Source: Health Products and Food Branch (CA) Revision Year: 2018
ELAVIL (amitriptyline hydrochloride) is contraindicated in:
Amitriptyline should not be used in in combination with a monoamine oxidase inhibitor (MAOI) due to the risk of serotonin syndrome (a combination of symptoms that may include agitation, confusion, tremor, myoclonus, and hyperthermia). Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving concomitant tricyclic antidepressants and MAOIs.
Treatment with a MAOI should be discontinued at least 14 days before initiating treatment with amitriptyline. Similarly, amitriptyline treatment should be discontinued at least 14 days before starting a MAOI (see DOSAGE AND ADMINISTRATION).
Amitriptyline should be used with caution in patients with a history of seizures, impaired liver function or blood dyscrasias. Due to its anticholinergic activity, amitriptyline should be used with caution in patients with a history of urinary retention, or with narrow-angle glaucoma or increased intraocular pressure.
As with other antidepressants, ELAVIL can cause mydriasis, which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles (see ADVERSE REACTIONS). Healthcare providers should inform patients to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye. In patients with narrow-angle glaucoma, even average doses may precipitate an attack.
Patients with cardiovascular disorders should be closely monitored. Tricyclic antidepressant drugs, including amitriptyline have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time and severe hypotension, particularly at high doses. Myocardial infarction and stroke have been reported with drugs of this class (see ADVERSE REACTIONS). Cardiac arrhythmias and severe hypotension may also occur at normal doses in patients with pre-existing cardiovascular disease. A few instances of unexpected deaths have been reported in patients with cardiovascular disorders. Therefore, these drugs should be used with caution in patients with a history of cardiovascular disease, such as myocardial infarction, congestive heart failure (see CONTRAINDICATIONS) and conduction abnormalities.
There has been a report of fatal dysrhythmia occurring as late as 56 hours after amitriptyline overdose.
Caution is recommended when amitriptyline is administered to hyperthyroid patients or those receiving thyroid medication. Cardiac arrhythmias may develop when tricyclic antidepressants are used concomitantly with thyroid medications.
Cases of QT interval prolongation and arrhythmia have been reported during the post-marketing period (see ADVERSE REACTIONS, Cardiovascular). Caution is advised in patients with significant bradycardia, in patients with uncompensated heart failure, or in patients concurrently taking QT-prolonging drugs (see PRECAUTIONS, Drug Interactions). Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) are also known to increase the proarrythmic risk.
Concurrent administration of amitriptyline and electroconvulsive therapy may increase the hazards of therapy. Such treatment should be limited to patients for whom it is essential.
Amitriptyline may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. Patients should be advised to avoid such tasks until they know how amitriptyline affects them.
Fertility: Amitriptyline reduced the pregnancy rate in rats. No data on the effects of amitriptyline on human fertility are available.
Pregnant Women: There are no adequate and well-controlled studies in pregnant women. When considering treatment with amitriptyline in pregnant women or women who may be come pregnant, the potential benefits must be weighed against the possible hazards to mother and child. Amitriptyline is not recommended during pregnancy unless clearly necessary and only after careful consideration of the risk/benefit.
Nursing Women: Amitriptyline and its metabolites are excreted in breast milk. Because of the potential for serious adverse reactions in infants from amitriptyline, a decision should be made whether to discontinue nursing or discontinue the drug.
Pediatrics: The safety and efficacy of amitriptyline have not been established in patients under 12 years of age. The use of amitriptyline in pediatric patients is not recommended (see DOSAGE and ADMINSTRATION).
Geriatrics (≥65 years of age): Geriatric patients are particularly sensitive to the anticholinergic side effects of tricyclic antidepressants including amitriptyline hydrochloride. Peripheral anticholinergic effects include tachycardia, urinary retention, constipation, dry mouth, blurred vision, and exacerbation of narrow angle glaucoma. Central nervous system anticholinergic effects include cognitive impairment, psychomotor slowing, confusion, sedation, and delirium. Elderly patients taking amitriptyline hydrochloride may be at increased risk for falls.
Elderly patients should be started on low doses of amitriptyline and observed closely due to the greater frequency of decreased hepatic function, concomitant disease and other drug therapy in elderly patients (see DOSAGE AND ADMINISTRATION).
The potency of amitriptyline is such that addition of other antidepressant drugs generally does not result in any additional therapeutic benefit. Untoward reactions have been reported after the combined use of antidepressant agents having varying modes of activity. Accordingly, combined use of amitriptyline and other antidepressant drugs should be undertaken only with due recognition of the possibility of potentiation and with a thorough knowledge of the pharmacology of both drugs. There have been no reports of untoward events when patients receiving amitriptyline were changed immediately to protriptyline or vice versa.
When amitriptyline is used to treat the depressive component of schizophrenia, activation or exacerbation of existing psychotic manifestation may occur. Likewise, patients with bipolar disorder may experience hypomanic or manic episodes and hyperactive or agitated patients may become overstimulated when treated with amitriptyline. Paranoid delusions, with or without associated hostility, may be exaggerated. A reduction in dose or discontinuation of amitriptyline may be indicated and administration of a neuroleptic such as a phenothiazine, be considered under these circumstances.
