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Amitriptyline

Also known as: Amitriptyline hydrochloride

Brand names: AMIROL ELAVIL SAROTEN TRIPTA

Interactions

Active ingredient Amitriptyline interacts in the following cases:

Drugs which prolong the QT-interval

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.

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.

CYP1A2 inhibitors

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.

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. 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.

CYP3A4 inhibitors

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.

Alcohol

Amitriptyline enhances the sedative effect of alcohol.

Ethanol

In the presence of ethanol amitriptyline free plasma concentrations and nortriptyline concentrations were increased.

Strong CYP3A4 inhibitors

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.

Strong CYP1A2 inhibitors

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.

Reduced liver function

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

Nitrates

Amitriptyline causes reduced effect of sublingual nitrates (owing to dry mouth).

MAOIs

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.

Diuretics

In concomitant use of amitriptyline with diuretics, there is increased risk of postural hypotension.

Diuretics inducing hypokalaemia

Caution is also advised for co-administration of amitriptyline and diuretics inducing hypokalaemia (e.g. furosemide).

Oral contraceptives

Oral contraceptives antagonise the antidepressant effect but side-effects may be increased due to increased plasma concentrations of tricyclics.

Thyroid preparations

Thyroid preparations increase the side effects and toxicity of amitriptyline and other tricyclic antidepressants.

Anesthetics

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.

Opioid analgesics

There is a possibility of increased sedation in concomitant use of amitriptyline with opioid analgesics.

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. Combination of amitriptyline with anticholinergic agents is not recommended.

Neuroleptics

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.

CNS depressants, alcohol

Amitriptyline may enhance the sedative effects of alcohol, barbiturates and other CNS depressants.

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). Combination of amitriptyline with sympathomimetic agents is not recommended.

Diabetes

Caution is needed when amitriptyline is given to diabetic patients, as blood sugar levels may be changed.

Schizophrenia

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.

Pre-existing hearth disease

Cardiac arrhythmias and severe hypotension are likely to occur with high dosages or in patients with pre-existing heart disease.

Lactation

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.

Altretamine

In concomitant use of amitriptyline with altretamine, there is isk of severe postural hypotension.

Apraclonidine, brimonidine

Concomitant use of amitriptyline with apraclonidine and brimonidine should be avoided.

Atazanavir

Atazanavir may increase the activity and toxicity of amitriptyline by reducing its metabolism.

Baclofen

Concomitant use of amitriptyline with baclofen enhances its muscle relaxant effect.

Carbamazepine

The plasma concentrations of carbamazepine may be reduced resulting in reduced antidepressant effect.

Cimetidine, methylphenidate, calcium-channel blockers

Cimetidine, methylphenidate and calcium-channel blockers (e.g. diltiazem and verapamil) may increase plasma levels of tricyclic antidepressants and accompanying toxicity.

Cisapride

Co-administration of cisapride with amitriptyline increases the risk of cardiotoxicity and arrhythmias.

Clonidine, betanidine and guanethidine

The antihypertensive effect of clonidine, betanidine and guanethidine may be reduced when co-administered with amitriptyline.

Disulfiram

Concomitant use of disulfiram with tricyclics may inhibit the metabolism of tricyclics. Delirium has been reported in patients taking amitriptyline with disulfiram.

Entacapone

Concomitant use of amitriptyline with entacapone should be avoided.

Ethchlorvynol

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.

Fluconazole

Increased serum concentrations have occurred in patients also taking fluconazole. Serious adverse effects have been reported due to increased amitriptyline plasma concentration.

Fluconazole, terbinafine

Antifungals such as fluconazole and terbinafine increase serum concentrations of tricyclics and accompanying toxicity. Syncope and torsade de pointes have occurred.

Fluoxetine

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

Fluvoxamine may increase the serum amitriptyline concentration, reducing its metabolism.

Galantamine

Co-administration of galantamine with amitriptyline may result in a competitive effect.

Grepafloxacin

Concomitant administration of grepafloxacin with amitriptyline increases the risk of cardiotoxicity and arrhythmias.

Adrenergic neurone blocker

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.

Linezolid

Concomitant use of amitriptyline with linezolid may result in CNS excitation and hypertension.

Lithium

Extrapyramidal reactions have been observed during concomitant administration of lithium and amitriptyline.

Mesoridazine

Co-administration of mesidridazine with amitriptyline increases the risk of cardiotoxicity and arrhythmias.

Methadone

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.

Rifampin

Rifampicin may reduce the activity of rifampicin by increasing its metabolism.

Ritonavir

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.

Selegiline

CNS toxicity has been reported in concomitant use of amitriptyline with selegiline.

Sibutramine

Concomitant use of amitriptyline with sibutramine is not recommended due to the increased risk of CNS toxicity.

Sparfloxacin

Co-administration of sparfloxacin with amitriptyline increases the risk of cardiotoxicity and arrhythmias.

Terbinafine

Terbinafine may reduce the metabolism and clearance of amitriptyline.

Thioridazine

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.

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. Combination of amitriptyline with thioridazine is not recommended.

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. Combination of amitriptyline with tramadol is not recommended.

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.

Hyperthyroid patients

Ηyperthyroid patients and those receiving thyroid medication drugs should be closely monitored. The dosage of all medications will need to be carefully adjusted.

Nefopam

There is a possibility of increased side effects in concomitant use of amitriptyline with nefopam.

Pregnancy

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).

Nursing Mothers

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.

Carcinogenesis, Mutagenesis and Fertility

Fertility

Amitriptyline reduced the pregnancy rate in rats.

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

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.