Tizercin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIZERZIN® (TISERCINÒ)

Composition:

Active substance: levomepromazine;

25 mg of levomepromazine (methotrimeprazine) in 1 ml of solution;

Excipients: anhydrous citric acid, monothioglycerin, sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: colorless, clear aqueous solution with a characteristic odor.

Pharmacotherapeutic group. Antipsychotic agents. Levomepromazine.

ATC code N05A A02.

Pharmacological Properties

Pharmacodynamics.

Tizercin**®** is a phenothiazine-class neuroleptic. Levomepromazine is an analogue of chlorpromazine with a more pronounced suppressive effect on psychomotor activity.

By blocking dopamine receptors in the thalamus, hypothalamus, reticular formation, and limbic system, levomepromazine suppresses the sensory system, reduces motor activity, and produces a pronounced sedative effect. In addition, it exerts antagonistic effects on other neurotransmitter systems (norepinephrine, serotonin, histamine, acetylcholine). Due to these properties, levomepromazine exhibits antiemetic, antihistaminic, antiadrenergic, and anticholinergic actions. Extrapyramidal side effects are less pronounced compared to those observed with potent neuroleptics. Levomepromazine is a potent antagonist of alpha-adrenergic receptors, although its cholinoblocking activity is weak. Levomepromazine increases the pain threshold (analgesic activity similar to morphine) and produces amnestic effects. Due to its ability to potentiate the effects of analgesics, levomepromazine can be used as an adjuvant agent in the management of severe chronic and acute pain. The maximum analgesic effect after intramuscular administration develops within 20–40 minutes and lasts for approximately 4 hours.

Pharmacokinetics.

After intramuscular administration, maximum plasma concentration is reached within 30–90 minutes.

Levomepromazine is extensively metabolized, forming sulfate and glucuronide conjugates, which are excreted by the kidneys. A small amount of the dose (1%) is excreted unchanged in urine and feces. The elimination half-life is 15–30 hours.

Clinical characteristics.

Indications.

Acute psychotic states accompanied by psychomotor agitation and severe anxiety:

• acute episodes of schizophrenia;
• other severe psychotic states.

Adjuvant therapy in chronic psychoses:

• chronic schizophrenia;
• chronic hallucinatory psychoses.

Contraindications.

• Hypersensitivity to the active substance, phenothiazines, or to any other component of the medicinal product;
• concomitant use with other antihypertensive agents;
• concomitant use with monoamine oxidase inhibitors (MAOIs) (see section "Interaction with other medicinal products and other forms of interaction");
• concomitant use with central nervous system (CNS) depressants (alcohol, general anesthetics, hypnotics);
• closed-angle glaucoma;
• urinary retention;
• Parkinson's disease;
• multiple sclerosis;
• myasthenia gravis, hemiplegia;
• severe cardiomyopathy (circulatory failure);
• severe renal or hepatic insufficiency;
• clinically significant hypotension;
• blood disorders;
• porphyria;
• breastfeeding;
• pediatric age under 12 years.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Tizercin**®** and antihypertensive drugs increases the risk of severe hypotension.

Concomitant use of Tizercin**®** and antihypertensive medicinal products should be avoided.

When used concomitantly with MAO inhibitors, the effect of Tizercin**®** may be prolonged and its adverse effects intensified; therefore, simultaneous use of Tizercin**®** and MAO inhibitors is not recommended.

Concomitant use of Tizercin**®** with medicinal products that prolong the QT interval (some class IA (quinidine, hydroquinidine, disopyramide) and class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, macrolide antibiotics, certain azole antifungals, cisapride, certain antidepressants, antihistamines, diuretics with hypokalemic effect) may result in additive effects and increase the incidence of arrhythmias.

Concomitant administration with propafenone should be avoided. Propafenone inhibits the metabolism of levomepromazine via cytochrome P450 2D6. Levomepromazine is a potent inhibitor of cytochrome P450 2D6. When levomepromazine is used concomitantly with other medicinal products metabolized by cytochrome P450 2D6, increased plasma concentrations of these drugs may occur, leading to enhanced or prolonged therapeutic effects as well as adverse reactions.

Caution should be exercised when combining Tizercin**®** with anticholinergic agents (tricyclic antidepressants, H1-antihistamines, certain antiparkinsonian agents, atropine, scopolamine, succinylcholine), as the anticholinergic effect may be enhanced (paralytic intestinal obstruction, urinary retention, glaucoma). Extrapyramidal side effects have occurred when used with scopolamine.

