Trittico, 150 mg 20 pcs.

Pharmacotherapeutic group: antidepressant

ATX code: N06AX05

Pharmacological properties

Pharmacodynamics

Trazodone is a triazolopyridine derivative effective for the treatment of depressive disorders, including depression associated with anxiety and sleep disorders, and characterized by a short latency period (about a week).

Trazodone is a serotonin reuptake inhibitor and 5-HT2 receptor antagonist whose activation is mainly associated with insomnia, anxiety, psychomotor agitation and changes in sexual function.

Unlike other psychotropic medications, trazodone is not contraindicated in glaucoma, urinary tract disorders, has no extrapyramidal effects, does not potentiate adrenergic transmission; due to the absence of anticholinergic activity, trazodone does not have the typical effects of tricyclic antidepressants on cardiac activity.

Pharmacokinetics

After an oral single dose of 75 mg of sustained-release trazodone, C_max of about 0.7 µg/mL is reached after t_max equal to 4 hours after administration, the AUC (area under the concentration-time curve) is about 8 µg/mL/h. After oral administration of a single dose of 150 mg trazodone with prolonged release C_max about 1.2 µg/mL is reached after t_max equal to 4 hours after administration, the AUC is about 18 µg/mL/h. The elimination half-life is about 12 hours.

A food interaction study showed no significant changes in C_max and AUC when using the drug Trittico, 150 mg sustained release tablets, before or after meals.

Studies in vitro on human liver microsomes have shown that trazodone is primarily metabolized by cytochrome P4503A4 (CYP3A4).

Indications

Active ingredient

Composition

One sustained-release tablet contains:

active ingredient: trazodone hydrochloride 150.0 mg;

excipients: saccharose (pressed sugar), carnauba wax, povidone K25 (polyvinylpyrrolidone), magnesium stearate.

How to take, the dosage

The tablets should be taken whole, without chewing, and with plenty of water.

The therapy should be started in the evening and gradually increased daily doses.

The drug can be taken regardless of meals.

The drug should be taken in cycles of at least one month.

Adults

75-150 mg/day as a single dose in the evening before bedtime. The dose may be increased to 300 mg/day divided into two doses.

In hospitalized patients, the dose may be gradually increased to 600 mg/day in repeated doses.

Elderly patients

In elderly or frail patients, the recommended daily dose should be reduced to 100 mg/day as fractional doses or as a single dose in the evening before bedtime. This dose may be gradually increased under medical supervision depending on the efficacy and tolerability of the drug. In most cases, a single dose of more than 100 mg should be avoided for these patients. A dose greater than 300 mg/day is usually not required.

Interaction

General

The sedative effects of antipsychotic, hypnotic, sedative, anxiolytic and antihistamine drugs may increase; in such cases, dose reduction is recommended.

The metabolism of antidepressants is accelerated due to the hepatic effects of oral contraceptives, phenytoin, carbamazepine and barbiturates. Metabolism of antidepressants is inhibited by cimetidine and some other antipsychotics.

CYP3A4 inhibitors

In vitro studies of the drug’s metabolism show that there is potential for drug interactions when trazodone is prescribed with cytochrome P4503A4 (CYP3A4) inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir and nefazodone. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone is required.

The use of CYP3A4 inhibitors should be avoided if possible.

Carbamazepine

The results of co-administration are seen in decreased plasma concentrations of trazodone. Concomitant administration of carbamazepine at a daily dose
400 mg resulted in a decrease in plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine to 76% and 60%, respectively. For this reason, patients taking trazodone in combination with carbamazepine should be continuously monitored for the need to increase trazodone dosage.

Tricyclic antidepressants

Simultaneous use with trazodone should be avoided because of the risk of interaction. Serotonin syndrome and cardiac side effects should be feared.

Fluoxetine

Rare cases of elevated plasma levels of trazodone and side effects have been reported when trazodone was combined with fluoxetine, a CYP1A2/2D6 inhibitor. The mechanism of their pharmacokinetic interaction has not been studied. Pharmacodynamic interaction (serotonin syndrome) cannot be excluded.

