Trittico

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRITTICO (Trittico®)

Composition:

Active substance: trazodone hydrochloride;

1 tablet contains trazodone hydrochloride 75 mg or 150 mg;

Excipients: sucrose, carnauba wax, povidone, magnesium stearate.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties:

75 mg tablets: elongated, biconvex tablets, white to yellowish-white, with two notches on both sides;

150 mg tablets: elongated, biconvex tablets, white to yellowish-white, with two notches on both sides.

Pharmacotherapeutic group. Psychoanaleptics. Antidepressants. Other antidepressants. ATC code N06AX05.

Pharmacological properties.

Pharmacodynamics.

Trazodone is a triazolopyridine derivative. It is effective in the treatment of depressive disorders, including depression associated with anxiety and sleep disturbances, and is characterized by a rapid onset of action (approximately 1 week).

Trazodone is a serotonin reuptake inhibitor and a 5-HT2 receptor antagonist. Activation of 5-HT2 receptors is generally associated with insomnia, anxiety, psychomotor agitation, and changes in sexual function.

Unlike other psychotropic drugs, trazodone is not contraindicated in glaucoma and urinary tract disorders. It does not produce extrapyramidal effects and does not potentiate adrenergic transmission. Trazodone lacks anticholinergic activity; therefore, it does not exert the typical cardiac effects associated with tricyclic antidepressants.

Pharmacokinetics.

After a single oral dose of 75 mg of prolonged-release trazodone, the maximum plasma concentration (Cmax) is approximately 0.7 μg/mL, reached at a Tmax of 4 hours; the area under the pharmacokinetic curve (AUC) is approximately 8 μg·h/mL. After a single oral dose of 150 mg of prolonged-release trazodone, Cmax is approximately 1.2 μg/mL, reached at a Tmax of 4 hours. The elimination half-life is approximately 12 hours, and AUC is approximately 18 μg·h/mL.

Food interaction studies have shown no significant changes in Cmax or AUC when Tritico prolonged-release tablets are administered in the fasting state or after food.

In vitro studies using human liver microsomes have shown that trazodone is metabolized primarily by cytochrome P450 3A4 (CYP3A4).

Trazodone is excreted predominantly in the urine as metabolites.

Clinical characteristics.

Indications.
Depressive disorders with/without anxiety.

Contraindications.
Known hypersensitivity to the drug or its components.
Alcohol intoxication and intoxication with hypnotics.
Acute myocardial infarction.

Interaction with other medicinal products and other forms of interactions.

General
The sedative effects of antipsychotics, hypnotics, anxiolytics, and antihistamines may be enhanced. Dose reduction of these agents is recommended.

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

CYP3A4 inhibitors
In vitro metabolism studies indicate a potential for drug interactions when trazodone is used concomitantly with cytochrome CYP3A4 inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir, and nefazodone. The use of CYP3A4 inhibitors may lead to a significant increase in plasma concentrations of trazodone. In vivo studies in healthy volunteers have confirmed that after administration of ritonavir 200 mg twice daily, plasma levels of trazodone increased more than two-fold, resulting in nausea, syncope, and arterial hypotension. Therefore, when trazodone is used concomitantly with a potent CYP3A4 inhibitor, a reduction in trazodone dosage is advisable.

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

Carbamazepine
When trazodone is used concomitantly with carbamazepine, plasma concentrations of trazodone decrease. When used concomitantly with carbamazepine at a dose of 400 mg daily, plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine are reduced by 76% and 60%, respectively. Close monitoring of the patient is required to determine whether an increase in trazodone dosage is necessary.

Tricyclic antidepressants
There is a risk of drug interaction; therefore, concomitant use with trazodone should be avoided. If used together, serotonin syndrome and adverse cardiovascular effects may be expected.

Fluoxetine
Rare cases of increased plasma levels of trazodone and occurrence of adverse effects have been reported during concomitant use of trazodone 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)
Isolated cases of interaction between trazodone and MAO inhibitors have been reported. Although some physicians practice concomitant use of these agents, it is not recommended to use trazodone together with MAO inhibitors or within 2 weeks after discontinuation of MAO inhibitors. Similarly, initiation of MAOI therapy within 1 week after discontinuation of trazodone is not recommended.

