Zalasta^® Q-tab (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

N05AH03 (Olanzapine)

Active Substance

Olanzapine (Rec.INN registered by WHO)

Dosage Forms

	Zalasta® Q-tab®	Orally disintegrating tablets, 5 mg: 28 or 56 pcs.
		Orally disintegrating tablets, 10 mg: 28 or 56 pcs.

Dosage Form, Packaging, and Composition

Orally disintegrating tablets, yellow with marbling, round, slightly biconvex; the presence of individual inclusions is allowed.

Excipients: mannitol, microcrystalline cellulose type 102, crospovidone, low-substituted hydroxypropyl cellulose LH-21, aspartame, calcium silicate, magnesium stearate.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Orally disintegrating tablets, yellow with marbling, round, slightly biconvex; the presence of individual inclusions is allowed.

Excipients: mannitol, microcrystalline cellulose type 102, crospovidone, low-substituted hydroxypropyl cellulose LH-21, aspartame, calcium silicate, magnesium stearate.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic agent (neuroleptic)

Pharmacological Action

Olanzapine is an antipsychotic agent (neuroleptic) with a broad pharmacological spectrum of action.

The antipsychotic effect is due to the blockade of dopamine D2 receptors in the mesolimbic and mesocortical systems; the sedative effect is due to the blockade of adrenergic receptors in the brainstem reticular formation; the antiemetic effect is due to the blockade of dopamine D2 receptors in the trigger zone of the vomiting center; the hypothermic effect is due to the blockade of dopamine receptors in the hypothalamus.

In addition, it affects muscarinic, adrenergic, H1-histamine, and some subclasses of serotonin receptors.

Olanzapine reliably reduces both positive (delusions, hallucinations) and negative symptoms (hostility, suspicion, emotional and social autism) of psychoses. It rarely causes extrapyramidal disorders.

Pharmacokinetics

The absorption of olanzapine is high and does not depend on food intake; the time required to reach the maximum plasma concentration (T_max) after oral administration is 5-8 hours.

It penetrates histohematic barriers, including the blood-brain barrier (BBB). It is metabolized in the liver, does not form active metabolites; the main circulating metabolite is glucuronide, which does not penetrate the BBB.

Smoking, gender, and age affect the T_1/2 and plasma clearance. In individuals over 65 years of age, T_1/2 is 51.8 hours and plasma clearance is 17.5 L/hour; in individuals under 65 years of age, it is 33.8 hours and plasma clearance is 18.2 L/hour.

Plasma clearance is lower in patients with hepatic impairment, women, and non-smokers compared to the corresponding groups of individuals. It is excreted mainly by the kidneys (60%) as metabolites.

Indications

• The drug is indicated for the treatment of schizophrenia.

Zalasta^® Q-tab effectively maintains the improvement of clinical symptoms during long-term treatment in patients with an initial positive response to the drug.

• The drug Zalasta^® Q-tab is indicated for the treatment of moderate or severe manic episodes.

In patients with manic episodes who have a good response to olanzapine therapy, the drug is indicated for the prevention of recurrence of mania in bipolar disorder.

ICD codes

Dosage Regimen

Zalasta^® Q-tab orally disintegrating tablets dissolve quickly in the oral cavity under the action of saliva, after which they are easily swallowed.

Since the tablets are fragile, after removal from the blister, they should be taken immediately. Alternatively, immediately before administration, the tablet can be dissolved in a full glass of water.

Zalasta^® Q-tab orally disintegrating tablets are bioequivalent to plain Zalasta^® tablets; the rate and extent of absorption, doses, and dosing regimen are also equivalent. Zalasta^® Q-tab can be used as an alternative to Zalasta^® tablets.

Since food does not affect the absorption of the drug, Zalasta^® Q-tab orally disintegrating tablets can be taken regardless of meals. In case of drug withdrawal, a gradual dose reduction is recommended.

Schizophrenia the recommended initial dose of the drug is 10 mg per day.

