Olanzapine, 10 mg 28 pcs

Pharmacotherapeutic group

Antipsychotic drug (neuroleptic)

ATC code

N05AH03

Pharmacodynamics:

Olanzapine is an antipsychotic (neuroleptic).

In preclinical studies, affinity for 5-NT_2A/2C– 5-NT₃– 5-NT₆-serotonin receptors; D₁– D₂– D₃– D₄– D₅-dopamine receptors; m-cholinoblocking effects are due to blockade of m_1-5-cholinoreceptors; also has an affinity for α₁-adreno- and H₁-histamine receptors. Antagonism to serotonin dopamine and m-cholinoreceptors has been detected in animal experiments. In vivo and in vitro olanzapine has a more pronounced affinity and activity toward 5-NT₂-serotonin receptors compared to D₂-dopamine receptors. According to electrophysiological studies, olanzapine selectively reduces excitability of mesolimbic dopaminergic neurons and at the same time has little effect on striatal nerve pathways involved in the regulation of motor functions.

Pharmacokinetics:

After oral administration olanzapine is well absorbed and its maximum plasma concentration is reached after 5-8 hours. The absorption of olanzapine is independent of food intake. Studies with different doses ranging from 1 mg to 20 mg have shown that plasma concentrations of olanzapine vary linearly and in proportion to the dose. Olanzapine is metabolized in the liver by conjugation and oxidation processes. The main circulating metabolite is 10-N-glucuronide, which theoretically does not penetrate the blood-brain barrier.

The CYP1A2 and CYP2D6 cytochrome P450 isoenzymes are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Both metabolites had significantly less pronounced in vivo pharmacological activity than olanzapine in animal studies. The main pharmacological activity of the drug is due to the parent substance olanzapine.

In healthy volunteers after oral administration, the mean half-life (T_1/2) was 33 hours (21-54 hours for 5-95%) and the mean plasma clearance of olanzapine was 26 l/h (12-47 l/h for 5-95%).

Pharmacokinetic parameters vary by smoking sex and age (see table):

.

Indications

Schizophrenia.

Bipolar affective disorder type I. Olanzapine as monotherapy or in combination with lithium or valproic acid is indicated for the treatment of acute manic or mixed episodes of bipolar affective disorder with/without psychotic manifestations and with/without rapid phase change. Olanzapine is indicated to prevent relapse in patients with bipolar disorder in whom olanzapine was effective in treating the manic phase.

In combination with fluoxetine, olanzapine is indicated for the treatment of a depressive episode within the structure of bipolar disorder.

Therapeutically resistant depression. In combination with fluoxetine, olanzapine is indicated for the treatment of therapeutically resistant depression in adult patients (major depressive episodes with a history of ineffective use of two antidepressants at a dose and duration of therapy adequate for the episode).

Active ingredient

Composition

1 film-coated tablet contains:

dosage 10 mg

active ingredient: olanzapine (olanzapine form 1) 10 mg;

excipients: lactose monohydrate (lactopress) (milk sugar) 148.4 mg; calcium stearate 1.6 mg;

coating composition: Opadray II (polyvinyl alcohol, partially hydrolyzed 1.6 mg; talc 0.592 mg; titanium dioxide E 171 0.8748 mg; macrogol (polyethylene glycol 3350) 0.808 mg; quinoline yellow aluminum varnish 0.1204 mg; sunset yellow aluminum varnish 0.0028 mg; iron oxide (II) yellow dye 0.0012 mg; indigo carmine aluminum varnish 0.0008 mg).

How to take, the dosage

Olanzapine can be taken regardless of meals because eating does not affect the absorption of the drug.

Schizophrenia

The recommended starting dose of olanzapine is 10 mg once daily. Therapeutic doses of olanzapine range from 5 mg to 20 mg daily. Daily dose should be chosen individually, depending on the clinical condition of the patient. Increasing the dose beyond the standard daily dose (10 mg) is recommended only after evaluating the clinical picture.

