Truxal

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRUKSAL (TRUXAL®)

Composition:

Active substance: chlorprothixene;

One tablet contains 25 mg or 50 mg of chlorprothixene hydrochloride;

Excipients: maize starch; lactose monohydrate; copovidone; glycerol (85%); microcrystalline cellulose; sodium croscarmellose; talc; magnesium stearate; OPADRY OY-S-9478 brown coating.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: 25 mg tablets – round, biconvex, film-coated tablets, dark brown in colour; 50 mg tablets – oval, biconvex, film-coated tablets, dark brown in colour.

Pharmacotherapeutic group.

Psycholeptics. Antipsychotics. Thioxanthene derivatives. Chlorprothixene.

ATC code N05AF03.

Pharmacological properties.

Pharmacodynamics.

Chlorprothixene is a neuroleptic from the thioxanthene group.

The antipsychotic effect of neuroleptics is associated with blockade of dopamine receptors, as well as a probable involvement of 5-HT (5-hydroxytryptamine) receptor blockade in this process.

Chlorprothixene has high affinity for 5-HT2 receptors and α1-adrenoceptors, making it similar in this respect to high-dose phenothiazines, levomepromazine, chlorpromazine, thioridazine, and the atypical neuroleptic clozapine. It has high histamine (H1) affinity equal to that of diphenhydramine. Chlorprothixene demonstrates high affinity for muscarinic cholinergic receptors. The receptor binding profile is quite similar to that of clozapine, although chlorprothixene has nearly 10 times greater affinity for dopamine receptors.

Chlorprothixene is a sedative neuroleptic with a broad range of indications.

Chlorprothixene reduces or eliminates anxiety, obsessive states, psychomotor agitation, restlessness, nervousness, and insomnia, as well as hallucinations, mania, and other psychotic symptoms. At low doses, it exerts an antidepressant effect, making it suitable for treatment of mental disorders associated with anxiety-agitation-depression syndrome and psychosomatic disorders.

Chlorprothixene does not cause addiction, dependence, or development of tolerance. Thus, chlorprothixene is effective in the treatment of both psychotic conditions and a wide spectrum of other mental disorders. In addition, chlorprothixene enhances the effect of analgesics, has its own analgesic effect, and possesses antipruritic and antiemetic properties.

Pharmacokinetics.

After oral administration of chlorprothixene, maximum plasma levels are observed approximately after 2 hours (range 0.5–6 hours). The mean bioavailability after oral administration is 12% (range 5–32%).

Protein binding in plasma is >99%. Chlorprothixene crosses the placental barrier.

Metabolism of chlorprothixene occurs mainly via sulfoxidation and N-demethylation.

The elimination half-life (T1/2β) is approximately 15 hours (range 3–29 hours). Systemic clearance (Cls) is approximately 1.2 L/min. Excretion occurs via feces and urine.

Chlorprothixene passes into breast milk in small amounts. The milk-to-plasma concentration ratio ranges from 1.2 to 2.6.

There is no information on pharmacokinetic parameters in patients with impaired liver or kidney function, or in elderly patients.

No differences in plasma concentration or elimination rate have been found between control subjects and alcoholics, regardless of whether they were sober or under the influence of alcohol at the time.

Clinical characteristics.

Indications.

Schizophrenia and other psychoses with psychomotor agitation, agitation, and anxiety disorders.

Contraindications.

Hypersensitivity to any component of the drug or to thioxanthene derivatives.

Circulatory collapse, central nervous system depression of any etiology (e.g., due to alcohol, barbiturate, or opioid intoxication), coma.

Chlorprothixene may cause QT interval prolongation. Persistent QT prolongation may increase the risk of life-threatening arrhythmias. Therefore, chlorprothixene is contraindicated in patients with a history of clinically significant cardiovascular disorders (e.g., bradycardia <50 beats/min, recent acute myocardial infarction, uncompensated heart failure, cardiac hypertrophy, arrhythmias requiring antiarrhythmic drugs of class IA or III) and in patients with a history of ventricular arrhythmias or torsades de pointes.