Manic episode the initial dose is 15 mg as a single dose in monotherapy or 10 mg per day as part of combination therapy.

Prevention of recurrence in bipolar disorder the recommended initial dose of the drug in remission is 10 mg per day. For patients already receiving Zalasta^® Q-tab for the treatment of a manic episode, maintenance therapy is carried out at the same doses.

During therapy with Zalasta^® Q-tab, in case of a new manic, mixed, or depressive episode, it may be necessary to increase the dose of the drug with additional treatment for mood disorders, according to clinical indications.

The daily dose of the drug for the treatment of schizophrenia, manic episode, or prevention of recurrence of bipolar disorder can range from 5 to 20 mg/day, depending on the patient’s clinical condition.

Increasing the dose above the recommended initial dose should only be done after an adequate repeated clinical assessment of the patient’s condition and is usually performed at intervals of at least 24 hours.

Special patient groups

In elderly patients, a reduction in the initial dose (to 5 mg per day) is usually not recommended, but is possible in patients over 65 years of age in the presence of risk factors (see section “Special Precautions”).

Patients with liver and/or kidney diseases are recommended to reduce the initial dose to 5 mg/day. In moderate hepatic insufficiency (cirrhosis, class A or B according to the Child-Pugh classification of hepatocellular insufficiency in patients with liver cirrhosis), the initial dose is 5 mg/day, with possible further dose increase with caution.

Women do not require dose adjustment compared to men.

In non-smoking patients, no dose adjustment is required compared to smoking patients (see section “Drug Interactions”).

If a patient has more than one factor that can affect drug absorption (female gender, elderly age, non-smoker), a reduction in the initial dose may be required. If necessary, a further dose increase may be possible with caution.

Adverse Reactions

Classification of the frequency of side effects (WHO)

Very common >1/10

Common from > 1/100 to < 1/10

Uncommon from > 1/1000 to < 1/100

Rare from >1/10000 to < 1/1000

Very rare from < 1/10000, including isolated reports.

From the central (CNS) and peripheral nervous system very common – drowsiness; common – dizziness, akathisia, parkinsonism, dyskinesia; rare – seizure syndrome (more often against the background of a history of seizure syndrome); very rare – neuroleptic malignant syndrome (see section “Special Precautions”), dystonia (including oculogyric crisis) and tardive dyskinesia.

Upon abrupt withdrawal of olanzapine, very rare symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been noted.

From the cardiovascular system common – arterial hypotension (including orthostatic); uncommon – bradycardia with or without collapse; very rare – QTc interval prolongation on ECG (see section “Special Precautions”), ventricular tachycardia/fibrillation and sudden death (see section “Special Precautions”), thromboembolism (including pulmonary embolism and deep vein thrombosis).

From the gastrointestinal tract: common – transient anticholinergic effects, including constipation and dry mouth; very rare – pancreatitis.

Metabolism and nutrition disorders very common – weight gain; common – increased appetite; very rare – hyperglycemia and/or decompensation of diabetes mellitus, sometimes manifesting as ketoacidosis or coma, including fatal outcome; hypertriglyceridemia, hypercholesterolemia, hypothermia.

Hepatobiliary disorders common – transient, asymptomatic increase in the level of “liver” transaminases (ALT, AST), especially at the beginning of treatment (see “Special Precautions”); rare – hepatitis (including hepatocellular, cholestatic, or mixed liver damage).

From the hematopoietic and lymphatic system common – eosinophilia; rare – leukopenia; very rare – thrombocytopenia, neutropenia.

From the musculoskeletal system very rare – rhabdomyolysis.

From the genitourinary system very rare – urinary retention, priapism.

From the skin and subcutaneous tissue uncommon – photosensitivity reactions.

Allergic reactions rare – skin rash; very rare – anaphylactoid reactions, angioedema, skin itching or urticaria.

Other common – asthenia, peripheral edema; very rare – alopecia.

