Amitriptyline Hydrochloride 25 mg/ 5 ml Oral Solution

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
AMITRIPTYLINE HYDROCHLORIDE
Available from:
Wockhardt UK Limited
ATC code:
N06AA; N06AA09
INN (International Name):
AMITRIPTYLINE HYDROCHLORIDE
Dosage:
25 mg/5ml
Pharmaceutical form:
Oral solution
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Non-selective monoamine reuptake inhibitors; amitriptyline
Authorization status:
Not marketed
Authorization number:
PA1339/024/001
Authorization date:
2010-11-26

Customer

Pinewood Healthcare

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2082

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Amitriptyline Hydrochloride 25mg/5ml oral solution

Leaflet

190 x 420mm

English

05/10/2018

Customer

Pinewood Healthcare

Item Code

Description

Component Type

Dimensions

Language

Market

Pharma Code No.

Paper GSM

Proof By

Proof No.

Date

Colours Used

Warning! We cannot accept responsibility for any errors in this proof after

approval. Whilst we take extreme care at all times to ensure accuracy to

our client’s brief, the final responsibility must be taken by our client.

IF YOU SIGN THIS PROOF YOU ARE SIGNIFYING

FULL APPROVAL OF DESIGN AND TEXT.

2082

45gsm

23LF01569PW

Black

Keyline (Non-Printing)

Text Free Area (Non-Printing)

Amitriptyline Hydrochloride 25mg/5ml oral solution

Leaflet

190 x 420mm

English

05/10/2018

Health Products Regulatory Authority

14 February 2019

CRN008T5S

Page 1 of 16

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amitriptyline Hydrochloride 25 mg/ 5 ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml of solution contains 25mg amitriptyline hydrochloride.

Excipients with known effect

Each 5ml of solution contains:

1mg propyl hydroxybenzoate (E216)

6mg methyl hydroxybenzoate (E218)

100mg propylene glycol

3.35g liquid maltitol

Approximately 10.5mg ethanol

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral solution.

A clear colourless to yellow solution with an orange/tangerine odour.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

the treatment of major depressive disorder in adults

the treatment of neuropathic pain in adults

the prophylactic treatment of chronic tension type headache (CTTH) in

adults

the prophylactic treatment of migraine in adults

the treatment of nocturnal enuresis in children aged 6 years and above

when organic pathology, including spina bifida and related disorders, have

been excluded and no response has been achieved to all other non-drug

and drug treatments, including antispasmodics and vasopressin-related

products. This medicinal product should only be prescribed by a healthcare

professional with expertise in the management of persistent enuresis.

4.2 Posology and method of administration

Posology

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Not all dosage schemes can be achieved with all the pharmaceutical forms/strengths.

The appropriate formulation/strength should be selected for the starting doses and

any subsequent dose increments.

Major depressive disorder

Dosage should be initiated at a low level and increased gradually, noting carefully

the clinical response and any evidence of intolerability.

Adults

Initially 25 mg 2 times daily (50 mg daily). If necessary, the dose can be increased by

25 mg every other day up to 150 mg daily divided into two doses.

The maintenance dose is the lowest effective dose.

Elderly patients over 65 years of age and patients with cardiovascular disease

Initially 10 mg – 25 mg daily.

The daily dose may be increased up to 100 mg – 150 mg divided into two doses,

depending on individual patient response and tolerability.

Doses above 100 mg should be used with caution.

The maintenance dose is the lowest effective dose.

Paediatric population

Amitriptyline should not be used in children and adolescents aged less than 18 years,

as long term safety and efficacy have not been established (see section 4.4).

Duration of treatment

The antidepressant effect usually sets in after 2 - 4 weeks. Treatment with

antidepressants is symptomatic and must therefore be continued for an appropriate

length of time usually up to 6 months after recovery in order to prevent relapse.

Neuropathic pain, prophylactic treatment of chronic tension type headache and

prophylactic treatment of migraine prophylaxis

Patients should be individually titrated to the dose that provides adequate analgesia

with tolerable adverse drug reactions. Generally, the lowest effective dose should be

used for the shortest duration required to treat the symptoms.

