increased mortality in observational studies may be that the characteristics of some patients using antipsychotics are unclear. Olanzapine is not approved for the treatment of dementia-related psychotic disorders (see [Precautions]).
Drug Name]
Generic name: Olanzapine tablets
English name: Olanzapine Tablets
Hanyu Pinyin: Aodanping Pian
Ingredients
Active ingredient: Olanzapine
Chemical name: 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine
Chemical structure formula.
Molecular formula: C17H20N4S
Molecular weight: 312.43
Properties
This product is film-coated tablets, light yellow to yellow after removing the coating.
Indications
Olanzapine is used for the treatment of schizophrenia.
For patients whose initial treatment with olanzapine is effective, consolidation therapy can effectively maintain clinical symptom improvement.
Olanzapine is used for the treatment of moderate and severe manic episodes.
For patients with manic episodes effectively treated with olanzapine, olanzapine can prevent the relapse of bipolar disorder.
Specification
(1) 2.5mg (2) 5mg (3) 10mg
Dosage
Adults
Schizophrenia
The recommended starting dose of olanzapine is 10mg/day, once a day.
Manic episode
The recommended starting dose is 15mg for monotherapy and 10mg once a day in combination therapy.
Prevention of bipolar disorder relapse
The recommended starting dose is 10mg/day. For patients treated with olanzapine for manic episodes, the maintenance therapy dose for relapse prevention is the same as before. For new manic episodes, mixed episodes or depressive episodes, olanzapine treatment should be continued (with appropriate dose adjustment if needed) and combined with adjunctive treatment for affective symptoms as clinically indicated.
The therapeutic dose for schizophrenia, manic episodes and prevention of relapse in bipolar disorder can be adjusted in the dose range of 5-20 mg/day depending on the individual clinical situation. It is recommended that the recommended starting dose be increased only after appropriate clinical reassessment and at intervals of not less than 24 hours. Olanzapine should be administered without regard to feeding factors, and food does not affect absorption. Gradual dose reduction should be considered at the time of discontinuation.
Special Populations
Patients with renal and/or hepatic impairment
A lower starting dose (5 mg) should be considered in this group of patients. Moderate hepatic insufficiency (cirrhosis, Child-Pugh)
grade A or B) is 5 mg and should be increased with caution.
Smokers
The starting dose and dose range for nonsmoking patients generally do not need to be adjusted relative to smokers. Smoking induces metabolism of olanzapine, and clinical evaluation is recommended to consider increasing the dose of olanzapine if needed.
When more than one factor that may slow metabolism is present (female, elderly, non-smoker), a lower starting dose should be considered. Dose increases should also be conservative when needed.
[Adverse Reactions].
The following is from the information in the foreign instructions for this product. This product is not approved for use in pediatric populations under 18 years of age in China.
Adults
The most common (occurring in ≥1 % of patients) adverse reactions reported in clinical trials associated with the use of olanzapine were drowsiness, weight gain, eosinophilia, elevated prolactin, cholesterol, glucose and triglyceride levels, glycosuria, increased appetite, dizziness, inability to sit still, parkinsonism, leukopenia, neutropenia, dyskinesia, postural hypotension, anticholinergic effects, hepatic transient asymptomatic elevation of transaminases, rash, malaise, fatigue, fever, arthralgia, increased alkaline phosphatase, increased gamma-glutamyl transpeptidase, hyperuricemia, high creatine phosphokinase and edema.
List of Adverse Reactions
The following table lists adverse reactions and laboratory findings from spontaneous reports and clinical trials. Within each frequency group, adverse reactions are listed in order of decreasing severity. The frequency terms listed are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), occasional (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), unknown (cannot be estimated from available data).
Very common Common Occasional Rare Unknown Blood and lymphatic system disorders Eosinophilia
Leukopenia10
Neutropenia10 Thrombocytopenia11 Immune system disorders Allergic reactions11 Metabolic and nutritional disorders Weight gain1
Elevated cholesterol levels2,3
Increased blood glucose levels4
Elevated triglyceride levels2,5
Diabetes
Increase in appetite Diabetes mellitus or worsening diabetes mellitus occasionally accompanied by ketoacidosis or coma, including some fatal cases11 Hypothermia12 Neurological disorders Drowsiness
dizziness
Inability to sit still6
Parkinson’s syndrome6
Movement disorders6 Epilepsy, in most cases a history of seizures or risk factors for seizures were reported11
Dystonia (including eye rolling)11
Delayed-onset dyskinesia11
amnesia9
Dysarthria
Stuttering11
Restless legs syndrome nerve blocker malignant syndrome12
Discontinuation reactions7,12
Heart disease Bradycardia
Prolonged QTc interval Ventricular tachycardia/ventricular fibrillation, sudden death11 Vascular disease Postural hypotension10 Thromboembolism (including pulmonary embolism and deep vein thrombosis) Respiratory, thoracic, and mediastinal disease Epistaxis9 Gastrointestinal disease Mild transient anticholinergic effects, including constipation and dry mouth and bloating9 Pancreatitis11 Hepatobiliary disease Transient, asymptomatic elevations of hepatic transaminases (ALT, AST), especially early in treatment Hepatitis (including hepatocellular, cholestatic, or mixed liver injury)11 Skin and subcutaneous tissue disorders Skin rash Photosensitivity reactions Alopecia with eosinophilia and drug reactions with systemic symptoms (DRESS) Musculoskeletal and connective tissue disorders Arthralgia9 Rhabdomyolysis11 Renal and urinary disorders Urinary incontinence, urinary retention, and
Urinary incontinence, urinary retention, urinary hesitancy11 Pregnancy, postpartum and perinatal disorders Neonatal withdrawal syndrome Reproductive and breast disorders Male erectile dysfunction
Reduced sexual desire in men and women Amenorrhea
Breast enlargement
Female breast overflow
Male breast feminization/breast enlargement Abnormal erection12 Systemic and drug administration site disorders Weakness Fatigue Edema
Fever10 Laboratory tests Elevated plasma prolactin levels8 Elevated alkaline phosphatase10
Elevated creatine phosphokinase11
Elevated gamma-glutamyl transpeptidase10
Elevated uric acid10 Increased total bilirubin 1 Clinically significant increases in body weight were observed in all baseline body mass index (BMI) categories. After short-term treatment (median duration 47 days), weight gain ≥7% of baseline weight was very common (22.2%), ≥15% was common (4.2%), and ≥25% was occasional (0.8%). Patient weight gain ≥7%, ≥15%, and ≥25% of baseline body weight was very common (64.4%, 31.7%, and 12.3%, respectively) after prolonged exposure (at least 48 weeks).