Bipolar affective disorder type I

For the treatment of a manic episode, the recommended starting dose of olanzapine is 15 mg once daily as monotherapy or 10 mg once daily in combination with lithium or valproic acid. Therapeutic doses of olanzapine range from 5 mg to 20 mg per day. The daily dose should be selected individually, depending on the clinical condition of the patient. Increasing the dose beyond the standard daily dose is recommended only after evaluation of the patient’s clinical condition and at intervals of at least 24 hours.

Supportive therapy in bipolar disorder: Patients who have taken olanzapine for treatment of a manic episode should continue supportive therapy at the same dose. In patients in remission, the recommended starting dose of olanzapine is 10 mg once daily. Thereafter, the daily dose needs to be adjusted individually, depending on the clinical condition of the patient, within a range of 5 mg to 20 mg per day.

For the treatment of a depressive episode olanzapine should be prescribed in combination with fluoxetine once daily in the evening regardless of meals. The starting dose is usually 5 mg of olanzapine and 20 mg of fluoxetine. Antidepressant activity has been confirmed with olanzapine at a dose of 6-12 mg (mean daily dose of 74 mg) and fluoxetine at a dose of 25-30 mg (mean daily dose of 393 mg). If necessary, it is possible to change the dose of both olanzapine and fluoxetine.

Therapeutically resistant depression

Olanzapine should be given in combination with fluoxetine once daily in the evening, regardless of meals. The starting dose is usually 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, it is allowed to change the dose of both olanzapine and fluoxetine. Antidepressant activity has been confirmed with olanzapine at a dose of 6-12 mg and fluoxetine at a dose of 25-30 mg.

General rules for choosing a daily dose when taken orally for special groups of patients.

Lowering the starting dose to 5 mg daily is recommended in elderly patients or patients with other clinical risk factors including severe renal impairment or moderate hepatic impairment. Reducing the starting dose may be recommended for patients with a combination of factors (female patients of advanced age non-smokers) that may slow down olanzapine metabolism.

Interaction

Metabolism of olanzapine may be altered by inhibitors or inducers of cytochrome P450 isoenzymes with specific activity against CYP1A2 isoenzyme. Clearance of olanzapine is increased in smoking patients and in patients taking carbamazepine (due to increased activity of CYP1A2 isoenzyme). Known potential inhibitors of CYP1A2 isoenzyme may decrease clearance of olanzapine. Olanzapine is not a potential inhibitor of CYP1A2 activity, therefore pharmacokinetics of drugs such as theophylline, which are mainly metabolized with the participation of CYP1A2 isoenzyme, is not changed during Olanzapine administration. A single dose of Olanzapine against the background of the therapy with the following drugs was not accompanied by inhibition of metabolism of these drugs: imipramine or its metabolite desipramine (CYP2D6 isoenzyme CYP3A isoenzyme CYP1A2) warfarin (CYP2C19 isoenzyme) theophylline (CYP1A2 isoenzyme) or diazepam (CYP3A4 isoenzyme CYP2C19). There is also no evidence of drug interaction when using olanzapine in combination with lithium and biperidine.

There have been no changes in the pharmacokinetics of ethanol at steady-state concentrations of olanzapine. However, administration of ethanol together with olanzapine may be accompanied by enhancement of pharmacological effects of olanzapine (sedative effect).

A single dose of aluminum- or magnesium-containing antacid or cimetidine did not impair bioavailability of olanzapine when taken orally. Co-administration of activated charcoal reduced the bioavailability of olanzapine when taken orally by up to 50-60%.

Fluoxetine (60 mg once or 60 mg daily for 8 days) causes an average 16% increase in maximum concentration (Cmax) of olanzapine and an average 16% decrease in clearance of olanzapine which has no clinical significance (no adjustment of olanzapine dose is necessary). The CYP1A2 isoenzyme inhibitor fluvoxamine decreases clearance of olanzapine increases Cmax olanzapine in non-smoking women by 54% and by 77% in smoking men. The mean increases in AUC of olanzapine are 52% and 108%, respectively. Low-dose olanzapine should be administered to patients who are co-treated with fluvoxamine.