Adults

Recommended doses are 25 mg - 75 mg daily in the evening. Doses above 100 mg

should be used with caution.

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The initial dose should be 10 mg - 25 mg in the evening. Doses can be increased

with 10 mg - 25 mg every 3 – 7 days as tolerated.

The dose can be taken once daily, or be divided into two doses. A single dose above

75 mg is not recommended.

The analgesic effect is normally seen after 2 - 4 weeks of dosing.

Elderly patients over 65 years of age and patients with cardiovascular disease

A starting dose of 10 mg - 25 mg in the evening is recommended.

Doses above 75 mg should be used with caution.

It is generally recommended to initiate treatment in the lower dose range as

recommended for adult. The dose may be increased depending on individual patient

response and tolerability.

Paediatric population

Amitriptyline should not be used in children and adolescents aged less than 18 years,

as safety and efficacy have not been established (see section 4.4).

Duration of treatment

Neuropathic pain

Treatment is symptomatic and should therefore be continued for an appropriate

length of time. In many patients, therapy may be needed for several years. Regular

reassessment is recommended to confirm that continuation of the treatment remains

appropriate for the patient.

Prophylactic treatment of chronic tension type headache and prophylactic treatment of

migraine in adults Treatment must be continued for an appropriate length of time.

Regular reassessment is recommended to confirm that continuation of the treatment

remains appropriate for the patient.

Nocturnal enuresis

Paediatric population

The recommended doses for:

children aged 6 to 10 years: 10 mg – 20 mg. A suitable dosage form should

be used for this age group.

children aged 11 years and above: 25 mg – 50 mg daily

The dose should be increased gradually.

Dose to be administered 1-1½ hours before bedtime.

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An ECG should be performed prior to initiating therapy with amitriptyline to exclude

long QT syndrome.

The maximum period of treatment course should not exceed 3 months.

If repeated courses of amitriptyline are needed, a medical review should be

conducted every 3 months.

When stopping treatment, amitriptyline should be withdrawn gradually.

Special populations

Reduced renal function

This medicinal product can be given in usual doses to patients with renal failure.

Reduced liver function

Careful dosing and, if possible, a serum level determination is advisable.

Cytochrome P450 inhibitors of CYP2D6

Depending on individual patient response, a lower dose of amitriptyline should be

considered if a strong CYP2D6 inhibitor (e.g. bupropion, quinidine, fluoxetine,

paroxetine) is added to amitriptyline treatment (see section 4.5).

Known poor metabolisers of CYP2D6 orCYP2C19

These patients may have higher plasma concentrations of amitriptyline and its active

metabolite nortriptyline. Consider a 50% reduction of the recommended starting

dose.

Method of administration

For oral administration only.

Discontinuation of treatment

When stopping therapy the drug should be gradually withdrawn during several

weeks.

Lower strength preparations are available.

Amitriptyline Hydrochloride 10mg/5ml Oral Solution is recommended for single

doses of 20mg or below.

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4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section

6.1.

Recent myocardial infarction. Any degree of heart block or disorders of cardiac

rhythm and coronary artery insufficiency.

Concomitant

treatment

with

MAOIs

(monoamine

oxidase

inhibitors)

contra-indicated (see section 4.5). Simultaneous administration of amitriptyline and

MAOIs

cause

serotonin

syndrome

combination

symptoms,

possibly

including agitation, confusion, tremor, myoclonus and hyperthermia).

Treatment with amitriptyline may be instituted 14 days after discontinuation of

irreversible non-selective MAOIs and minimum one day after discontinuation of the

reversible moclobemide. Treatment with MAOIs may be introduced 14 days after

discontinuation of amitriptyline.

Severe liver disease.

In children under 6 years of age

4.4 Special warnings and precautions for use

Cardiac arrhythmias and severe hypotension are likely to occur with high dosage.

They may also occur in patients with pre-existing heart disease taking normal dosage.