2 The mean elevated fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of abnormal lipid regulation at baseline.
3 Fasting total cholesterol levels were observed to range from normal (<5.17 mmol/l) to elevated (≥6.2 mmol/l) at baseline. A change in fasting total cholesterol level from a critical value at baseline (≥5.17 – <6.2 mmol/l) to an elevated level (≥6.2 mmol/l) was very common.
4 Fasting glucose levels were observed from normal (<5.56 mmol/l) to elevated (≥7 mmol/l) at baseline. A change in fasting glucose from a baseline threshold (≥5.56 – <7 mmol/l) to elevated (≥7 mmol/l) was very common.
5 Fasting triglyceride levels were observed from normal (<1.69 mmol/l) to elevated (≥2.26 mmol/l) at baseline. It was common for fasting triglycerides to change from a baseline threshold (≥1.69 mmol/l – <2.26 mmol/l) to elevated (≥2.26 mmol/l).
6 In clinical trials, the prevalence of Parkinson’s syndrome and dystonia in patients in the olanzapine-treated group had higher values, but there was no statistically significant difference between them and the placebo group. The incidence of Parkinson’s syndrome, inability to sit still, and dystonia was lower in olanzapine-treated patients compared with the titrated dose group of haloperidol. In the absence of detailed information on the individual patient’s history of acute and delayed extrapyramidal movement disorders, it is not possible to conclude that olanzapine is less likely to cause delayed dyskinesia and/or other delayed extrapyramidal syndromes.
7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, and vomiting have been reported when olanzapine is abruptly discontinued.
8 In clinical trials of up to 12 weeks, about 30% of olanzapine-treated patients had plasma prolactin concentrations above the upper limit of the normal range, whereas their baseline prolactin values were normal. The majority of these patients had milder elevations, remaining below twice the upper limit of the normal range.
9Adverse events identified from clinical trials in the olanzapine comprehensive database.
10As assessed by measurements from clinical trials in the olanzapine comprehensive database.
11Adverse events identified from spontaneous post-marketing reports whose incidence was determined using the olanzapine comprehensive database.
12Adverse events identified from spontaneous postmarketing reports whose incidence was estimated using the upper limit of the 95% confidence interval of the olanzapine comprehensive database.
Long-term exposure (at least 48 weeks)
The proportion of patients presenting with weight gain, glucose, total/low density/high density lipoprotein cholesterol or triglyceride adverse events and clinically significant changes increased over time. In adult patients completing 9-12 months of treatment, the mean rate of glycemic increase slowed after approximately 6 months.
Additional Information for Special Populations
In clinical trials in elderly patients with dementia, there was a higher incidence of death and adverse cerebrovascular disease in the olanzapine treatment group compared to the placebo group (see [Precautions]). Among the adverse reactions associated with the use of olanzapine in this group, gait abnormalities and falls were very common. Pneumonia, elevated body temperature, drowsiness, erythema, visual hallucinations, and urinary incontinence were common.
In clinical trials in patients with drug (dopamine agonist)-induced psychosis associated with Parkinson’s disease, worsening of Parkinson’s disease symptoms and hallucinations were commonly reported, more frequently than in the placebo group.
In a clinical trial in bipolar manic patients, the incidence of neutropenia with the combination of valproate and olanzapine was 4.1%; a potential contributing factor may be high levels of plasma valproate. Coadministration of olanzapine with lithium or valproate resulted in an increased incidence of tremor, dry mouth, increased appetite, and weight gain (³10%). Reports of speech disturbances are also common. During olanzapine co-treatment with lithium or bispropionate, 17.4% of patients during the acute treatment period (up to 6 weeks) had a weight gain of ³7% from baseline weight. Long-term olanzapine treatment (up to 12 months) for relapse prevention in patients with bipolar disorder was associated with a ³7% weight gain from baseline in 39.9% of patients.
Pediatric patients
Although no clinical studies were designed to compare adolescents and adults, data from adolescent trials were comparable to those from adult trials.
The following table summarizes the adverse reactions reported to occur more frequently in adolescent patients (ages 13-17 years) than in adult patients or in short-term clinical trials in adolescent patients only. Clinically significant weight gain (≥7%) occurred more frequently in the adolescent population compared to adults with comparable exposure. Both the degree of weight gain and the proportion of adolescent patients who experienced clinically significant weight gain were higher in adolescents with long-term exposure (at least 24 weeks) than in adolescents with short-term exposure.
Within each frequency group, adverse reactions are listed in order of decreasing severity. The frequency terms listed are defined as follows: very common (≥1/10), common (≥1/100 to <1/10).