Phenothiazines
Cases of severe orthostatic hypotension have been observed when trazodone is used concomitantly with phenothiazines such as chlorpromazine, fluphenazine, levomepromazine, and perphenazine.

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

Alcohol
The sedative effects of alcohol are intensified under the influence of trazodone. Patients should avoid alcohol consumption during trazodone therapy.

Levodopa
Antidepressants may accelerate the metabolism of levodopa.

Other agents
Concomitant use of trazodone with medicinal products known to prolong the QT interval may increase the risk of ventricular arrhythmias, including polymorphic ventricular tachycardia (torsade de pointes). These agents should be used concomitantly with trazodone with caution.

Trazodone is only a very weak inhibitor of norepinephrine reuptake and does not affect the arterial pressure response to tyramine; therefore, an effect of trazodone on the hypotensive action of guanethidine-like compounds is not expected. However, studies in laboratory animals have shown that trazodone may inhibit most of the rapid effects of clonidine.

Although no drug interactions have been reported with concomitant use of antihypertensive agents of other types and trazodone, the possibility of potentiation of effects should be considered.

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

Oral anticoagulants and/or antiplatelet agents: Rare reports of effects on anticoagulant activity (laboratory test deviations and/or appearance of clinical signs and symptoms) with increased bleeding have been reported.

Cases of changes in prothrombin time have been reported in patients receiving trazodone and warfarin concomitantly.

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

Special precautions for use.

Use in children and adolescents

Trazodone should not be used in children and adolescents. In clinical trials involving children and adolescents, suicidal behaviour (suicide attempts and suicidal ideation) and hostility (mainly aggression, oppositional behaviour and anger) were observed more frequently in the antidepressant group than in the placebo group. Furthermore, there are currently no data on the long-term safety of trazodone use in children and adolescents with regard to its effects on growth, sexual maturation, and cognitive and behavioural development.

Suicide / suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicidal behaviour). This risk persists until significant remission occurs. Lack of improvement may be observed during the first few weeks of therapy or longer. Patients should be closely monitored until such improvement occurs. General clinical experience suggests that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicidal behaviour or those who had a high degree of suicidal ideation prior to starting therapy are at higher risk of developing suicidal thoughts or suicide attempts, and therefore require careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in psychiatric disorders showed that patients under 25 years of age had a higher risk of suicidal behaviour in the antidepressant group compared to the placebo group.

Treatment with this medicinal product should be accompanied by close monitoring of patients, particularly those at high risk, especially at the beginning of treatment and after dose changes. Patients (and caregivers) should be advised to monitor for any clinical worsening, suicidal thoughts or behaviour, or unusual changes in behaviour, and to seek immediate medical advice if such symptoms occur.

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

Careful dose selection and regular monitoring are recommended in patients with the following conditions:

• Epilepsy; in such patients, the dose should not be abruptly increased or decreased;
• Hepatic or renal impairment, particularly severe;
• Cardiac diseases, such as angina pectoris, conduction disorders or atrioventricular block of various degrees; recent myocardial infarction;
• Hyperthyroidism;
• Urinary retention, e.g. due to prostate hyperplasia, although such problems are not expected, as the anticholinergic effect of trazodone is negligible;
• Acute angle-closure glaucoma, elevated intraocular pressure, although significant changes are not expected, as the anticholinergic effect of trazodone is negligible.

If jaundice develops in a patient, trazodone therapy should be discontinued.

When antidepressants are used in patients with schizophrenia or other psychotic disorders, psychotic symptoms may be exacerbated. Paranoid thoughts may become more pronounced. In patients with bipolar disorder, the depressive phase may shift to a manic phase during trazodone therapy. In such cases, trazodone treatment should be discontinued.

Drug interactions leading to serotonin syndrome / neuroleptic malignant syndrome have been reported with concomitant use of trazodone and other serotonergic medicinal products, such as other antidepressants (e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and MAO inhibitors) and neuroleptics. Cases of neuroleptic malignant syndrome with fatal outcome have been reported with concomitant use of trazodone and neuroleptics known to be associated with this syndrome. More detailed information is provided in the sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects".