QT interval prolongation

Cases of QT interval prolongation and arrhythmia have been reported during the

post-marketing period. Caution is advised in patients with significant bradycardia, in

patients with uncompensated heart failure,or in patients concurrently taking

QT-prolonging drugs. Electrolyte disturbances (hypokalaemia, hyperkalaemia,

hypomagnesaemia) are known to be conditions increasing the proarrythmic risk.

Anaesthetics given during tri/tetracyclic antidepressant therapy may increase the risk

of arrhythmias and hypotension. If possible, discontinue this medicinal product

several days before surgery; if emergency surgery is unavoidable, the anaesthetist

should be informed that the patient is being so treated.

Great care is necessary if amitriptyline is administered to hyperthyroid patients or to

those receiving thyroid medication, since cardiac arrhythmias may develop.

Elderly patients are particularly susceptible to orthostatic hypotension.

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This medical product should be used with caution in patients with convulsive

disorders, urinary retention, prostatic hypertrophy, hyperthyroidism, paranoid

symptomatology and advanced hepatic or cardiovascular disease, pylorus stenosis

and paralytic ileus.

In patients with the rare condition of shallow anterior chamber and narrow chamber

angle, attacks of acute glaucoma due to dilation of the pupil may be provoked.

Suicide/suicidal thoughts

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 behaviour or thoughts and unusual changes in behaviour and to

seek medical advice immediately if these symptoms present.

In manic-depressives, a shift towards the manic phase may occur; should the patient

enter a manic phase amitriptyline should be discontinued.

As described for other psychotropics, amitriptyline may modify insulin and glucose

responses calling for adjustment of the antidiabetic therapy in diabetic patients; in

addition the depressive illness itself may affect patients' glucose balance.

Hyperpyrexia has been reported with tricyclic antidepressants when administered

with anticholinergic or with neuroleptic medications, especially in hot weather.

After prolonged administration, abrupt cessation of therapy may produce withdrawal

symptoms such as headache, malaise, insomnia and irritability.

Amitriptyline should be used with caution in patients receiving SSRIs (see sections 4.2

and 4.5).

Nocturnale nuresis

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An ECG should be performed prior to initiating therapy with amitriptyline to exclude

long QT syndrome. Amitriptyline for enuresis should not be combined with an

anticholinergic drug. Suicidal thoughts and behaviours may also develop during early

treatment with antidepressants for disorders other than depression; the same

precautions observed when treating patients with depression should therefore be

followed when treating patients with enuresis.

Paediatric population

Long-term safety data in children and adolescents concerning growth, maturation

and cognitive and behavioural development are not available (see section 4.2).

Excipient Warnings

This product contains liquid maltitol. Patients with rare hereditary problems of

fructose should not take this medicine. Daily quantities of 10g or more may have a

mild laxative effect. Calorific value 2.3 kcal/g maltitol.

Methyl and propyl hydroxybenzoates are contained in this product which may cause

allergic reactions (possibly delayed).

This product contains small amounts of ethanol (alcohol), less than 100mg per dose.

This product contains 100 mg propylene glycol in each 5ml dose which is equivalent

to 20mg/ml.

4.5 Interaction with other medicinal products and other forms of interactions

Potential for amitriptyline to affect other medicinal products

Contraindicated combinations

MAOIs (non-selective as well as selective A(moclobemide) and B(selegiline))

- risk of "serotonin syndrome" (see section 4.3).

Combinations that are not recommended

Sympathomimetic agents: Amitriptyline may potentiate the cardiovascular effects of

adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and

phenylpropanolamine (e.g. as contained in local and general anaesthetics and nasal

decongestants).

Adrenergic neurone blockers: Tricyclic antidepressants may counteract the

antihypertensive effects of centrally acting antihypertensives such as guanethidine,

betanidine, reserpine, clonidine and methyldopa. It is advisable to review all

antihypertensive therapy during treatment with tricyclic antidepressants.

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Anticholinergic agents:Tricyclic antidepressants may potentiate the effects of these

drugs on the eye, central nervous system, bowel and bladder; concomitant use of

these should be avoided due to an increased risk of paralytic ileus, hyperpyrexia, etc.