Laboratory parameters very common – hyperprolactinemia, but clinical manifestations (e.g., gynecomastia, galactorrhea, and breast enlargement) are rare. In most patients, prolactin levels spontaneously normalized without discontinuing therapy. Uncommon – increased level of creatine phosphokinase (CPK); very rare – increased level of alkaline phosphatase (ALP) and total bilirubin.

In elderly patients with dementia, studies have recorded a higher frequency of deaths and cerebrovascular disorders (stroke, transient ischemic attacks). Gait disturbances and falls were very common in this category of patients. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations, and urinary incontinence were also frequently observed.

Among patients with drug-induced (on the background of dopamine agonist use) psychoses in Parkinson’s disease, worsening of parkinsonian symptoms and the development of hallucinations were frequently reported.

There are data on the development of neutropenia (4.1%) during combination therapy with valproic acid in patients with bipolar mania. Concurrent therapy with valproic acid or lithium contributes to an increased frequency (> 10%) of tremor, dry mouth, increased appetite, and weight gain. Speech disorders (from 1 to 10%) were also frequently reported. In the first 6 weeks of combination therapy with lithium, the frequency of weight gain increases. Long-term therapy with olanzapine (up to 12 months) for the prevention of recurrence in patients with bipolar disorder was accompanied by an increase in body weight.

Contraindications

• Hypersensitivity to olanzapine or other components of the drug;
• Angle-closure glaucoma;
• Children under 18 years of age (efficacy and safety have not been established);
• Lactation period.

With caution renal failure, hepatic failure, prostatic hyperplasia, paralytic ileus, epilepsy, history of seizure syndrome, leukopenia and/or neutropenia of various origins, myelosuppression of various origins, including myeloproliferative diseases, hypereosinophilic syndrome, cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, congenital QT interval prolongation on ECG (prolongation of the corrected QT interval (QTc) on ECG) or in the presence of conditions potentially capable of causing QT interval prolongation (e.g., concurrent administration of drugs that prolong the QT interval, congestive heart failure, hypokalemia, hypomagnesemia), elderly age, as well as concurrent use of other centrally acting drugs; phenylketonuria, immobilization, pregnancy.

Use in Pregnancy and Lactation

Due to limited experience with the use of the drug in pregnant women, Olanzapine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.

Women should be informed of the need to inform their doctor about an occurred or planned pregnancy during olanzapine therapy. There are isolated reports of tremor, arterial hypertension, lethargy, and drowsiness in children born to mothers who took Olanzapine in the third trimester of pregnancy.

A study found that Olanzapine is excreted in breast milk. The average dosage (mg/kg) received by the infant at steady-state maternal concentration was 1.8% of the mother’s olanzapine dose (mg/kg). Breastfeeding is not recommended during olanzapine therapy.

Use in Hepatic Impairment

Use with caution in patients suffering from hepatic insufficiency.

Use in Renal Impairment

Use with caution in patients suffering from renal insufficiency.

Pediatric Use

The drug is contraindicated in children under 18 years of age (efficacy and safety have not been established).

Special Precautions

There are very rare reports of the development of hyperglycemia and/or decompensation of diabetes mellitus, sometimes accompanied by the development of ketoacidosis or ketoacidotic coma, including reports of several fatal cases.

In some cases, weight gain preceding decompensation was noted, which could have been a predisposing factor. Patients suffering from diabetes mellitus or with risk factors for developing this disease are recommended to have regular clinical monitoring and blood glucose level control. If lipid levels change, therapy adjustment is required.

Upon abrupt discontinuation of olanzapine, very rarely (less than 0.01%) the following symptoms may develop: sweating, insomnia, tremor, anxiety, nausea, or vomiting. When discontinuing the drug, a gradual dose reduction is recommended.

Anticholinergic activity. Since clinical experience with olanzapine in people with comorbidities is limited, the drug should be prescribed with caution to patients with prostatic hyperplasia, paralytic ileus.

Experience with the use of olanzapine in patients with psychoses in Parkinson’s disease induced by dopaminomimetics. Olanzapine is not recommended for the treatment of psychoses in Parkinson’s disease induced by dopaminomimetics. Symptoms of parkinsonism and hallucinations are exacerbated. At the same time, Olanzapine was not superior to placebo in the effectiveness of treating psychoses.

