Zolafran fast

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLAFREN FAST (ZOLAFRENFAST)

Composition:

Active substance: olanzapine;

1 tablet contains 10 mg or 20 mg of olanzapine;

Excipients: mannite (E 421), crospovidone, aspartame (E 951), orange flavor, colloidal silicon dioxide anhydrous, sodium stearyl fumarate.

Pharmaceutical form. Orally disintegrating tablets.

Main physicochemical properties:

10 mg tablets: yellow, flat, round tablets, engraved "10" on one side, 8 mm in diameter, without visible specks or inclusions;

20 mg tablets: yellow, flat, round tablets, engraved "20" on one side, 10 mm in diameter, without visible specks or inclusions.

Pharmacotherapeutic group. Antipsychotic agents. ATC code N05AH03.

Pharmacological Properties.

Pharmacodynamics.

Olanzapine is an antipsychotic and antimanic medicinal agent that also stabilizes mood, with a spectrum of pharmacological activity mediated through its effects on various receptors.

Preclinical studies have demonstrated olanzapine binding to serotonin receptors 5HT2A/2C, 5HT3, 5HT6, dopamine receptors D1, D2, D3, D4, D5, muscarinic receptors M1–M5, the adrenergic α1 receptor, and the histamine H1 receptor. Behavioral studies in animals administered olanzapine have shown antagonism of olanzapine at both serotonin (5HT) and dopamine as well as cholinergic receptors. Olanzapine exhibits higher binding affinity for serotonin 5HT2 receptors than for dopamine D2 receptors in both in vitro and in vivo models. Electrophysiological studies have demonstrated that olanzapine selectively reduces excitability of mesolimbic (A10) dopaminergic neurons, while exerting minimal effects on striatal (A9) pathways associated with motor function. Olanzapine suppresses conditioned avoidance response, indicating antipsychotic activity at doses lower than those causing catalepsy, a sign of motor side effects. Unlike other antipsychotic agents, olanzapine enhances responses to stimuli in anxiety tests.

Following a single 10 mg oral dose of olanzapine in healthy volunteers undergoing positron emission tomography (PET), olanzapine demonstrated greater binding to 5HT2A receptors than to dopamine D2 receptors. Furthermore, analysis of images obtained via single-photon emission computed tomography (SPECT) in schizophrenia patients revealed that olanzapine-responsive patients exhibited lower striatal D2 receptor binding compared to patients responsive to other antipsychotics or risperidone, but higher than clozapine-responsive patients.

Clinical Efficacy

In two out of two placebo-controlled and two out of three comparative controlled trials involving over 2900 patients with schizophrenia exhibiting positive and negative symptoms, olanzapine demonstrated statistically significant improvement in both negative and positive symptoms.

In international double-blind comparative trials involving 1484 patients with schizophrenia, schizoaffective disorder, and associated disorders with varying degrees of depressive symptoms (16.6 points on the Montgomery-Åsberg Depression Rating Scale), a prospective secondary analysis from baseline to endpoint demonstrated statistically significant mood improvement (p = 0.001) with olanzapine treatment (-6.0) compared to haloperidol (-3.1).

In patients with manic or mixed episodes of bipolar disorder, olanzapine demonstrated high efficacy in reducing manic symptoms within 3 weeks compared to placebo and sodium valproate. Olanzapine also showed comparable efficacy to haloperidol in terms of the proportion of patients achieving symptomatic remission from mania and depression at weeks 6 and 12 of treatment. In a study combining lithium or valproate with olanzapine 10 mg for 2 weeks, significant reduction in manic symptoms was observed compared to monotherapy with lithium or valproate after 6 weeks of treatment.

In a 12-month relapse prevention study in patients who achieved remission with olanzapine and were subsequently randomized to receive olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo in the primary endpoint of bipolar disorder relapse. Olanzapine also showed statistically significant advantages over placebo in preventing recurrence of mania or depression.

In a subsequent 12-month relapse prevention study in patients who achieved remission with combination therapy of olanzapine and lithium and were then randomized to receive either olanzapine or lithium alone, olanzapine did not demonstrate statistically significant superiority over lithium in the primary endpoint of bipolar disorder relapse (olanzapine 30%, lithium 38.3%, p = 0.055).

