Trazodone MS tablets 100 mg No. 30

Instructions for use Trazodone MS tablets 100 mg No. 30

Composition

active ingredient: trazodone hydrochloride;

1 tablet contains: trazodone hydrochloride 50 mg, 100 mg;

Excipients: corn starch; lactose, monohydrate; polyvidone K30; calcium hydrogen phosphate; microcrystalline cellulose 102; sodium starch glycolate (type A); magnesium stearate.

Dosage form

Pills.

Main physicochemical properties:

50 mg tablets: round, standard convex tablet of almost white color, diameter: 8.9 - 9.2 mm, thickness: 4.2 - 4.6 mm;

100 mg tablets: oblong, almost white tablet with 3 score lines, length: 18.4 – 18.7 mm, width: 6.6 – 6.8 mm, thickness: 4.4 – 4.7 mm.

Pharmacotherapeutic group

Psychoanaleptics. Antidepressants. Other antidepressants. ATX code N06A X05.

Pharmacological properties

Pharmacodynamics

Trazodone is a triazolopyridine derivative. It is effective in the treatment of depressive states, including depression associated with anxiety and sleep disorders, and has a rapid onset of action (about 1 week). Trazodone is a serotonin reuptake inhibitor and 5-HT2 receptor antagonist, the activation of which is usually associated with the appearance of insomnia, anxiety, psychomotor agitation, and changes in sexual function.

Unlike other psychotropic drugs, trazodone is not contraindicated in glaucoma and urinary disorders, it does not exhibit extrapyramidal effects and does not potentiate adrenergic transmission. Trazodone is devoid of anticholinergic activity, therefore it does not exhibit the effects on cardiac function typical of tricyclic antidepressants.

Pharmacokinetics

Trazodone is rapidly absorbed from the gastrointestinal tract and extensively metabolized. The metabolic pathways of trazodone include n-oxidation and hydroxylation. The metabolic m-chlorophenylpiperazine is active. Trazodone is excreted in the urine almost entirely as its metabolites, in free or conjugated form. Elimination of trazodone is biphasic, with a terminal half-life of 5 to 13 hours. Trazodone is excreted in breast milk.

An approximately two-fold increase in terminal phase half-life and significantly higher plasma concentrations of trazodone were found in 10 patients aged 65 to 74 years compared with 12 patients aged 23 to 30 years after a 100 mg dose of trazodone. It has been suggested that there is an age-related decrease in hepatic metabolism of trazodone.

In vitro studies in human liver microsomes have shown that trazodone is metabolized primarily by cytochrome P4503A4 (CYP3A4) to form m-chlorophenylpiperazine, although the role of this pathway in the overall clearance of trazodone in vivo has not been fully determined.

Indication

Relieving symptoms of all types of depression, including depression accompanied by anxiety.

Contraindication

Known hypersensitivity to the drug or its components.

Alcohol intoxication and intoxication with sleeping pills.

Acute myocardial infarction.

Interaction with other medicinal products and other types of interactions

General

The sedative effects of antipsychotics, hypnotics, anxiolytics and antihistamines may be enhanced. A reduction in the dose of these agents is recommended.

Oral contraceptives, phenytoin, carbamazepine, and barbiturates, due to their effects on the liver, accelerate the metabolism of antidepressants. Cimetidine and some other antipsychotics slow down the metabolism of antidepressants.

CYP3A4 inhibitors

In vitro drug metabolism studies suggest the potential for drug interactions when trazodone is administered concomitantly with CYP3A4 inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir and nefazodone. The use of CYP3A4 inhibitors is likely to result in significant increases in trazodone plasma concentrations. Ritonavir use at the start of treatment or when reinitiating treatment in patients receiving trazodone will increase the potential for excessive sedation, cardiovascular and gastrointestinal effects. In vivo studies in healthy volunteers have shown that after administration of ritonavir 200 mg twice daily, trazodone plasma levels increased more than 2-fold, resulting in nausea, syncope and hypotension. Therefore, when using trazodone simultaneously with a strong CYP3A4 inhibitor, it would be advisable to reduce the dose of trazodone.

However, if possible, the concomitant use of trazodone and potent CYP3A4 inhibitors should be avoided altogether.

Carbamazepine

When trazodone is used simultaneously with carbamazepine, the plasma concentrations of trazodone are reduced. When used simultaneously with carbamazepine at a dose of 400 mg per day, the plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine were reduced by 76% and 60%, respectively. The patient's condition should be carefully monitored to determine the need for an increase in the dose of trazodone. Trazodone is well tolerated by depressed patients with schizophrenia who have received standard phenothiazine therapy, as well as by depressed patients with Parkinson's disease who have received levodopa treatment.

