Molipaxin 50mg Capsules

Molipaxin 100mg Capsules

Trazodone hydrochloride 50mg or 100mg per capsule.

For excipients see 6.1

Capsules.

Anxiety, depression, mixed anxiety and depression.

Route of administration: Oral.

DEPRESSION:

Adults:

Initially 150mg/day in divided doses after food or as a single dose on retiring.

This may be increased up to 300mg/day in a single or divided doses. The major portion of a divided dose to be taken on retiring. The dose may be further increased to 600mg/day in divided doses in hospitalised patients.

Elderly:

For very elderly or frail patients initially 100mg/day in divided doses or as a single night-time dose. This may be increased, under supervision, according to efficacy and tolerance. It is unlikely that 300mg/day will be exceeded.

Children:

There are insufficient data to recommend the use of Molipaxin in children.

DEPRESSION ACCOMPANIED BY ANXIETY:

As for depression.

ANXIETY:

75mg/day increasing to 300mg/day as necessary.

Tolerability may be improved by taking Molipaxin after food.

Known sensitivity to trazodone and any of the excipients.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suiciderelated 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 Molipaxin is prescribed can also be associated with an increased risk of suiciderelated events. In addition, these conditions may be comorbid 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 suiciderelated 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 metaanalysis of placebocontrolled 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.

Care should be exercised when administering Molipaxin to patients suffering epilepsy, avoiding in particular, abrupt increases or decreases in dosage.

Molipaxin should be administered with care in patients with severe hepatic, renal or cardiac disease.

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

In vitro drug metabolism studies suggest that there is a potential for drug interactions when Molipaxin 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 Molipaxin will increase the potential for excessive sedation, cardiovascular, and gastrointestinal effects. If Molipaxin is used with a potent CYP3A4 inhibitor, a lower dose of Molipaxin should be considered. However, the co-administration of Molipaxin and potent CYP3A4 inhibitors should be avoided where possible.

Carbamazepine reduced plasma concentrations of trazodone when coadministered. Patients should be closely monitored to see if there is a need for an increased dose of Molipaxin when taken with carbamazepine.

Although no untoward effects have been reported, Molipaxin may enhance the effects of muscle relaxants and volatile anaesthetics. Similar considerations apply to combined administration with sedative and anti-depressant drugs, including alcohol. Molipaxin has been well tolerated in depressed schizophrenic patients receiving standard phenothiazine therapy and also in depressed parkinsonian patients receiving therapy with levodopa.

Possible interactions with monoamine oxidase inhibitors have occasionally been reported. Although some clinicians do give both concurrently, we do not recommend concurrent administration with MAOIs, or within two weeks of stopping treatment with these compounds. Nor do we recommend giving MAOIs within one week of stopping Molipaxin

Since Molipaxin 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 Molipaxin may inhibit most of the acute actions of clonidine. In the case of other types of antihypertensive drug, although no clinical interactions have been reported, the possibility of potentiation should be considered.

Concurrent use with Molipaxin may result in elevated serum levels of digoxin or phenytoin. Monitoring of serum levels should be considered in these patients.

Although studies in animals have not shown any direct teratogenic effect, the safety of Molipaxin in human pregnancy has not been established. On basic principles, therefore, its use during the first trimester should be avoided.

The possibility of Molipaxin being excreted in the milk should also be considered in nursing mothers.

As with all other drugs acting on the central nervous system, patients should be warned against the risk of handling machinery and driving.

Cases of suicidal ideation and suicidal behaviours have been reported during Molipaxin therapy or early after treatment discontinuation (see section 4.4).

Molipaxin is a sedative antidepressant and drowsiness, sometimes experienced during the first days of treatment, usually disappears on continued therapy.

Anticholinergic-like symptoms do occur but the incidence is similar to placebo.

The following symptoms, most of which are commonly reported in cases of untreated depression, have also been recorded in small numbers of patients receiving Molipaxin therapy: dizziness, headache, nausea and vomiting, weakness, decreased alertness, weight loss, tremor, dry mouth, bradycardia, tachycardia, postural hypotension, oedema, constipation, diarrhoea, blurred vision, restlessness, confusional states, insomnia and skin rash.

Blood dyscrasias, including agranulocytosis, thrombocytopenia and anaemia, have been reported on rare occasions. Adverse effects on hepatic function, including jaundice and hepatocellular damage, sometimes severe, have been rarely reported. Should such effects occur, Molipaxin should be discontinued immediately.

As with other drugs with alpha-adrenolytic activity, Molipaxin 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 Molipaxin immediately.