MAO inhibitors

Possible interactions with monoamine oxidase inhibitors (MAOIs) have been reported. Although some physicians prescribe the two drugs simultaneously, the use of trazodone concomitantly with MAO inhibitors or within two weeks after completion of the MAO inhibitors is not recommended. Use of MAO inhibitors within one week of therapy with trazodone is also not recommended.

Phenothiazines

Cases of severe orthostatic hypotension have been reported when used concomitantly with phenothiazines such as chlorpromazine, fluphenazine, perphenazine.

Anesthetics/myorelaxants

Trazodone hydrochloride may increase the effects of muscle relaxants and volatile anesthetics; use with caution.

Alcohol

Trazodone increases the sedative effects of alcohol. Alcohol should be avoided during therapy with trazodone.

Levodopa

Antidepressants may accelerate the metabolism of levodopa.

Other

The concomitant use of trazodone with drugs that prolong the QT interval may increase the risk of ventricular arrhythmias, including polymorphic ventricular tachycardia. Caution is necessary when using them together with trazodone.

Since trazodone is a weak norepinephrine reuptake inhibitor and does not alter the blood pressure response to tyramine, effects on the hypotensive effects of guanethidine-type compounds are unlikely. However, animal studies suggest that trazodone may inhibit most of the acute effects of clonidine. For other antihypertensive drugs, the possibility of potentiation should be considered, although no interaction has been clinically proven.

Side effects may occur more frequently when trazodone is used concomitantly with preparations containing St. John’s Wort (Hypericum perforatum).

There have been reported cases of changes in prothrombin time in patients taking trazodone and warfarin concomitantly.

The concomitant use of digoxin or phenytoin with trazodone may increase serum levels of digoxin and phenytoin. Serum levels of digoxin and phenytoin in such patients should be monitored.

Special Instructions

Application in children and adolescents (under 18 years)

Trazodone should not be used in children and adolescents under 18 years of age.

Suicidal ideation/suicidal thoughts or worsening of clinical symptoms

The risk of suicidal ideation, self-harm, or suicide is increased in depressed states. This risk persists until significant remission occurs. Because improvement may not occur within the first few weeks of treatment or longer, patients should be closely monitored until improvement occurs. Overall clinical experience suggests that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicidal events, or patients who exhibit a significant degree of suicidal ideation prior to treatment, are known to have a higher risk of suicidal ideation or attempted suicide and should be closely monitored during treatment. Results of a meta-analysis of placebo-controlled clinical trials of antidepressants used in adults with psychiatric disorders showed an increased risk of suicidal behavior in patients younger than 25 years old on antidepressants compared to placebo.

Careful monitoring of patients, especially those at high risk, should accompany drug therapy, especially in its early stages and after dose changes. Patients (and their caregivers) should be warned to monitor for any clinical deterioration, suicidal behavior or suicidal ideation, and unusual behavioral changes, and to consult a specialist immediately if such symptoms occur. To minimize the potential risk of suicide attempts, especially at the beginning of treatment, the lowest dose necessary should be given on a case-by-case basis.

Trazodone therapy should be discontinued if jaundice develops.

The use of antidepressants in patients with schizophrenia or other psychiatric disorders may lead to a possible worsening of psychiatric symptoms. Paranoid thoughts may worsen. When treated with trazodone, depressive episodes can range from manic-depressive to manic psychosis. In this case, trazodone should be discontinued.

. When trazodone is used concomitantly with drugs with serotonergic activity, such as other antidepressants (e.g., tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors, and MAO inhibitors) and neuroleptics, interactions with the development of serotonin syndrome or malignant neuroleptic syndrome have been described. Fatal malignant neuroleptic syndrome has been reported in cases coadministered with neuroleptics, for which this syndrome was a known possible adverse drug reaction.