Olanzapine is not indicated for the treatment of psychoses and/or behavioral disorders in dementia, due to increased mortality and an increased risk of cerebrovascular disorders (stroke, transient ischemic attacks). The increased mortality is not dependent on the dose of olanzapine or the duration of therapy. Risk factors predisposing to increased mortality include: age over 65 years, dysphagia, sedation, insufficient nutrition and dehydration, lung diseases (e.g., pneumonia, including aspiration pneumonia), concurrent use of benzodiazepines. However, the increased frequency of death in the olanzapine groups compared to placebo was not dependent on these risk factors.

During therapy with antipsychotics, improvement in the patient’s clinical condition occurs over a period of several days to several weeks. During this period, the patient requires careful monitoring.

Liver function disorders. At the beginning of therapy, an asymptomatic increase in liver transaminases (ALT and AST) is possible. In patients with initially elevated AST and/or ALT levels, with hepatic insufficiency and conditions potentially limiting liver functional capabilities, as well as those taking hepatotoxic drugs, caution should be exercised when prescribing olanzapine. If ALT and/or AST increase during therapy with the drug, medical supervision of the patient is recommended and, possibly, a reduction in the drug dose. If hepatitis (including hepatocellular, cholestatic, or mixed) is diagnosed, Olanzapine should be discontinued.

Hematological changes. The drug should be used with caution in patients with leukopenia and/or neutropenia of any origin, drug-induced myelosuppression, as well as during radiation or chemotherapy, due to concomitant diseases, in patients with hypereosinophilic conditions or myeloproliferative diseases. Neutropenia was frequently noted with the concurrent use of olanzapine and valproic acid (see section “Adverse Reactions”).

Neuroleptic malignant syndrome (NMS). NMS is a potentially life-threatening condition associated with antipsychotic (neuroleptic) therapy, including olanzapine. Clinical manifestations of NMS: fever, muscle rigidity, impaired consciousness, autonomic disturbances (unstable pulse or labile blood pressure, tachycardia, increased sweating, arrhythmias). Additional symptoms of NMS: increased CPK, myoglobinuria (against the background of rhabdomyolysis) and acute renal failure. If symptoms of NMS develop, as well as an increase in body temperature for no apparent reason, all neuroleptics, including Olanzapine, must be discontinued.

Seizure disorder. Olanzapine should be prescribed with caution to patients with a history of seizures or with factors that lower the seizure threshold. Seizures have been reported rarely during treatment with olanzapine.

Tardive dyskinesia. Therapy with olanzapine was associated with a significantly lower incidence of tardive dyskinesia compared to haloperidol. The risk of developing tardive dyskinesia increases with the duration of treatment. If signs of this condition appear in a patient taking Olanzapine, the drug should be discontinued or its dose reduced. Dyskinesia symptoms may temporarily worsen after drug discontinuation.

Overall CNS activity. Caution should be exercised when using other centrally acting drugs and alcohol concomitantly.

Cerebrovascular adverse events, including stroke in elderly patients with dementia. Postural hypotension is observed infrequently in the elderly. In patients over 65 years of age, periodic blood pressure monitoring is recommended. Olanzapine should be prescribed with caution to patients with a known prolongation of the QTc interval, especially the elderly, those with congenital long QT syndrome, congestive heart failure, myocardial hypertrophy, hypokalemia, and hypomagnesemia.

Cases of venous thromboembolism have been reported very rarely (less than 0.01%) during treatment with olanzapine. A causal relationship between olanzapine therapy and venous thrombosis has not been established. Since patients with schizophrenia often have acquired risk factors for venous thrombosis, all other possible factors (e.g., immobilization) should be identified and preventive measures taken.

Zalasta^® Quicktab tablets contain aspartame, a source of phenylalanine. The drug may be unsafe for people suffering from phenylketonuria.

