Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use

Trittico is not generic to other medicines containing Trazodone. When switching other medicines containing trazodone to Trittico, patient must be medically monitored.
In clinical trials, suicidal behaviour (suicide attempts and suicidal thoughts) and hostility (predominantly aggressiveness, oppositional behaviour and anger) have been observed more frequently in children and adolescents treated with antidepressants than in those treated with a placebo. Moreover, long-term safety data on children and adolescents regarding growth, maturation and cognitive and behavioural development are not available.


Suicide/suicidal thoughts or clinical worsening
Depression is associated with increased risk of suicidal thoughts, self-harm and suicide (suicide/related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicidal behaviour or thoughts, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in the treatment of psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients under 25 years old.

Close supervision of patients and in particular those at high risk should always accompany drug therapy with antidepressants, especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted of the need to monitor for any clinical worsening, suicidal behaviour or thoughts or unusual changes in behaviour and to seek medical advice immediately if these symptoms appear.

To minimise the potential risk of suicide attempts, particularly at the start of treatment, only restricted quantities of trazodone should be prescribed at each visit.

It is recommended that careful dosing and regular monitoring be adopted in patients with:
• Epilepsy - in particular, abrupt dosage increases or decreases should be avoided
• Hepatic or renal impairment, particularly if severe
• Heart disease, such as angina pectoris, conduction disorders or AV blocks of different degrees, recent myocardial infarction
• Hyperthyroidism
• Micturition disorders, such as prostate hypertrophy
• Acute narrow angle glaucoma, increased intraocular pressure, although major changes have not yet been observed, due to the minor anticholinergic effect of trazodone.

Should jaundice occur in a patient, treatment must be withdrawn. Given the hepatic metabolism and the risk of hepatotoxicity, periodical monitoring of liver functions is recommended (see sections 4.8 and 5.2).

Administration of antidepressants in patients with schizophrenia or other psychotic disorders may result in a possible worsening of psychotic symptoms. Paranoid thoughts may be intensified. During treatment with trazodone, a depressive episode may change from manic depressive psychosis into manic psychosis. If this occurs, trazodone treatment must be discontinued.

Interactions in terms of serotonin syndrome/neuroleptic malignant syndrome have been reported in the event of concomitant use of other serotonergically acting substances (e.g. tricyclic antidepressants, SSRIs, SNRIs and MAO inhibitors) and neuroleptics. Cases of neuroleptic malignant syndrome with fatal outcome have been reported in cases of coadministration with neuroleptics, for which this syndrome is a known possible adverse drug reaction (see sections 4.5 and 4.8 for further information).

Agranulocytosis may present with influenza-like symptoms. Blood tests should therefore be performed if the patient develops a sore throat and fever.

Hypotension, including orthostatic hypotension and syncope, has been reported in patients taking trazodone. Concomitant administration of antihypertensive therapy with trazodone may require a reduction in the dose of the antihypertensive drug.

Caution is advised in patients taking serotonergic agents such as trazodone concomitantly with 
anticoagulant and/or antiplatelet agents, and in patients with a known bleeding tendency.

Elderly (from 65 Years of age)
Elderly patients are often more sensitive to the effects of antidepressants and, in particular, may more often experience orthostatic hypotension, drowsiness and other anticholinergic effects of trazodone.
Careful consideration should be given to the potential additive effects with concomitant treatment use, such as with other psychotropics or antihypertensives, or in the presence of risk factors such as comorbidities, which can exacerbate these reactions.
Patients (and caregivers of patients) should be informed of the potential onset of these reactions and should be monitored closely for such effects at the start of treatment and before and following dose increases.

Following therapy with trazodone, particularly for a prolonged period, an incremental dosage reduction prior to withdrawal is recommended, to minimise the occurrence of withdrawal symptoms, characterised by nausea, headache, and malaise.

There is no evidence that trazodone possesses any addictive properties.

As with other antidepressants, cases of QT interval prolongation have been reported rarely with trazodone.
Special precautions should be taken when administering trazodone with other medicinal products known to prolong the QT interval. Trazodone should be used with caution in patients with cardiovascular disease, including conditions associated with prolongation of the QT interval.

CYP3A4 inhibitors may lead to a significant increase in the plasma concentration of trazodone. See section 4.5 for further information.

As with other drugs with alpha-adrenolytic activity, cases of priapism have been reported rarely during treatment with trazodone. This may be treated with an intracavernosal injection of an alpha-adrenergic agent such as adrenaline or metaraminol. However there are reports of trazodone-induced priapism which have required surgical intervention or led to permanent sexual dysfunction. Patients developing this suspected adverse drug reaction should cease trazodone immediately.

Interference with urine tests
When immunoassays are used for drug screening in urine, a cross-reactivity of the trazodone metabolite meta-Chlorophenylpiperazine (m-CPP) which is structurally similar to methylenedioxymethamphetamine (MDMA, ecstasy), may cause false positivity for amphetamine. In these cases, it is recommended to perform a confirmation analysis by mass spectrometry (MS) techniques.


Important information about some of the excipients
Film-coated tablets
Trittico 50 mg and 100 mg film-coated tablets contain:
- lactose: patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product; 
- castor oil: may cause stomach upset and diarrhoea;
- sodium: this medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially sodiu -free .

Trittico 50 mg film-coated tablets contain sunset yellow (E110)
Sunset yellow (E110): may cause allergic reactions.



Effects on Driving

4.7     Effects on ability to drive and use machines

Trazodone has minor or moderate influence on the ability to drive and use machines. Patients should be warned of the risks of driving or using machines, unless they are sure they are not affected by drowsiness, sedation, dizziness, confusional state or blurred vision.