The possibility of suicide is inherent in depression and remains during treatment. High risk patients should be closely supervised throughout treatment. To minimize the risk of intentional overdose, prescriptions for ELAVIL should be written for the smallest possible quantity consistent with good patient management.
Discontinue the drug several days before elective surgery if possible.
Both elevation and lowering of blood glucose levels have been reported.
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS.
Tricyclic antidepressants may potentiate the cardiovascular effects of sympathomimetic drugs. Close supervision and careful adjustment of dosage are required when amitriptyline is administered with sympathomimetic drugs, including epinephrine combined with local anesthetics.
Tricyclic antidepressants may potentiate the effects of anticholinergic drugs on the eye, central nervous system, bowel and bladder and close supervision and careful adjustment of dosage are required. Paralytic ileus, urinary retention or acute glaucoma may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs, particularly in elderly or hospitalized patients.
Hyperpyrexia has been reported when tricyclic antidepressants are administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather.
Tricyclic antidepressants may counteract the antihypertensive effects of centrally acting antihypertensives such as clonidine and methyldopa. It is advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.
Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants.
Amitriptyline may enhance the response to alcohol and the effects of barbiturates and other CNS depressants.
Delirium has been reported with concurrent administration of amitriptyline and disulfiram.
The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (CYP 2D6) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by CYP 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).
In addition, certain drugs that inhibit the activity of CYP 2D6 make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given a drug that inhibits CYP 2D6 as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for CYP 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit CYP 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome CYP 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. Monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of CYP 2D6.
Drugs which prolong the QT-interval including antiarrhythmics (e.g., quinidine,sotalol, disopyramide,amiodarone some antipsychotics (e.g., pimozide, haloperidol), antidepressants (e.g., fluoxetine, tricyclic/tetracyclic antidepressants); macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, tacrolimus); quinolone antibiotics (e.g., ciprofloxacin); antimalarials (e.g., quinine, chloroquine); azole antifungals (e.g., ketoconazole); domperidone; 5-HT3 receptor antagonists (e.g., ondansetron); tyrosine kinase inhibitors (e.g., sunitinib); histone deacetylase inhibitors (e.g., vorinostat); and, beta-2 adrenoceptor agonists (e.g., salmeterol) 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) (see WARNINGS, QT Interval Prolongation).
Note: Included in the listing which follows are a few adverse reactions which have not been reported with this specific drug. However, pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when amitriptyline is administered.
Psychiatric: drowsiness, fatigue, activation of latent schizophrenia, disorientation, confusional states, hallucinations, delusions, hypomanic reactions, disturbed concentration, nightmares, insomnia, restlessness, agitation, excitement, jitteriness, anxiety, giddiness.
Neurological: epileptiform seizures, coma, dizziness, tremors, numbness, tingling, parasthesias of the extremities, peripheral neuropathy, headache, ataxia, alteration in EEG patterns, extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia, dysarthria, tinnitus, incoordination, and slurred speech.
Anticholinergic: urinary retention, dilatation of the urinary tract, constipation, paralytic ileus, especially in the elderly, hyperpyrexia, dry mouth, blurred vision, disturbance of accommodation, increased intraocular pressure, precipitation of latent glaucoma, aggravation of existing glaucoma, and mydriasis. Amitriptyline hydrochloride tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.
Cardiovascular: myocardial infarction, stroke, non-specific ECG changes and changes in AV conduction, prolonged conduction time, asystole, hypotension, syncope, hypertension, palpitation, QT interval prolongation, arrhythmias, heart block, ventricular tachycardia, fibrillation, unexpected death in patients with cardiovascular disorders.
Hematologic: bone marrow depression, including agranulocytosis, leukopenia, eosinophilia, purpura, thrombocytopenia.
Allergic: skin rash, urticaria, photosensitization, edema of the face and tongue, itching.
Gastrointestinal: nausea, epigastric distress, heartburn, vomiting, hepatitis (including altered liver function and jaundice), anorexia, stomatitis, peculiar taste, diarrhea, parotid swelling, black tongue.
Endocrine: testicular swelling, gynecomastia and impotence in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, elevation and lowering of blood sugar levels, syndrome of inappropriate ADH (antidiuretic hormone) secretion.
Miscellaneous: weakness, increased perspiration, edema, urinary frequency, alopecia, increased appetite, weight gain, weight loss.
Withdrawal Symptoms: Abrupt cessation of treatment after prolonged administration may produce nausea, headache, and malaise. Gradual dosage reduction has been reported to produce, within 2 weeks, transient symptoms including irritability, restlessness, and dream and sleep disturbance. These symptoms are not indicative of addiction. Rare instances have been reported of mania or hypomania occurring within 2 to 7 days following cessation of chronic therapy with tricyclic antidepressants.
Other reported adverse reactions for which a relationship could not be established include lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor), hepatic failure and ageusia.
A syndrome resembling neuroleptic malignant syndrome (NMS) has been very rarely reported after starting or increasing the dose of amitriptyline, with and without concomitant medications known to cause NMS. Symptoms have included muscle rigidity, fever, mental status changes, diaphoresis, tachycardia, and tremor.
Very rare cases of serotonin syndrome have been reported with amitriptyline in combination with other drugs that have a recognized association with serotonin syndrome.
Very rare cases of cardiomyopathy have been reported with amitriptyline.
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