In an 18-month study, after stabilization of manic or mixed episodes using olanzapine, patients were maintained on lithium or valproate as mood stabilizers. Long-term combination therapy with olanzapine plus lithium or valproate did not demonstrate statistically significant superiority over monotherapy with lithium or valproate in delaying relapse of bipolar disorders, as defined by syndromal (diagnostic) criteria.

Children

Experience with the use of olanzapine in adolescents (aged 13 to 17 years) is limited to data from short-term efficacy studies in schizophrenia (6 weeks) and bipolar mania (3 weeks) involving fewer than 200 adolescents. The initial dose of olanzapine was 2.5 mg, titrated up to 20 mg daily. During olanzapine treatment, adolescents showed significantly greater weight gain compared to adults. Adolescents also exhibited increased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and prolactin compared to adults. Data on maintenance of therapeutic effect and long-term outcomes are limited and derived from open-label, uncontrolled clinical trials.

Pharmacokinetics.

Olanzapine in orally disintegrating tablets is bioequivalent to olanzapine in coated tablets, demonstrating similar rate and extent of absorption. Olanzapine in orally disintegrating tablets may be used as an alternative to olanzapine in coated tablets.

Absorption

The drug is well absorbed after oral administration, with maximum plasma concentration (Cmax) reached within 5–8 hours. Food intake does not affect olanzapine absorption. Absolute bioavailability of the oral formulation compared to intravenous administration has not been established.

Distribution

Plasma protein binding of olanzapine is approximately 93% across a concentration range of 7 to 1000 ng/mL. Olanzapine binds primarily to albumin and α1-acid glycoprotein.

Metabolism

Olanzapine is metabolized in the liver via conjugation and oxidation. The primary circulating metabolite is 10-N-glucuronide, 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, which exhibit significantly lower pharmacological activity in vivo than olanzapine in animal studies. The predominant pharmacological activity is attributed to the parent compound, olanzapine.

Elimination

After oral administration, the mean elimination half-life of olanzapine in volunteers varied according to age and sex.

In healthy elderly volunteers (aged 65 years and older), the mean elimination half-life was longer (51.8 vs. 33.8 hours) and plasma clearance lower (17.5 vs. 18.2 L/h) compared to younger volunteers. Pharmacokinetic variations observed in elderly volunteers remain within the range observed in younger volunteers. In 44 schizophrenia patients aged 65 years and older receiving doses of 5–20 mg daily, no distinct adverse reaction profile was observed.

In women compared to men, the mean elimination half-life was longer (36.7 vs. 32.3 hours) and plasma clearance lower (18.9 vs. 27.3 L/h). However, olanzapine (5–20 mg) demonstrated a comparable safety profile in both women (n = 467) and men (n = 869).

Renal Impairment

In patients with renal impairment (creatinine clearance < 10 mL/min) compared to healthy volunteers, no significant differences were observed in mean elimination half-life (37.7 vs. 32.4 hours) or plasma clearance (21.2 vs. 25.0 L/h). Studies indicate that approximately 57% of radiolabeled olanzapine is excreted in urine, primarily as metabolites.

Hepatic Impairment

In a small study of hepatic impairment involving 6 patients with clinically significant (Child-Pugh class A (n = 5) and B (n = 1)) cirrhosis, minimal impact on the pharmacokinetics of oral olanzapine (2.5–7.5 mg, single dose) was observed: patients with mild to moderate hepatic dysfunction showed slightly increased systemic clearance and faster elimination half-life compared to patients without hepatic dysfunction (n = 3). Among cirrhotic patients, more were smokers (4/6; 67%) compared to those without hepatic dysfunction (0/3; 0%).

Smoking Patients

In non-smokers compared to smokers (both men and women), the mean elimination half-life was longer (38.6 vs. 30.4 hours) and plasma clearance lower (18.6 vs. 27.7 L/h).

Plasma clearance of olanzapine is lower in elderly patients compared to younger patients, in women compared to men, and in non-smokers compared to smokers. Nevertheless, factors such as age, sex, and smoking have minimal impact on olanzapine plasma clearance and elimination half-life compared to overall inter-individual variability.

No differences in olanzapine pharmacokinetics were observed in clinical trials involving European, Japanese, and Chinese patients.

Adolescents and Adults

Olanzapine pharmacokinetics in adolescents and adults are similar. In clinical trials, mean exposure to olanzapine was approximately 27% higher in adolescents than in adult patients. Demographic differences between adolescents and adults include lower average body weight and fewer smokers among adolescent patients. These factors likely contribute to the higher mean exposure to olanzapine observed in adolescents.

