TRITTICO Film-coated tablet Ref.[115939] Active ingredients: Trazodone

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, although problems would not be anticipated as the anticholinergic effect of trazodone is negligible

Angle-Closure Glaucoma, as with other antidepressants, trazodone can cause mydriasis, which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles. Healthcare providers should inform patients to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.

Should jaundice occur in a patient, treatment must be withdrawn.

Severe hepatic disorders with potential fatal outcome have been reported with trazodone use (see adverse reaction section). Patients should be instructed to report immediately signs such as asthenia, anorexia, nausea, vomiting, abdominal pain or icterus to a physician. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately, and withdrawal of trazodone therapy be considered. (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

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.

It is recommended that the patient/caregiver is informed of the potential onset for these reactions and monitored closely for such effects after starting treatment, as well as 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 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;
• sodium: this medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'
• sunset yellow (E110): may cause allergic reactions.

General

The sedative effects of antipsychotics, hypnotics, sedatives, anxiolytics, and antihistaminic drugs may be intensified; dosage reduction is recommended in such instances.

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

CYP3A4 inhibitors

In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is co- administered with cytochrome P4503A4 inhibitors (CYP3A4), such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir and nefazodone. CYP3A4 inhibitors may lead to a significant increase in the plasma concentration of trazodone. It has been confirmed by in vivo studies in healthy volunteers, that a ritonavir dose of 200 mg BID increases the plasma levels of trazodone greater than two-fold, leading to nausea, syncope and hypotension. Therefore, if trazodone is administered with a potent CYP3A4 inhibitor, a reduction in the dose of trazodone is needed. However, coadministration of trazodone and potent CYP3A4 inhibitors should be avoided where possible.

Carbamazepine

Coadministration of carbamazepine and trazodone results in reduced trazodone plasma concentrations. Concomitant use of carbamazepine 400 mg daily led to a decrease in plasma levels of trazodone and its active metabolite m-Chlorophenylpiperazine of 76% and 60%, respectively. For this reason, patients taking trazodone in combination with carbamazepine should be closely monitored to assess whether there is a need for an increased dose of trazodone.

Tricyclic antidepressants

Concomitant use with trazodone should be avoided due to the risk of interaction. Carefully evaluate the possibility of onset of serotonin syndrome and cardiovascular adverse effects.

Fluoxetine

Rare cases have been reported of elevated trazodone plasma levels and adverse effects when trazodone had been combined with fluoxetine, a CYP1A2/2D6 cytochrome inhibitor. The mechanism underlying a pharmacokinetic interaction is not fully understood. A pharmacodynamic interaction (serotonin syndrome) cannot be excluded.

Monoamine oxidase inhibitors (MAOIs)

Possible interactions with monoamine oxidase inhibitors (MAOIs) have occasionally been reported. Although some physicians do give both concurrently, use of trazodone concomitantly with MAOIs, or within two weeks after discontinuation of MAOI treatment, is not recommended. The administration of MAOIs within one week of stopping trazodone treatment is also not recommended.

Phenothiazines

Severe orthostatic hypotension has been observed in the event of concomitant use of phenothiazines, e.g. chlorpromazine, fluphenazine, levomepromazine, and perphenazine.

Anaesthetics and muscle relaxants

Trazodone hydrochloride may enhance the effects of muscle relaxants and volatile anaesthetics, and caution should be exercised in such instances.

Alcohol

Trazodone intensifies the sedative effects of alcohol. Alcohol intake should be avoided during trazodone therapy.

Levodopa

Antidepressants can accelerate the metabolism of levodopa.

Other

Concomitant use of trazodone with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including "torsades de pointes". Caution should be taken when these drugs are co-administered with trazodone.

Since trazodone is only a weak inhibitor of noradrenaline re-uptake and does not modify the blood pressure response to tyramine, interference with the hypotensive action of guanethidine-like compounds is unlikely. However, studies in laboratory animals suggest that trazodone may inhibit most of the acute actions of clonidine. In the case of other types of antihypertensive drugs, although no clinical interactions have been reported, the possibility of potentiation should be considered.

Undesirable effects may be more frequent during concomitant use of plant-based medicinal preparations containing St John's Wort (Hypericum perforatum).

Oral anticoagulant and/or antiplatelet agents: altered anti-coagulant functions (laboratory values and/or clinical signs and symptoms) with increased bleeding have rarely been reported.

There have been reports of changes in prothrombin time in patients receiving trazodone and warfarin. Combination of trazodone with digoxin and phenytoin may result in elevated levels of these chemicals in the blood. Monitor plasma concentrations in these patients.

Pregnancy

Trazadone should only be administered during pregnancy if considered essential by the physician. Data on a limited number (<200) of exposed pregnancies indicate that there are no adverse effects of trazodone on pregnancy or on the health of the foetus/newborn. To date, no other relevant epidemiological data are available. The safety of Trazodone hydrochloride in human pregnancy has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or postnatal development at therapeutic doses (see section 5.3). On basic principles, therefore, its use during the first trimester should be avoided. Caution should be taken when trazodone is administered to pregnant women. When trazodone is used until delivery, newborns should be monitored for withdrawal syndromes.

Breastfeeding

Limited data indicate that excretion of trazodone in human milk is low, but levels of the active metabolite are not known. Given the lack of data, the decision on the use of trazodone during breastfeeding must be made taking into account the benefits of breastfeeding and the benefits of trazodone therapy for the woman.

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.

Cases of suicidal thoughts and behaviour have been reported during trazodone therapy or soon after discontinuation of treatment.

The following symptoms, some of which are commonly reported in cases of untreated depression, have also been recorded in patients receiving trazodone therapy:

¹ Fluid and electrolyte status should be monitored in symptomatic patients.
² See also section 4.4.
³ Trazodone is an antidepressant with sedative properties and drowsiness is sometimes seen in the first few days of treatment, but this generally disappears as therapy continues
⁴ Studies in animals have shown that trazodone is less cardiotoxic than tricyclic antidepressants, and clinical studies suggest that it is less likely to cause cardiac arrhythmias in humans. Clinical studies in patients with pre-existing heart disease indicate that trazodone can be arrhythmogenic in some patients of that population.
⁵ Adverse effects on hepatic function, sometimes severe, have been reported rarely.
⁶ See also section 4.4.

Not applicable.