There is a risk of drug interactions, so concomitant use with trazodone should be avoided. In case of concomitant use, the development of serotonin syndrome and adverse effects on the cardiovascular system should be expected.

Fluoxetine

Rare cases of increased trazodone plasma levels and adverse effects have been reported when trazodone was co-administered with fluoxetine (a CYP1A2/2D6 inhibitor). The mechanism underlying this pharmacokinetic interaction is not fully understood. A pharmacodynamic interaction (serotonin syndrome) cannot be excluded.

Monoamine oxidase inhibitors (MAOIs)

There have been isolated reports of possible interactions between trazodone and MAO inhibitors. Although some physicians practice concomitant use of these agents, the use of trazodone concomitantly with MAO inhibitors or within 2 weeks of their discontinuation is not recommended. It is also not recommended to initiate MAO inhibitor therapy within 1 week of discontinuing trazodone.

Phenothiazines

Cases of severe orthostatic hypotension have been observed with concomitant use of phenothiazines, such as chlorpromazine, fluphenazine, levomepromazine, perphenazine.

Anesthetics/muscle relaxants

Trazodone hydrochloride may potentiate the effects of muscle relaxants and volatile anesthetics. Such combinations should be used with caution.

Alcohol

The sedative effects of alcohol are more pronounced under the influence of trazodone. The patient should avoid drinking alcohol during treatment with trazodone.

Levodopa

Antidepressants can accelerate the metabolism of levodopa.

Other means

The risk of ventricular arrhythmias, including torsade de pointes, may be increased when trazodone is used concomitantly with drugs known to prolong the QT interval. These drugs should be used with caution when used concomitantly with trazodone.

Trazodone is only a very weak inhibitor of norepinephrine reuptake and does not affect the blood pressure response to tyramine therapy, so trazodone should not be expected to affect the hypotensive effects of guanethidine-like compounds. However, in laboratory animal studies, trazodone has been shown to inhibit most of the rapid effects of clonidine.

Although no drug interactions have been reported when other types of antihypertensive drugs are used concomitantly with trazodone, the possibility of potentiation of effects should be considered.

The frequency of undesirable effects may increase when trazodone is used concomitantly with preparations containing St. John's wort (Hypericum perforatum).

Cases of changes in prothrombin time values have been reported in patients receiving concomitant treatment with trazodone and warfarin.

Serum levels of digoxin or phenytoin may be increased when these agents are administered concomitantly with trazodone. Serum levels of these agents should be monitored in patients receiving such therapy.

Application features

Use in children and adolescents

Trazodone should not be used in children and adolescents. In a clinical trial in children and adolescents, suicidal behavior (suicide attempt and suicide planning) and hostility (predominantly aggression, oppositional behavior, and anger) were more frequently observed in the antidepressant group than in the placebo group. In addition, there are currently no data on the long-term safety of the drug in children and adolescents with regard to its effects on growth, puberty, and cognitive and behavioral development.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicidal behavior). This risk persists until significant remission occurs. No improvement may occur during the first few weeks of therapy or longer. Patients should be closely monitored until such improvement occurs. General clinical experience indicates that the risk of suicide may be increased in the early stages of recovery.

Other psychiatric conditions for which Trazodone MC is prescribed may also be associated with an increased risk of suicide-related events. In addition, these conditions may coexist with major depressive disorder. The same precautions observed in the treatment of patients with major depressive disorder should be observed in the treatment of patients with other psychiatric disorders.

Patients should be closely monitored during treatment with this medicine, particularly those at high risk, especially at the start of treatment and after dose changes. Patients (and caregivers of patients) should be alerted to monitor for any clinical signs of worsening of their condition, suicidal behaviour or thoughts, and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

To minimize the potential risk of suicide attempts, especially at the beginning of therapy, the physician should prescribe only limited amounts of trazodone to the patient at each visit.

It is recommended to carefully select the dosage regimen and regularly monitor patients with the following conditions:

Epilepsy (the dose should not be increased or decreased suddenly in such patients);

· liver or kidney dysfunction, especially severe;

· heart disease such as angina pectoris, cardiac conduction disorders or atrioventricular block of varying degrees; recent myocardial infarction;

· hyperthyroidism;

· urinary disorders, for example in case of prostatic hypertrophy, although such problems are not expected, since the anticholinergic effect of trazodone is insignificant;

· acute angle-closure glaucoma, increased intraocular pressure, although significant changes in the condition are not expected, since the anticholinergic effect of trazodone is insignificant.