Clinical Characteristics.

Indications.

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical response during long-term therapy in patients who have responded to initial treatment.

Olanzapine is indicated for the treatment of moderate to severe manic episodes.

Olanzapine is indicated for the prevention of recurrent episodes in patients with bipolar disorder who have responded to olanzapine treatment for mania.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients; known risk of angle-closure glaucoma.

Interaction with other medicinal products and other forms of interaction.

Drug interaction studies have been conducted only in adults.

Interactions potentially affecting olanzapine

Since olanzapine is metabolized by the CYP1A2 isoenzyme, substances that specifically induce or inhibit this isoenzyme may affect olanzapine pharmacokinetics.

CYP1A2 inducers

Olanzapine metabolism may be induced by smoking and concomitant use of carbamazepine, leading to reduced olanzapine concentrations. Mild to moderate increases in olanzapine clearance have been observed. Clinical conclusions are limited, but clinical monitoring is recommended and dose adjustment of olanzapine may be necessary.

CYP1A2 inhibitors

Fluvoxamine, a specific CYP1A2 inhibitor, significantly reduces olanzapine metabolism. This results in a mean increase in Cmax of 54% in non-smoking women and 77% in smoking men after fluvoxamine administration. The mean increase in the area under the concentration-time curve (AUC) of olanzapine is 52% and 108%, respectively. For patients receiving fluvoxamine or other CYP1A2 inhibitors such as ciprofloxacin, reduced doses of olanzapine are required. Dose reduction of olanzapine should be considered when initiating treatment with a CYP1A2 inhibitor.

Reduced bioavailability

Activated charcoal reduces the oral bioavailability of co-administered olanzapine by 50–60%; therefore, it should be administered at least 2 hours before or 2 hours after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), a single dose of antacids containing aluminum and magnesium, or cimetidine do not significantly affect olanzapine pharmacokinetics.

Potential effect of olanzapine on other medicinal products

Olanzapine may antagonize the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit major CYP450 isoenzymes (e.g., 1A2, 2D6, 2C9, 2C19, 3A4) in vitro. Therefore, no significant interactions are expected, as confirmed in in vivo studies where no inhibition of olanzapine metabolism was observed with co-administration of active substances such as tricyclic antidepressants (mainly metabolized by CYP2D6), warfarin (CYP2C9), theophylline (CYP1A2), or diazepam (CYP3A4 and 2C19).

No interactions between olanzapine and lithium or biperiden have been reported.

Therapeutic monitoring of plasma valproate levels did not reveal the need for dose adjustment of valproate when co-administered with olanzapine.

General central nervous system (CNS) activity

Olanzapine should be used with caution in patients receiving ethanol or other medicinal products that may cause CNS depression.

Concomitant use of olanzapine with anti-Parkinson agents in patients with Parkinson’s disease and dementia is not recommended.

QTc interval

Olanzapine should be administered with caution when used concomitantly with other agents known to prolong the QTc interval.

Special precautions for use.

During antipsychotic therapy, clinical improvement in patients may take from several days to several weeks. Close monitoring of patients is required during this period.

Psychosis and/or behavioral disorders associated with dementia

Olanzapine is not recommended for use in patients with psychosis and/or behavioral disturbances associated with dementia due to increased mortality and risk of cerebrovascular events. In placebo-controlled clinical trials (6–12 weeks duration) involving elderly patients (mean age 78 years) with psychosis and/or behavioral disturbances related to dementia, the incidence of death was twice as high in patients receiving olanzapine compared to placebo (3.5% vs. 1.5%, respectively). Increased mortality was not related to the dose of olanzapine (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may contribute to increased mortality include age ≥65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary diseases (pneumonia with or without aspiration), and concomitant use of benzodiazepines. However, mortality rates were higher with olanzapine therapy than with placebo regardless of risk factors.

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatal cases, were observed during these clinical trials. The incidence of cerebrovascular adverse reactions was three times higher in patients receiving olanzapine compared to those receiving placebo (1.3% vs. 0.4%, respectively). All patients who experienced cerebrovascular adverse reactions while receiving olanzapine or placebo had risk factors. Age ≥75 years and vascular/mixed type dementia were identified as risk factors for cerebrovascular adverse reactions during olanzapine therapy. The efficacy of olanzapine was not established in these studies.