In in vitro studies using human liver microsomes have shown that olanzapine slightly inhibits the formation of valproate glucuronide (the main metabolic pathway of valproate). Valproate also slightly affects the metabolism of olanzapine in vitro. Therefore, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely.

According to in vitro studies using human liver microsomes, olanzapine has also shown very little potential to inhibit the activity of the following cytochrome P450 isoenzymes: CYP1A2 isoenzyme CYP2C9 isoenzyme CYP2C19 isoenzyme CYP2D6 isoenzyme CYP3A.

Special Instructions

Malignant neuroleptic syndrome. Malignant neuroleptic syndrome (MNS) can occur with treatment with any neuroleptic, including Olanzapine. Clinical manifestations of MNS include significant increases in body temperature muscular rigidity changes in mental status and autonomic disturbances (unstable pulse or blood pressure tachycardia cardiac arrhythmias increased sweating). Additional signs may include increased creatine phosphokinase levels myoglobinuria (rhabdomyolysis) and acute renal failure. Clinical manifestations of MNS or significant increases in body temperature without other symptoms of MNS require withdrawal of all neuroleptics including olanzapine.

Late dyskinesia. In comparative studies lasting more than 6 weeks, treatment with olanzapine was significantly less likely to develop dyskinesia requiring drug correction than use of haloperidol. However, the risk of tardive dyskinesia with prolonged treatment with neuroleptics should be considered. If signs of tardive dyskinesia develop, dose reduction or withdrawal of Olanzapine is recommended. Symptoms of tardive dyskinesia may increase or manifest after drug withdrawal.

Application in elderly patients with psychosis against a background of dementia. Cerebrovascular adverse events (e.g., stroke, transient ischemic attack) including fatalities have been reported in studies of olanzapine in elderly patients with psychosis with dementia. In placebo-controlled trials, there was a higher incidence of cerebro-vascular adverse events in patients in the olanzapine group compared to the placebo group (13% vs. 04%, respectively).

These patients had prior risk factors (history of cerebrovascular events (history) transient ischemic attack arterial hypertension smoking) as well as comorbidities and/or medication use over time associated with cerebrovascular events.

The efficacy of olanzapine in elderly patients with dementia psychosis has not been established. In this category of patients in placebo-controlled clinical trials, the mortality rate in the olanzapine group was higher than in the placebo group (35% vs. 15%, respectively). The main risk factors for increased mortality in this group of patients treated with olanzapine are age ≥80 years, sedation combined with benzodiazepines, or the presence of pulmonary pathology (e.g. pneumonia with or without aspiration). Older patients with dementia psychosis receiving therapy with atypical psychotics are at increased risk of death compared to placebo. Olanzapine is not recommended for the treatment of patients with psychosis against a background of dementia.

There is insufficient data to establish differences in the incidence of cerebrovascular events and/or mortality (compared to placebo) and risk factors in this group of patients when olanzapine is given by oral and intramuscular injections.

Liver function disorders. In isolated cases, administration of Olanzapine usually in the early stages of therapy was accompanied by transient asymptomatic elevation of hepatic serum transaminases (aspartate aminotransferase and alanine aminotransferase). Rare cases of hepatitis were noted. Very rare cases of hepatic cholestasis and other mixed liver damage have been noted. Particular caution is required when serum aspartate aminotransferase and/or alanine aminotransferase values increase in patients with liver function insufficiency with limited liver functional reserve or in patients receiving treatment with potentially hepatotoxic drugs. In case of increase of aspartate aminotransferase and/or alanine aminotransferase values during treatment with olanzapine it is required to monitor the patient closely and reduce the dose if necessary.

Hyperglycemia and diabetes mellitus. A higher prevalence of diabetes mellitus has been noted in patients with schizophrenia. Very rare cases of hyperglycemia have been reported in the development of diabetes mellitus or exacerbation of pre-existing diabetes mellitus ketoacidosis and diabetic coma. A causal relationship between antipsychotic medications and these conditions has not been established. Clinical monitoring of patients with diabetes mellitus or with risk factors for its development is recommended.