If the patient develops jaundice, trazodone therapy should be discontinued.

Severe liver disease, which may be fatal, has been reported with trazodone (see section 4.8). Patients should immediately report symptoms such as asthenia, anorexia, nausea, vomiting, abdominal pain or jaundice to their doctor. Investigations, including clinical examination and biological assessment of liver function, should be performed immediately and discontinuation of trazodone therapy should be considered.

When using antidepressants in patients with schizophrenia or other psychotic disorders, psychotic symptoms may worsen. Paranoid thoughts may become more pronounced. During treatment with trazodone, the depressive phase of manic-depressive psychosis may change to a manic phase. In this case, trazodone should be discontinued.

Drug interactions with serotonin syndrome/neuroleptic malignant syndrome have been reported with concomitant use of other serotonergic medicinal products, such as other antidepressants (e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and MAOIs) and neuroleptics. Cases of fatal neuroleptic malignant syndrome have been reported with concomitant use of the drug with neuroleptics for which this syndrome is a known possible adverse reaction. For more detailed information, see sections “Interaction with other medicinal products and other forms of interaction” and “Adverse reactions”.

Since agranulocytosis may present clinically as a flu-like illness, sore throat and fever, laboratory blood tests should be checked if these symptoms occur.

Hypotension, including orthostatic hypotension and somnolence, has been reported in patients receiving trazodone therapy.

Attention should be paid to possible additive effects when used concomitantly with other medicinal products, such as other psychotropic or antihypertensive agents, or to the presence of risk factors, such as concomitant disease, that may enhance such reactions.

It is recommended to inform the patient/caregiver about the possibility of such reactions and to monitor more closely for the occurrence of such effects after initiation of therapy, before and after dose increases.

When antihypertensive agents are used concomitantly with trazodone, a reduction in the dose of the antihypertensive agent may be necessary. Elderly patients are often more susceptible to the undesirable effects of antidepressants, especially orthostatic hypotension, and to other anticholinergic effects.

When ending a course of trazodone therapy, especially if the course was long-term, it is recommended to gradually reduce the dose until the drug is completely discontinued in order to minimize the likelihood of withdrawal symptoms, which include nausea, headache, and general malaise.

There is currently no evidence that trazodone hydrochloride is habit-forming.

Very rare cases of QT prolongation have been reported with trazodone, an effect also seen with other antidepressants. Caution should be exercised when trazodone is used concomitantly with medicinal products known to prolong the QT interval. Trazodone should be used with caution in patients with known cardiovascular disease, including those associated with QT prolongation.

As with other drugs with alpha-adrenergic blocking activity, trazodone has very rarely been associated with priapism. If this occurs, an intracavernosal injection of an alpha-adrenergic agent such as adrenaline or metaraminol should be administered. However, cases of trazodone-induced priapism have been reported where surgical intervention was necessary or where permanent sexual dysfunction resulted. Trazodone should be discontinued immediately in patients suspected of having this adverse reaction.

Trazodone MS contains lactose. Patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency should not take this medicine.

Use during pregnancy or breastfeeding

Pregnancy

Data obtained from the study of a limited number (

As a general rule, its use should be avoided during the first trimester.

This drug should be used with caution in pregnant women. If trazodone is used in the mother before delivery, the infant should be monitored for possible withdrawal syndrome after birth, taking into account the benefit to the mother/risk to the fetus.

Breastfeeding period

Limited data indicate that trazodone is excreted in human milk in small amounts. Due to insufficient data, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue trazodone therapy should be made taking into account the benefit of breast-feeding for the child and the benefit of trazodone therapy for the mother.

Ability to influence reaction speed when driving vehicles or other mechanisms

Trazodone has minor or moderate influence on the ability to drive and use machines. Patients should be warned that before driving or operating machinery, it is necessary to ensure that there is no drowsiness, sedation, dizziness, confusion or blurred vision while taking trazodone.

Method of administration and doses

The drug is administered orally.

Depression.

Adults: Initial dose of 150 mg per day divided into several doses, taken after meals or as a single dose in the evening before bedtime.

The dose may be increased to 300 mg per day, which should be divided into several doses or taken as a single dose. The majority of the divided dose should be taken in the evening before bedtime. For patients who are inpatients, the dose may be increased to 600 mg per day, which should be divided into several doses.