Parkinson’s disease

Olanzapine is not recommended for the treatment of psychosis associated with dopamine agonists in patients with Parkinson’s disease. In clinical trials, worsening of Parkinsonian symptoms and hallucinations occurred very frequently and more often than with placebo (see also section "Adverse reactions"). In treating psychotic symptoms, olanzapine therapy was not more effective than placebo. In these studies, patients were required to be stable on the lowest effective dose of anti-Parkinson medications (dopamine agonists), and to continue the same anti-Parkinson medications throughout the study. Olanzapine therapy was initiated at a dose of 2.5 mg/day, titrated up to a maximum of 15 mg/day.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal syndrome associated with antipsychotic drugs. Rare cases of NMS have been reported during olanzapine use. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered consciousness, and signs of autonomic instability (irregular pulse or blood pressure changes, tachycardia, diaphoresis, and cardiac arrhythmia). Additional signs may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. The presence of NMS or hyperthermia without full clinical expression of NMS requires immediate discontinuation of all antipsychotic drugs, including olanzapine.

Hyperglycemia and diabetes mellitus

Hyperglycemia and/or development or worsening of pre-existing diabetes mellitus, sometimes associated with ketoacidosis or diabetic coma, have been reported infrequently, including fatal cases (see section "Adverse reactions"). Prior weight gain has sometimes been reported and may be a risk factor. Clinical monitoring according to established guidelines is recommended, including measurement of blood glucose at the beginning of treatment, at 12 weeks, and annually thereafter. Patients receiving antipsychotic medications, including Zolafren Fast, should be monitored for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus or risk factors for developing diabetes should be monitored regularly for worsening glycemic control. Body weight should also be monitored regularly, e.g., at the beginning of treatment, at 4 weeks, 8 weeks, 12 weeks, and quarterly thereafter.

Changes in lipid concentrations

In placebo-controlled clinical trials, undesirable changes in lipid concentrations were observed in patients treated with olanzapine (see section "Adverse reactions"). If lipid abnormalities occur, appropriate management should be initiated, especially in patients with lipid metabolism disorders or risk factors for such disorders. Patients receiving antipsychotic medications, including Zolafren Fast, should have lipid levels monitored regularly according to established guidelines for antipsychotic therapy, e.g., at the beginning of treatment, at 12 weeks, and every 5 years thereafter.

Anticholinergic activity

Despite in vitro evidence of anticholinergic activity of olanzapine, clinical trials have shown a low incidence of anticholinergic-related adverse effects. However, due to limited clinical experience with olanzapine in patients with comorbid conditions, caution should be exercised when prescribing the drug to patients with clinically significant prostatic hypertrophy, paralytic ileus, or similar conditions.

Liver function parameters

Transient, asymptomatic elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels have frequently been observed with olanzapine use, especially at the beginning of treatment. Caution and ongoing monitoring are required in patients with elevated ALT and/or AST levels or signs and symptoms of hepatic dysfunction. Olanzapine should be used with caution in patients with elevated ALT and/or AST, signs and symptoms of liver dysfunction, conditions associated with hepatic insufficiency, or those receiving potentially hepatotoxic drugs. Olanzapine should be discontinued if hepatitis (including hepatocellular, cholestatic, or mixed liver injury) is diagnosed.

Neutropenia

Olanzapine should be used cautiously in patients with low leukocyte and/or neutrophil counts for any reason, patients receiving drugs that may cause neutropenia, patients with a history of drug-induced bone marrow suppression or toxicity, patients with bone marrow suppression due to concomitant diseases, radiation, or chemotherapy, and patients with hypereosinophilia or myeloproliferative disorders. Neutropenia is a common adverse reaction when valproate and olanzapine are used concomitantly (see section "Adverse reactions").

Discontinuation of treatment

Acute symptoms such as excessive sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported rarely (≥0.01% to <0.1%) following abrupt discontinuation of therapy.

QT interval

In clinical trials, clinically significant QT interval prolongation (Fridericia-corrected QT interval [QTcF] ≥500 milliseconds [ms] at any time after treatment initiation in patients with baseline QTcF <500 ms) was infrequent (≥0.1% to <1%) in patients treated with olanzapine. No significant difference in frequency of associated cardiac adverse reactions was observed compared to placebo. However, caution is advised when prescribing olanzapine concomitantly with drugs that prolong the QTc interval, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia.