Drugs which prolong the QT-interval including antiarrhythmics such as quinidine, the

antihistamines astemizole and terfenadine, some antipsychotics (notably pimozide

and sertindole), cisapride, halofantrine, and sotalol, may increase the likelihood of

ventricular arrhythmias when taken with tricyclic antidepressants.

Use caution when using amitriptyline and methadone concomitantly due to a

potential for additive effects on the QT interval and increased risk of serious

cardiovascular effects.

Caution is also advised for co-administration of amitriptyline and diuretics inducing

hypokalaemia (e.g. furosemide)

Thioridazine: Co-administration of amitriptyline and thioridazine (CYP2D6 substrate)

should be avoided due to inhibition of thioridazine metabolism and consequently

increased risk of cardiac side effects.

T r a

m ado l

Concomitant

tramadol

CYP2D6

substrate)

tricyclic

antidepressants (TCAs), such as amitriptyline increases the risk for seizures and

serotonin

syndrome.

Additionally,

this

combination

inhibit

metabolism

of tramadol

active

metabolite

thereby

increasing

tramadol

concentrations potentially causing opioid toxicity.

Antifungals such as fluconazole and terbinafine increase serum concentrations of

tricyclics and accompanying toxicity. Syncope and torsade de pointes have occurred.

Combinations requiring precautions for use

CNS depressants: Amitriptyline may enhance the sedative effects of alcohol,

barbiturates and other CNS depressants.

Potential of other medicinal products to affect amitriptyline

Tricyclic antidepressants (TCA) including amitriptyline are primarily metabolised by

the hepatic cytochrome P450 isozymes CYP2D6 and CYP2C19, which are

polymorphic in the population. Other isozymes involved in the metabolism of

amitriptyline are CYP3A4, CYP1A2 and CYP2C9.

CYP2D6 inhibitors: The CYP2D6 isozyme can be inhibited by a variety of drugs, e.g.

neuroleptics, serotonin reuptake inhibitors, beta blockers, and antiarrhythmics.

Examples of strong CYP2D6 inhibitors include bupropion, fluoxetine, paroxetine and

quinidine. These drugs may produce substantial decreases in TCA metabolism and

marked increases in plasma concentrations. Consider to monitor TCA plasma levels,

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whenever a TCA is to be co-administered with another drug known to be an inhibitor

of CYP2D6. Dose adjustment of amitriptyline may be necessary (see section 4.2).

Other Cytochrome P450 inhibitors: Cimetidine, methylphenidate and calcium- channel

blockers (e.g. diltiazem and verapamil) may increase plasma levels of tricyclic

antidepressants and accompanying toxicity. Antifungals such as fluconazole (CYP2C9

inhibitor) and terbinafine (CYP2D6 inhibitor) have been observed to increase serum

levels of amitriptyline and nortriptyline.

The CYP3A4 and CYP1A2 isozymes metabolise amitriptyline to a lesser extent.

However, fluvoxamine (strong CYP1A2 inhibitor) was shown to increase amitriptyline

plasma concentrations and this combination should be avoided. Clinically relevant

interactions may be expected with concomitant use of amitriptyline and strong

CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir.

Tricyclic antidepressants and neuroleptics mutually inhibit the metabolism of each

other; this may lead to a lowered convulsion threshold, and seizures. It may be

necessary to adjust the dosage of these drugs.

Cytochrome P450 inducers: Oral contraceptives, rifampicin, phenytoin, barbiturates,

carbamazepine and St. John's Wort (Hypericumperforatum)may increase the

metabolism of tricyclic antidepressants and result in lowered plasma levels of tricyclic

antidepressants and reduced antidepressant response.

In the presence of ethanol amitriptyline free plasma concentrations and nortriptyline

concentrations were increased.

Amitriptyline plasma concentration can be increased by sodium valproate and

valpromide. Clinical monitoring is therefore recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy

For amitriptyline only limited clinical data are available regarding exposed

pregnancies. Animal studies have shown reproductive toxicity (see section 5.3).