Metabolic and nutritional disorders
Very common: weight gain13, elevated triglyceride levels14, increased appetite
Common: elevated cholesterol levels15 Neurological disorders
Very common: sedation (including: drowsiness, lethargy, sleepiness) Gastrointestinal disorders
Common: Dry mouth liver and biliary disorders
Very common: elevated liver transaminases (ALT/AST) Laboratory tests
Very common: decreased total bilirubin, increased GGT, and elevated plasma prolactin levels.16.13 Weight gain of ≥7% of baseline body weight (kg) was very common (40.6%), ≥15% of baseline body weight (7.1%), and ≥25% (2.5%) after short-term treatment (median duration of 22 days). After prolonged exposure (at least 24 weeks), 89.4% gained ≥7%, 55.3% gained ≥15%, and 29.1% gained ≥25% of baseline body weight.
14 A change from the baseline threshold (≥1.016 mmol/l – <1.467 mmol/l) to elevated (≥1.467 mmol/l) fasting triglycerides was observed in cases with normal (<1.016 mmol/l) fasting triglyceride levels at baseline, and a change from the baseline threshold (≥1.016 mmol/l – <1.467 mmol/l) to elevated (≥1.467 mmol/l) fasting triglycerides.
15 A change from a normal (<4.39 mmol/l) to an elevated (≥5.17 mmol/l) baseline fasting total cholesterol level was commonly observed. Changes from baseline critical levels (≥4.39 – <5.17 mmol/l) to elevated (≥5.17 mmol/l) fasting total cholesterol were very common.
Elevated plasma prolactin levels were reported in 1647.4% of adolescent patients.
Contraindications]
Olanzapine is contraindicated in patients with known hypersensitivity to any of the ingredients of this product. Olanzapine is contraindicated in patients with a known risk of narrow-angle glaucoma.
Precautions]
The following information is taken from the product’s foreign instructions. This product is not approved in China for use in pediatric populations under 18 years of age.
During treatment with antipsychotics, improvement of clinical symptoms in patients may take several days or even weeks, during which time the patient should be closely monitored.
Dementia-associated psychotic and/or behavioral disorders
Treatment with olanzapine is not recommended for patients with dementia-associated psychotic and/or behavioral disorders because of the increased risk of death and cerebrovascular events. In a placebo-controlled clinical trial (6-12 weeks), subjects were older adults (mean age 78 years) with dementia-associated psychotic and/or behavioral disorders. Compared with placebo, patients treated with olanzapine had a 2-fold increase in mortality (3.5%, 1.5%, respectively). However, the increased incidence of mortality did not correlate with the dose of olanzapine (mean daily dose of 4.4 mg) or the duration of treatment. Risk factors for elevated mortality included age >65 years, dysphagia, sedation status, malnutrition and dehydration, pulmonary disease (e.g., aspiration or non-aspirated pneumonia), or concomitant benzodiazepine use. However, excluding these risk factors, mortality rates were still higher in patients treated with olanzapine than in those treated with placebo.
In the same clinical trial, cerebrovascular adverse events (CVAE, i.e., stroke, transient ischemic attack) were reported, which included cases of death. The incidence of cerebrovascular adverse events was three times higher in patients treated with olanzapine than with placebo (1.3%, 0.4%, respectively). All patients treated with olanzapine and placebo who developed cerebrovascular adverse events had pre-existing risk factors. Risk factors for CVAE associated with olanzapine treatment included age >75 years and vascular/mixed dementia. The effectiveness of olanzapine was not confirmed in these trials.
Parkinson’s disease
Olanzapine is not recommended for the treatment of Parkinson’s disease and psychosis associated with dopamine agonists. In clinical trials, worsening of Parkinson’s symptoms or more common and frequent hallucinations than placebo have been reported in such patients taking olanzapine, which has comparable efficacy to placebo for psychotic symptoms in these patients. In these trials, patients were asked to maintain a steady state with the lowest effective dose of antiparkinsonian medication (dopamine agonist) at the beginning and to maintain consistency in the type and dose of antiparkinsonian medication used throughout the trial. The starting dose of olanzapine was 2.5 mg/day and was adjusted to a maximum of 15 mg/day at the discretion of the investigator.
Neuroblocker Malignant Syndrome (NMS)
NMS is a potentially lethal disorder associated with antipsychotic medications. NMS has been rarely reported in patients treated with olanzapine. clinical manifestations of NMS include hyperthermia, muscle tonicity, altered mental status, and unstable phenomena of vegetative nervous system function (irregular pulse or blood pressure, tachycardia, sweating, and arrhythmias). Other signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Discontinuation of all antipsychotic medications, including olanzapine, is required if the patient presents with clinical manifestations of NMS or if there is unexplained hyperthermia without other clinical manifestations of NMS.
Hyperglycemia and diabetes mellitus
The development or progression of hyperglycemia and/or diabetes mellitus occasionally accompanied by ketoacidosis or coma, including some cases of death, has been occasionally reported. Some cases have been reported with previous weight gain, which may be a contributing factor, and appropriate clinical monitoring, such as measuring the patient’s blood glucose values at baseline, 12 weeks of olanzapine treatment, and annually thereafter, is recommended in accordance with guidelines for antipsychotic use. Patients on any antipsychotic medication (including olanzapine tablets) should be observed for signs and symptoms of hyperglycemia (e.g., thirst, polyuria, bulimia, and malaise), patients with diabetes mellitus and the presence of risk factors for diabetes mellitus should be monitored regularly for blood glucose to avoid worsening, and weight should be monitored regularly (e.g., at baseline, 4 weeks, 8 weeks, 12 weeks, and each quarter thereafter of treatment with olanzapine).