Because agranulocytosis can manifest itself as a flu-like syndrome, sore throat and fever, it is recommended to monitor the blood count if these symptoms occur.

Cases of hypotension, including orthostatic hypotension and syncope, have been reported in patients taking trazodone. Concomitant use with antihypertensive drugs may require reduction of the dose of the antihypertensive drug.

Elderly patients

Elderly patients are often more susceptible to antidepressants; in particular, orthostatic hypotension, somnolence, and other anticholinergic effects of trazodone have been reported more frequently.

Particular attention should be paid to potential additive effects due to concomitant use of other psychotropic or antihypertensive drugs or when there are risk factors, such as comorbidities, that may exacerbate these reactions.

It is recommended that the patient or caregiver be informed of the possible occurrence of such effects. Their occurrence should be carefully monitored in the patient after initiation of therapy, before and after titration at an increasing dose.

In long-term therapy with trazodone, gradual dose reduction is recommended before withdrawing the drug to minimize withdrawal symptoms such as nausea, headache, and malaise.

There is no evidence that trazodone hydrochloride has any addictive properties.

As with other antidepressants, very rare cases of QT interval prolongation have been reported with trazodone. Caution should be exercised when prescribing trazodone with medications that prolong the QT interval.

Trazodone should be used with caution in patients with known cardiovascular disease, including QT interval prolongation. Strong CYP3A4 inhibitors may increase serum trazodone levels.

As with other drugs with alpha-adrenolytic activity, trazodone is very rarely associated with priapism. This can be corrected by intracavernosal injection of an alpha-adrenergic agent such as adrenaline or metharaminol. However, there are reports of trazodone-induced priapism that have required surgery or resulted in permanent sexual dysfunction. Patients who develop this suspected adverse reaction should discontinue trazodone immediately.

Influence on urinalysis results

When immunoassays are used to monitor drugs in urine, the reactivity of the trazodone metabolite meta-chlorophenylpiperazine (m-CPP), which is structurally similar to methylenedioxymethamphetamine (MDMA, Ecstasy), may cause a false-positive reaction for amphetamine. In these cases, confirmatory analysis by mass spectrometry is recommended.

Influence on ability to drive, operate machinery

Trazodone has little or no effect on the ability to drive or operate machinery. Patients should be advised of the risks of driving or operating machinery until they are certain that they are not experiencing drowsiness, lethargy, dizziness, confusion, or blurred vision.

Synopsis

Contraindications

Cautions

Cautious dosing and regular monitoring of patients with the following conditions are recommended:

Side effects

Suicidal ideation and suicidal behavior have been reported during trazodone therapy or in the early period after completion of therapy.

The following symptoms, some of which have also been reported in cases of untreated depression, have been reported in patients taking trazodone.

Organ system class (MedDRA) Frequency unknown (frequency cannot be determined from available data)

Blood and lymphatic system disorders Agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, anemia/p>

Immune system disorders Allergic reactions

Endocrine system disorders Syndrome of inadequate secretion of antidiuretic hormone (ADH SNS)

/p>

Metabolic and nutritional disorders Hyponatremia1, weight loss, anorexia, increased appetite

Mental disorders Suicidal thoughts or suicidal behavior2, confusion, insomnia, disorientation, mania, restlessness, nervousness, agitation (very rarely escalating to delirium attacks), delirium, aggressive reaction, hallucinations, nightmares, decreased libido, withdrawal syndrome

/p>

Nervous system disorders Serotonin syndrome, seizures, malignant neuroleptic syndrome, dizziness, vertigo, headache, drowsiness3, restlessness, decreased alertness, tremor, visual disturbance, memory disturbance, myoclonic seizures, pronounced aphasia, paresthesia, dystonia, change of taste

/p>

Heart disorders Cardiac arrhythmia4 (including polymorphic ventricular tachycardia), palpitations, premature ventricular contractions, two consecutive complexes of premature ventricular contractions, ventricular tachycardia, bradycardia, tachycardia, prolongation of the QT interval