Since agranulocytosis may clinically present as influenza-like symptoms, sore throat and fever, blood counts should be checked if these symptoms occur.

Cases of arterial hypotension, including orthostatic hypotension and syncope, have been reported in patients receiving trazodone therapy. Concomitant use of antihypertensive agents and trazodone may require a reduction in the dose of the antihypertensive agent.

Use with caution in patients taking serotonergic agents such as trazodone concomitantly with anticoagulants and/or antiplatelet agents, and in patients with a predisposition to bleeding.

Elderly patients are often more susceptible to adverse effects of antidepressants, particularly orthostatic hypotension, somnolence, and other anticholinergic effects.

Potential additive effects should be considered when trazodone is used concomitantly with other medicinal products such as other psychotropic or antihypertensive agents, or in the presence of risk factors such as concomitant diseases that may enhance such reactions.

Patients (and caregivers) should be informed about the possibility of such reactions and advised to monitor carefully for their occurrence, especially after initiation of therapy and after dose increases.

At the end of trazodone treatment, particularly after prolonged therapy, gradual dose reduction is recommended until complete discontinuation to minimize the likelihood of withdrawal symptoms such as nausea, headache and general malaise.

Currently, there is no evidence that trazodone hydrochloride causes dependence.

Rare cases of QT interval prolongation have been reported with trazodone use — an effect also observed with other antidepressants. Trazodone should be used with caution concomitantly with medicinal products known to prolong the QT interval. Caution is also advised in patients with diagnosed cardiovascular diseases, including those associated with QT interval prolongation.

Serum levels of trazodone may increase when used concomitantly with potent inhibitors of cytochrome CYP3A4. More detailed information is provided in the section "Interaction with other medicinal products and other forms of interaction".

Like other medicinal products with alpha-adrenergic blocking activity, trazodone has very rarely caused priapism. In such cases, intracavernosal injection of an alpha-adrenergic agent such as adrenaline or metaraminol should be administered. However, cases of trazodone-induced priapism requiring surgical intervention or resulting in permanent sexual dysfunction have been reported. Trazodone should be discontinued immediately in patients suspected of this adverse reaction.

Trittiko, prolonged-release tablets, contains sucrose. This medicinal product should not be used in patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency.

If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Effect on urine testing

When using immunological tests to detect drugs in urine, cross-reactivity of the trazodone metabolite m-chlorophenylpiperazine (m-CPP), which is structurally similar to methylenedioxymethamphetamine (MDMA, ecstasy), may lead to false-positive amphetamine results. In such cases, confirmation by mass spectrometry (MS) is recommended.

Use during pregnancy or breastfeeding

Pregnancy

Data from studies involving a limited number of (<200) pregnant women exposed to trazodone suggest no adverse effects on pregnancy course or fetal/neonatal health. Currently, no other adequate epidemiological data are available. Animal studies do not indicate any direct or indirect harmful effects of trazodone, administered at therapeutic doses, on pregnancy, embryonal/fetal development, parturition or postnatal development.

Trazodone should be used with caution in pregnant women. If trazodone is used during pregnancy, the newborn should be monitored after delivery for possible withdrawal syndrome, taking into account the benefit to the mother and risk to the fetus.

Breastfeeding

Limited data indicate that trazodone passes into breast milk in small amounts, but the concentration of the active metabolite is unknown. Due to insufficient data, the decision on whether to continue or discontinue breastfeeding or trazodone therapy should be based on the benefit of breastfeeding to the child and the benefit of trazodone therapy to the mother.

Ability to affect reaction speed when driving vehicles or operating machinery

Trazodone has a minor to moderate effect on the ability to drive vehicles and operate machinery. Patients should be advised to ensure that they do not experience somnolence, sedation, dizziness, confusion or blurred vision while taking trazodone before driving or operating machinery.

Dosage and Administration

The medication should be used only in adults.

The tablet with two parallel lines on the surface can be divided into three parts to allow gradual dose escalation depending on the severity of the disease, body weight, age, and general condition of the patient.

