Trittico (Trazodon)

One tablet with prolonged release contains:

active substance: trazodon hydrochloride 150.0 mg;

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

Pharmacotherapy group: antidepressant

ATX code: N06AX05

Pharmacological properties

Pharmacodynamics

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

Trazodon is a serotonin reuptake inhibitor and 5-HT2 receptor antagonist, the activation of which is mainly associated with insomnia, anxiety, psychomotor excitation and changes in sexual function.

Unlike other psychotropic drugs, trazodon is not contraindicated in glaucoma, urinary tract diseases, does not have extrapyramid effects, does not potentiate adrenergic transmission; due to the absence of anticholinergic activity, trazodon does not have typical effects of tricyclic antidepressants

Pharmacokinetics

After oral administration of a single dose of 75 mg of trazodon with prolonged release, Cmax about 0.7 μg/ml is achieved through tmax equal to 4 hours after administration, AUC (area under the concentration-time curve) is about 8 μg/ml/h. After oral administration of a single dose of 150 mg of trazodon with prolonged release of Cmax about 1.2 μg/ml is achieved through tmax equal to 4 hours after administration, AUC is about 18 μg/ml/h. The half-life is about 12 hours.

The study of interaction with food did not reveal significant changes in Cmax and AUC when using the drug Tritico, a tablet with prolonged release of 150 mg, before or after meals.

In vitro studies on human liver microsomes have shown that trazodon is mainly metabolized by cytochrome P4503A4 (CYP3A4).

Pregnancy

Data on the limited number of pregnant women who took the drug during pregnancy (< 200) did not reveal side effects of trazodon on pregnancy and fetal/newborn health. There are no other epidemiological data available.

Animal studies have not revealed direct or indirect negative effects on pregnancy, embryonic/fetal fetal development, delivery or postnatal development in therapeutic doses.

Studies of teratogenicity in rats revealed an increase in embryoletility when using the drug only in doses toxic to the mother's body (300-450 mg/kg/day). Embryoletal effects and rare cases of congenital anomalies were observed in rabbits when using the drug only in doses toxic to the mother's body (150-450 mg/kg/day). The absence of direct effect on the embryo is confirmed by studies of the penetration of trazodon through the placental barrier in rats: only minor concentrations of trazodon were found in embryo tissues and amniotic waters.

The drug should be prescribed to pregnant women only if the potential benefits for a woman justify possible risks to the fetus. When used before delivery, newborns should be observed for withdrawal syndrome.

Breastfeeding period

Limited data show that a small amount of trazodon enters breast milk, but the level of active metabolite is unknown. Due to insufficient data, the decision to continue/terminate taking the drug or to continue/terminate breastfeeding should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.

• known hypersensitivity to trazodon or any auxiliary substance;
• alcoholic intoxication and intoxication with sleeping pills;
• acute myocardial infarction;
• sucrose/isomaltose deficiency, fructose intolerance, glucose galactose malabsorption, as the drug contains sucrose;
• age up to 18 years (security is not established).

With caution

Careful dosage and regular monitoring of patients with the following conditions are recommended:

• epilepsy, especially a sharp increase or decrease in the dose;
• patients with liver and/or renal failure, especially severe;
• patients with heart diseases such as angina pectoris, conduction disorders or atrioventricular (AV) blockade of varying degrees, myocardial infarction (early recovery period);
• hyperthyroidism;
• urination disorders, such as prostate hypertrophy, despite the slight anticholinergic effect of trazodon;

acute closed-angle glaucoma, increased intraocular pressure, although no major changes are expected due to the slight anticholinergic effect of trazodon.

Suicidal thinking and suicidal behavior were reported during trazodon therapy or in the early period after the completion of therapy.

The following symptoms, some of which were also noted in cases of untreated depression, were recorded in patients taking trazodon.

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

Blood and lymphatic disorders Agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, anemia

Immune system disorders Allergic reactions

Endocrine system disorders Inadequate secretion syndrome of antidiuretic hormone (SNA ADH)

Metabolic and nutritional disorders Hyponatriemia1, weight loss, anorexia, increased appetite

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

Nervous system disorders Serotonin syndrome, seizures, malignant neuroleptic syndrome, dizziness, vertigo, headache, drowsiness3, anxiety, reduced vigilance, tremors, visual impairment, memory disorders, myoclonal seizures, severe aphasia, paresthesia, dystonia, taste change

Heart disorders Heart arrhythmia4 (including polymorphic ventricular tachycardia), heart rate, premature ventricular contraction, two consecutive complexes of premature ventricular contractions, ventricular tachycardia, bradycardia, tachycardia, elongation of the QT interval

Vascular disorders Orthostatic hypotension, arterial hypertension, fainting

Disorders from the respiratory system, chest and mediastinum Nasal congestion, shortness of breath

Disorders of the gastrointestinal tract Nausea, vomiting, dry mouth, constipation, diarrhea, dyspepsia, abdominal pain, gastroenteritis, increased salivation, paralytic intestinal obstruction

Liver and biliary tract disorders

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

Skin and subcutaneous tissue disorders Skin rash, itching, hyperhidrosis

Musculoskeletal and connective tissue disorders Limb pain, back pain, myalgia, arthralgia

Kidney and urinary tract disorders Urine disorder

Sexual and breast disorders Priapism6

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

Laboratory and instrumental data Increased liver enzyme levels

General

The sedative effect of antipsychotic, sleeping pills, sedative, anxiolytic and antihistamine drugs may increase; in such cases, a dose reduction is recommended.

