Zadopax 50mg & 100mg Capsule

ZADOPAX is indicated in the treatment of depression and mixed anxiety and depression.

The dosage is dependent upon the diagnosis and the severity of the condition and the individual patientu2019s response. The daily dosage is usually administered in three divided doses.

Adults: Depression: The optimal dosage is between 300 - 400 mg/day. It is suggested that a starting dose of 150 mg/day is given for the first week, increasing to 300 mg/day u2013 400 mg/day according to the clinical response. The dose may be further increased to 600 mg/day in divided doses in hospitalised patients.

Mixed anxiety and depression: The recommended starting dose is between 100 u2013 150 mg/day. When depression is the predominant symptom, a dose of 300 u2013 400 mg daily may be required to obtain a satisfactory response.

Special populations

Elderly: For very elderly or frail patients the recommended initial starting dose is reduced to 100 mg/day given in divided doses or as a single night-time dose. This may be incrementally increased, under supervision, according to efficacy and tolerance. In general, single doses above 100 mg should be avoided in these patients. It is unlikely that 300 mg/day will be exceeded.

Paediatric population

Children and adolescents under 18 years of age: ZADOPAX is not recommended for use in children and adolescents under 18 years of age.

Method of administration

For oral use.

• Known hypersensitivity to trazodone or to any of the excipients listed in section 6.1.
• Combined use with other psychotropic medicines should only be undertaken with due recognition of the possibility of potentiation (see Interactions).
• Concurrent administration with monoamine oxidase inhibitors (MAOIs), or within two weeks of stopping treatment with these compounds. Administration of MAOIs within one week of stopping ZADOPAX.
• Alcohol intoxication and intoxication with hypnotics.
• Acute myocardial infarction (see section 4.4).

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 medicinal products 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 medicinal product 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 ZADOPAX 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. Should jaundice occur in a patient, ZADOPAX therapy must be withdrawn.

Severe hepatic disorders with potential fatal outcome have been reported with trazodone use (see section 4.8). Patients should be instructed to report immediately signs such as asthenia, anorexia, nausea, vomiting, abdominal pain or icterus to a medical practitioner. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately, and withdrawal of ZADOPAX therapy be considered.

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 u2013 depressive psychosis into a manic phase. In that case ZADOPAX must be stopped.

Interactions in terms of serotonin syndrome/malignant neuroleptic syndrome have been described in case of concomitant use of other serotonergically acting substances like other antidepressants (e.g. tricyclic antidepressants, SSRI's, SNRI's and MAO-inhibitors) and neuroleptics. Malignant neuroleptic syndromes with fatal outcome have been reported in cases of co-administration with neuroleptics, for which this syndrome is a known possible adverse medicinal product reaction, (see sections 4.5 and 4.8).

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 ZADOPAX may require a reduction in the dose of the antihypertensive medicinal product.

Elderly patients may more often experience orthostatic hypotension, somnolence and other anticholinergic effects of trazodone. Careful consideration should be given to the potential for additive effects with concomitant medicine use such as with other psychotropics or antihypertensives or in the presence of risk factors such as comorbid disease, which may exacerbate these reactions. It is recommended that the patient/carer is informed of the potential for these reactions and monitored closely for such effects following initiation of therapy, prior to and following upward dose titration.

Following therapy with ZADOPAX, 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.

Cases of QT interval prolongation have been reported with trazodone. Caution is advised when prescribing ZADOPAX with medicinal products known to prolong QT interval. ZADOPAX should be used with caution in patients with known cardiovascular disease including those associated with prolongation of the QT interval.

Potent CYP3A4 inhibitors may lead to increases in trazodone serum levels. See section 4.5.

Trazodone has been associated with priapism. This may be treated with an intracavernosum injection of an alpha-adrenergic medicine 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 ZADOPAX immediately.

Paediatric population

Use in children and adolescents under 18: ZADOPAX should not be used in children and adolescents under 18 years old. Suicidal behaviour (suicidal attempt and suicidal planning) and hostility (essentially aggressiveness, opposing behaviour and anger) has been observed in a clinical study on children and adolescents treated with antidepressant more frequently than with placebo. Moreover, long-term safety data on children and adolescents regarding growth, maturation and cognitive and behavioural development are not available.

Excipients: lactose ZADOPAX contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take ZADOPAX.

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

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

In vitro medicinal product metabolism studies suggest that there is a potential for medicinal product interactions when trazodone is given with potent CYP3A4 inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir, and nefazodone. It is likely that potent CYP3A4 inhibitors may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. Exposure to ritonavir during initiation or resumption of treatment in patients receiving ZADOPAX will increase the potential for excessive sedation, cardiovascular, and gastrointestinal effects. It has been confirmed in in-vivo studies in healthy volunteers, that a ritonavir dose of 200 mg BID increased the plasma levels of trazodone by greater than two-fold, leading to nausea, syncope and hypotension. If ZADOPAX is used with a potent CYP3A4 inhibitor, a lower dose of ZADOPAX should be considered. However, the co-administration of ZADOPAX and potent CYP3A4 inhibitors should be avoided where possible.

Carbamazepine reduced plasma concentrations of trazodone when co-administered. Concomitant use of carbamazepine 400 mg daily led to a decrease of plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine of 76% and 60%, respectively. Patients should be closely monitored to see if there is a need for an increased dose of ZADOPAX when taken with carbamazepine.