Hematologic changes. The use of Olanzapine in patients with clozapine-dependent neutropenia or agranulocytosis (history) was not accompanied by recurrence of these disorders.

Dopaminergic antagonism. Olanzapine exhibits antagonism to dopamine and can theoretically inhibit the effects of levodopa and dopamine agonists.

Parkinson’s disease. The use of olanzapine in the treatment of psychosis induced by dopamine receptor agonists in Parkinson’s disease is not recommended.

In clinical studies in patients with psychosis induced by taking the drug (dopamine receptor agonist) in Parkinson’s disease, an increase in Parkinsonian symptoms was noted very frequently (≥10%) and with a higher frequency than in the placebo group. Hallucinations were also noted very frequently (≥10%) and with a higher frequency than in the placebo group.

Changes in lipid profile. In placebo-controlled studies, adverse changes in the lipid spectrum have been observed in patients receiving olanzapine. Clinical monitoring is recommended (see side effects).

Developmental risk of sudden death. Clinical experience with any neuroleptic including olanzapine showed a similar dose-dependent doubling of the risk of death due to acute heart failure compared to death due to acute heart failure in patients not using neuroleptics.

Convulsions. Olanzapine should be used with caution in patients with a history of seizures or those exposed to factors that lower the seizure threshold. Seizures have rarely been observed in such patients when treated with olanzapine.

M-cholinoblocking activity. In clinical trials, olanzapine therapy has rarely been associated with m-cholinoblocking side effects. However, clinical experience with olanzapine in patients with comorbidities is limited so caution is advised when prescribing olanzapine to patients with clinically significant prostatic hyperplasia paralytic bowel obstruction closed-angle glaucoma and similar conditions.

Neutropenia. Caution should be used with olanzapine in patients with low leukocyte and/or neutrophil counts in the blood; receiving drugs that may cause neutropenia; with suppression of bone marrow function due to radiation or chemotherapy disease; and in patients with eosinophilia and/or myeloproliferative diseases. Neutropenia has been reported mainly when olanzapine is combined with valproate.

The duration of the QT interval. Clinically significant QT interval prolongation (Friedericia-adjusted QT interval [QTcF] ≥500 msec in patients with baseline QTcF < 500 msec) in patients receiving olanzapine has not been frequently observed in clinical trials against no significant difference with placebo in the incidence of cardiac adverse events. However, as with other antipsychotics, caution is recommended when prescribing olanzapine in combination with agents able to prolong QT interval, especially in elderly patients with congenital prolongation of QT interval congestive heart failure myocardial hypertrophy hypokalemia and hypomagnesemia.

Cancellation of therapy. In the case of abrupt withdrawal of olanzapine, acute development of sweating insomnia tremors anxiety nausea and vomiting have been reported extremely rarely (<001%).

Thromboembolism. The development of venous thromboembolism during therapy with olanzapine has been reported extremely rarely (< 001%). A causal relationship between olanzapine administration and venous thromboembolism has not been established. However, taking into account that patients with schizophrenia often have acquired risk factors for venous thromboembolism, a comprehensive evaluation of all possible risk factors for this complication, including immobilization of patients, should be performed and necessary preventive measures taken.

General activity with respect to the CNS. Given olanzapine’s main effect on the CNS, caution should be exercised when using olanzapine in combination with other centrally acting medications and alcohol.

Postural hypotension. Postural hypotension has been infrequently observed in clinical studies of olanzapine in the elderly. As with other antipsychotics, periodic blood pressure monitoring is recommended when olanzapine is prescribed for patients over 65 years of age.

Children and adolescents under 18 years of age. Olanzapine is not recommended for use in children and adolescents under 18 years of age due to insufficient data on efficacy and safety. In short-term studies conducted in adolescents 13-17 years old, greater increases in body weight and changes in lipid and prolactin concentrations were noted than in similar studies in adults.