Treatment should begin with evening doses, increasing the dose daily according to physician's recommendations.

Prolonged-release tablets may be taken before or after food intake.

Treatment should last at least 1 month.

Adults: 75–150 mg once daily in the evening before bedtime.

The dose may be increased up to 300 mg/day, which should be divided into two doses.

For hospitalized patients, the dose may be increased up to 600 mg/day, which should be divided into several doses.

Elderly patients: initial dose of 100 mg/day taken once in the evening or divided into several doses. The dose may be gradually increased as indicated for adults, depending on clinical response. In general, single doses exceeding 100 mg should be avoided in these patients. Doses above 300 mg/day are rarely required.

Hepatic impairment: trazodone is extensively metabolized in the liver and has been associated with hepatotoxicity. Therefore, it should be prescribed with caution in patients with hepatic impairment, especially in cases of severe impairment. Periodic monitoring of liver function may be recommended.

Renal impairment: dose adjustment is generally not required, but caution is advised when prescribing to patients with severe renal impairment.

Children. Not recommended for use in children.

Overdose.

Most commonly observed symptoms of overdose include drowsiness, dizziness, nausea, and vomiting. In severe cases, coma, tachycardia, arterial hypotension, hyponatremia, seizures, and respiratory depression may occur.

Cardiac symptoms may include bradycardia, QT interval prolongation, and polymorphic ventricular tachycardia (torsade de pointes).

Symptoms may appear within 24 hours after overdose or later.

Concomitant overdose of trazodone and other antidepressants may lead to serotonin syndrome.

Treatment of overdose

There is no specific antidote. Activated charcoal should be administered to adults who have ingested more than 1 g of trazodone, or to children who have ingested more than 150 mg of trazodone, within 1 hour of overdose detection. In other cases in adults, gastric lavage may be considered within 1 hour after ingestion of potentially life-threatening doses.

Patient monitoring is required for at least 6 hours after drug ingestion (or 12 hours in case of extended-release formulation). Blood pressure, pulse, and Glasgow Coma Scale (GCS) scores should be monitored. In case of decreased GCS score, oxygen saturation should be monitored.

Cardiac monitoring is necessary in symptomatic patients.

Isolated brief seizures do not require treatment. For frequent or prolonged seizures, intravenous diazepam (0.1–0.3 mg/kg body weight) or lorazepam (4 mg for adults and 0.05 mg/kg for children) should be administered.

If these measures do not control seizures, intravenous phenytoin infusion may be considered. Oxygen should be administered and acid-base balance and metabolic disturbances corrected as needed.

In cases of arterial hypotension and excessive sedation, symptomatic and supportive therapy should be provided. If severe arterial hypotension persists, the use of inotropic agents such as dopamine or dobutamine should be considered.

Side effects.

Cases of suicidal ideation and suicidal behavior have been reported during therapy with trazodone or shortly after its discontinuation.

The symptoms listed below have also been observed in patients receiving trazodone therapy, some of which are common in untreated depression.

1 In patients with relevant symptoms, fluid levels and electrolyte balance should be monitored.

2 See also section "Special precautions for use".

3 Trazodone is a sedative antidepressant, and drowsiness sometimes experienced by patients during the first days of therapy usually disappears with continued use of the drug.

4 Animal studies have shown that trazodone has less cardiotoxicity compared to tricyclic antidepressants, and clinical data suggest that trazodone is less likely to cause cardiac arrhythmias in humans. However, clinical studies involving patients with pre-existing heart disease indicate that trazodone may have arrhythmogenic effects in some individuals within this population.

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

6 See also section "Special precautions for use".

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in places inaccessible to children.

Packaging.

Trittiko 75 mg: 30 tablets in three PVC/aluminum blisters containing 10 tablets each, or 30 tablets in two PVC/aluminum blisters containing 15 tablets each, in a cardboard package.

Trittiko 150 mg: 20 tablets in two PVC/aluminum blisters containing 10 tablets each, in a cardboard package.

Prescription status. Prescription only.

Manufacturer. Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.p.A.

Manufacturer's location and address of its place of business. Via Vecchio del Pino, 22 – 60131 Ancona (AN), Italy.