Chemical formula: C₂₀H₂₃N Molecular mass: 277.403 g/mol PubChem compound: 2160
Amitriptyline interacts in the following cases:
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. Combination of amitriptyline with drugs which prolong the QT-interval is not recommended.
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.
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. Combination of amitriptyline with anticholinergic agents is not recommended.
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). Combination of amitriptyline with sympathomimetic agents is not recommended.
The CYP1A2 isozyme metabolise amitriptyline to a lesser extent. However, fluvoxamine (strong CYP1A2 inhibitor) was shown to increase amitriptyline plasma concentrations and this combination should be avoided.
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. 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.
The CYP3A4 isozyme metabolise amitriptyline to a lesser extent. Clinically relevant interactions may be expected with concomitant use of amitriptyline and strong CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir.
Amitriptyline enhances the sedative effect of alcohol.
In the presence of ethanol amitriptyline free plasma concentrations and nortriptyline concentrations were increased.
The CYP3A4 and CYP1A2 isozymes metabolise amitriptyline to a lesser extent. Clinically relevant interactions may be expected with concomitant use of amitriptyline and strong CYP3A4 inhibitors such asketoconazole, itraconazole and ritonavir.
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.
Careful dosing and, if possible, a serum level determination is advisable in amitriptyline administration.
Amitriptyline causes reduced effect of sublingual nitrates (owing to dry mouth).
Concomitant use of amitriptyline with MAOIs results in CNS excitation and hypertension. Severe convulsions and fatalities have occurred. Therefore, amitriptyline should not be given with a MAOI, and a minimum of 14 days should elapse between discontinuing a MAOI and starting amitriptyline. After this time, amitriptyline should be used cautiously and dosage increased gradually.
In concomitant use of amitriptyline with diuretics, there is increased risk of postural hypotension.
Caution is also advised for co-administration of amitriptyline and diuretics inducing hypokalaemia (e.g. furosemide).
Oral contraceptives antagonise the antidepressant effect but side-effects may be increased due to increased plasma concentrations of tricyclics.
Thyroid preparations increase the side effects and toxicity of amitriptyline and other tricyclic antidepressants.
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.
There is a possibility of increased sedation in concomitant use of amitriptyline with opioid analgesics.
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.
Amitriptyline may enhance the sedative effects of alcohol, barbiturates and other CNS depressants.
Caution is needed when amitriptyline is given to diabetic patients, as blood sugar levels may be changed.
When used for the depressive component of schizophrenia, amitriptyline should be used with caution as it may aggravate psychotic symptoms. In manic-depressives, a shift towards the manic phase may occur. Paranoid delusions, with or without associated hostility, may be aggravated. A major tranquilliser should be given concurrently in such cases, or dosage of amitriptyline reduced.
Cardiac arrhythmias and severe hypotension are likely to occur with high dosages or in patients with pre-existing heart disease.
In concomitant use of amitriptyline with altretamine, there is isk of severe postural hypotension.
Concomitant use of amitriptyline with apraclonidine and brimonidine should be avoided.
Atazanavir may increase the activity and toxicity of amitriptyline by reducing its metabolism.
Concomitant use of amitriptyline with baclofen enhances its muscle relaxant effect.
The plasma concentrations of carbamazepine may be reduced resulting in reduced antidepressant effect.
Cimetidine, methylphenidate and calcium-channel blockers (e.g. diltiazem and verapamil) may increase plasma levels of tricyclic antidepressants and accompanying toxicity.
Co-administration of cisapride with amitriptyline increases the risk of cardiotoxicity and arrhythmias.
The antihypertensive effect of clonidine, betanidine and guanethidine may be reduced when co-administered with amitriptyline.
Concomitant use of disulfiram with tricyclics may inhibit the metabolism of tricyclics. Delirium has been reported in patients taking amitriptyline with disulfiram.
Concomitant use of amitriptyline with entacapone should be avoided.
Caution is advised if patients receive large doses of ethchlorvynol concurrently with amitriptyline. Transient delirium has been reported in patients treated with 1g ethchlorvynol and 75mg to 150mg of amitriptyline.
Increased serum concentrations have occurred in patients also taking fluconazole. Serious adverse effects have been reported due to increased amitriptyline plasma concentration.
Antifungals such as fluconazole and terbinafine increase serum concentrations of tricyclics and accompanying toxicity. Syncope and torsade de pointes have occurred.
Fluoxetine markedly inhibits cytochrome P450 II D6, which is involved in the metabolism of a number of tricyclic antidepressants. Patients should be monitored for increased antidepressant plasma levels and toxicity when fluoxetine is used concurrently. Adjustment of the antidepressant dosage may be necessary.
Fluvoxamine may increase the serum amitriptyline concentration, reducing its metabolism.
Co-administration of galantamine with amitriptyline may result in a competitive effect.
Concomitant administration of grepafloxacin with amitriptyline increases the risk of cardiotoxicity and arrhythmias.
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. Combination of amitriptyline with adrenergic neurone blockers is not recommended.
Concomitant use of amitriptyline with linezolid may result in CNS excitation and hypertension.
Extrapyramidal reactions have been observed during concomitant administration of lithium and amitriptyline.
Co-administration of mesidridazine with amitriptyline increases the risk of cardiotoxicity and arrhythmias.
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.
There is a possibility of increased side effects in concomitant use of amitriptyline with nefopam.
Rifampicin may reduce the activity of rifampicin by increasing its metabolism.
Based on the known metabolism of amitriptyline, the protease inhibitor, ritonavir, may increase the serum levels of amitriptyline. Therefore, careful monitoring of therapeutic and adverse effects is recommended when these drugs are administered concomitantly.
CNS toxicity has been reported in concomitant use of amitriptyline with selegiline.
Concomitant use of amitriptyline with sibutramine is not recommended due to the increased risk of CNS toxicity.
Co-administration of sparfloxacin with amitriptyline increases the risk of cardiotoxicity and arrhythmias.
Terbinafine may reduce the metabolism and clearance of amitriptyline.
Avoid concomitant use with pimozide or thioridazine because of increased risk of ventricular arrhythmias. Concomitant use with antipsychotics may increase plasma concentrations of tricyclic antidepressants and increase the anticholinergic side-effects of phenothiazines and possibly clozapine.
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. Combination of amitriptyline with thioridazine is not recommended.
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. Combination of amitriptyline with tramadol is not recommended.
Ηyperthyroid patients and those receiving thyroid medication drugs should be closely monitored. The dosage of all medications will need to be carefully adjusted.
For amitriptyline only limited clinical data are available regarding exposed pregnancies.
Animal studies have shown reproductive toxicity.
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.
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.
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.
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