Thromboembolism

A temporal association between olanzapine treatment and venous thromboembolism has been reported infrequently (≥0.1% to <1%). A causal relationship between olanzapine treatment and venous thromboembolism has not been established. However, considering that patients with schizophrenia are often predisposed to thromboembolic events, all potential risk factors, such as patient immobilization, should be considered and appropriate preventive measures taken.

General CNS activity

Due to the predominant central nervous system (CNS) effects of olanzapine, additional precautions are necessary when olanzapine is taken with other centrally acting drugs, including alcohol consumption. In vitro studies with dopamine antagonists have shown that olanzapine may antagonize the effects of direct and indirect dopamine agonists.

Seizures

Olanzapine should be used cautiously in patients with a history of seizures or factors that lower the seizure threshold. Seizures have been reported infrequently during olanzapine treatment. In most of these cases, patients had a history of epilepsy or an increased risk of seizures.

Tardive dyskinesia

In comparative clinical trials of one year or less duration, olanzapine was associated with a statistically significantly lower incidence of treatment-emergent dyskinesia. Due to the increasing risk of tardive dyskinesia with long-term use of antipsychotic drugs, a gradual dose reduction or discontinuation of the drug should be considered if signs or symptoms of tardive dyskinesia appear. These symptoms may worsen or even emerge after discontinuation of treatment.

Orthostatic hypotension

Cases of orthostatic hypotension have been reported infrequently in elderly patients during clinical trials. Periodic blood pressure monitoring is recommended for patients aged 65 years and older during olanzapine use.

Sudden cardiac death

Post-marketing reports have described cases of sudden cardiac death in patients taking olanzapine. According to a retrospective observational cohort study, the risk of sudden cardiac death in patients taking olanzapine was nearly doubled compared to patients not taking antipsychotics. The risk associated with olanzapine use corresponds to that of other atypical antipsychotics included in a combined analysis.

Children and adolescents

Olanzapine is not recommended for use in children and adolescents. In studies of patients aged 13–17 years, various adverse reactions were observed, including weight gain, metabolic parameter changes, and increased prolactin levels. The long-term consequences of these adverse effects have not been studied and remain unknown (see sections "Pharmacological properties" and "Adverse reactions").

Aspartame

This medicine contains up to 1.6 mg of aspartame per tablet.

Aspartame is a source of phenylalanine. This may be harmful to people with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine accumulates because the body cannot properly eliminate it.

Sodium

This medicine contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

There are no adequate and well-controlled studies of olanzapine use in pregnant women. Patients should inform their physician if they are pregnant or plan to become pregnant during olanzapine treatment. Since clinical experience with olanzapine in pregnancy is limited, the drug should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.

Newborns whose mothers have taken antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, the symptoms of which may vary in severity and duration after birth. Symptoms such as agitation, hypertension, hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders have been reported. Therefore, newborns should be carefully monitored.

In studies of healthy breastfeeding women, olanzapine was detected in breast milk. The average infant dose (mg/kg) without risk was estimated at 1.8% of the maternal dose (mg/kg). Patients should not breastfeed while taking olanzapine.

Ability to affect driving or operating machinery.

Studies on the effect of olanzapine on driving or operating machinery have not been conducted. Since olanzapine may cause somnolence and dizziness, patients should be warned about the potential danger of operating machinery, including motor vehicles.

Method of Administration and Dosage

Adults

Schizophrenia. The recommended initial dose of olanzapine is 10 mg once daily.

Manic episodes. The recommended initial dose of olanzapine as monotherapy is 15 mg per day or 10 mg per day when used in combination therapy.

Prevention of recurrent episodes in patients with bipolar disorder. The recommended initial dose is 10 mg per day. Patients with bipolar disorder who have been treated with olanzapine for manic episodes should continue receiving olanzapine at the same dosage for prevention of recurrent episodes. If a new manic, depressive, or mixed episode occurs, treatment should be continued (with dose optimization if necessary) along with supportive therapy for managing mood disorder symptoms, as clinically indicated.

Treatment of schizophrenia, manic episodes, and prevention of relapse in bipolar disorder. The daily dose should be individualized based on clinical status within a range of 5 to 20 mg per day. Increases from the recommended initial dose should be made at intervals of not less than 24 hours and only after clinical evaluation. Olanzapine may be administered without regard to meals, as food does not affect its absorption. Discontinuation of the drug should be carried out gradually.

