Trazodone Hydrochloride 100mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Trazodone Hydrochloride 100mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Trazodone Hydrochloride 100mg
(For the full list of excipients, see section 6.1)
3 PHARMACEUTICAL FORM
Capsules
Hard gelatin, size 2, yellow-violet coloured capsules.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Anxiety
Depression
Mixed anxiety and depression.
4.2 Posology and method of administration
Depression:
a) 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 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.
b) Older people: For very elderly or frail patients, the recommended initial dose is reduced to 100 mg a day, administered in divided doses or as a single night time dose. This may be incrementally increased, as described under Adults, under supervision, according to tolerance and efficacy. In general, single doses above 100 mg should be avoided in these patients. It is unlikely that a dose of 300 mg per day will be exceeded.
c) Paediatric population: Trazodone is not recommended for use in children below the age of 18 years due to a lack of data on safety.
Decrease of the side-effects (increase of the resorption and decrease of the peak plasma concentration) can be reached by taking trazodone hydrochloride after a meal.
Patients with hepatic Impairment:
Trazodone undergoes extensive hepatic metabolism, see section 5.2, and has also been associated with hepatotoxicity, see sections 4.4 and 4.8. 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.
Patients with renal Impairment:
No dosage adjustment is usually necessary, but caution should be exercised when prescribing for patients with severe renal impairment (see also section 4.4 and 5.2).
Depression accompanied by anxiety: as for depression
Anxiety:
75mg/day increasing to 300mg/day as necessary.
Tolerability may be improved by taking trazodone hydrochloride after food.
4.3 Contraindications
• Known sensitivity to trazodone and any of the excipients.
• Alcohol intoxication and intoxication with hypnotics.
• Acute myocardial infarction.
4.4 Special warnings and precautions for use
Paediatric populationTrazodone should not be used in children and adolescents under 18. Suicidal behaviour (suicidal attempt and suicidal planning) and hostility (essentially aggressiveness, opposing behaviour and anger) has been observed in 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.
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 Hydrochloride 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.
Should jaundice occur in a patient, trazodone therapy must be withdrawn.
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.
Interactions in terms of serotonine 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 drug reaction. See Sections 4.5 and 4.8 for further information.
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.
Elderly patients may more often experience orthostatic hypotension, somnolence and other anti cholinergic effects of trazodone. Careful consideration should be given to the potential for additive effects with concomitant medication 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 of initiation of therapy, prior to and following upward dose titration.
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.
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.
Potent CYP3A4 inhibitors may lead to increases in trazodone serum levels. See Section 4.5
for further information.
As with other drugs with alpha-adrenolytic activity, trazodone hydrochloride has very rarely been associated with priapism. This may be treated with an intra-cavernosal 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 hydrochloride Capsules immediately.
Care should be exercised when administering trazodone hydrochloride to patients suffering epilepsy, avoiding in particular, abrupt increases or decreases in dosage.
4.5 Interaction with other medicinal products and other forms of interaction
General: The sedative effects of antipsychotics, hypnotics, sedatives, anxiolytics, and antihistaminic drugs 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.
CYP3A4 inhibitors: Drug metabolism studies in vitro are indicative 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. 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 twofold, leading to nausea, syncope and hypotension. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered. However, coadministration of trazodone and potent CYP3A4 inhibitors should be avoided where possible.
Carbamazepine: Co-administration results in reduced plasma concentrations of trazodone. Concomitant use of carbamazepine 400 mg daily led to a decrease of plasma concentrations of trazadone and its active metabolite m-chlorophenylpiperazine of 76 % and 60 % respectively. Patients should be closely monitored to ascertain if an increased trazodone dosage is required.
Tricyclic antidepressants: concurrent administration should be avoided due to the risk of interaction. The prescriber should be aware of the possibility of serotonine syndrome and cardiovascular side effects.
Fluoxetine: rare cases have been reported of elevated trazodone plasma levels and adverse effects when trazodone had been combined with fluoxetine, a CYP1A2/2D6 inhibitor. The mechanism underlying a pharmacokinetic interaction is not fully understood. A pharmacodynamic interaction (serotonine syndrome) could not be excluded.
Phenothiazines: Severe orthostatic hypotension has been observed in case of concomitant use of phenothiazines, like e.g. chlorpromazine, fluphenazine, levomepromazine, perphenazine.
Anaesthetics/muscle relaxants: Trazodone hydrochloride may enhance the effects of muscle relaxants and volatile anaesthetics, and caution should be exercised in such instances.
Alcohol: Trazodone intensifies the sedative effects of alcohol. Alcohol should be avoided
during trazodone therapy.
Levodopa: Antidepressants can accelerate the metabolism of levodopa.
Other
Concomitant use of trazodone with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Caution should be used when these drugs are coadministered with trazodone.
Similar considerations apply to combined administration with sedative and antidepressant drugs, including alcohol. Trazodone hydrochloride 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 MAOI’s, or within two weeks of stopping treatment with these compounds. Nor do we recommend giving MAOIs within one week of stopping Trazodone Hydrochloride Capsules.
