TRAZODONE HYDROCHLORIDE

Posology Adults:

According to severity, treatment should be initiated at 75 to 150 mg per day as a single evening dose and then increased to 200 or 300 mg per day, respectively, at the end of the first week. In hospitalised patients with exceptionally severe depression, dosage may be further increased to a maximum of 600 mg per day in divided doses.

4). This may be incrementally increased, under supervision, according to efficacy and tolerance. In general, single doses above 100mg should be avoided in these patients. Doses above 300mg/day are unlikely to be required.

Children:

There are insufficient data on safety to recommend the use of trazodone in children below the age of 18 years. Therefore trazodone is not recommended for use in this age group. 8). Therefore caution should be exercised when prescribing for patients with hepatic impairment, particularly in cases of severe hepatic impairment.

Periodic monitoring of liver function may be considered. 2).

Method of administration:

For oral use A decrease in side-effects (increase of the resorption and decrease of the peak plasma concentration) can be reached by taking trazodone hydrochloride after a meal.

4). The following symptoms, some of which are commonly reported in cases of untreated depression, have also been recorded in patients receiving trazodone therapy. MedDRA System Organ Class Frequency not known (cannot be estimated from the available data) Blood and the Blood dyscrasias (including agranulocytosis, lymphatic system disorders thrombocytopenia, eosinophilia, leucopenia and anaemia) Immune system disorders Allergic reactions Endocrine disorders Syndrome of Inappropriate Antidiuretic Hormone Secretion Metabolism and nutrition disorders Hyponatraemia1, weight loss, anorexia, increased appetite Psychiatric disorders Suicidal ideation or suicidal behaviours2, confusional state, insomnia, disorientation, mania, anxiety, nervousness, agitation (very occasionally exacerbating to delirium), delusion, aggressive reaction, hallucinations, nightmares, libido decreased, withdrawal syndrome Nervous system disorders Serotonin syndrome, convulsion, neuroleptic malignant syndrome, dizziness, vertigo, headache, drowsiness3, restlessness, decreased alertness, tremor, blurred vision, memory disturbance, myoclonus, expressive aphasia, paraesthesia, dystonia, taste altered Cardiac disorders Cardiac arrhythmias4 (including Torsade de Pointes, palpitations, premature ventricular contractions, ventricular couplets, ventricular tachycardia), bradycardia, tachycardia, ECG abnormalities (QT prolongation)2 Vascular disorders Orthostatic hypotension, hypertension, syncope Respiratory, thoracic and mediastinal disorders Nasal congestion, dyspnoea Gastrointestinal disorders Nausea, vomiting, dry mouth, constipation, diarrhoea, dyspepsia, stomach pain, gastroenteritis, increased salivation, paralytic ileus Hepato-biliary disorders Hepatic function abnormalities (including jaundice and hepatocellular damage)5, cholestasis intrahepatic, severe hepatic disorders such as hepatitis/ fulminant hepatitis, hepatic failure with potential fatal outcome.

Skin and subcutaneous tissue disorders Skin rash, pruritus, hyperhidrosis Musculoskeletal and connective tissue disorders Pain in limb, back pain, myalgia, arthralgia Renal and urinary disorders Micturition disorder Reproductive system and breast disorders Priapism6 General disorders and administration site conditions Weakness, oedema, influenza-like symptoms, fatigue, chest pain, fever Investigations Elevated liver enzymes 1Fluid and electrolyte status should be monitored in symptomatic patients.

4. 3Trazodone is a sedative antidepressant and drowsiness, sometimes experienced during the first days of treatment, usually disappears on continued therapy. 4Studies in animals have shown that trazodone is less cardiotoxic than the tricyclic antidepressants, and clinical studies suggest that the drug may be less likely to cause cardiac arrhythmias in man.

Clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population. 5Adverse effects on hepatic function, sometimes severe, have been rarely reported. Should such effects occur, trazodone should be immediately discontinued.

4. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Suicide/suicidal thoughts or clinical worsening Depression is associated with an 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. Other psychiatric conditions for which trazodone is prescribed can also be associated with an increased risk of suicide-related events.

In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be 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 adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

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

To minimise the potential risk of suicide attempts, particularly at therapy initiation, only restricted quantities of trazodone should be prescribed at each occasion. It is recommended that careful dosing and regular monitoring is adopted in patients with the following conditions: • Epilepsy, specifically abrupt increases or decreases of dosage should be avoided • Patients with hepatic or renal impairment, particularly if severe • Patients with cardiac disease, such as angina pectoris, conduction disorders or AV blocks of different degree, recent myocardial infarction • Hyperthyroidism • Micturition disorders, such as prostate hypertrophy, although problems would not be anticipated as the anticholinergic effect of trazodone is only minor • Acute narrow angle glaucoma, raised intra-ocular pressure, although major changes would not be anticipated due to the minor anticholinergic effect of trazodone.

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 therapy with trazodone a depressive phase can change from a manic-depressive psychosis into a manic phase.

In that case trazodone must be stopped. g. tricyclic antidepressants, SSRI’s, SNRI’s and MAO inhibitors) and neuroleptics. 8 ). 5). If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Agranulocytosis Since agranulocytosis may clinically reveal itself with influenza-like symptoms, sore throat, and fever, in these cases it is recommended to check haematology. Hypotension, including orthostatic hypotension and syncope, has been reported to occur in patients receiving trazodone.

Concomitant administration of antihypertensive therapy with trazodone may require a reduction in the dose of the antihypertensive drug. Following therapy with trazodone, particularly for a prolonged period, an incremental dosage reduction to withdrawal is recommended, to minimise the occurrence of withdrawal symptoms, characterised by nausea, headache, and malaise.

There is no evidence that trazodone hydrochloride possesses any addictive properties. QT prolongation As with other antidepressant drugs, cases of QT interval prolongation have been reported with trazodone very rarely. Caution is advised when prescribing trazodone with medicinal products known to prolong QT interval.

Trazodone should be used with caution in patients with known cardiovascular disease including those associated with prolongation of the QT interval. 5 for further information). Priapism As with other drugs with alpha-adrenolytic activity, trazodone has very rarely been associated with priapism.

This may be treated with an intracavernosum 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 reaction should cease trazodone immediately. Undesirable effects may be more common during concomitant use of trazodone and herbal preparations […]

1. • Alcohol intoxication and intoxication with hypnotics. • Acute myocardial infarction.