Lipid alterations
Abnormal changes in lipids have been observed in placebo-controlled clinical trials in patients treated with olanzapine. Alterations in lipids, particularly in patients with dyslipidemia and the presence of risk factors for dyslipidemia, should be monitored appropriately in the clinical setting, and patients on any antipsychotic medication (including olanzapine tablets) should be monitored for lipids at regular intervals (e.g., baseline, 12 weeks of olanzapine treatment, and every 5 years thereafter) according to guidelines for antipsychotic use.
Anticholinergic activity
Isolated experiments have demonstrated the anticholinergic activity of olanzapine, but few events related to anticholinergic effects have occurred in clinical trials. However, clinical experience with olanzapine in the treatment of patients with co-morbidities is limited, and it is recommended that olanzapine be used with caution in patients with prostatic hypertrophy or paralytic intestinal obstruction and related conditions.
Liver function
Patients often experience transient asymptomatic elevations of hepatic aminotransferases (ALT/AST) during drug administration, especially early in treatment. Therefore, olanzapine should be used with caution in patients with elevated ALT and/or AST, in patients with signs or symptoms of hepatic impairment, in patients who have demonstrated limited hepatic decompensation, and in patients who have been treated with potentially hepatotoxic drugs. Olanzapine therapy should be discontinued in the presence of diagnosed hepatitis (including hepatocellular, biliary depression, or mixed liver injury).
Neutropenia
Olanzapine should be used with caution in patients with reduced white blood cell and/or neutrophil counts from any cause, in patients taking drugs that cause neutropenia, in patients with a history of drug-induced myelosuppression/toxic effects, in patients with myelosuppression due to co-morbidities, radiation therapy or chemotherapy, and in patients with eosinophilia or myelodysplasia. Neutropenia is common when olanzapine is combined with sodium valproate.
Discontinuation reactions
The following acute symptoms, such as sweating, insomnia, tremor, anxiety, nausea or vomiting, are rare with abrupt discontinuation of olanzapine (≥0.01% and<0.1%).
QT interval
Clinically significant prolongation of the QTc interval (baseline QTcF<500 msec in patients with [QTcF] ≥500 msec at any point after baseline) was occasionally seen in clinical trials in patients treated with olanzapine, with no statistically significant difference in the cardiac-related events that occurred compared with placebo. However, caution should be exercised when combining olanzapine with other agents known to prolong the QTc interval, especially in elderly patients, congenital long QT syndrome, congestive heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia.
Venous embolism
A temporal association between treatment with olanzapine and the development of venous embolism has been occasionally (≥0.1% and <1%) reported, and the link between the two has not been confirmed. However, because patients with schizophrenia are often at risk for acquired venous embolism, all risk factors that may be associated with venous embolism (e.g., immobilization of the patient) should be considered and preventive measures should be taken.
General central nervous system effects
Considering the fundamental CNS effects of olanzapine, caution should be exercised when combining it with other centrally active drugs or when using it in patients who have consumed alcohol. Because isolated olanzapine exhibits dopamine antagonism, it may antagonize the effects of direct or indirect dopamine agonists.
Convulsions
Olanzapine should be used with caution in patients with a history of convulsive seizures and with factors that lower the convulsive threshold. Occasional reports of olanzapine induced convulsions have been reported, and the majority of these cases report a history of convulsions and risk factors for convulsions.
Delayed-onset dyskinesia
In controlled studies of one year or less duration, olanzapine was significantly associated with a lower incidence of treatment-related dyskinesia. However, long-term use of the drug increases the risk of delayed-onset dyskinesia. Therefore, if patients treated with olanzapine develop signs or symptoms of delayed dyskinesia, a dose reduction or discontinuation of the drug should be considered. These symptoms may worsen or worsen transiently after discontinuation of treatment.
Postural hypotension
Postural hypotension has occasionally been reported in clinical trials of olanzapine in the treatment of elderly patients. Regular monitoring of patients’ blood pressure is recommended when treating patients over 65 years of age with olanzapine.
Sudden cardiac death
Sudden cardiac death in patients due to olanzapine use has been reported in post-marketing reports of olanzapine. In a retrospective observational study, the risk of sudden cardiac death in patients treated with olanzapine was approximately twice that of patients not taking antipsychotics. The results of a combined study of this study showed that olanzapine had a comparable risk of causing this event to other atypical antipsychotics.
Pediatric Patients
Clinical trials in patients aged 13-17 years have shown multiple adverse effects: including weight gain, metabolic changes, and increased prolactin.
Lactose
Olanzapine tablets contain lactose. It is contraindicated in patients with rare hereditary galactose intolerance, lactase deficiency, and glucose-galactose malabsorption.
Effects on the ability to drive and operate machinery
No studies have been conducted on the effects of olanzapine on the ability to drive and operate machinery. Because olanzapine can cause drowsiness and dizziness, patients should exercise caution when operating machinery, including motor vehicles.
Pregnant women and nursing mothers
Pregnancy
There have been no adequate controlled trial studies in women during pregnancy. Patients who are pregnant or who are planning to become pregnant during olanzapine treatment should inform their physician. Due to limited experience, this drug should only be used when the possible benefit outweighs the potential risk to the fetus.
Mothers who use antipsychotics (including olanzapine) during the second trimester of pregnancy are at risk for neonates with varying degrees and duration of adverse effects (including extrapyramidal symptoms and/or withdrawal reactions), and agitation, hypertonia, hypotonia, tremor, lethargy, respiratory distress, and feeding disorders have been reported. Therefore, newborns should be closely monitored.
Breastfeeding
In a lactation study in healthy women, olanzapine was excreted through breast milk. The mean infant drug exposure at steady state (mg/kg) was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breastfeed their infants if they are taking olanzapine.
Fertility
The effect on fertility is not known.
[Pediatric Use].
