4.1. Therapeutic indications

Amitriptyline Hydrochloride Film-coated Tablet is indicated for:

• 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 with any of the other pharmacological and non-pharmacological 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

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.

Pediatric 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 in adults

The dose must be adjusted individually in each patient, 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:

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

Recommended doses are 25 mg - 75 mg daily in the evening. Doses above 100 mg should be used with caution.

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.

Pediatric 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 period 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 period 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 will be administered 1-1½ hours before bedtime.

An ECG should be performed prior to initiating therapy with amitriptyline to rule out long QT syndrome.

Duration of treatment

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 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

Oral administration

The tablets should be swallowed with water.

Discontinuation of treatment

When stopping therapy the drug should be gradually withdrawn during several weeks.

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) is contra- indicated (see section 4.5). 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.

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 decompensated 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.

It is necessary to take special care if amitriptyline is administered to hyperthyroid patients or to those treated with thyroid medication, as 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 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. Because improvement may not be achieved during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. Clinical experience indicates that, overall, 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 therefore should receive close 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.

Therefore, patients should be closely monitored during treatment particularly those at high risk, especially in early treatment and after dose changes. Patients (and caregivers of patients) should be be advised of the need to monitor the occurrence 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).

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 behaviors 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.

Pediatric population

Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioral development are not available (see section 4.2).

Serotonin syndrome

Concomitant administration of Amitriptyline tablets and buprenorphine/opioids may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Warnings about excipients

Amitriptyline Hydrochloride Film-coated Tablet contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 Hydrochloride should be withdrawn immediately, treatment with Amitriptyline Hydrochloride must not be restarted in this patient at any time and, an alternative treatment should be considered (as appropriate).

4.5. Interaction with other medicinal products and other forms of interaction

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.

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

Tramadol: Concomitant use of tramadol (a CYP2D6 substrate) and tricyclic antidepressants (TCAs), such as amitriptyline increases the risk for seizures and serotonin syndrome.

Additionally, this combination can inhibit the metabolism of tramadol to the active metabolite and 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, 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).

Caution is advised in case of concomitant administration of amitriptyline with duloxetine, a moderate CYP2D6 inhibitor.

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 (Hypericum perforatum) 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.

Valproate sodium and valpromide may increase the plasma concentration of Amitriptyline. Therefore, clinical follow-up is recommended.

Amitriptyline tablets should be used cautiously when co-administered with: Buprenorphine/opioids as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).

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).

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, and thrombocytopenia.

Immune system disorders

Not known

Anaphylaxis, angioedema.

Uncommon

Face oedema, tongue oedema.

Metabolism and nutrition Disorders

Rare

Decreased appetite.

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 (in schizophrenic patients), suicidal thoughts or behaviour*.

Not Known

Paranoia

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 eye

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.

Common

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.

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

Rare

Alopecia, photosensitivity reaction.

Not known

Drug reaction with eosinophilia and systemic symptoms (DRESS)

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.

*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.

Summary of safety profile:

Severe cutaneous adverse reactions (SCARs), including drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with amitriptyline (see section 4.4).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 QRScomplex, 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.

Ingestion of 750 mg 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 and seizures.

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.

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.