Patients taking olanzapine should exercise caution when driving vehicles and engaging in potentially hazardous activities that require increased concentration and rapid psychomotor reactions because olanzapine may cause drowsiness.

Synopsis

Contraindications

Identified hypersensitivity to any of the ingredients of the drug.

Lactase deficiency lactose intolerance glucose-galactose malabsorption.

Application in children.The efficacy and safety of olanzapine in persons under 18 years of age has not been proven.

With caution:

Hepatic failure clinically significant prostatic hypertrophy closed-angle glaucoma paralytic intestinal obstruction.

Olanzapine should be used with caution in patients with decreased peripheral blood leukocyte and/or neutrophil counts due to various causes; with signs of oppressed or toxic bone marrow function due to medication (history); with suppressed bone marrow function due to concomitant radio disease or chemotherapy (history); with hypereosinophilia or myeloproliferative disease.

Olanzapine should be used with caution in patients with a history of epileptic seizures or in the presence of factors lowering the seizure threshold. Seizures have rarely been observed in such patients during treatment with olanzapine.

In view of the main effect of olanzapine on the CNS, caution should be exercised when using olanzapine in combination with other centrally acting drugs and alcohol.

Side effects

The table below summarizes the major adverse effects and their frequency reported during clinical trials and/or in the post-registration period.

Very common

(≥10%)

Frequent

(< 10% and ≥1%)

/p>

Infrequent

(≥01% &< 1%)

Frequency unknown

(frequency cannot be determined from available data)

Disorders of the circulatory and lymphatic systems

/p>

Eosinophilia

Leukopenia

Neutropenia

Thrombocytopenia

Immune system disorders

Allergic reactions

Metabolic and nutritional disorders

Increased body weight1

Elevated cholesterol concentration23

Increased glucose concentration4

Elevated triglyceride concentration25

Glucosuria

Decreased appetite

Development or decompensation of diabetes mellitus in some cases accompanied by ketoacidosis and diabetic coma, including fatal hypothermia

Decreased appetite

Hypothermia/p>

Nervous system disorders

Sleepiness

Dizziness Acathisia6 Parkinsonism6 Dyskinesia6

Withdrawal syndrome7

Cardiac disorders

Bradycardia prolongation of the QTc interval

Long QTc interval/p>

Ventricular tachycardia/ventricular fibrillation sudden death

Vascular disorders

Orthostatic hypotension

Pulmonary artery thromboembolism

Deep vein thrombosis

Disorders of the digestive system

/p>

Short-term anticholinergic effects including constipation and dry mouth

Pancreatitis

Liver and biliary tract disorders/p>

Transient increase in “hepatic” transferase activity (ALT ACT) especially in the early period of treatment

Hepatitis (including hepatic-cellular hepatocellular or mixed)

/p>

Skin and subcutaneous tissue disorders

Rash

/p>

Reaction of photosensitivity

Alopecia

Musculoskeletal disorders

Rhabdomyolysis

Renal and urinary tract disorders

Urinary incontinence

Delayed onset of urination

Disorders of the genitals and the mammary gland

/p>

Priapism

General disorders

Asthenia

Fatigue

/p>

Oedema

Laboratory findings

Increase in plasma prolactin concentration8

Increase in creatine phosphokinase activity Increase in total bilirubin concentration

Increase in alkaline phosphatase activity

1 There was a clinically significant increase in body weight for all patient groups regardless of body mass index. An increase in body weight of 7% or more of the mean value after a short course of treatment (mean duration of 47 days) was observed very frequently (222%) an increase of 15% or more was frequent (42%) and an increase of 25% or more was infrequent (08%).

In patients receiving long-term treatment (at least 48 weeks), increases of ≥7% ≥15% and ≥25% were very frequent (644% 317% 123%, respectively).

2The mean increase in fasting lipid concentrations (low-density lipoprotein (LDL) cholesterol and triglycerides) was more pronounced in patients without baseline signs of lipid metabolism disorders.