Antidepressant metabolism accelerates due to the hepathic effects of oral contraceptives, phenytoin, carbamazepine and barbiturates. Metabolism of antidepressants is inhibited with cimetidine and some other antipsychotic drugs.

CYP3A4 inhibitors

Studies of the metabolism of the drug in vitro show that there is potential for drug interaction when trazodon is prescribed with cytochrome inhibitors P4503A4 (CYP3A4), such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir and nefazodon If trazodon is used with a powerful inhibitor CYP3A4, a lower dose of trazodon is required.

The use of CYP3A4 inhibitors should be avoided as much as possible.

Karbamazepin

The results of joint use are expressed in a decrease in the concentration of trazodon in plasma. Simultaneous administration of carbamazepine at a daily dose
400 mg led to a decrease in the concentration of trazodon in blood plasma and its active metabolite m-chlorophenylpiperazine to 76% and 60%, respectively. For this reason, patients taking trazodon in combination with carbamazepine should be constantly observed for the need to increase the dosage of trazodon.

Tricyclic antidepressants

Simultaneous administration with trazodon should be avoided due to the risk of interaction. You should beware of serotonin syndrome and side effects on cardiac activity.

Fluoxetine

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

MAO inhibitors

Possible interaction with monoamine oxidase inhibitors (MAO) was reported. Despite the fact that some doctors prescribe two drugs at the same time, the use of trazodon simultaneously with MAO inhibitors or within two weeks after the completion of MAO inhibitors is not recommended. The use of MAO inhibitors within one week after trazodon therapy is also not recommended.

Phenothiazins

Cases of serious orthostatic hypotension were noted in case of simultaneous use with phenothiazines, such as chlorpromazine, flufenazine, perfenazine.

Anesthetics/myorelaxants

Thrasodon hydrochloride can enhance the effects of myorelaxants and volatile anesthetics, it must be used with caution.

Alcohol

Trazodon enhances the sedative effect of alcohol. Alcohol consumption during trazodon therapy should be avoided.

Levodopa

Antidepressants can accelerate levodopa metabolism.

Other

Simultaneous administration of trazodon with drugs that extend the QT interval can increase the risk of ventricular arrhythmia, including polymorphic ventricular tachycardia. Care must be taken when used in conjunction with trazodon.

Since trazodon is a weak inhibitor of reverse capture of norepinephrine and does not change the blood pressure reaction to tyramine, the effect on the hypotensive effect of huanetidin compounds is unlikely. However, animal studies suggest that trazodon can inhibit most of the acute effect of clonidine. For other antihypertensive drugs, the possibility of potentiation should be taken into account, although clinical interaction has not been proven.

Side effects can manifest themselves more often when using trazodon simultaneously with drugs containing Hypericum Perforatum.

Cases of prothrombin time changes were reported in patients who took both trazodon and warfarin at the same time.

Simultaneous use of digoxin or phenytoin with trazodon can lead to increased levels of digoxin and phenytoin in blood serum. The level of digoxin and phenytoin in the serum in such patients should be monitored.

The tablets should be taken entirely without chewing and washed down with enough water.

Therapy should begin with evening administration and gradual increase in daytime doses.

The drug can be taken regardless of the meal.

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

Adults

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

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

Elderly patients

For elderly or weakened patients, the recommended daily dose should be reduced to 100 mg/day in fractional doses or as a single dose in the evening before bedtime. This dose can be gradually increased under the supervision of a doctor depending on the effectiveness and tolerance of the drug. In most cases, a single dose of more than 100 mg should be avoided for these patients. Usually a dose exceeding 300 mg/day is not required.

Symptoms: drowsiness, dizziness, nausea, vomiting. In more severe cases, coma, tachycardia, hypotension, hyponatremia, seizures and respiratory arrest were reported. With regard to cardiac activity, these can be bradycardia, lengthening of the QT interval and polymorphic ventricular tachycardia.

Symptoms can occur within 24 hours or later after an overdose. An overdose of trazodon in combination with other antidepressants can cause serotonin syndrome.

Treatment: there is no specific trazodont antidote. Activated carbon can be used by adults who have taken more than 1 g of trazodon or children who have taken more than 150 mg of trazodon within 1 hour after the onset of symptoms. As an alternative therapy, adults can be washed their stomach for 1 hour after taking a potentially life-threatening dose.

It is necessary to monitor at least 12 hours after taking the drug, as well as control the level of blood pressure, pulse and Glasgow coma scale. If the Glasgow coma scale is reduced, oxygen saturation of the blood is controlled. Cardiac function control is necessary in patients with appropriate symptoms.

