1. Name Of The Medicinal Product
Trazodone 50mg Capsules
2. Qualitative And Quantitative Composition
Capsule containing 50mg of Trazodone Hydrochloride.
For excipients see 6.1
3. Pharmaceutical Form
Capsule, hard
4. Clinical Particulars
4.1 Therapeutic Indications
Relief of symptoms in all types of depression including depression accompanied by anxiety.
4.2 Posology And Method Of Administration
Route of administration: Oral.
Adults:
Starting dose 150mg/day in divided doses. This may be increased to 300mg/day in a single dose or divided doses.
Elderly or Frail:
Starting dose 100mg/day in divided doses or as a single dose. This may be increased, under supervision, according to efficacy and tolerance. Doses above 300mg/day are unlikely to be required.
Children:
There are insufficient data to recommend the use of trazodone in children.
Trazodone controlled release capsules should be swallowed whole and not chewed.
Tolerability may be improved by taking trazodone after food.
4.3 Contraindications
Known hypersensitivity to trazodone and to any of the excipients.
4.4 Special Warnings And Precautions For Use
Trazodone should be administered with caution in patients of thyroid disease, psychosis/mania, the elderly, close angle glaucoma, anaesthesia, porphyria and urinary retention.
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.
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 behavior or thoughts and unusual changes in behavior and to seek medical advice immediately if these symptoms present.
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.
Care should be exercised when administering trazodone to patients suffering epilepsy, avoiding in particular, abrupt increases or decreases in dosage.
Trazodone 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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Anti-histamines: Possible increased antimuscarinic and sedative effects when tricyclic- related antidepressants given with antihistamines
Diazoxide: Enhanced hypotensive effect when tricyclic related antidepressant given with diazoxide
Sibutramine: Increased risk of CNS toxicity when tricyclic-related antidepressants given with sibutramine.
Vasodilator Antihypertensives: Enhanced hypotensive effect when tricyclic-related antidepressants given with hydralazine or sodium nitroprusside
CYP3A4 inhibitor
In vitro drug metabolism studies suggest that there is a potential for drug 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 Trazodone will increase the potential for excessive sedation, cardiovascular, and gastrointestinal effects. If Trazodone is used with a potent CYP3A4 inhibitor, a lower dose of Trazodone should be considered. However, the co-administration of Trazodone and potent CYP3A4 inhibitors should be avoided where possible.
Although no untoward effects have been reported, trazodone may enhance the effects of muscle relaxants and volatile anaesthetics. Similar considerations apply to combined administration with sedative and anti-depressant drugs, including alcohol. Trazodone 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 trazodone.
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 drug, although no clinical interactions have been reported, the possibility of potentiation should be considered.
Concurrent use with trazodone may result in elevated serum levels of digoxin or phenytoin. Monitoring of serum levels should be considered in these patients.
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 Trazodone when taken with carbamazepine.
4.6 Pregnancy And Lactation
Although studies in animals have not shown any direct teratogenic effect, the safety of trazodone in human pregnancy has not been established. On basic principles, therefore, its use during the first trimester should be avoided.
The possibility of trazodone being excreted in the milk should also be considered in nursing mothers.
4.7 Effects On Ability To Drive And Use Machines
As with all other drugs acting on the central nervous system, patients should be warned against the risk of handling machinery and driving.
4.8 Undesirable Effects
Trazodone 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 trazodone 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, trazodone should be discontinued immediately.
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.
Cases of suicidal ideation and suicidal behaviors have been reported during trazodone therapy or early after treatment discontinuation (see section 4.4).
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 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.
Trazodone has had no effect on arterial blood pCO2 or pO2 levels in patients with severe respiratory insufficiency due to chronic bronchial or pulmonary disease.
There have been occasional reports of serotonin syndrome and convulsions associated with the use of Trazodone, especially when associated with other psychotropic drugs. Neuroleptic malignant syndrome may, very rarely, arise in the course of treatment with Trazodone.
Hyponatraemia has been reported in association with treatment with this product. Fluid and electrolyte status should be monitored in symptomatic patients.
4.9 Overdose
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. 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, e.g. dopamine or dobutamine.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Trazodone is a potent antidepressant. It also has anxiety reducing activity. Trazodone 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 trazodone 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.
5.2 Pharmacokinetic 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.
5.3 Preclinical Safety Data
None stated.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose Monohydrate
Colloidal silica anhydrous
Magnesium Stearate
Capsule shell- Body composition
Titanium dioxide (E171)
Indigo Carmine (E132)
Yellow iron Oxide (E172)
Gelatin
Cap composition
Erythrosine (E 127)
Patent Blue V (E 131)
Titanium dioxide (E 171)
Gelatin
6.2 Incompatibilities
None stated.
6.3 Shelf Life
24 months
6.4 Special Precautions For Storage
Do not store above 25°C. Keep in the original packaging.
6.5 Nature And Contents Of Container
Blister packs (PVC coated blisters backed by aluminium foil) available in pack sizes of 28, 56, 84 & 112 capsules.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
Goldshield Pharmaceuticals Ltd
NLA Tower
12-16 Addiscombe Road
Croydon
CRO OXT
United Kingdom
8. Marketing Authorisation Number(S)
PL 12762/0130
9. Date Of First Authorisation/Renewal Of The Authorisation
12 July 2004
10. Date Of Revision Of The Text
02/02/2010
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