The safety and efficacy of this product in pediatric and adolescent patients under 18 years of age in China has not been established.
Geriatric Use]
A lower starting dose (5 mg/day) is not usually used, but a lower starting dose should be considered for the elderly aged 65 years and older if clinically indicated.
Drug Interactions]
Interaction studies have been conducted in adults only.
Potential interactions affecting olanzapine
Because olanzapine is metabolized by CYP1A2, substances that specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
Induction of CYP1A2
The metabolism of olanzapine can be induced by smoking and carbamazepine, leading to a decrease in olanzapine blood levels. Only a mild to moderate increase in olanzapine clearance has been observed. The effect on clinical outcomes is relatively limited, but clinical monitoring is still recommended and an increase in olanzapine dose may be considered if necessary.
Inhibition of CYP1A2
Fluvoxamine is a specific CYP1A2 inhibitor that significantly inhibits the metabolism of olanzapine. Olanzapine Cmax increased by a mean of 54% in female nonsmokers and 77% in male smokers after administration of fluvoxamine. the AUC increased by a mean of 52% and 108%, respectively. Therefore, a lower starting dose of olanzapine should be considered for patients who are on fluvoxamine or other CYP1A2 inhibitors (e.g., ciprofloxacin). In turn, the dosage of olanzapine should be reduced appropriately for patients starting CYP1A2 inhibitors.
Reduced bioavailability
Activated carbon reduces the bioavailability of oral olanzapine by 50-60% and should therefore be used at least 2 hours before or after olanzapine dosing.
No significant effect of fluoxetine (a CYP2D6 inhibitor), single doses of antacids (aluminum, magnesium) or cimetidine on the pharmacokinetics of olanzapine has been found.
Potential effects of olanzapine on other drugs
Olanzapine directly and indirectly antagonizes dopamine receptor agonists.
In vitro, olanzapine does not inhibit the major CYP450 isozymes (e.g., 1A2, 2D6, 2C9, 2C19, 3A4). An in vivo study did not find that olanzapine inhibited tricyclic antidepressants (representing most of the CYP2D6 pathway), warfarin (CYP2C9), cholecalciferol (CYP1A2), or valium (CYP3A4 and 2C19), and as confirmed in this study, no specific interactions were expected.
Olanzapine showed no drug-drug interactions when co-administered with lithium salts or dicyclohexaprofenol.
Therapeutic monitoring of valproate plasma levels showed that valproate dosing did not require adjustment when olanzapine combination therapy was used.
General central nervous system activity
Caution should be exercised when patients consume alcohol or receive medications that can cause CNS depression.
The combination of olanzapine with antiparkinsonian drugs is not recommended for patients with Parkinson’s and dementia.
QTc interval
Caution should be exercised when combining olanzapine with drugs that are known to increase the QTc interval.
Drug overdose]
Signs and symptoms
The following symptoms are very common with olanzapine overdose (incidence >10%), including tachycardia, agitation/aggression, dysarthria, extrapyramidal symptoms, and decreased levels of arousal (from sedation to coma).
Other important manifestations of olanzapine overdose include delirium, convulsions, coma, malignant syndrome, respiratory depression, shortness of breath, hypertension or hypotension, cardiac arrhythmias (occurring in less than 2% of overdoses), and cardiopulmonary arrest. The lowest lethal dose of olanzapine reported to date is 450 mg, but survival after an acute overdose of approximately 2 g of olanzapine orally has also been reported.
Overdose management
There is no specific antidote for olanzapine. Emetics are not recommended. Conventional overdose management (e.g., gastric lavage, administration of activated carbon) may be used. The oral bioavailability of olanzapine is reduced by 50-60% when an activated carbon preparation is given.
At the same time, vital organ function should be monitored and treated according to clinical manifestations, including management of hypotension, circulatory collapse and maintenance of respiratory function. The use of epinephrine, dopamine, or other sympathomimetic agents with beta-agonistic effects is contraindicated, as beta-agonists can exacerbate symptoms of hypotension. Monitoring of cardiovascular function is required to observe possible arrhythmias. Patients should be monitored closely and continuously until they return to normal.
Clinical trials]
Schizophrenia
Adults
Two short-term (6-week) controlled clinical trials in inpatients with schizophrenia meeting DSM-III-R diagnostic criteria determined the efficacy of oral olanzapine in the treatment of schizophrenia. One of these studies was designed with a haloperidol monotherapy group as a positive control, but the trial did not compare the two drugs across the entire range of clinically meaningful doses.
These studies used several instruments to evaluate psychotic symptoms, among which the Brief Psychiatric Rating Scale (BPRS) is a commonly used psychiatric rating scale consisting of multiple entries that is commonly used to evaluate the efficacy of medication for schizophrenia. psychotic symptoms (disorganized speech and behavior, hallucinations, paranoia, and bizarre thinking) of the BPRS are considered to be a very useful tool. The second classical scale, the Clinical General Impression Inventory (CGI), is a rating of the overall clinical impression of the patient by a rater who is very familiar with the manifestations of schizophrenia. In addition, two recently developed scales were adopted; these include the 30-entry Positive and Negative Symptom Scale (PANSS), a scale consisting of 18 entries from the BPRS, and the Scale for Assessment of Negative Symptoms (SANS). The following clinical trials are summarized below with a focus on the following indicators: PANSS total score and/or BPRS total score; BPRS psychotic symptom cluster; PANSS negative symptom subscale or SANS; and CGI severity. The trial results were as follows.
(1) In a 6-week placebo-controlled clinical trial (n=149) set up with two fixed olanzapine dose groups, 1 mg/day and 10 mg/day (once daily), olanzapine 10 mg/day (but not 1 mg/day) was superior in terms of PANSS total score (and BPRS total score calculated from it), BPRS psychotic symptom cluster, PANSS negative symptom score and CGI severity were superior to placebo.
