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TRAZODONE HYDROCHLORIDE 50 MG/5 ML ORAL SOLUTION

Active substance(s): TRAZODONE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Trazodone Hydrochloride 50 mg/5 ml Oral solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5 ml contains 50 mg of Trazodone hydrochloride.
Each 5 ml contains 1 g of Glycerol and 1.4 g of Sorbitol.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Oral Solution.
Clear, colourless solution with a pungent taste and orange flavour.

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
Posology
Adults

Starting dose is 150 mg/day in divided doses after food or as a single dose
before retiring. This may be increased to 300 mg/day, the major portion of
which is preferably taken on retiring. In hospitalised patients dosage may be
further increased to 600 mg/day.
Paediatric population
There are insufficient data on safety to recommend the use of trazodone in
children below the age of 18 years.
Older people
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
(see section 4.4).
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. Doses above 300 mg/day are unlikely to be required.
A decrease in side-effects (increase of the resorption and decrease of the peak
plasma concentration) can be reached by taking trazodone hydrochloride after
a meal.
In conformity with current psychiatric opinion, it is suggested that trazodone
be continued for several months after remission. Cessation of trazodone
treatment should be gradual.
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.
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).
Method of administration
Oral.
4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1.
Alcohol intoxication and intoxication with hypnotics.
Acute myocardial infarction.

4.4

Special warnings and precautions for use
Paediatric population
Trazodone 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.
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 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.
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.
Severe hepatic disorders with potential fatal outcome have been reported with
trazodone use (see adverse reaction section). Patients should be instructed to
report immediately signs such as asthenia, anorexia, nausea, vomiting,
abdominal pain or icterus to a physician. Investigations including clinical
examination and biological assessment of liver function should be undertaken
immediately, and withdrawal of trazodone 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 – 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 MAOinhibitors) and neuroleptics. Malignant neuroleptic
syndromes with fatal outcome have been reported in cases of coadministration 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 anticholinergic 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 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 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.
Trazodone contains sorbitol. 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
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.

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. 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 trazodone is used with a potent CYP3A4
inhibitor, a lower dose of trazodone should be considered. However, the coadministration of trazodone and potent CYP3A4 inhibitors should be avoided
where possible.
Carbamazepine reduced plasma concentrations of trazodone when coadministered. Concomitant use of carbamazepine 400 mg daily led to a
decrease of plasma concentrations of trazadone and its active metabolite mchlorophenylpiperazine of 76 % and 60 %, respectively. Patients should be
closely monitored to see if there is a need for an increased dose of trazodone
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 drugs, including alcohol. Trazodone intensifies the sedative
effects of alcohol. Alcohol should be avoided during trazodone 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: 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 (serotonin
syndrome) could not be excluded.
Possible interactions with monoamine oxidase inhibitors have occasionally
been reported. Although some clinicians do give both concurrently, use of
trazodone with MAOIs, or within two weeks of stopping treatment with these
compounds is not recommended. The giving of MAOIs within one week of
stopping trazodone is also not recommended.

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 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 co-administered with 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.
Undesirable effects may be more frequent when trazodone is administered
together with preparations containing Hypericum perforatum (St Johns wort).
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.
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
Pregnancy
Data on a limited number (< 200) of exposed pregnancies indicate no adverse
effects of Trazodone hydrochloride on pregnancy or on the health of the
fetus/newborn child. To date, no other relevant epidemiological data are
available. The safety of Trazodone hydrochloride in human pregnancy has not
been established. Animal studies do not indicate direct or indirect harmful
effects with respect to pregnancy, embryonal/fetal 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 hydrochloride is used until delivery, newborns should be monitored
for the occurrence of withdrawal symptoms.

Lactation
Limited data indicate that excretion of Trazodone hydrochloride 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
breastfeeding or to continue/discontinue therapy with Trazodone
hydrochloride should be made taking into account the benefit of breast-feeding
to the child and the benefit of Trazodone hydrochloride 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. As with all other drugs acting on the central nervous system,
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 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.
MedDRA System
Organ
Class
Blood and the
lymphatic
system disorders
Immune system
disorders
Endocrine disorders
Metabolism and
nutrition
disorders

Psychiatric disorders

Frequency not known (cannot be estimated from the
available data)
Blood dyscrasias (including agranulocytosis,
thrombocytopenia,
eosinophilia, leucopenia and anaemia)
Allergic reactions
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Hyponatraemia1, weight loss, anorexia, increased appetite
Suicidal ideation or suicidal behaviours2, 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

Cardiac disorders

Vascular disorders
Respiratory, thoracic
and
mediastinal disorders
Gastrointestinal
disorders
Hepato-biliary
disorders
Skin and
subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Renal and urinary
disorders
Reproductive system
and
breast disorders
General disorders and
administration site
conditions
Investigations
1

Serotonin syndrome, convulsion, neuroleptic malignant
syndrome, dizziness, vertigo, headache, drowsiness3,
restlessness, decreased alertness, tremor, blurred vision,
memory disturbance, myoclonus, expressive aphasia,
paraesthesia, dystonia, taste altered
Cardiac arrhythmias4 (including Torsade de Pointes,
palpitations,
premature ventricular contractions, ventricular couplets,
ventricular tachycardia), bradycardia, tachycardia, ECG
abnormalities (QT prolongation)2
Orthostatic hypotension, hypertension, syncope
Nasal congestion, dyspnoea
Nausea, vomiting, dry mouth, constipation, diarrhoea,
dyspepsia, stomach pain, gastroenteritis, increased salivation,
paralytic ileus
Hepatic function abnormalities (including jaundice and
hepatocellular damage)5 , cholestasis intrahepatic, severe
hepatic disorders such as hepatitis/fulminant hepatitis,
hepatic failure with potential fatal outcome.
Skin rash, pruritus, hyperhidrosis

Pain in limb, back pain, myalgia, arthralgia
Micturition disorder
Priapism6
Weakness, oedema, influenza-like symptoms, fatigue, chest
pain, fever
Elevated liver enzymes

Fluid and electrolyte status should be monitored in symptomatic patients.
See also Section 4.4.
3
Trazodone is a sedative antidepressant and drowsiness, sometimes
experienced during the first days of treatment, usually disappears on continued
therapy.
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.
2

5

Adverse effects on hepatic function, sometimes severe, have been rarely
reported. Should such effects occur, trazodone should be immediately
discontinued.
6
See also section 4.4.
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.
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 national reporting system:
Yellow Card Scheme.
Website: ww.mhra.gov.uk/yellowcard.

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 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
ATC code: N06A X05. Other antidepressants.
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

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Glycerol
Sorbitol solution 70% non-crystallising
Benzoic acid
Saccharin sodium
Orange flavour
Sodium hydroxide solution (for pH-adjustment)
Purified water

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
30 months.

6.4

Special precautions for storage

Store below 25ºC. Keep the bottle in the outer carton in order to protect from
light.
Once opened use within 1 month.
6.5

Nature and contents of container
Type III PhEur, 125 ml amber glass bottle, sealed with a polyethylene screw
cap with polypropylene child resistant cap, containing 120 ml of solution.

6.6

Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Alissa Healthcare Research Limited
Unit 5
Fulcrum 1
Solent Way
Whiteley, Fareham
Hampshire
United Kingdom
PO15 7FE

8

MARKETING AUTHORISATION NUMBER(S)
PL 30322/0012

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
24/01/2017

10

DATE OF REVISION OF THE TEXT
24/01/2017

+ Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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