Orally disintegrating tablets should be placed in the mouth, where they rapidly disintegrate. Since orally disintegrating tablets are fragile, they should be taken immediately after opening the blister pack. Alternatively, the tablet may be dissolved in a full glass of water or another beverage (orange juice, apple juice, milk, or coffee) immediately before administration.

Special patient populations

Elderly patients

A lower initial dose (5 mg per day) is generally not required. However, consideration should be given to initiating treatment with a lower dose in patients aged 65 years and older if clinically indicated (see section "Special precautions").

Patients with renal and/or hepatic impairment

A lower initial dose (5 mg per day) may be considered for these patients. In patients with moderate hepatic impairment (cirrhosis, Child-Pugh class A or B), the initial dose should be 5 mg, and dose escalation should be performed cautiously.

Gender

Dose adjustment based on patient gender is not required.

Smoking patients

Initial dose and dose adjustments should not routinely be altered based on smoking status. Tobacco smoking may induce olanzapine metabolism. Clinical monitoring is recommended, and dose increase should be considered if needed (see section "Interaction with other medicinal products and other forms of interaction"). If more than one factor affecting reduced metabolism is present (female gender, advanced age, non-smoking status), a lower initial dose should be considered. Dose increases, when indicated, should be performed conservatively. In cases where a 2.5 mg dose increase is deemed necessary, other olanzapine dosage forms allowing administration of 2.5 mg should be used.

Children

Olanzapine is not recommended for use in children under 18 years of age due to insufficient data on safety and efficacy.

Overdose

Very common symptoms of overdose (>10%) include tachycardia, agitation/aggression, dysarthria, various extrapyramidal symptoms, and decreased level of consciousness ranging from sedation to coma.

Other significant complications of overdose include delirium, seizures, coma, risk of neuroleptic malignant syndrome, respiratory depression, aspiration, arterial hypertension or hypotension, cardiac arrhythmia (<2% of overdose cases), and cardiopulmonary shock. Fatal outcomes have been reported following acute overdose at doses up to 450 mg, although survival has been documented after acute ingestion of up to 2 g of olanzapine orally.

Treatment

There is no specific antidote. Agents that induce emesis are not recommended. Standard overdose management procedures are recommended (e.g., gastric lavage, administration of activated charcoal). Concomitant administration of activated charcoal has been shown to reduce olanzapine bioavailability by 50–60% following oral intake.

Symptomatic treatment and monitoring of vital functions should be implemented according to clinical manifestations, including management of arterial hypotension and circulatory insufficiency, as well as respiratory support. Adrenaline (epinephrine), dopamine, and other sympathomimetics with beta-agonist activity should not be used, as beta-stimulation may worsen hypotension. Cardiovascular monitoring is required to detect possible arrhythmias. Close medical supervision and monitoring should continue until full recovery of the patient.

Adverse reactions

The most common adverse reactions (observed in ≥1% of patients) associated with olanzapine use during clinical trials: somnolence, weight gain, eosinophilia, increased prolactin levels, increased blood levels of cholesterol, glucose, and triglycerides, glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia, dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic transaminases, rash, asthenia, increased fatigue, hyperthermia, arthralgia, increased levels of alkaline phosphatase, gamma-glutamyl transferase, uric acid, creatine phosphokinase, and edema.

Table 1 summarizes the main adverse reactions and their frequency as determined during clinical trials and/or based on post-marketing experience.

Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (frequency cannot be estimated from the available data).