Effect on the ability to drive vehicles and operate machinery

Since Olanzapine may cause drowsiness and dizziness, patients should exercise caution when operating technical devices, including driving a car.

Overdose

Symptoms very common (> 10%) symptoms of olanzapine overdose are: tachycardia, agitation/aggression, dysarthria, various extrapyramidal symptoms, decreased level of consciousness from lethargy to coma; occurring in less than 2% of cases: delirium, convulsions, coma, neuroleptic malignant syndrome, respiratory depression, aspiration, arterial hypertension or hypotension, cardiac arrhythmias; in very rare cases – cardiopulmonary failure. The minimum dose of olanzapine in an acute overdose with a fatal outcome is 450 mg, the maximum dose recorded in an overdose with a favorable outcome (survival) is 1500 mg.

Treatment there is no specific antidote. Inducing vomiting is not recommended. It is necessary to perform: gastric lavage, administration of activated charcoal (reduces the bioavailability of olanzapine by 60%), symptomatic treatment with monitoring of vital functions, including treatment of arterial hypotension and vascular collapse, and maintenance of respiratory function. The use of epinephrine, dopamine, or other sympathomimetics with beta-adrenergic activity is not recommended, as the latter may worsen arterial hypotension. Cardiovascular monitoring is necessary to detect possible arrhythmias. The patient should be under continuous medical supervision until complete recovery.

Drug Interactions

Potential drug interactions affecting the metabolism of olanzapine Olanzapine is metabolized by the CYP1A2 enzyme, therefore inhibitors or inducers of cytochrome P450 isoenzymes that exhibit specific activity against CYP1A2 may affect the pharmacokinetic parameters of olanzapine.

Inducers of CYP1A2 the clearance of olanzapine may be increased in smoking patients or with the concomitant use of carbamazepine, leading to a decrease in plasma concentration of olanzapine. Clinical monitoring is recommended, as some cases may require an increase in the drug dose.

Inhibitors of CYP1A2 fluvoxamine, a specific inhibitor of CYP1A2, significantly reduces the clearance of olanzapine. The mean increase in C_max of olanzapine after fluvoxamine administration was 54% in non-smoking women and 77% in smoking men. The mean increase in the area under the curve AUC of olanzapine in these patient categories was 52% and 108%, respectively. In patients taking fluvoxamine or any other CYP1A2 inhibitor (e.g., ciprofloxacin), it is recommended to initiate olanzapine therapy at lower doses. A reduction in the olanzapine dose may also be required if CYP1A2 inhibitors are added to the therapy.

Drug interactions affecting/not affecting the bioavailability of olanzapine activated charcoal reduces the absorption of orally administered olanzapine by 50-60%, so it should be taken no less than 2 hours before or after taking olanzapine.

Fluoxetine (a CYP450 inhibitor), a single dose of magnesium- or aluminum-containing antacids, or cimetidine do not affect the pharmacokinetics of olanzapine.

Potential of olanzapine to affect other drugs

Olanzapine may antagonize the effects of direct and indirect dopamine agonists. In in vitro conditions, Olanzapine does not inhibit the major CYP450 isoenzymes (e.g., 1A2, 2D6, 2C9, 2C19, 3A4). In vivo, no inhibition of the metabolism of the following active substances was found: tricyclic antidepressants (CYP2D6), warfarin (CYP2C9), theophylline (CYP1A2), and diazepam (CYP3A4 and 2C19).

No interaction was identified with concomitant use of lithium or biperiden. Therapeutic monitoring of plasma valproic acid levels showed that no dose adjustments of valproic acid are required when co-administered with olanzapine (see the “Adverse Reactions” section).

Caution should be exercised when using other centrally acting drugs concomitantly. Although a single dose of alcohol (45 mg/70 kg) has no pharmacokinetic effect, alcohol intake together with olanzapine may be accompanied by an enhancement of the depressant effect on the CNS.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F), in the original packaging. Keep out of reach of children.

Shelf Life

The shelf life is 5 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.