Trazodone Hydrochloride 50mg/5ml Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Trazodone hydrochloride 50mg/5ml Oral Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5ml contains 50mg of trazodone hydrochloride.
Each 5ml contains 1g of Glycerol and 2g of Sorbitol.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Oral Solution
A clear, colourless to pale yellow coloured liquid, with orange odour, free from foreign particles
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Relief of symptoms in all types of depression including depression accompanied by anxiety.
Symptoms of depression likely to respond in the first week of treatment include depressed mood, insomnia, anxiety, somatic symptoms and hypochondriasis.
4.2 Posology and method of administration
Route of administration
Oral Solution
Recommended dosage
Adults:
Starting dose is 150mg/day in divided doses after food or as a single dose before retiring. This may be increased to 300mg/day, the major portion of which is preferably taken on retiring. In hospitalised patients dosage may be further increased to 600mg/day.
Children:
There are insufficient data to recommend the use of trazodone in children. Elderly or Frail:
For elderly or very frail patients initial starting dose 100mg/day in divided doses or as a single night-time dose. This may be increased, under supervision, according to efficacy and tolerance. Doses above 300mg/day are unlikely to be required.
Tolerability may be improved by taking Trazodone hydrochloride oral solution after food.
In conformity with current psychiatric opinion, it is suggested that Trazodone hydrochloride oral solution be continued for several months after remission. Cessation of Trazodone hydrochloride oral solution treatment should be gradual.
4.3 Contraindications
Hypersensitivity to trazodone or to other ingredients of the product
4.4 Special warnings and precautions for use
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.
Trazodone should be administered with care in patients with severe hepatic, renal or cardiac disease.
Care should be exercised when administering trazodone to patients suffering epilepsy, avoiding in particular, abrupt increases or decreases in dosage.
Potent CYP3A4 inhibitors may lead to increases in trazodone serum levels. See section 4.5 for further information.
Trazodone hydrochloride oral solution contains sorbitol hence patients with rare hereditary problems of fructose intolerance should not take this medicine.
Trazodone hydrochloride oral solution also contains glycerol which may cause, headache, stomach upset and diarrhoea.
4.5 Interaction with other medicinal products and other forms of interaction
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 hydrochloride oral solution 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.
Carbamazepine reduced plasma concentrations of trazodone when co administered. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taken with carbamazepine.
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.
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.
4.6 Fertility, 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.
Trazodone should only be administered during pregnancy and lactation if considered essential by the physician.
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
Cases of suicidal ideation and suicidal behaviours have been reported during trazodone therapy or early after treatment discontinuation (see section 4.4).
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.
In contrast to the tricyclic antidepressants, trazodone 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 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.
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.
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.
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
Pharmcotherapeutic group: Other Antidepressants ATC Code: N06A X05
Trazodone is a triazolopyridine derivative which differs chemically from other currently available antidepressants. Although trazodone bears some resemblance to the benzodiazepines, phenothiazines and tricyclic antidepressants, its pharmacological profile differs from each of these classes of drugs. The basic idea for the development of trazodone was the hypothesis that depression involves an imbalance of the mechanism responsible for the emotional integration of unpleasant experiences. Consequently, new animal models of depression consisting of responses to unpleasant or noxious stimuli, instead of the current tests related to the aminergic theory of depression, were used in studying the drug. Trazodone inhibits serotonin uptake into rat brain synaptosomes and by rat platelets at relatively high concentrations and inhibits brain uptake of noradrenaline in vitro only at very high concentrations. It possesses antiserotonin-adrenergic blocking and analgesic effects. The anticholinergic activity of trazodone is less than that of the tricyclic antidepressants in animal studies and this has been confirmed in therapeutic trials in depressed patients.
The electroencephalographic profile of trazodone in humans is distinct from that of the tricyclic antidepressants or the benzodiazepines, although bearing some resemblance to these agents in its effect in certain wavebands. Studies of the cardiovascular effects of trazodone in humans, His bundle and surface electrocardiograms in dogs, and experience with overdosage in man indicate that trazodone is less liable than imipramine to cause important adverse effects on the heart. However, studies in depressed patients with significant cardiac impairment suggest that trazodone may aggravate existing ventricular arrhythmias in a small undefined subgroup of such patients.
5.2 Pharmacokinetic properties
Peak plasma concentrations are attained about 1.5 hours after oral administration of trazodone. Absorption is delayed and somewhat enhanced by food. The area under the plasma concentration-time curve is directly proportional to dosage after oral administration of 25 to 100mg. Trazodone is extensively metabolised, less than 1% of an oral dose being excreted unchanged in the urine. The main route of elimination is via the kidneys with 70 to 75% of an oral dose being recovered in the urine within the first 72 hours of ingestion. The elimination half-life for unchanged drug has been reported to be about 7 hours.
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.
5.3 Preclinical safety data
None stated
6.1 List of excipients
Benzoic Acid Glycerol Sorbitol liquid
Orange flavour (contains propylene glycol)
Sodium Saccharin Sodium Hydroxide Purified Water
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products
6.3 Shelf life
Shelf life of the medicinal product as packaged for sale: 3 years
6.4 Special precautions for storage
Store in the original package (bottle) in order to protect from light. This medicinal product does not require any special temperature storage conditions.
6.5 Nature and contents of container
Amber, type III glass bottles with tamper evident child resistant closure. Pack size 120ml
Special precautions for disposal
6.6
No special requirements.
7 MARKETING AUTHORISATION HOLDER
PRIMEGEN Limited Unit 15 Moorcroft,
Harlington Road,
Uxbridge,
UB8 3HD UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 43659/0010
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18/04/2011
10 DATE OF REVISION OF THE TEXT
09/02/2015
11 DOSIMETRY (IF APPLICABLE)
INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)