In contrast to the tricyclic antidepressants, Molipaxin is devoid of anticholinergic activity. Consequently, troublesome side effects such as dry mouth, blurred vision and urinary hesitancy have occurred no more frequently than in patients receiving placebo therapy. This may be of importance when treating depressed patients who are at risk from conditions such as glaucoma, urinary retention and prostatic hypertrophy.

Studies in animals have shown that Molipaxin 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. Arrhythmias identified include isolated premature ventricular contractions, ventricular couplets, and short episodes (3-4 beats) of ventricular tachycardia.

There have been occasional reports of serotonin syndrome and convulsions associated with the use of Molipaxin, especially when associated with other psychotropic drugs. Neuroleptic malignant syndrome may, very rarely, arise in the course of treatment with Molipaxin.

Hyponatraemia has been reported in association with treatment with this product. Fluid and electrolyte status should be monitored in symptomatic patients.

Molipaxin has had no effect on arterial blood pCO₂ or pO₂ levels in patients with severe respiratory insufficiency due to chronic bronchial or pulmonary disease.

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 Molipaxin in combination with other antidepressants may cause serotonin syndrome.

MANAGEMENT

There is no specific antidote to trazodone. Activated charcoal should be considered in adults who have ingested more than 1 g trazodone, or in children who have ingested more than 150 mg trazodone within 1 hour of presentation. Alternatively, in adults, gastric lavage may be considered within 1 hour of ingestion of a potentially life-threatening overdose.

Observe for at least 6 hours after ingestion (or 12 hours if a sustained release preparation has been taken). Monitor BP, pulse and GCS. Monitor oxygen saturation if GCS is reduced. Cardiac monitoring is appropriate in symptomatic patients.

Single brief convulsions do not require treatment. Control frequent or prolonged convulsions with intravenous diazepam (0.1-0.3 mg/kg body weight) or lorazepam (4 mg in an adult and 0.05 mg/kg in a child). If these measures do not control the fits, an intravenous infusion of phenytoin may be useful. Give oxygen and correct acid base and metabolic disturbances as required.

Treatment should be symptomatic and supportive in the case of hypotension and excessive sedation. If severe hypotension persists consider use of inotropes, eg dopamine or dobutamine

ATC code: N06A X05. Other antidepressants.

Molipaxin is a potent antidepressant. It also has anxiety reducing activity. Molipaxin is a triazolopyridine derivative chemically unrelated to known tricyclic, tetracyclic and other antidepressant agents. It has negligible effect on noradrenaline re-uptake mechanisms. Whilst the mode of action of Molipaxin is not known precisely, its antidepressant activity may concern noradrenergic potentiation by mechanisms other than uptake blockade. A central antiserotonin effect may account for the drug's anxiety reducing properties.

Trazodone is rapidly absorbed from the gastro-intestinal tract and extensively metabolised. Paths of metabolism of Trazodone include n-oxidation and hydroxylation. The metabolic m-chlorophenylpiperazine is active. Trazodone is excreted in the urine almost entirely in the form of its metabolites, either in free or in conjugated form. The elimination of Trazodone is biphasic, with a terminal elimination half-life of 5 to 13 hours. Trazodone is excreted in breast milk.

There was an approximate two-fold increase in terminal phase half-life and significantly higher plasma concentrations of Trazodone in 10 subjects aged 65 to 74 years compared with 12 subjects aged 23 to 30 years following a 100mg dose of Trazodone. It was suggested that there is an age-related reduction in the hepatic metabolism of Trazodone.

In vitro studies in human liver microsomes show that trazodone is metabolised by cytochrome P4503A4 (CYP3A4) to form m-chlorophenylpiperazine. Whilst significant, the role of this pathway in the total clearance of trazodone in vivo has not been fully determined.

None stated.

Lactose

Magnesium stearate

Gelatin

Titanium dioxide E171

Erythrosine E127

Indigo Carmine E132

Red iron oxide E172

Yellow iron oxide E172

Ink (1028 (S-1-27794) or 1014 (SW-9008) Black)

None stated.

60 months.

Blister packs: Store below 30ºC in a dry place.

50mg: PVdC coated 250μm PVC blisters sealed with 20μm aluminium foil: contents 84 capsules.

100mg: PVdC coated 250μm PVC blisters sealed with 20μm aluminium foil: contents

56 capsules.

Not applicable.

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

50mg: PL 04425/0609

100mg: PL 04425/0180

26 August 2009

26 August 2009

POM