Single short cramps do not require therapy. Frequent or long seizures are corrected by administering diazepam intravenously (0.1-0.3 mg/kg body weight) or lorazepam (4 mg adults or 0.05 mg/kg body weight for children).

If these measures do not allow for the control of seizures, intravenous administration of phenytoin may be recommended. To correct the acid-base balance and metabolic disorders, oxygen should be used inhaled.

In case of hypotension and excessive sedative effect, symptomatic and supportive therapy should be carried out. If severe hypotension persists, the use of dopamine or dobutamine should be considered.

Use in children and adolescents (under 18 years of age)

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

Suicide/suicidal thoughts or deterioration of clinical symptoms

In depressive conditions, the risk of suicide thoughts, self-harm or suicide is increased. This risk remains until a pronounced remission occurs. Since the improvement may not occur during the first few weeks of treatment or more, patients should be under strict control before improvement occurs. According to general clinical experience, the risk of suicide can increase in the early stages of recovery.

It is known that patients with a history of suicide events, or patients who show a significant degree of suicidal thinking before treatment, have a higher risk of suicidal thoughts or suicide attempts, and should be closely monitored during treatment. The results of a meta-analysis of placebo-controlled clinical studies of antidepressants used in adults with mental disorders showed an increased risk of suicidal behavior in patients under 25 years of age against the background of taking antidepressants compared to placebo.

Careful monitoring of patients, especially those at high risk, should accompany drug therapy, especially at its early stages and after dose changes. It is necessary to warn patients (and caregivers) of the need to monitor any clinical deterioration, suicidal behavior or suicidal thoughts, unusual behavioral changes, and immediately seek expert advice if such symptoms occur. To minimize the potential risk of suicide attempts, especially at the beginning of treatment, the minimum required dose should be prescribed on a case-by-case basis.

In case of jaundice, trazodon therapy should be discontinued.

The use of antidepressants in patients with schizophrenia or other mental disorders can lead to a possible deterioration of mental symptoms. Paranoid thoughts can increase. In treatment with trazodon, depressive attacks can range from manic-depressive to manic psychosis. In this case, the trazodon should be canceled.

When using trazodon simultaneously with drugs with serotonergic activity, such as other antidepressants (e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors, selective serotonin and norepinephrine and MAO inhibitors) and neuroleptics, interactions with the development of Malicant neuroleptic syndrome with death was registered in cases of joint use with neuroleptics, for which this syndrome was a known possible undesirable drug reaction.

Since agranulocytosis can manifest itself as influenza-like syndrome, sore throat and fever, it is recommended to control the blood picture when these symptoms appear.

Cases of hypotension were reported, including orthostatic hypotension and syncopal condition in patients taking trazodon. Simultaneous use with antihypertensive drugs may require a reduction in the dose of the antihypertensive drug.

Elderly patients

Elderly patients are often more susceptible to antidepressants, in particular, cases of orthostatic hypotension, drowsiness and other anticholinergic effects of trazodon are more common.

Particular attention should be paid to potential additive effects in connection with the simultaneous use of other psychotropic or antihypertensive drugs or in the presence of risk factors, such as concomitant diseases, that may exacerbate these reactions.

It is recommended that the patient or caregiver be informed of the possible occurrence of such effects. It is necessary to carefully monitor their manifestation in the patient after the beginning of therapy, before and after titration at an increasing dose.

In case of long-term trazodon therapy, it is recommended to gradually reduce the dose before canceling the drug to minimize withdrawal symptoms such as nausea, headache, malaise.

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

As with other antidepressants, cases of elongation of the QT interval with trazodon have been reported very rarely. Care should be taken when prescribing trazodon with drugs that extend the QT interval.

Trazodon should be used with caution in patients with known cardiovascular diseases, including the lengthening of the QT interval. Strong CYP3A4 inhibitors can lead to an increase in trazodon levels in blood serum.

As with other drugs with alpha-adrenolithic activity, trazodon is very rarely associated with primapism. This can be corrected by intracavernous injection of an alpha-adrenergic agent such as adrenaline or meteraminol. However, there are reports of trazodon-induced prapism that required surgery or led to permanent sexual dysfunction. Patients who develop this alleged adverse reaction should immediately stop taking trazodon.

Impact on urine analysis results

When using immunotests to control narcotic substances in the urine, the reactivity of the metabolite trazodon meta-chlorophenylpiperazine (m-CPP), which is structurally similar to methylenedioxymethamphetamine (MDMA, ecstasy), can cause a false positive reaction to amphet In these cases, it is recommended to conduct a confirmation analysis using the mass spectrometry method.

Impact on the ability to drive vehicles, mechanisms

Trazodon has a slight or small impact on the ability to drive vehicles or mechanisms. The patient should be warned of the risk when driving vehicles or working with mechanisms until he is sure that he or she is not drowsy, lethargy, dizziness, confusion or blurred vision.

Tablets with prolonged release, 150 mg.

10 tablets in a blister made of PVC / aluminum foil.

2 or 6 blisters each, together with instructions for use in a cardboard pack.