Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: ACCORD HEALTHCARE LIMITED, SAGE HOUSE, 319 PINNER ROAD, HARROW, MIDDLESEX, HA1 4HG, UNITED KINGDOM
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.
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.
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 proarrhythmic 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.
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).
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.
Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are not available (see section 4.2).
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
MAOIs (non-selective as well as selective A (moclobemide) and B (selegiline)) - risk of “serotonin syndrome” (see section 4.3).
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.
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).
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.
Alpha2-adrenoceptor stimulants: Concomitant use of apraclonidine and brimonidine should be avoided.
Altretamine: Risk of severe postural hypotension.
Anaesthetics: Concomitant therapy may increase the risk of arrhythmias and hypotension. If surgery is necessary, the anaesthetist should be informed that a patient is being so treated (see section 4.4).
Analgesics: There is a possibility of increased side effects with nefopam. There is a possibility of increased sedation with opioid analgesics.
Antibacterials: Concomitant use with linezolid may result in CNS excitation and hypertension.
Anxiolytics and hypnotics: Concomitant use enhances the sedative effect. Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients treated with 1g ethchlorvynol and 75mg to 150mg of amitriptyline.
Disulfiram: Concomitant use may inhibit the metabolism of tricyclics. Delirium has been reported in patients taking amitriptyline with disulfiram.
Diuretics: Increased risk of postural hypotension.
Dopaminergics: Concomitant use with entacapone should be avoided. CNS toxicity has been reported with selegiline.
Muscle relaxants: Concomitant use of baclofen enhances its muscle relaxant effect.
Nitrates: Reduced effect of sublingual nitrates (owing to dry mouth).
Oestrogens and progestogens: Oral contraceptives antagonise the antidepressant effect but side-effects may be increased due to increased plasma concentrations of tricyclics.
Sibutramine: Concomitant use is not recommended due to the increased risk of CNS toxicity.
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).
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.
Amitriptyline reduced the pregnancy rate in rats (see section 5.3).
No data on the effects of amitriptyline on human fertility are available.
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.
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)
Frequency not known (cannot be estimated from the available data)
Rare: Bone marrow depression, agranulocytosis, leucopenia, eosinophilia, thrombocytopeniaand purpura
Rare: Decreased appetite.
Frequency not known: Elevation or lowering of blood sugar levels. Increased appetite. Anorexia.
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*.
Frequency not known:__ Paranoia.
Very common: Somnolence, tremor, dizziness, headache, drowsiness, speech disorder (dysarthria).
Common: Disturbance in attention, dysgeusia. paresthesia, ataxia.
Uncommon: Convulsion.
Very rare: Akathisia, polyneuropathy.
Frequency not known: Weakness, disturbed concentration, disorientation, delusions, restlessness, peripheral neuropathy, inco-ordination extrapyramidal disorder.
Very common: Accommodation disorder.
Common: Mydriasis.
Very rare: Acute glaucoma.
Frequency not known: Blurres vision, dry eye.
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.
Frequency not known: Hypersensitivity myocarditis,myocardial infarction
Very common: Orthostatic hypotension.
Uncommon: Hypertension.
Frequency not known: Hyperthermia, stroke.
Very common: Congested nose.
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, tongue oedema.
Rare: Salivary gland enlargement, ileus paralytic.
Frequency not known: Epigastric distress, stomatitis, black tongue.
Rare: Jaundice.
Uncommon: Hepatic impairment (e.g. cholestatic liver disease).
Not known: Hepatitis.
Very common: Hyperhidrosis.
Uncommon: Rash, urticaria, face oedema.
Rare: Alopecia, photosensitivity reaction.
Common: Micturition disorders.
Uncommon: Urinary retention.
Common: Erectile dysfunction.
Uncommon: Galactorrhoea.
Rare: Gynaecomastia.
Frequency not known: Breast enlargement, testicular swelling, libido fluctuations, interference with sexual function, syndrome of inappropriate ADH secretion.
Common: Fatigue, feeling thirst.
Rare: Pyrexia.
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.
Abrupt withdrawal after prolonged administration has caused nausea, headache and malaise. Gradual withdrawal has been associated with transient symptoms such as dream and sleep disturbances, irritability and restlessness during the first two weeks of dosage reduction. These are not thought to be signs associated with addiction. Mania or hypomania have been reported rarely within 2-7 days of stopping therapy with tricyclic antidepressants.
As dosages used in enuresis are low compared to those used for depression, side-effects are less frequent. The most common are drowsiness and anticholinergic effects. Infrequently, mild sweating and itching have been reported. Behavioural changes have been observed in children receiving tricyclics for treatment of enuresis.
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 Yellow Card Scheme at Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow card in the google play or Apple App store.
None known.
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