Chlorprothixene is contraindicated in patients with uncorrected hypokalemia and hypomagnesemia.

Chlorprothixene is contraindicated in patients with hereditary long QT syndrome or established acquired QT prolongation (QTc >450 msec in males and >470 msec in females).

Concomitant use with medicinal products that significantly prolong the QT interval.

Interaction with other medicinal products and other forms of interaction.

Combinations requiring caution during use.

Chlorprothixene may enhance the sedative effects of alcohol, barbiturates, and central nervous system depressants.

Neuroleptics may potentiate or diminish the effects of antihypertensive agents; the hypotensive effect of guanethidine and similarly acting agents is reduced.

Concomitant use of neuroleptics and lithium increases the risk of neurotoxicity.

Tricyclic antidepressants and neuroleptics mutually inhibit each other's metabolism.

Chlorprothixene may reduce the efficacy of levodopa and adrenergic agents, and combination with metoclopramide and piperazine increases the risk of extrapyramidal disorders.

Neuroleptic agents are metabolized by the hepatic cytochrome P450 system. Medicinal products that are inhibitors of the CYP2D6 cytochrome system (e.g., paroxetine, fluoxetine, chloramphenicol, disulfiram, isoniazid, MAO inhibitors, oral contraceptives, to a lesser extent buspirone, sertraline, or citalopram) may increase plasma levels of chlorprothixene.

Concomitant use of chlorprothixene and agents with anticholinergic activity enhances anticholinergic effects.

The antihistaminic effect of chlorprothixene may diminish or abolish the alcohol/disulfiram reaction.

QT interval prolongation associated with antipsychotic agents may be exacerbated when used concomitantly with other agents capable of significantly prolonging the QT interval. Combination of such agents is contraindicated. Relevant classes include:

• Class Ia and III antiarrhythmic agents (e.g., quinidine, amiodarone, sotalol, dofetilide);
• Certain antipsychotics (e.g., thioridazine);
• Certain macrolides (e.g., erythromycin);
• Certain antihistamines (e.g., terfenadine, astemizole);
• Certain quinolones (e.g., gatifloxacin, moxifloxacin).

The above list is not exhaustive; combinations with other individual medicinal products capable of significantly prolonging the QT interval (e.g., cisapride, lithium) should also be avoided.

Medicinal products that alter electrolyte balance, e.g., thiazide diuretics (hypokalemia), and agents that increase chlorprothixene concentration should also be used with caution, as they may increase the risk of QT interval prolongation and life-threatening arrhythmias.

Special precautions for use.

Truxal should be used with caution in patients with Parkinson's syndrome or organic brain syndrome, epileptic disorders, progressive diseases of the liver, kidneys or cardiovascular system, patients with myasthenia gravis, prostatic hyperplasia or narrow-angle glaucoma. Truxal should be used with caution in elderly patients who are susceptible to orthostatic disturbances.

Caution is required when administering Truxal to patients with the following conditions:

• pheochromocytoma;
• prolactin-dependent neoplasia;
• severe hypotension;
• hematological disorders;
• hyperthyroidism;
• urinary disorders, urinary retention, pyloric stenosis, intestinal obstruction.

There is a risk of developing neuroleptic malignant syndrome (hyperthermia, muscle rigidity, altered consciousness, autonomic dysfunction) with the use of any neuroleptic agent. Among patients in whom fatal outcomes have been observed, those with pre-existing organic brain syndrome, mental retardation, opioid and alcohol abuse predominate.

Treatment: discontinue neuroleptic agents. Symptomatic treatment and general supportive measures should be applied. Dantrolene and bromocriptine may be used. Symptoms may persist for more than a week after administration of oral neuroleptics.

Acute attacks of glaucoma due to pupillary dilation may occur in patients with the rare condition of shallow anterior chamber depth and narrow chamber angle.

Like other psychotropic agents, chlorprothixene may alter sensitivity to insulin and glucose, requiring adjustment of antidiabetic therapy in diabetic patients.