Since trazodone hydrochloride is only a very weak inhibitor of noradrenaline reuptake 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 hydrochloride may inhibit most of the acute actions of clonidine. In the case of other types of antihypertensive drugs, although no clinical interactions have been reported, the possibility of potentiation should be considered.
Undesirable effects may be more frequent when trazodone is administered together with preparations containing Hypericum perforatum.
There have been reports of changes in prothrombin time in patients concomitantly receiving trazodone and warfarin.
Concurrent use with Trazodone may result in elevated serum levels of digoxin or phenytoin. Monitoring of serum levels should be considered in these patients.
4.6 Fertility, pregnancy and lactation
Pregnancy:
Data on a limited number (< 200) of exposed pregnancies indicate no adverse effects of trazodone on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development at therapeutic doses (see section 5.3). Caution should be exercised when prescribing to pregnant women. On basic principles, therefore, its use during the first trimester should be avoided. When trazodone is used until delivery, newborns should be monitored for the occurrence of withdrawal symptoms.
Breast-feeding:
The possibility of trazodone hydrochloride being excreted in the milk should also be considered in nursing mothers. Limited data indicate that excretion of trazodone in human breast milk is low, but levels of the active metabolite are not known. Due to the paucity of data, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with trazodone should be made taking into account the benefit of breast-feeding to the child and the benefit of trazodone therapy to the woman.
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
Cases of suicidal ideation and suicidal behaviours have been reported during Trazodone hydrochloride therapy or early after treatment discontinuation (see section 4.4).
The following symptoms, some of which are commonly reported in cases of untreated depression, have also been recorded in patients receiving trazodone therapy.
List of adverse reactions
The frequencies of adverse events are not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
Not known: Blood dyscrasias (including agranulocytosis, thrombocytopenia, eosinophilia, leucopenia and anaemia)
Immune system disorders
Not known: Allergic reactions
Endocrine disorders
Not known: Syndrome of Inappropriate Antidiuretic Hormone Secretion
Metabolism and nutrition disorders
Not known: Hyponatraemia (fluid and electrolyte status should be monitored in symptomatic patients), weight loss, anorexia, increased appetite
Psychiatric disorders
Not known: Suicidal ideation or suicidal behaviours (see section Special warnings and precautions for use), 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
Not known: Serotonin syndrome, convulsion, neuroleptic malignant syndrome, dizziness, vertigo, headache, drowsiness (trazodone is a sedative antidepressant and drowsiness, sometimes experienced during the first days of treatment, usually disappears on continued therapy), restlessness, decreased alertness, tremor, blurred vision, memory disturbance, myoclonus, expressive aphasia, paraesthesia, dystonia, taste altered
Cardiac disorders
Not known: Cardiac arrhythmias (including torsade de pointes, palpitations,
premature ventricular contractions, ventricular couplets, ventricular tachycardia), bradycardia, tachycardia, ECG abnormalities (QT-Prolangation).
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.
Vascular disorders
Not known: Orthostatic hypotension, hypertension, syncope
Respiratory, thoracic and mediastinal disorders
Not known: Nasal congestion, dyspnoea
Gastrointestinal disorders
Not known: Nausea, vomiting, dry mouth, constipation, diarrhoea, dyspepsia, stomach pain,
gastroenteritis, increased salivation, paralytic ileus Hepatobiliary disorders
Not known: Hepatic function abnormalities (including jaundice and hepatocellular damage), cholestasis intrahepatic.
Adverse effects on hepatic function, sometimes severe, have been rarely reported. Should such effects occur, trazodone should be immediately discontinued.
Skin and subcutaneous tissue disorders
Not known: Skin rash, pruritus, hyperhydrosis
Musculoskeletal and connective tissue disorders
Not known: Pain in limb, back pain, myalgia, arthralgia
Renal and urinary disorders
Not known: Micturition disorders
Reproductive system and breast disorders
Not known: Priapism (see section Special warnings and precautions for use)
General disorders and administration site conditions
Not known: Weakness, oedema, influenza-like symptoms, fatigue, chest pain, fever
Investigations
Not known: Elevated liver enzymes
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
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 within 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 hydrochloride. 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. Treatment should be symptomatic and supportive in the case of hypotension and excessive sedation.
Observe for at least 6 hours after ingestion (or 12 hours if a sustained release preparation has been taken). Monitor BP, pulse and Glasgow Coma Scale (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 hydrochloride is a potent antidepressant. It also has anxiety reducing activity. Trazodone hydrochloride is a triazolopyridine derivative chemically unrelated to known tricyclic, tetracyclic and other antidepressant agents. It has negligible effect on noradrenaline reuptake 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 anxiolytic 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 hydroxyl ati on. The metabolite 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 approximately 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 consists of:
Gelatin
Titanium Dioxide (E171)
Yellow Iron Oxide (E172)
Patent Blue V (E131)
Erythrosin (127)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
No special precautions for storage.
6.5 Nature and contents of container
PVdC coated, PVC/Aluminium foil blister strips in pack sizes of 7, 14, 21, 28, 30, 42, 56, 63, 84 & 100 capsules.
Not all pack sizes may be marketed.
Special precautions for disposal
6.6
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/1631
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21st October 2004
10 DATE OF REVISION OF THE TEXT
19/03/2014