Amitriptyline is not recommended during pregnancy unless clearly necessary and

only after careful consideration of the risk/benefit.

During chronic use and after administration in the final weeks of pregnancy, neonatal

withdrawal symptoms can occur. This may include irritability, hypertonia , tremor,

irregular breathing, poor drinking and loud crying and possibly anticholinergic

symptoms (urinary retention, constipation).

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Breast-feeding

Amitriptyline and its metabolites are excreted into breast milk (corresponding to

0.6% - 1 % of the maternal dose). A risk to the suckling child cannot be excluded. A

decision must be made whether to discontinue breast-feeding or to

discontinue/abstain from the therapy of this medicinal product taking into account

the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Amitriptyline reduced the pregnancy rate in rats (see section 5.3).

No data on the effects of amitriptyline on human fertility are available.

4.7 Effects on ability to drive and use machines

Amitriptyline is a sedative drug.

Patients who are prescribed psychotropic medication may be expected to have some

impairment in general attention and concentration and should be cautioned about

their ability to drive or operate machinery. These adverse effects can be potentiated

by the concomitant intake of alcohol.

4.8 Undesirable effects

Amitriptyline may induce side effects similar to other tricyclic antidepressants. Some

of the below mentioned side effects e.g. headache, tremor, disturbance in attention,

constipation and decreased libido may also be symptoms of depression and usually

attenuate when the depressive state improves.

In the listing below the following convention is used:

MedDRA system organ class / preferred term; Very common (> 1/10);

Common (> 1/100, < 1/10);

Uncommon (> 1/1,000, < 1/100);

Rare (> 1/10,000, < 1/1,000);

Very rare (<1/10,000);

Not known (cannot be estimated from the available data).

MedDRA SOC

Frequency

Preferred Term

Blood and lymphatic system disorders

Rare

Bone marrow depression, agranulocytosis, leucopenia,

eosinophilia, thrombocytopenia.

Metabolism and nutrition disorders

Rare

Decreased appetite.

Metabolism and nutrition disorders

Not known

Anorexia, elevation or lowering of blood sugar levels.

Psychiatric disorders

Very common

Aggression.

Common

Confusional state, libido decreased, agitation.

Uncommon

Hypomania, mania, anxiety, insomnia, nightmare.

Rare

Delirium (in elderly patients), hallucination, suicidal

thoughts or behaviour*.

Not Known

Paranoia.

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Nervous system disorders

Very common

Somnolence, tremor, dizziness, headache, drowsiness,

speech disorder (dysarthria).

Common

Disturbance in attention, dysgeusia. paresthesia, ataxia.

Uncommon

Convulsion.

Very rare

Akathisia, polyneuropathy.

Not known

Extrapyramidal disorder.

Eye disorders

Very common

Accommodation disorder.

Common

Mydriasis.

Very rare

Acute glaucoma.

Not known

Dry eyes

Ear and labyrinth disorders

Uncommon

Tinnitus.

Cardiac disorders

Very common

Palpitations, tachycardia.

Common

Atrioventricular block, bundle branch block.

Uncommon

Collapse conditions, worsening of cardiac failure.

Rare

Arrhythmia.

Very rare

Cardiomyopathies, torsades de pointes.

Not known

Hypersensitivity myocarditis.

Vascular disorders

Very common

Orthostatic hypotension.

Uncommon

Hypertension.

Not known

Hyperthermia.

Respiratory, thoracic, and mediastinal disorders

Very common

Congested nose.

Very rare

Allergic inflammation of the pulmonary alveoli and of

the lung tissue, respectively (alveolitis, Löffler's

syndrome).

Gastrointestinal disorders

Very common

Dry mouth, constipation, nausea.

Uncommon

Diarrhoea, vomiting, tongue oedema.

Rare

Salivary gland enlargement, ileus paralytic.

Hepatobiliary disorders

Rare

Jaundice.

Uncommon

Hepatic impairment (e.g. cholestatic liver disease).

Not known

Hepatitis.

Skin and subcutaneous tissue disorders

Very common

Hyperhidrosis.