(2) In a 6-week placebo-controlled clinical trial (n = 253) with three fixed-dose olanzapine groups (5 ± 2.5 mg/day, 10 ± 2.5 mg/day, and 15 ± 2.5 mg/day) administered once daily, the two highest dose groups of olanzapine (actual mean doses of 12 mg/day and 16 mg/day, respectively) were superior in BPRS total scores, BPRS psychotic symptom cluster and CGI severity than the placebo group; the SANS score was better in the highest dose group of olanzapine than in the placebo group. No clear advantage was found in the high-dose group compared with the medium-dose group.
(3) In a long-term clinical trial, adult outpatients (n=326) who met DSM-IV criteria for schizophrenia and were treated with a fixed dose of olanzapine open for at least 8 weeks were randomly assigned to either the continuation of the current dose of olanzapine treatment (dose range 10-20 mg/day) or the placebo group. Follow-up was planned for 12 months to observe patients for relapse, defined as an increase in BPRS-positive symptoms or hospital admission. However, the trial results met the criteria for early termination of the trial because the relapse rate was too high in the placebo group compared with the olanzapine group. For the primary indicator of time to relapse, olanzapine was superior to placebo. Thus, olanzapine was more effective than placebo in maintaining efficacy in patients who were stable on olanzapine for approximately 8 weeks and had a follow-up period of up to 8 months.
Subgroup (race and gender) analysis of this outcome did not reveal any differences in effectiveness.
Bipolar Disorder
Adults
Monotherapy – Two short-term (3 weeks, 4 weeks) placebo-controlled clinical trials determined the therapeutic effect of oral olanzapine in acute manic episodes or mixed episodes. Subjects were patients with bipolar I affective disorder who met DSM-IV diagnostic criteria for manic episodes or mixed episodes. These subjects included patients with or without psychotic features, and with or without a rapid cycling course.
The primary instrument used to evaluate manic symptoms in these clinical trials was the Young Mania Scale (Y-MRS). This scale has 11 entries and is commonly used to evaluate the degree of manic symptoms (irritability, disruptive/aggressive behavior, sleep, elevated state of mind, gregariousness, increased activity, increased sexuality, language/thinking disorder, thought content, appearance, and self-awareness) ranging from 0 (no manic features) to 60 (maximum score). The primary indicator of efficacy in these clinical trials was the change in total Y-MRS score relative to baseline. The results of the trials were as follows.
(1) In a 3-week placebo-controlled clinical trial (n = 67), olanzapine at doses ranging from 5-20 mg/day once daily, with a starting dose of 10 mg/day, was superior to placebo in terms of Y-MRS total score subtraction. In another concurrent clinical trial of the same design, olanzapine showed a similar difference in efficacy but did not outperform placebo on the Y-MRS total score subtraction, probably due to sample size and study unit variability.
(2) In a 4-week placebo-controlled clinical trial (n = 115), olanzapine doses ranged from 5-20 mg/day once daily, with a starting dose of 15 mg/day. Olanzapine was superior to placebo on the Y-MRS total score subtraction.
(3) In another clinical trial, 361 patients met the DSM-IV diagnostic criteria for manic or mixed episodes of bipolar disorder. And the initial open treatment with olanzapine at an average of 5-20 mg/day for approximately 2 weeks was effective. These patients were randomized to continue with the same dose of olanzapine (n = 225) or placebo (n = 136) and observed for relapse. During double-blind treatment, approximately 50% of patients in the olanzapine group discontinued the trial by day 59, compared with 50% of patients in the placebo group by day 23. During the open trial, a reduction in total Y-MRS score to ≤12 and HAM-D21 score to ≤8 was defined as effective. Relapse was defined as an increase in total Y-MRS score or total HAM-D21 score to ≥15 or hospitalization for a manic or depressive episode during the double-blind trial. The time to relapse was significantly longer in patients who continued olanzapine treatment during the randomized trial.
Combination lithium or valproate – Two controlled clinical trials determined the therapeutic effect of oral olanzapine in combination with lithium or valproate in patients with acute manic episodes who met DSM-IV criteria for a manic episode or mixed episode of bipolar I affective disorder. Patients were present with or without psychotic symptoms and with or without a rapid cyclic course. The trial results were as follows.
(1) In a 6-week placebo-controlled combination trial, 175 outpatients who were not adequately controlled by lithium or valproate therapy for manic or mixed symptoms (Y-MRS ≥16) were randomized to add olanzapine or placebo in combination with the original medication used. Olanzapine (dose range 5-20 mg/day once daily, starting dose 10 mg/day) combined with lithium or valproate treatment (treatment range 0.6 mEq/L-1.2 mEq/L or 50 μg/mL -125 μg/mL, respectively) was superior to lithium or valproate treatment alone on the Y-MRS total score subtraction.
(2) In a second 6-week placebo-controlled combination trial, 169 outpatients whose manic or mixed symptoms (Y-MRS ≥16) were not adequately controlled by lithium or valproate treatment. Randomized to add olanzapine or placebo in combination with the original medication used. Olanzapine (dose range 5-20 mg/day once daily, starting dose 10 mg/day) in combination with lithium or valproate treatment (treatment range 0.6 mEq/L-1.2 mEq/L or 50 μg/mL -125 μg/mL, respectively) was superior to lithium or valproate treatment alone on the Y-MRS total score subtraction.
Pharmacology and Toxicology
Pharmacological effects
The mechanism of action of olanzapine, like other drugs used to treat schizophrenia, is not known. However, the action of olanzapine in the treatment of schizophrenia may be through antagonism of dopamine and 5-hydroxytryptamine 2 (5HT2). The mechanism by which olanzapine treats acute manic or mixed episodes associated with type I bipolar disorder is not known.