Chlorprothixene should be used with caution in patients with a history of cardiovascular disease or congenital QT prolongation syndrome due to the risk of malignant arrhythmias.

ECG monitoring is mandatory before initiating chlorprothixene therapy. Chlorprothixene is contraindicated if the QT interval during such examination exceeds 450 msec in males or 470 msec in females.

The need for ECG monitoring during treatment should be determined individually for each patient. The dose should be reduced if QT prolongation occurs, and therapy should be discontinued if QT exceeds 500 msec.

Periodic monitoring of electrolyte levels is recommended.

Concomitant use with other neuroleptics should be avoided.

Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic agents. Since patients receiving antipsychotic agents often have acquired VTE risk factors, all possible VTE risk factors should be identified before and during chlorprothixene therapy, and preventive measures should be taken.

Priapism has been reported with antipsychotic agents that have α-adrenergic blocking effects, and chlorprothixene may also share this potential. Severe priapism may require medical intervention. Patients should be informed about the need for immediate medical assistance if signs or symptoms of priapism develop.

Elderly patients

Increased risk of cerebrovascular adverse events:

In randomized, placebo-controlled clinical trials of some atypical antipsychotics in populations of patients with dementia, an approximately threefold increased risk of cerebrovascular adverse events has been observed. The mechanism of this increased risk is unknown. An increased risk cannot be excluded for other antipsychotics or other patient populations. Chlorprothixene should be used with caution in patients with risk factors for stroke.

Increased risk of mortality in elderly patients with dementia:

Clinical studies have shown that elderly patients with dementia treated with antipsychotic agents have a slightly increased risk of mortality compared to those not treated with antipsychotics. Data to assess the magnitude of risk are limited, and the reason for the increased risk is unknown.

Chlorprothixene is not indicated for the treatment of behavioral disorders associated with dementia.

The drug should be prescribed cautiously, considering the risk of adverse effects, particularly rare (and potentially irreversible) tardive dyskinesias, and the dose and duration of therapy should be regularly reviewed.

Patients undergoing long-term treatment, especially at high doses, should be carefully monitored and periodically evaluated with the aim of reducing dosage.

Truxal may lower the seizure threshold; therefore, antiepileptic treatment should be individually adjusted in patients with epilepsy.

Truxal may impair thermoregulation; therefore, patients should be advised to exercise caution when using the drug under extreme temperatures.

The CNS effects of Truxal, as well as its antiemetic properties, may mask symptoms of certain diseases.

Patients undergoing long-term Truxal therapy should have regular monitoring of psychological and neurological status, blood counts, and liver function.

Excipients

The tablets contain lactose monohydrate. This product should not be administered to patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Clinical experience with use in pregnant women is limited. Chlorprothixene should not be administered during pregnancy unless the expected benefit to the patient outweighs the potential risk to the fetus.

Newborns whose mothers have taken antipsychotic agents (including chlorprothixene) during the third trimester of pregnancy may be at risk of adverse effects, including extrapyramidal symptoms or withdrawal symptoms, which may vary in severity and duration after birth. Cases of agitation, hypertension, hypotension, tremor, somnolence, respiratory distress, or feeding difficulties have been reported. Therefore, newborns require close monitoring.

Preclinical data are insufficient to assess reproductive toxicity.

Chlorprothixene is excreted in breast milk in low concentrations; its effect on the infant when therapeutic doses are used is unlikely. The dose received by the infant through breast milk is approximately 2% of the maternal daily dose adjusted for body weight. Breastfeeding may continue during chlorprothixene therapy if clinically indicated, but monitoring of the infant is recommended, especially during the first four weeks after birth.

Fertility

Cases of hyperprolactinemia, galactorrhea, amenorrhea, absence of ejaculation, and erectile dysfunction have been reported. These conditions may negatively affect male and/or female sexual function and fertility.