Uncommon

Rash, urticaria, face oedema.

Rare

Alopecia, photosensitivity reaction.

Renal and urinary disorders

Common

Micturition disorders.

Uncommon

Urinary retention.

Reproductive system and breast disorders

Common

Erectile dysfunction.

Uncommon

Galactorrhoea.

Rare

Gynaecomastia.

General disorders and administration site conditions

Common

Fatigue, feeling thirst.

Rare

Pyrexia.

Investigations

Very common

Weight increased.

Common

Electrocardiogram abnormal, electrocardiogram QT

prolonged, electrocardiogram QRS complex prolonged,

hyponatremia.

Uncommon

Intraocular pressure increased.

Rare

Weight decreased.

Liver function test abnormal, blood alkaline

phosphatase increased, transaminases increased.

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*Case reports of suicidal thoughts or behaviour were reported during the treatment

with or just after conclusion of the treatment with amitriptyline (see section 4.4).

Epidemiological studies, mainly conducted in patients 50 years of age and older,

show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The

mechanism leading to this risk is unknown.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel:

+353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail:

medsafety@hpra.ie.

4.9 Overdose

Symptoms

Anticholinergic symptoms: Mydriasis, tachycardia, urinary retention, dry mucous

membranes, reduced bowel motility. Convulsions. Fever. Sudden occurrence of CNS

depression. Lowered consciousness progressing into coma. Respiratory depression.

Cardiac symptoms: Arrhythmias (ventricular tachyarrhythmias, torsade de pointes,

ventricular fibrillation). The ECG characteristically show prolonged PR interval,

widening of the QRS-complex, QT prolongation, T-wave flattening or inversion, ST

segment depression, and varying degrees of heart block progressing to cardiac

standstill. Widening of the QRS-complex usually correlates well with the severity of

the toxicity following acute overdoses. Heart failure, hypotension, cardiogenic shock.

Metabolic acidosis, hypokalemia, hyponatraemia.

Ingestion of 750mg or more by an adult may result in severe toxicity. The

effects in overdose will be potentiated by simultaneous ingestion of alcohol

and other psychotropic. There is considerably individual variability in response to

overdose.

Children are especially susceptible to cardiotoxicity, seizures and hyponatraemia.

During awakening possibly again confusion, agitation and hallucinations and ataxia.

Treatment

1. Admission to hospital (intensive care unit) if required. Treatment is symptomatic

and supportive.

2. Assess and treat ABC's (airway, breathing and circulation) as appropriate. Secure

an IV access.

Close monitoring even in apparently uncomplicated cases.

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3. Examine for clinical features. Check urea and electrolytes—look for low potassium

and monitor urine output. Check arterial blood gases—look for acidosis. Perform

electrocardiograph—look for QRS>0.16 seconds

4. Do not give flumazenil to reverse benzodiazepine toxicity in mixed overdoses.

5. Consider gastric lavage only if within one hour of a potentially fatal overdose.

6. Give 50 g of charcoal if within one hour of ingestion.

7. Patency of the airway is maintained by intubation, where required. Treatment in

respirator is advised to prevent a possible respiratory arrest. Continuous

ECG-monitoring of cardiac function for 3-5 days. Treatment of the following will be

decided on a case by case basis:

- Wide QRS-intervals, cardiac failure and ventricular arrhythmias

- Circulatory failure

- Hypotension

- Hyperthermia

- Convulsions

- Metabolic acidosis.

8. Unrest and convulsions may be treated with diazepam.

9. Patients who display signs of toxicity should be monitored for a minimum of

12 hours.

10. Monitor for rhabdomyolysis if the patient has been unconscious for a

considerable time.

11. Since overdosage is often deliberate, patients may attempt suicide by other

means during the recovery phase. Deaths by deliberate or accidental overdosage

have occurred with this class of medicament.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidepressants - Non-selective monoamine reuptake

inhibitor (tricyclic antidepressant)

ATC Code: N06A A09

Mechanism of action

Amitriptyline is a tricyclic antidepressant and an analgesic. It has marked

anticholinergic and sedative properties. It prevents the re-uptake, and hence the

inactivation of noradrenaline and serotonin at nerve terminals. Reuptake prevention

of these monoamine neurotransmitters potentiate their action in the brain. This

appears to be associated with the antidepressant activity.