/p>

Vascular disorders Hypotension, arterial hypertension, syncope

Restive system, thoracic and mediastinal disorders Nasal congestion, dyspnea

Gastrointestinal disorders Nausea, vomiting, dry mouth, constipation, diarrhea, dyspepsia, abdominal pain, gastroenteritis, hypersalivation, paralytic ileus

deprivation of the gastrointestinal tract/p>

Hepatic and biliary tract disorders

Liver function disorders (including jaundice and liver cell damage)5, intrahepatic cholestasis

/p>

Skin and subcutaneous tissue disorders Skin rash, itching, hyperhidrosis

Musculoskeletal and connective tissue disorders Pain in extremities, back pain, myalgia, arthralgia

Repnal and urinary tract disorders Urinary disorders

Disorder of urination/p>

Genital and mammary disorders Priapism6

General disorders and disorders at the site of administration Weakness, swelling, flu-like symptoms, fatigue, chest pain, fever

Laboratory and instrumental findings Elevated liver enzymes

Overdose

Symptoms: sleepiness, dizziness, nausea, vomiting. In more severe cases, coma, tachycardia, hypotension, hyponatremia, seizures, and respiratory arrest have been reported. With respect to cardiac activity, these may include bradycardia, prolongation of the QT interval, and polymorphic ventricular tachycardia.

The symptoms may appear within 24 hours or later after an overdose. Trazodone overdose in combination with other antidepressants may cause serotonin syndrome.

Treatment: There is no specific antidote for trazodone. Activated charcoal may be used in adults who have taken more than 1 g of trazodone or in children who have taken more than 150 mg of trazodone within 1 hour of onset of symptoms. As an alternative therapy, adults may be given gastric lavage within 1 hour of taking a potentially life-threatening dose.

Monitoring for at least 12 hours after drug administration is required, as well as monitoring of blood pressure, pulse rate, and Glasgow Coma Scale scores. If Glasgow Coma Scale values are reduced, blood oxygen saturation should be monitored. Cardiac function monitoring is necessary in symptomatic patients.

Single brief seizures do not require therapy. Frequent or prolonged seizures are corrected with intravenous diazepam (0.1-0.3 mg/kg body weight) or lorazepam (4 mg in adults or 0.05 mg/kg body weight in children).

If these measures do not control seizures, intravenous phenytoin may be recommended. Oxygen by inhalation should be used to correct acid-base balance and metabolic disorders.

In case of hypotension and excessive sedation, symptomatic and supportive therapy should be given. If severe hypotension persists, the use of dopamine or dobutamine should be considered.

Pregnancy use

Pregnancy

Data from a limited number of pregnant women who took the drug during pregnancy (< 200) showed no adverse effects of trazodone on pregnancy and fetal/newborn health. No other available epidemiologic data are available.

Animal studies have found no direct or indirect adverse effects on pregnancy, fetal/fetal development, delivery or postnatal development at therapeutic doses.

The studies of teratogenicity in rats have revealed an increase in embryo lethality when the drug is used only at doses that are toxic to the mother (300-450 mg/kg/day). Embryoletal effects and rare cases of congenital anomalies were observed in rabbits when the drug was used only in doses toxic to the mother (150-450 mg/kg/day). The absence of direct effect on the embryo is confirmed by studies of trazodone penetration through the placental barrier in rats: only minor concentrations of trazodone were found in the tissues of embryos and amniotic fluid.

The drug should be administered to pregnant women only if the potential benefit to the woman justifies the possible risks to the fetus. When used prior to delivery, newborns should be monitored for withdrawal syndrome.

Breastfeeding

Limited data show that a small amount of trazodone passes into breast milk, but the level of the active metabolite is unknown. Due to insufficient data, the decision to continue/discontinue the drug or to continue/continue breastfeeding should be made considering the benefit of breastfeeding to the baby and the benefit of therapy to the mother.