Table 1

Very common	Common	Uncommon	Rare	Frequency not known
From the blood and lymphatic system
	Eosinophilia, leukopenia10, neutropenia10		Thrombocytopenia11
From the immune system
		Hypersensitivity11
From the metabolism and nutrition
Increased body weight1	Increased cholesterol levels2,3, increased glucose levels4, increased triglyceride levels2,5, glucosuria, increased appetite	Development or worsening of diabetes, sometimes associated with ketoacidosis or coma, including fatal outcomes11	Hypothermia12
From the nervous system
Somnolence	Dizziness, akathisia6, parkinsonism6, dyskinesia6	Seizures, mostly with history or risk factors11, dystonia (including ocular symptoms)11, tardive dyskinesia11, amnesia9, dysarthria, stuttering, restless legs syndrome	Neuroleptic malignant syndrome (NMS)12, withdrawal syndrome7,12
From the cardiac system
		Bradycardia, prolongation of QT interval	Ventricular tachycardia/ fibrillation, sudden fatal outcome11
From the vascular system
Orthostatic hypotension10		Thromboembolism (including pulmonary embolism and deep vein thrombosis)
From the respiratory system, thoracic organs and mediastinal disorders
		Nosebleed9
From the gastrointestinal tract
	Mild, transient anticholinergic effects, including constipation and dry mouth	Abdominal distension9, hypersalivation	Pancreatitis11
From the hepatobiliary system
	Transient, asymptomatic fluctuations in liver transaminase levels (ALT and AST), especially at the beginning of treatment		Hepatitis (including hepatocellular, cholestatic, or mixed liver injury)11
From the skin and subcutaneous tissue
	Rash	Photosensitivity reactions, alopecia		Drug reaction with eosinophilia and systemic symptoms (DRESS)
From the musculoskeletal and connective tissue system
	Arthralgia9		Rhabdomyolysis11
Kidney and urinary system
		Incontinence, urinary retention, difficult urination11
Pregnancy, postpartum and perinatal period
				Withdrawal syndrome in newborns
From the reproductive system and mammary glands
	Erectile dysfunction in men, decreased libido in women and men	Amenorrhea, breast enlargement, galactorrhea in women, gynecomastia/ breast enlargement in men	Priapism12
General disorders and administration site conditions
	Asthenia, increased fatigue, edema, pyrexia10
Investigations
Increased plasma prolactin concentration8	Increased alkaline phosphatase10, increased creatine phosphokinase11, increased gamma-glutamyl transferase10, increased uric acid level10	Increased total bilirubin level

1 Clinically significant weight gain was observed in all BMI (body mass index) patient categories. With short-term treatment (mean duration of 47 days), weight gain of ≥ 7% occurred very commonly (22.2% of cases), ≥ 15% occurred commonly (4.2% of cases), and ≥ 25% occurred uncommonly (0.8% of cases). In patients receiving long-term therapy (at least 48 weeks), weight gain of ≥ 7%, ≥ 15%, and ≥ 25% occurred very commonly (in 64.4%, 31.7%, and 12.3% of cases, respectively).

2 Mean increases in fasting lipid levels (total cholesterol, LDL-C, and triglycerides) were more pronounced in patients who did not have lipid dysregulation prior to starting treatment.

3 Observed in patients with normal baseline fasting levels (< 5.17 mmol/L) that increased to high levels (≥ 6.2 mmol/L). Rapid increases in fasting total cholesterol levels from baseline (≥ 5.17 to < 6.2 mmol/L) to high levels (≥ 6.2 mmol/L) were reported very commonly.

4 Observed in patients with normal baseline fasting levels (< 5.56 mmol/L) that increased to high levels (≥ 7 mmol/L). Rapid increases in fasting glucose levels from baseline (≥ 5.56 to < 7 mmol/L) to high levels (≥ 7 mmol/L) were reported very commonly.

5 Observed in patients with normal baseline fasting levels (< 1.69 mmol/L) that increased to high levels (≥ 2.26 mmol/L). Rapid increases in fasting triglyceride levels from baseline (≥ 1.69 to < 2.26 mmol/L) to high levels (≥ 2.26 mmol/L) were reported very commonly.

6 During clinical studies, the incidence of parkinsonism and dystonia in patients treated with olanzapine was higher, but clinically insignificant, compared to the placebo group. The incidence of parkinsonism, akathisia, and dystonia in patients treated with olanzapine was lower than with titrated doses of haloperidol. Due to lack of information on the history of acute or tardive extrapyramidal movement disorders, it cannot be established that olanzapine causes less tardive dyskinesia and/or other late extrapyramidal syndromes.

7 Upon abrupt discontinuation of olanzapine therapy, acute symptoms were reported: increased sweating, insomnia, tremor, feelings of anxiety, nausea, and vomiting.

8 During clinical studies (up to 12 weeks), plasma prolactin concentrations exceeded the upper limit of normal in 30% of patients treated with olanzapine who had normal baseline prolactin levels. In most patients, this increase was moderate and remained within values less than twice the upper normal limit.