There is an increased risk of arrhythmias when neuroleptics are used concomitantly with certain antimicrobial agents (such as sparfloxacin, moxifloxacin, and intravenous erythromycin), tetracyclic antidepressants (e.g., maprotiline), other neuroleptics (e.g., phenothiazines, pimozide, sertindole).

When used concomitantly with CNS depressants (narcotics, general anesthetics, anxiolytics, sedative-hypnotics, tranquilizers, tricyclic antidepressants), the CNS effects are potentiated.

Tizercin**®** reduces the effect of CNS stimulants (amphetamines) when used concomitantly.

Under the influence of Tizercin**®**, the antiparkinsonian effect of levodopa is markedly reduced due to antagonistic interaction caused by neuroleptic-induced blockade of dopaminergic receptors.

When Tizercin**®** is used concomitantly with oral antidiabetic agents, their effectiveness is reduced and hyperglycemia may develop.

Concomitant use of Tizercin**®** and labetalol enhances the effects of both drugs due to mutual inhibition of metabolism. When these drugs are used together, the dose of one or both agents should be reduced. Such an interaction cannot be excluded when other beta-blockers are used.

Photosensitization may be increased when Tizercin**®** is used concomitantly with medicinal products having photosensitizing effects.

Concomitant alcohol consumption during Tizercin**®** therapy may enhance CNS depressant effects, increasing the likelihood of extrapyramidal side effects; therefore, simultaneous use of Tizercin**®** and alcohol is not recommended.

Concomitant use with vitamin C reduces avitaminosis associated with Tizercin**®** use.

Special precautions for use.

If allergic reactions of any type occur, the drug should be discontinued immediately.

It is recommended to rotate injection sites for intramuscular injections of levomepromazine to prevent local tissue reactions to the drug.

Tizercin**®** should be used with particular caution when co-administered with anticholinergic agents.

Administration of the drug to patients with hepatic and/or renal insufficiency requires special attention due to the risk of drug accumulation and toxicity.

Elderly patients (especially those with dementia) are more prone to developing postural hypotension and are more sensitive to the anticholinergic and sedative effects of phenothiazines. In addition, they are also susceptible to extrapyramidal side effects. Therefore, treatment of such patients should be initiated with low doses, which should be gradually increased.

When prescribing Tizercin**®** to patients at increased risk of stroke, the benefit-risk ratio should be carefully evaluated.

Increased mortality in elderly patients with dementia

Results from two large observational studies showed that elderly patients with dementia treated with antipsychotics had an increased mortality rate compared to those not receiving these drugs. However, available data do not allow reliable assessment of the extent of risk or the causes of increased mortality.

Tizercin**®** is not indicated for the treatment of behavioral disorders associated with dementia.

To prevent the development of postural hypotension, the patient should remain lying down for 30 minutes after administration of the first dose. If dizziness occurs frequently after drug administration, the patient should be advised to remain in bed after each dose.

Injection sites should be rotated, as local skin irritation or damage to adjacent tissues may occur.

Caution should be exercised when administering the drug to patients with a history of cardiovascular disorders, particularly elderly patients and those with congestive heart failure or hemodynamic instability. An ECG should be performed before initiating treatment with Tizercin**®** to exclude the presence of cardiovascular disease that may contraindicate therapy. As with other phenothiazines, QT interval prolongation, arrhythmias, and very rarely ventricular fibrillation/torsades de pointes have been observed during treatment with Tizercin**®**.

Tizercin**®** should be prescribed with great caution in patients with risk factors for arrhythmia. If the clinical situation allows, the absence of the following risk factors for arrhythmia should be confirmed before initiating treatment: bradycardia or second- to third-degree atrioventricular block, metabolic disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, starvation or alcohol abuse, personal or family history of prolonged QT interval, ventricular arrhythmia or torsades de pointes, concomitant use of neuroleptics, concomitant use of other drugs that may provoke bradycardia, electrolyte imbalances, decreased intraventricular conduction, or QT interval prolongation.

Risk of venous thromboembolism (VTE)

An increased incidence of venous thromboembolism (VTE) has been reported in association with the use of neuroleptics. Since patients treated with neuroleptics often have acquired risk factors for VTE, these should be identified before and during treatment, and appropriate preventive measures should be implemented.

