AMITRIPTYLINE

Posology 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.

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. 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. 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. 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. g. 5). Known poor metabolisers of CYP2D6 or CYP2C19 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 The tablets should be swallowed with water. Discontinuation of treatment When stopping therapy the drug should be gradually withdrawn during several weeks.

Summary of safety profile:

Amitriptyline may induce side effects similar to other tricyclic antidepressants. g. headache, tremor, disturbance in attention, constipation and decreased libido may also be symptoms of depression and usually attenuate when the depressive state improves.

4) 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. Not known' Anaphylaxis, angioedemaImmune system disorders Uncommon Face oedema.

tongue oedema Common Hyponatremia. Rare Decreased appetite. Metabolism and nutrition disorders Not known Anorexia, elevation or lowering of blood sugar levels. 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*. Psychiatric disorders Not known Paranoia. Very common Somnolence, tremor, dizziness, headache, drowsiness, speech disorder (dysarthria).

Common Disturbance in attention, dysgeusia. paresthesia, ataxia. Nervous system disorders Uncommon Convulsion. Very rare Akathisia, polyneuropathy. Not known Extrapyramidal disorder. Very common Accommodation disorder. Common Mydriasis. Very rare Acute glaucoma.

Eye disorders Not known Dry eye Ear and labyrinth disorders Uncommon Tinnitus. 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. Cardiac disorders Not known Hypersensitivity myocarditis. Very common Orthostatic hypotension. Uncommon Hypertension. Vascular disorders Not known Hyperthermia. Respiratory, thoracic, and mediastinal disorders Very rare Allergic inflammation of the pulmonary alveoli and of the lung tissue, respectively (alveolitis, Löffler’s syndrome).

Very common Dry mouth, constipation, nausea. Uncommon Diarrhoea, vomiting. Rare Salivary gland enlargement, ileus paralytic. Gastrointestinal disorders Not known Epigastric distress, stomatitis Rare Jaundice. g. cholestatic liver disease).

Hepatobiliary disorders Not known Hepatitis. Very common Hyperhidrosis. Uncommon Rash, urticaria Rare Alopecia, photosensitivity reaction. Renal and urinary disorders Uncommon Urinary retention. Common Erectile dysfunction. Uncommon Galactorrhoea.

Reproductive system and breast disorders Rare Gynaecomastia. General disorders and administration site conditions Rare Pyrexia. Very common Weight increased. Common Electrocardiogram abnormal, electrocardiogram QT prolonged, electrocardiogram QRS complex prolonged.

Investigations Uncommon Intraocular pressure increased. Rare Weight decreased. Liver function test abnormal, blood alkaline phosphatase increased, transaminases increased. 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.

Side-effects in enuresis:

Behavioural changes have been observed in children receiving tricyclics for treatments of enuresis. Dosages used in enuresis are low compared with those used in depression and side-effects are therefore less frequent. The most common are drowsiness and anticholinergic effects.

The only other side-effects, reported infrequently at these dosages, have been mild sweating and itching. The recommended dosage must not be exceeded.

Withdrawal symptoms:

The symptoms associated with withdrawal of tricyclic antidepressants, particularly after prolonged administration, include gastrointestinal disturbances such as nausea; generalised somatic symptoms such as malaise, chills, headache and increased perspiration; irritability, restlessness, anxiety and agitation; sleep disturbances (insomnia and vivid dreams); parkinsonism or akasthisia; hypomania or mania (reported rarely, occurring within 2-7 days of stopping chronic therapy with tricyclic antidepressants); cardiac arrhythmias.

These symptoms are not indicative of addiction. Withdrawal symptoms seem to be more common and more severe in children. Adverse reactions such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers had taken tricyclic antidepressants in the last trimester of pregnancy.

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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple APP Store.

Amitriptyline should be used with caution in patients with a history of epilepsy, and in those with impaired liver function or phaeochromocytoma. Severe cutaneous reactions Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported in association with amitriptyline treatment.

Most of these reactions occurred within 2 to 6 weeks. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for cutaneous reactions. If signs and symptoms suggestive of these reactions appear, amitriptyline should be withdrawn immediately, treatment with amitriptyline must not be restarted in this patient at any time and, an alternative treatment should be considered (as appropriate).

Blood sugar concentrations may be altered in diabetic patients. When used for the depressive component of schizophrenia, amitriptyline may aggravate psychotic symptoms. 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. 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.

5). Nocturnal enuresis 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.

2).

1. Recent myocardial infarction. Any degree of heart block or disorders of cardiac rhythm and coronary artery insufficiency. 5). Simultaneous administration of amitriptyline and MAOIs may cause serotonin syndrome (a combination of 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. Porphyria In children under 6 years of age.