9 Adverse reactions were identified from clinical trials in the integrated olanzapine database.

10 Assessment of measured values was determined from clinical trials in the integrated olanzapine database.

11 Adverse reactions were identified from spontaneous post-marketing reports with frequency established based on the integrated olanzapine database.

12 Adverse reactions were identified from spontaneous post-marketing reports with frequency estimated using the upper limit of the 95% confidence interval based on the integrated olanzapine database.

Effects with long-term use (at least 48 weeks)

The percentage of patients experiencing adverse reactions such as clinically significant weight gain, changes in glucose, total cholesterol/LDL-C/HDL-C, or triglyceride levels continuously increased. In adult patients who completed 9–12 months of therapy, the rate of increase in fasting blood glucose slowed approximately after 6 months of treatment.

Adverse reactions in specific populations

In clinical trials involving elderly patients with dementia, olanzapine therapy was associated with increased mortality and cerebrovascular adverse reactions compared to placebo. Very common adverse reactions associated with olanzapine use in this patient group were gait disturbance and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations, and urinary incontinence were commonly observed.

In clinical trials among patients with medication-induced (dopamine agonist) psychosis associated with Parkinson’s disease, worsening of parkinsonian symptoms and hallucinations occurred very commonly and more frequently than in the placebo group.

In one clinical study, neutropenia was observed in 4.1% of patients with bipolar mania treated with olanzapine in combination with valproate; a possible cause may be elevated plasma valproate levels. With olanzapine used in combination with lithium or valproate, tremor, dry mouth, increased appetite, and weight gain were observed in ≥ 10% of patients. Speech disorder was also reported. During olanzapine therapy in combination with lithium or valproate, weight gain of ≥ 7% BMI was observed in 17.4% of patients during intensive treatment (up to 6 weeks). Long-term olanzapine treatment (up to 12 weeks) for prevention of relapse in patients with bipolar disorders was associated with weight gain of ≥ 7% BMI in 39.9% of patients.

Children

Olanzapine is not indicated for treatment of children and adolescents under 18 years of age. Clinical studies comparing olanzapine use in adolescents and adults have not been conducted. However, data from studies in children were compared with results from adult studies.

Below are adverse reactions that occurred more frequently in adolescents (aged 13–17 years) than in adults, or adverse reactions identified only during short-term clinical trials in adolescents. Clinically significant weight gain (≥ 7%) was more frequently observed in adolescents compared to adults. With long-term treatment (at least 24 weeks), clinically significant weight gain was higher than with short-term treatment.

The frequency of the adverse reactions listed below, in decreasing order of incidence, is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10).

Metabolism and nutrition disorders Very common: weight gain13, increased triglyceride levels14, increased appetite. Common: increased cholesterol levels15.

Nervous system disorders Very common: sedation (including hypersomnia, lethargy, somnolence).

Gastrointestinal disorders Common: dry mouth.

Hepatobiliary disorders Very common: increased levels of liver transaminases (ALT and AST);

Investigations Very common: decreased total bilirubin levels, increased gamma-glutamyl transferase levels, increased plasma prolactin levels16.

13 After short-term treatment (mean duration was 22 days), weight gain of ≥ 7% was observed very commonly (40.6% of cases), weight gain of ≥ 15% was observed commonly (7.1% of cases), and weight gain of ≥ 25% occurred in 2.5% of cases. During long-term treatment (at least 24 weeks), weight gain of ≥ 7% was observed in 89.4% of patients, of ≥ 15% in 55.3%, and of ≥ 25% in 29.1% of patients.

14 Observed in patients with normal baseline fasting levels (< 1.016 mmol/L) that increased to high levels (≥ 1.467 mmol/L), as well as a marked increase in fasting triglyceride levels from initial levels (≥ 1.016 to < 1.467 mmol/L) to high levels (≥ 1.467 mmol/L).

15 Observed in patients with normal baseline fasting cholesterol levels (< 4.39 mmol/L) that increased to high levels (≥ 5.17 mmol/L). A marked increase in fasting total cholesterol levels from initial levels (≥ 4.39 to < 5.17 mmol/L) to high levels (≥ 5.17 mmol/L) was reported very commonly.

16 Elevated plasma prolactin levels were observed in 47.4% of adolescents.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 7 tablets per blister. 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sp. z o.o. "Adamed Pharma", Poland.

Manufacturer's address and location of business activity.

ul. Marsz. J. Piłsudskiego 5, 95-200 Pabianice, Poland.