The mechanism of action also includes ion-channel blocking effects on sodium,

potassium and NMDA channel at both central and spinal cord level. The

noradrenaline, sodium and the NMDA effects are mechanisms known to be involved

in the maintenance of neuropathic pain, chronic tension type headache prophylaxis

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and migraine prophylaxis. The pain-reducing effect of amitriptyline is not linked to its

anti- depressive properties.

Tricyclic antidepressants possess affinity for muscarinic and histamine H1 receptors

to varying degrees.

Clinical efficacy and safety

The efficacy and safety of amitriptyline has been demonstrated in treatments of the

following indications in adults:

Major Depressive Disorder

Neuropathic Pain

Chronic tension type headache prophylaxis

Migraine prophylaxis

The efficacy and safety of amitriptyline has been demonstrated for treatments of

nocturnal enuresis in children aged 6 years and above (see section 4.1).

The recommended doses are provided in section 4.2. For treatment of depression,

doses of up to 200 mg daily and, occasionally, up to 300 mg daily have been used in

severely depressed patients in hospital only.

The antidepressant and analgesic effects usually set in after 2-4 weeks; the sedative

action is not delayed.

5.2 Pharmacokinetic properties

Amitriptyline is readily absorbed from the gastro intestinal tract. Peak plasma

concentrations occur within about 6 hours of oral administration. Since amitriptyline

slows gastro intestinal transit time, absorption may be delayed, particularly in

overdosage. Amitriptyline is demethylated in the liver to the primary active

metabolite, nortriptyline. The metabolism pathway includes N-oxidation and

conjugation with glucuronic acid. It is distributed extensively into plasma and tissue

protein. It has a half life from 9 to 25 hours. It will cross the placental barrier and is

excreted in breast milk. It is excreted in urine in the form of metabolites.

5.3 Preclinical safety data

Amitriptyline inhibited ion channels, which are responsible for cardiac repolarization

(hERG channels), in the upper micromolar range of therapeutic plasma

concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia

(see section 4.4).

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The genotoxic potential of amitriptyline has been investigated in various in vitroand

invivo studies. Although these investigations revealed partially contradictory results,

particularly a potential to induce chromosome aberrations cannot be excluded.

Long-term carcinogenicity studies have not been performed.

In reproductive studies teratogenic effects were not observed in mice, rats, or rabbits

when amitriptyline was given orally at doses of 2-40 mg/kg/day (up to 13 times the

maximum recommended human amitriptyline dose of 150 mg/day or 3 mg/kg/day

for a 50-kg patient). However, literature data suggested a risk for malformations and

delays in ossification of mice, hamsters, rats and rabbits at 9 33 times the maximum

recommended dose. There was a possible association with an effect on fertility in rats,

namely a lower pregnancy rate. The reason for the effect on fertility is unknown.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Methyl hydroxybenzoate (E218)

Propyl hydroxybenzoate (E216)

Propylene glycol

Ascorbic acid

Orange flavour 10950-56 (contains ethanol).

Orange/tangerine flavour 10888-56 (contains ethanol).

Sucralose powder

Liquid maltitol

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

Unopened: 24 months

After first opening: 1 month

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original bottle and outer carton in order to protect from light.

Health Products Regulatory Authority

14 February 2019

CRN008T5S

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6.5 Nature and contents of container

150 ml amber soda glass (type III) bottle fitted with a 28 mm white child resistant

tamper evident cap, with expanded polyethylene (EPE) liner, and outer cardboard

carton.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Limited

Ash Road North

Wrexham

LL13 9UF

United Kingdom

8 MARKETING AUTHORISATION NUMBER

PA1339/024/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26

November 2010

Date of last renewal: 29

September 2012

10 DATE OF REVISION OF THE TEXT

February 2019

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