Olanzapine has high affinity for the following receptors: 5-hydroxytryptamine 2A (5HT2A), 5-hydroxytryptamine 2C (5HT2C), and 5-hydroxytryptamine 6 (5HT6) receptors (Ki 4, 11, and 5nM, respectively), dopamine D1 to D4 receptors (Ki 11-31nM), histamine H1 receptors (Ki 7nM), and adrenergic α1 receptors (Ki 19nM) . Olanzapine has moderate affinity for 5-hydroxytryptamine 3 (5HT3) receptors (Ki of 57nM), muscarinic M1 to M5 receptors (Ki of 73, 96, 132, 32, 48nM, respectively). Olanzapine had weak affinity for GABAA, BZD, and adrenergic beta receptors (Ki > 10 μM).
In addition to antagonism of dopamine and 5-HT2, the affinity of olanzapine for other receptors may explain some of its other therapeutic effects and side effects. The anticholinergic effect of olanzapine may be caused by its antagonism of muscarinic M1 to 5 receptors. The drowsy effect of olanzapine may be caused by its antagonism of histamine H1 receptors. The upright hypotensive effect of olanzapine may be caused by its antagonism of adrenergic a1 receptors.
Toxicological studies
General Toxicology
Single dose toxicity: signs of toxicity in rodents administered orally were characteristic of a potent neuroleptic: decreased activity, coma, tremors, clonic convulsions, salivation, and slowed body weight gain, with LD50s of approximately 210 mg/kg (mice) and 175 mg/kg (rats). Clinical signs include sedation, ataxia, tremor, increased heart rate, respiratory distress, miosis, and loss of appetite. Single oral administration of doses up to 100 mg/kg in monkeys can result in prostration, and higher doses can result in a semi-conscious state.
Repeated dosing toxicity: The primary effects of olanzapine were found to be central nervous system depression, anticholinergic effects, and peripheral hematologic abnormalities in a 3-month trial in mice, a 1-year trial in rats, and dogs. CNS depression gradually develops tolerance. Growth parameters were reduced at high doses. Reversible changes consistent with increased prolactin levels are produced in rats, including decreased ovarian and uterine weights and morphological changes in the vaginal epithelium and mammary glands.
In animal studies with olanzapine, the major hematologic changes included reversible peripheral blood cytopenia in individual dogs administered at a dose of 10 mg/kg (equivalent to 17 times the maximum recommended human oral dose in terms of body surface area), a dose-related decrease in lymphocytes and neutrophils in mice, and a decrease in lymphocytes in rats. A small number of dogs administered at a dose of 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia 1 to 10 months after dosing. Mice dosed at 10 mg/kg (twice the maximum recommended human oral dose in terms of body surface area) showed dose-related reductions in lymphocyte and neutrophil counts when administered for 3 months. Non-specific reductions in lymphocytes and body weight gain were observed in rats given 22.5 mg/kg (11 times the maximum recommended human oral dose in terms of body surface area) for 3 months or 16 mg/kg (8 times the maximum recommended human oral dose in terms of body surface area) for 6 or 12 months. No bone marrow cytotoxicity was observed in the animal tests performed. Normal or high bone marrow cell counts suggest that the reduction in circulating blood cells may be a peripheral factor (non-myeloid).
Genotoxicity
The results of olanzapine Ames test, CHO cell chromosome aberration test, rat hepatocyte out-of-program DNA synthesis test, mouse lymphoma cell test, mouse in vivo micronucleus test, and Chinese hamster in vivo bone marrow sister chromatid interchange test were all negative.
Reproductive toxicity
In the rat fertility and reproductive behavior test, mating ability (non-fertility) was impaired in male rats given 22.4 mg/kg/day orally (11 times the maximum recommended human oral dose in terms of body surface area), and fertility was reduced in female rats given 3 mg/kg/day orally (1.5 times the maximum recommended human oral dose in terms of body surface area). Mating ability of male rats was restored after discontinuation of the drug. In female rats, the pre-mating period was prolonged and the mating index decreased at a dose of 5 mg/kg/day (2.5 times the maximum recommended human oral dose in terms of body surface area). Olanzapine may delay ovulation because of the prolonged interestrus and delayed estrus in rats at a dose of 1.1 mg/kg/day (0.6 times the maximum recommended human oral dose in terms of body surface area).
In the teratogenic sensitivity test, no teratogenic effect was observed in rats at a dose of 18 mg/kg/day and rabbits at a dose of 30 mg/kg/day (9 and 30 times the maximum recommended human oral dose in terms of body surface area, respectively). In the rat test, early fetal absorption and fetal death increased at a dose of 18 mg/kg/day, and the gestation period was prolonged at a dose of 10 mg/kg/day (5 times the maximum recommended human oral dose in terms of body surface area). In rabbit studies, fetal toxicity (e.g., increased fetal resorption and decreased fetal weight) was observed at maternal toxicity doses of 30 mg/kg/day.
Olanzapine can be transported via the placenta into rat fetuses.