Elderly patients: In very elderly or debilitated patients, the recommended initial dose is reduced to 100 mg per day, given in divided doses or as a single dose at bedtime (see section 4.4). The dose may be increased gradually under supervision based on clinical response and tolerability. In general, single doses of more than 100 mg should be avoided in these patients. Doses exceeding 300 mg per day are rarely required.

Children: There is insufficient safety data to recommend the use of trazodone in children under 18 years of age.

Depression accompanied by anxiety:

Method of administration and dosage as for depression.

Anxiety disorder.

The initial dose of 75 mg per day is increased to 300 mg per day if necessary.

To minimize side effects (increased absorption and decreased maximum plasma concentration), the drug is best taken after meals.

Hepatic impairment: Trazodone is extensively metabolised in the liver (see section 5.1) and has been associated with hepatotoxicity (see sections 4.4 and 4.8). Therefore, the drug should be administered with caution to patients with hepatic impairment, especially in cases of severe impairment. Periodic monitoring of liver function may be recommended.

Renal impairment: Usually no dose adjustment is necessary, but caution should be exercised in patients with severe renal impairment.

Children. Do not use in children.

Overdose

The most common symptoms of overdose are drowsiness, dizziness, nausea and vomiting. In severe cases, coma, tachycardia, hypotension, hyponatremia, convulsions and respiratory failure have occurred.

Cardiac symptoms may include bradycardia, QT prolongation, and torsade de pointes.

Symptoms may appear within 24 hours of the overdose or later.

Simultaneous overdose of trazodone and other antidepressants may cause serotonin syndrome.

There is no specific antidote. Adults who have ingested more than 1 g of trazodone or children who have ingested more than 150 mg of trazodone should be given activated charcoal within 1 hour of the overdose being detected. In other cases, gastric lavage may be appropriate in adults within 1 hour of ingestion of potentially life-threatening doses. The patient should be monitored for at least 6 hours after ingestion (or 12 hours if the sustained-release formulation is used). Blood pressure, pulse and Glasgow Coma Scale (GCS) should be monitored. In the event of a decrease in the GCS score, oxygen saturation should be monitored.

Cardiac monitoring is necessary in symptomatic patients.

If isolated short-term seizures occur, no treatment is required. For frequent or prolonged seizures, administer intravenous diazepam (0.1-0.3 mg/kg body weight) or lorazepam.

(4 mg for adults and 0.05 mg/kg for children).

If these measures do not control the seizures, intravenous phenytoin may be appropriate. If necessary, the patient should be given oxygen and acid-base and metabolic disturbances should be corrected.

In case of hypotension and excessive sedation, symptomatic and supportive treatment should be used. If severe hypotension persists, the use of inotropic agents, such as dopamine or dobutamine, should be considered.

Adverse reactions

Suicidal ideation and suicidal behavior have been reported during or shortly after treatment with trazodone. In patients with severe respiratory failure due to chronic bronchial or pulmonary disease, trazodone had no effect on arterial pCO2 or pO2.

The following symptoms have also been reported in patients treated with trazodone, some of which are common in untreated depression.

1 Fluid and electrolyte balance should be monitored in symptomatic patients.

2 See also the section “Application features”.

4 Animal studies have shown that trazodone is less cardiotoxic than tricyclic antidepressants, and clinical data suggest that trazodone is less likely to cause cardiac arrhythmias in humans. Clinical data in patients with pre-existing heart disease suggest that trazodone may have arrhythmogenic effects in some patients in this population.

5 Rare cases of adverse effects, sometimes severe, on liver function have been reported.

6 See also the section “Application features”.

Reporting of suspected adverse reactions.

Any suspected adverse reactions should be reported in accordance with legal requirements. In case of adverse reactions and questions regarding the safety of the medicinal product, please contact us via the feedback form on the website: www.ukraine.medochemie.com

Expiration date

3 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging to protect from light and moisture, out of the reach of children.

Packaging

10 tablets in a blister; 3 blisters in a cardboard box.

Vacation category

According to the recipe.

Manufacturer/applicant.

1. Medochemie LTD (Factory AZ) / Medochemie LTD (Factory AZ).

2. Pharmaceutical Analytical Laboratory Duiven B.V.

Location of the manufacturer and its address of place of business/location of the applicant and/or representative of the applicant.

1. 2 Michael Erakleous Street, Agios Athanassios Industrial Area, Agios Athanassios, Limassol, 4101, Cyprus.

2. Dijkgraaf 30, Duiven, 6921 RL, Netherlands.