3An increase in cholesterol concentration from normal fasting (< 517 mmol/L) to elevated (≥62 mmol/L) was frequently observed. Changes in cholesterol concentration from borderline fasting (≥517 < 62 mmol/L) to elevated (>62 mmol/L) were very frequent.

4 An increase in glucose concentration from normal fasting values (<556 mmol/l) to elevated (≥7 mmol/l) was frequently observed. Changes in glucose concentration from borderline fasting (>556 – < 7 mmol/L) to elevated (≥7 mmol/L) were very frequent.

5 An increase in triglyceride concentration from normal fasting values (<169 mmol/L) to elevated (≥226 mmol/L) was frequently observed. Changes in triglyceride concentration from borderline fasting (≥169 to < 226 mmol/L) to elevated (≥226 mmol/L) were very frequent.

6 In clinical trials, cases of parkinsonism and dystonia were more frequent in patients taking olanzapine but the difference with the placebo group was not statistically significant.

In patients taking olanzapine, the incidence of parkinsonism and akathisia dystonia was less frequent than in patients receiving titrated doses of haloperidol. Because of the lack of detailed information about patients’ history of acute and tardive dyskinesias, it cannot be concluded at this time that olanzapine is less likely to cause the development of tardive dyskinesias or other tardive extrapyramidal syndromes.

7 Symptoms such as sweating insomnia tremor anxiety nausea and vomiting have been observed when olanzapine is abruptly withdrawn.

8 In clinical trials lasting up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal in approximately 30% of patients with normal baseline prolactin levels. In most of these patients, the increase in prolactin concentration was moderate and less than twice the upper limit of normal. Genital and breast dysfunctions possibly related to olanzapine treatment (amenorrhea, breast enlargement, gynecomastia in women and breast enlargement in men) were uncommon in patients treated with olanzapine. Sexual dysfunction possibly associated with olanzapine administration (erectile dysfunction in men decreased libido in men and women) were frequently observed.

Unwanted effects in special patient groups

A very common (≥10%) adverse effect of olanzapine in clinical trials in patients with psychosis associated with dementia was gait disturbance and falls.

The common (< 10% and ≥1%) adverse effects of olanzapine in elderly patients with psychosis associated with dementia were urinary incontinence and pneumonia.

In clinical studies in patients with psychosis induced by administration of the drug (dopamine receptor agonist) in Parkinson’s disease, an increase in Parkinsonian symptoms was noted very frequently (≥10%) and with a higher frequency than in the placebo group. Hallucinations were also noted very frequently (≥10%) and with a higher frequency than in the placebo group.

In patients with bipolar mania receiving olanzapine in combination with lithium or valproic acid, very frequent (>10%) adverse effects were increased body weight dry mouth increased appetite tremor and frequent (<10% and ≥1%) speech disorders.

Overdose

Symptoms. Very common (frequency ≥10%) symptoms are tachycardia agitation/aggressiveness articulation disorder various extrapyramidal disorders and impaired consciousness of varying severity (from sedation to coma). Other clinically significant effects of olanzapine overdose are delirium seizures malignant neuroleptic syndrome respiratory depression aspiration increased or decreased blood pressure (BP) cardiac arrhythmias (< 2% of overdoses) cardiac and respiratory arrest. The minimum dose in acute overdose with fatal outcome is 450 mg maximum in overdose with favorable outcome (survival) is 1500 mg.

Treatment. There is no specific antidote for olanzapine. Inducing vomiting is not recommended. Standard overdose procedures (gastric lavage, administration of activated charcoal) may be indicated. Co-administration of activated charcoal has been shown to reduce the bioavailability of olanzapine when taken orally to 50-60%. Symptomatic treatment in accordance with the clinical condition and control of vital organ functions, including treatment of arterial hypotension, circulatory disorders and maintenance of respiratory function are indicated. Dopamine epinephrine and other sympathomimetics that are beta-adrenoreceptor agonists should not be used as stimulation of these receptors may exacerbate arterial hypotension.

Pregnancy use

Similarities