Carcinogenicity
Carcinogenicity tests were conducted in mice and rats by oral administration. In two 78-week tests in mice, olanzapine doses were 3, 10, and 30/20 mg/kg/day (0.8 to 5 times the maximum recommended human oral dose in terms of body surface area) and 0.25, 2, and 8 mg/kg/day (0.06 to 2 times the maximum recommended human oral dose in terms of body surface area), respectively. In a rat test for 2 years, the doses were 0.25, 1, 2.5, and 4 mg/kg/day in males and 0.25, 1, 4, and 8 mg/kg/day in females (equivalent to 0.13-2 and 0.13-4 times the maximum recommended human oral dose, respectively, in terms of body surface area). In a mouse test, the incidence of hepatic hemangiomas and hemangiosarcomas was significantly increased in female mice given a dose of 8 mg/kg/day. In another trial, no increase in the incidence of hepatic hemangiomas and hemangiosarcomas was seen in female mice at doses of 10 and 30/20 mg/kg/day (2 to 5 times the maximum recommended oral human dose in terms of body surface area), but the incidence of early mortality was high in males at 30/20 mg/kg/day. A significant increase in the incidence of mammary adenomas and adenocarcinomas was observed in female mice at ≥2 mg/kg/day and in female rats at ≥4 mg/kg/day (0.5 and 2 times the maximum recommended oral dose in humans, respectively, in terms of body surface area). Studies have shown that long-term administration of antipsychotics can elevate prolactin levels in rodents. In the olanzapine carcinogenicity test, serum prolactin levels were not measured, but in the subchronic toxicity test, using the same doses as in the carcinogenicity test, olanzapine increased serum prolactin levels in rats by up to 4-fold. The increased incidence of mammary tumors in rodents after long-term administration of other antipsychotics is thought to be mediated through prolactin. The relevance of prolactin-mediated endocrine tumors in rodents to humans is unclear.
[Pharmacokinetics].
Absorption
Olanzapine is well absorbed after oral administration and reaches peak plasma drug concentration within 5-8 hours. Drug absorption is not affected by food. The absolute bioavailability of oral compared to intravenous administration has not been determined.
Distribution
Plasma protein binding of olanzapine is approximately 93% over a concentration range of approximately 7ng/mL to 1000ng/mL. Olanzapine is primarily bound to albumin and alpha 1 acidic glycoprotein.
Biotransformation
Olanzapine is metabolized in the liver primarily via glucuronide-binding and oxidative pathways. The major circulating metabolite in the circulatory system is 10-N-glucuronide conjugate, which does not cross the blood-brain barrier. Cytochrome P450 CYP1A2 and P450 CYP2D6 contribute to the formation of N-desmethyl and 2-hydroxymethyl metabolites. Animal studies showed that the in vivo pharmacological activity of both metabolites was significantly lower than that of olanzapine. The primary pharmacological activity was derived from the parent drug olanzapine.
Elimination
When administered orally to healthy volunteers, both age and sex were influential factors in the mean terminal elimination half-life of olanzapine.
Healthy elderly (65 years and older) subjects showed prolonged mean drug elimination half-life (51.8hr and 33.8hr, respectively) and slowed drug elimination (clearance of 17.5L/hr and 18.2L/hr, respectively) compared to healthy younger subjects. The pharmacokinetic variability observed in the elderly was within the range of variability observed in the younger population. 44 elderly schizophrenic patients over 65 years of age given 5-20 mg/day olanzapine did not show any specific adverse events.
Female subjects had longer mean drug elimination half-lives (36.7hr and 32.3hr, respectively) and slower drug clearance (clearance 18.9L/hr and 27.3L/hr, respectively) than male subjects. However, safety results showed that olanzapine (5-20 mg) had a comparable safety profile in female patients (n=467) as in male patients (n=869).
Renal injury
The mean elimination half-life of the drug was 37.7hr and 32.4hr in patients with renal failure (creatinine clearance <10ml/min) and healthy subjects, respectively, and drug clearance was not significantly different at 21.1L/hr and 25.0L/hr, respectively. A material balance study showed that approximately 57% of radiolabeled olanzapine was present in the urine, primarily as a metabolite.
Smokers
Smoking patients with mild hepatic impairment had a prolonged mean drug elimination half-life (39.3hr) and reduced clearance (18.0L/hr) compared to regular smoking patients. The situation was similar in nonsmoking patients (elimination half-life and clearance of 48.8hr and 14.1L/hr, respectively). Non-smoking patients had a longer mean elimination half-life (38.6hr vs. 30.4hr) and a lower clearance rate (18.6L/hr vs. 27.7L/hr) compared to smoking patients (men and women).
Plasma clearance of olanzapine was reduced in elderly, female subjects and nonsmokers compared to younger, male subjects and smokers. However, the effects of age, sex or smoking or not on olanzapine clearance and half-life were small compared to the overall inter-individual variability.
In studies of Caucasian, Japanese and Chinese subjects, there were no differences in olanzapine pharmacokinetics between the three groups. The cytochrome P450 isoform CYP2D6 profile did not affect olanzapine metabolism.
Pediatric patients
Adolescents (13-17 years): The pharmacokinetic properties of olanzapine were similar in adolescents and adults. Results from clinical studies indicate that mean olanzapine exposure is approximately 27% higher in adolescents than in adults. Demographic differences between adolescents and adults include lower mean body weight and fewer adolescent smokers. Such factors may be related to the higher mean exposure observed in adolescents.
[Storage].
Store under shade and seal.
Packaging
Aluminum blister package, 7 tablets/box, 14 tablets/box, 28 tablets/box, 56 tablets/box
Expiration date
(1) 2.5mg: 24 months
(2) 5mg: 24 months
(3) 10mg: 18 months
Execution standard
Approval number
Drug marketing license holder
Company name: Zhejiang Huahai Pharmaceutical Co.
Registered Address: Flood Bridge, Linhai City, Zhejiang Province
Manufacturer
Company name: Zhejiang Huahai Pharmaceutical Co.
Production Address: Flood Bridge, Linhai City, Zhejiang Province
Postal code: 317024
Telephone number: 0576-85010288
Fax number: 0576-85016013
Web
Address: www.huahaipharm.com