If hyperthermia occurs during antipsychotic therapy, the possibility of neuroleptic malignant syndrome (NMS) should always be considered. NMS is a potentially fatal condition characterized by symptoms such as muscle rigidity, hyperthermia, altered mental status, autonomic dysfunction (unstable blood pressure, tachycardia, arrhythmias, diaphoresis), and catatonia. Laboratory findings may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. The presence of these symptoms indicates possible NMS, and treatment with Tizercin**®** must be discontinued immediately. Treatment should also be discontinued even in the absence of clinical signs of NMS if unexplained hyperthermia occurs during therapy with Tizercin**®**. If, after recovery, further antipsychotic treatment is required, the choice of therapy should be thoroughly re-evaluated.

Tolerance to the sedative effects of phenothiazines and cross-tolerance among antipsychotic agents has been reported. This tolerance may manifest as withdrawal symptoms following abrupt discontinuation after high-dose or prolonged use: nausea, vomiting, headache, tremor, diaphoresis, tachycardia, insomnia, and restlessness. In view of this phenomenon, the drug should always be discontinued gradually.

Many neuroleptic drugs, including Tizercin**®**, may lower the seizure threshold and cause EEG changes. Therefore, in epileptic patients, clinical parameters and EEG findings should be monitored closely during dose titration.

Cholestatic (jaundice-like) hepatotoxic reactions, known to occur with chlorpromazine, may also occur with other phenothiazines. This reaction depends on individual patient sensitivity and resolves completely after discontinuation of treatment. Therefore, liver function should be monitored regularly during prolonged therapy.

Agranulocytosis and leukopenia have been observed in some patients treated with phenothiazines; therefore, despite the very low frequency of these events, regular blood monitoring is recommended during prolonged treatment with Tizercin**®**.

Since cases of hyperglycemia have been reported in patients receiving atypical antipsychotics, appropriate monitoring of blood glucose levels is recommended at the start of treatment with injectable forms of levomepromazine in patients with diabetes or risk factors for diabetes.

Alcoholic beverages are contraindicated during treatment with Tizercin**®** and for 4–5 days after discontinuation.

Regular monitoring of the following parameters is recommended before and throughout the treatment period:

• Blood pressure (especially in patients with hemodynamic instability or those prone to hypotension);
• Liver function (particularly in patients with liver disease);
• Blood count (in case of fever, pharyngitis, or suspicion of leukopenia or agranulocytosis);
• Serum calcium and magnesium levels;
• ECG (in patients with cardiovascular disorders and in elderly patients);
• Serum calcium, magnesium, and potassium levels.

Use during pregnancy or breastfeeding.

The safety of use during pregnancy has not been established. In some cases, congenital malformations have been observed in children whose mothers used phenothiazines during pregnancy; however, a causal relationship with phenothiazines has not been established. Due to the lack of controlled clinical data, the drug should not be used during pregnancy unless the potential benefit outweighs the possible risk to the fetus/child.

There is a risk of adverse reactions in newborns exposed to antipsychotic drugs (including levomepromazine) during the third trimester of pregnancy, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in the postnatal period. Symptoms reported include agitation, hypertension, hypotension, tremor, somnolence, respiratory disturbances, or feeding difficulties. Therefore, such newborns should be closely monitored.

Levomepromazine is excreted in breast milk; therefore, its use during breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery.

At the beginning of treatment, patients taking Tizercin**®** should refrain from driving and from work requiring high attention and rapid psychomotor reactions. Subsequent restrictions depend on the individual patient's response to treatment.

Method of Administration and Dosage

Parenteral administration of the drug is indicated when oral administration is not possible. For bedridden patients, the drug should be administered at a dose of 75–100 mg/day (in 2–3 divided doses), with monitoring of arterial pressure and heart rate. For intramuscular administration, the drug must be injected deeply into the muscle. For intravenous administration, the solution must be diluted and administered slowly by drip infusion (50–100 mg of Tizercin**®** in 250 mL of 0.9% sodium chloride solution or 5% glucose solution). The medicinal product may be administered only by a physician or nurse.

Children. The drug is contraindicated in children under 12 years of age.

Children are highly sensitive to the hypotensive or sedative effects of levomepromazine; therefore, a reduced daily dose (25–50 mg, divided into two doses) is recommended.

Overdose.