Trazodone may enhance the effects of muscle relaxants and volatile anaesthetics, and caution should be exercised in such instances. Similar considerations apply to combined administration with sedative and antidepressant medicinal products, including alcohol. Trazodone intensifies the sedative effects of alcohol. Alcohol should be avoided during ZADOPAX therapy. Trazodone has been well tolerated in depressed schizophrenic patients receiving standard phenothiazine therapy and also in depressed parkinsonian patients receiving therapy with levodopa. Antidepressants can accelerate the metabolism of levodopa.

Tricyclic antidepressants: Concurrent administration should be avoided due to the risk of interaction. Serotonin syndrome and cardiovascular side effects are possible.

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

Possible interactions with monoamine oxidase inhibitors have occasionally been reported. Use of ZADOPAX with MAOIs, or within two weeks of stopping treatment is contraindicated (see section 4.3). The giving of MAOIs within one week of stopping ZADOPAX is also contraindicated (see section 4.3).

Phenothiazines: Severe orthostatic hypotension has been observed in case of concomitant use of phenothiazines, like e.g. chlorpromazine, fluphenazine, levomepromazine, perphenazine.

Other: Concomitant use of trazodone with medicinal products known to prolong the QT interval may increase the risk of ventricular dysrhythmias, including torsade de pointes. Caution should be used when these medicinal products are co-administered with ZADOPAX.

Since trazodone is only a very 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 medicinal product, although no clinical interactions have been reported, the possibility of potentiation should be considered.

Undesirable effects may be more frequent when ZADOPAX is administered together with preparations containing Hypericum perforatum (St John's Wort).

Tryptophan: Since both ZADOPAX and tryptophan lead to an increase in 5-HT level at the synapse via different mechanisms of action, there is a possibility of a pharmacodynamic interaction which may lead to serotonin syndrome.

There have been reports of changes in prothrombin time in patients concomitantly receiving trazodone and warfarin. Concurrent use with ZADOPAX may result in elevated serum levels of digoxin or phenytoin. Monitoring of serum levels should be considered in these patients.

Pregnancy

The safety of Trazodone in human pregnancy has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development at therapeutic doses. On basic principles, therefore, its use during the first trimester should be avoided.

Caution should be exercised when prescribing to pregnant women. When Trazodone is used until delivery, newborns should be monitored for the occurrence of withdrawal symptoms.

Lactation

ZADOPAX is excreted in the breastmilk and may have an effect on the breastfeeding infant. Mothers on treatment with ZADOPAX should not breastfeed their infants.

Trazodone has minor or moderate influence on the ability to drive and use machines. Patients should be cautioned against the risks of driving or operating machinery until they are sure they are not affected by drowsiness, sedation, dizziness, confusional states, or blurred vision.

a) Summary of the safety profile

Cases of suicidal ideation and suicidal behaviours have been reported during ZADOPAX therapy or early after treatment discontinuation (see section 4.4). ZADOPAX has had no effect on arterial blood pCO2 or pO2 levels in patients with severe respiratory insufficiency due to chronic bronchial or pulmonary disease.

b) Tabulated summary of adverse reactions

The table below shows all adverse medicinal product reactions (ADRs) observed during clinical trials and post market spontaneous reports with Trazodone Hydrochloride.

Frequent (u2265 1/100) Less frequent (< 1/100) Not known (cannot be estimated from the available data)

System Organ Class Frequency Frequent Less Frequent Not known

Blood and the lymphatic system disorders Blood dyscrasias (including agranulocytosis, thrombocytopenia, anaemia) (see section 4.4) Eosinophilia, leucopenia

Immune system disorders Allergic reactions

Endocrine disorders Syndrome of Inappropriate Antidiuretic Hormone Secretion

Metabolism and nutrition disorders Hyponatraemia*, weight loss, anorexia, increased appetite

Psychiatric disorders Confusional states Suicidal ideation or suicidal behaviours (see section 4.4), insomnia, disorientation, mania, anxiety, nervousness, agitation (very occasionally exacerbating to delirium), delusion, aggressive reaction, hallucinations, nightmares, libido decreased, withdrawal syndrome

Nervous system disorders Headache, dizziness, drowsiness, tremor, excitement

Serotonin syndrome, convulsion, neuroleptic malignant syndrome, vertigo, restlessness, decreased alertness, blurred vision, memory disturbance, myoclonus, expressive aphasia, paraesthesia, dystonia, taste altered, irritability

Eye disorders Blurred vision

Cardiac disorders Bradycardia or tachycardia Cardiac dysrhythmias4 (including Torsade de Pointes, palpitations, premature ventricular contractions, ventricular couplets, short episodes (3 u2013 4 beats) of ventricular tachycardia), ECG abnormalities (QT prolongation)) (see section 4.4)

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) (see section 4.4), cholestasis intrahepatic, severe hepatic disorders such as hepatitis/fulminant hepatitis and hepatic failure with potentially 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 Priapism (see section 4.4)

General disorders and administration site conditions Weakness Oedema, influenza-like symptoms, fatigue, chest pain, fever

Investigations Elevated liver enzymes

Description of selected adverse reactions

* Fluid and electrolyte status should be monitored in symptomatic patients. Trazodone is a sedative antidepressant and drowsiness, sometimes experienced during the first days of treatment, usually disappears on continued therapy.

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

Features of toxicity

The most frequently reported reactions to overdose have included drowsiness, dizziness, nausea and vomiting. In more serious cases coma, tachycardia, hypotension, hyponatraemia, convulsions and respiratory failure have been reported. Cardiac features may include bradycardia, QT prolongation and torsade de pointes. Symptoms may appear 24 hours or more after overdose.

Overdoses of Trazodone in combination with other antidepressants may cause serotonin syndrome.

Management

There is no specific antidote to trazodone. The stomach should be emptied as quickly as possible and symptomatic and supportive therapy is given.