If clinically significant hyperprolactinemia, galactorrhea, amenorrhea, or sexual dysfunction occurs, dose reduction (if possible) or discontinuation of the drug should be considered. Effects after discontinuation of the drug are reversible.

Ability to affect reaction speed when driving or operating machinery

Truxal is a sedative agent. Truxal, as well as the underlying psychiatric disorders, may impair attention, reaction ability, behavior, and psychomotor functions. Patients taking Truxal should not drive or operate hazardous machinery until they know how they personally respond to the medication.

Dosage and Administration

Dosage should be individually adjusted. The initial dose should be low, then gradually increased relatively quickly until optimal therapeutic effect is achieved.

Schizophrenia and other psychoses with psychomotor agitation, agitation, and anxiety disorders

Initial dose: 50–100 mg/day, gradually increased to achieve optimal effect. The usual optimal dose is 300 mg/day; in individual cases, it may be increased up to 1200 mg/day, if necessary.

The maintenance dose is usually 100–200 mg/day.

Due to its strong sedative effect, lower doses should be taken during the day and higher doses in the evening.

Renal and hepatic impairment

Careful dose titration is recommended, and, if possible, serum level monitoring should be performed.

Children

Chlorprothixene is not recommended for use in children under 18 years of age, as there is insufficient clinical data on efficacy and safety in children and adolescents.

Overdose

Symptoms: drowsiness, coma, shock, extrapyramidal disorders, hyper- or hypothermia.

In severe cases – kidney damage.

When overdose occurs concomitantly with agents affecting cardiac function, ECG changes, QT prolongation, torsades de pointes, cardiac arrest, and ventricular arrhythmias have been reported.

Treatment: symptomatic and supportive therapy. After oral ingestion, gastric lavage should be performed as soon as possible; activated charcoal may be administered. Measures to support respiratory and cardiovascular functions should be taken. Adrenaline (epinephrine) should not be used, as it may lead to further decrease in blood pressure. Seizures may be controlled with diazepam, and extrapyramidal symptoms may be managed with biperiden.

Lethal doses in adults may range from 2.5–4 g, and in children approximately 4 mg/kg body weight. Survival has been reported in adults after ingestion of 10 g, and in a three-year-old child after ingestion of 1000 mg.

Adverse reactions

Undesirable effects are mostly dose-dependent. Their frequency and severity are more pronounced at the beginning of therapy and decrease during continued treatment.

Extrapyramidal disorders may develop, particularly in the initial phase of treatment. In most cases, they can be managed by dose reduction and/or antiparkinsonian drugs. Routine prophylactic use of the latter is not recommended. Dose reduction or, if possible, discontinuation of chlorprothixene therapy is recommended. In cases of persistent akathisia, benzodiazepines or propranolol are recommended.

The frequency of adverse reactions listed in the table below is defined as:

very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), or very rare (<1/10,000).

There have been reports of rare cases of QT prolongation, ventricular arrhythmias—ventricular fibrillation, ventricular tachycardia, torsades de pointes—and sudden death associated with the use of medicinal products belonging to the therapeutic class of antipsychotics, including chlorprothixene.

Sudden discontinuation of chlorprothixene may lead to withdrawal symptoms, the most common of which are nausea, vomiting, anorexia, diarrhea, rhinorrhea, sweating, myalgia, paresthesia, insomnia, restlessness, anxiety, and agitation. Patients may also experience dizziness, fluctuating sensations of heat or cold, and tremor. Symptoms usually begin within 1–4 days after discontinuation and gradually subside within 7–14 days.

Cases of priapism, a persistent and usually painful erection of the penis that may lead to erectile dysfunction, have been reported during treatment with medicinal products belonging to the therapeutic class of antipsychotics; frequency is unknown (see section "Special precautions for use").

Shelf life. 5 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

25 mg tablets – 100 tablets in a container; 1 container in a cardboard box.

50 mg tablets – 50 tablets in a container; 1 container in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

H. Lundbeck A/S / H. Lundbeck A/S.

Manufacturer's address.

Ottiliavej 9, 2500 Valby, Denmark.