Symptoms

Loss of consciousness, tachycardia, ECG changes, hypothermia, dyskinesia.

Alterations in vital functions (arterial hypotension, hyperthermia), disturbances in cardiac conduction (prolongation of QT interval, ventricular tachycardia/fibrillation, ventricular tachycardia (torsade de pointes), atrioventricular block), extrapyramidal symptoms, sedative effect, central nervous system excitation (epileptic seizures), and neuroleptic malignant syndrome.

Treatment

Monitoring is recommended for the following parameters: acid-base status, fluid and electrolyte balance, renal function, urine output, liver enzyme levels, ECG in patients with neuroleptic malignant syndrome, as well as serum creatine phosphokinase levels and body temperature.

Symptomatic treatment should be administered according to the results of monitoring these vital parameters. In cases of arterial hypotension: intravenous fluid administration, Trendelenburg position, and use of dopamine and/or norepinephrine (due to the proarrhythmic effect of Tizercin**®**, a resuscitation kit should be readily available; ECG monitoring is required when administering dopamine and/or norepinephrine). Epinephrine (adrenaline) must not be used in patients taking neuroleptics. Lidocaine (lignocaine) should be avoided, and antiarrhythmic drugs with a prolonged duration of action should also be avoided as much as possible.

Seizures may be controlled with diazepam; in cases of recurrent seizures, phenytoin or phenobarbital may be used. Mannitol should be administered only if rhabdomyolysis develops. There is no specific antidote.

Forced diuresis, hemodialysis, and hemoperfusion are ineffective.

Treatment of neuroleptic malignant syndrome includes immediate discontinuation of neuroleptics and management using cooling measures. Sodium dantrolene may be used.

Neuroleptics should be used with caution if further administration is necessary.

Adverse reactions.

Cardiovascular system: the most serious adverse effect of the drug is most often postural hypotension, accompanied by weakness, dizziness, or fainting. Tachycardia, Adams–Stokes syndrome, QT interval prolongation (proarrhythmic effect, arrhythmia torsade de pointes), cardiac arrhythmias, cardiac arrests that may lead to sudden death may also occur.

Blood and lymphatic system disorders: pancytopenia, agranulocytosis, leukopenia, eosinophilia, thrombocytopenia; venous thromboembolism, including cases of pulmonary embolism and deep vein thrombosis.

Immune system disorders: anaphylactic reactions, laryngeal edema, peripheral edema, asthma.

Central nervous system: disorientation, confusion, visual hallucinations, slurred speech, extrapyramidal symptoms (dyskinesia, dystonia, parkinsonism, opisthotonus, hyperreflexia), epileptic seizures, increased intracranial pressure, reactivation of psychotic symptoms, catatonia, neuroleptic malignant syndrome.

Endocrine system and metabolism: galactorrhea, menstrual disorders, weight loss. In some patients treated with phenothiazine, pituitary adenoma has been observed. However, further studies are required to establish a causal relationship with the drug.

Urinary and reproductive system: discoloration of urine, difficulty in urination, very rarely – chaotic uterine contractions; priapism.

Gastrointestinal tract: dry mouth, abdominal discomfort, nausea, vomiting, constipation which may lead to the development of paralytic intestinal obstruction, liver damage (jaundice, cholestasis); necrotizing enterocolitis, which may be fatal.

Skin and subcutaneous tissue disorders: photosensitivity, erythema, urticaria, pigmentation, exfoliative dermatitis.

Eye disorders: lens and corneal opacities, pigmentary retinopathy.

Hypersensitivity reactions: laryngeal edema, peripheral edema, anaphylactoid reactions, asthma, allergic reactions.

Other: heat stroke in hot and humid environments; vitamin deficiency; glucose intolerance, hyperglycemia, withdrawal syndrome in newborns.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store at a temperature not exceeding 25°C in a place protected from light. Keep out of reach of children.

Incompatibility.

Do not mix in the same container with other medicinal products except those specified in the section "Dosage and administration".

Packaging. 1 ml in a clear glass ampoule of hydrolytic class I with two color-coded rings: red, blue, and a break point mark; 5 ampoules in a blister pack; 2 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer. EGIS Pharmaceuticals PLC, Hungary.

Manufacturer's name and address of the place of business.

1165 Budapest, Bokenyfoldi ut. 118-120, Hungary / 1165, Budapest, Bokenyfoldi ut. 118-120, Hungary