Side Effects of Elavil (amitriptyline)

Elavil (amitriptyline) is a tricyclic antidepressant (TCA) used for treating depression. The brand name Elavil is no longer available in the U.S.

Individuals with depression may have an imbalance in neurotransmitters. Elavil increases levels of the neurotransmitters norepinephrine and serotonin, and blocks the action of the neurotransmitter acetylcholine. 

It is believed that restoring the balance of these different neurotransmitters in the brain helps alleviate depression. Elavil is used off-label to treat postherpetic neuralgia and eating disorders, and to prevent migraines.

Common side effects of Elavil include:

• fast heart rate,
• blurred vision,
• urinary retention,
• dry mouth,
• constipation,
• sexual dysfunction,
• weight gain or loss, and
• low blood pressure on standing (orthostatic hypotension).

Withdrawal symptoms such as the following may occur if Elavil is discontinued abruptly:

• dizziness,
• headache,
• nausea, and
• restlessness.

Serious side effects of Elavil include:

• increased risk of seizures in patients with seizures,
• increased inability to urinate in patients with prostate enlargement, and
• elevated pressure in the eyes of some patients with glaucoma.

Drug interactions of Elavil include monoamine oxidase inhibitors (MAOIs), which can result high fever, convulsions, and even death when these drugs are used together.

Elavil can cause severe high blood pressure when used with epinephrine.

Alcohol blocks the antidepressant action of Elavil but increases its sedative effect.

Cimetidine can increase blood levels of Elavil and its side effects by preventing the elimination of Elavil.

Safety of Elavil during pregnancy is not established. Elavil is secreted in human milk and potentially can adversely affect nursing infants.

Sometimes troublesome side effects include:

• fast heart rate,
• blurred vision,
• urinary retention,
• dry mouth,
• constipation,
• sexual dysfunction
• weight gain or loss, and
• low blood pressure on standing (orthostatic hypotension).

Rare side effects include:

• rash,
• hives,
• seizures, and
• hepatitis.

Amitriptyline is used with caution in patients with seizures since it can increase the risk of seizures.

Amitriptyline also is used with caution in patients with prostate enlargement because of the risk of increasing the inability to urinate.

Amitriptyline can cause elevated pressure in the eyes of some patients with glaucoma.

If amitriptyline is discontinued abruptly, dizziness, headache, nausea, and restlessness may occur. Withdrawal symptoms may occur when even a few doses are missed. Therefore, it is recommended that the dose of antidepressant be reduced gradually when therapy is discontinued.

Within each category the following adverse reactions are listed in order of decreasing severity. Included in the listing 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.

Cardiovascular: Myocardial infarction; stroke; nonspecific ECG changes and changes in AV conduction; heart block; arrhythmias; hypotension, particularly orthostatic hypotension; syncope; hypertension; tachycardia; palpitation.

CNS and Neuromuscular: Coma; seizures; hallucinations; delusion; confusional states; disorientation; incoordination; ataxia; tremors; peripheral neuropathy; numbness, tingling and paresthesias of the extremities; extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia; dysarthria; disturbed concentration; excitement; anxiety; insomnia; restlessness; nightmares; drowsiness; dizziness; weakness; fatigue; headache; syndrome of inappropriate ADH (antidiuretic hormone) secretion; tinnitus; alteration in EEG patterns.

Anticholinergic: Paralytic ileus; hyperpyrexia; urinary retention; dilatation of the urinary tract; constipation; blurred vision, disturbance of accommodation, increased ocular pressure, mydriasis; dry mouth.

Allergic: Skin rash; urticaria; photosensitization; edema of face and tongue.

Hematologic: Bone marrow depression including agranulocytosis, leukopenia, thrombocytopenia; purpura; eosinophilia.

Gastrointestinal: Rarely hepatitis (including altered liver function and jaundice); nausea; epigastric distress; vomiting; anorexia; stomatitis; peculiar taste; diarrhea; parotid swelling; black tongue.

Endocrine: Testicular swelling and gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido; impotence; elevation and lowering of blood sugar levels.

Other: Alopecia; edema; weight gain or loss; urinary frequency; increased perspiration.

Withdrawal Symptoms: After prolonged administration, abrupt cessation of treatment may produce nausea, headache, and malaise. Gradual dosage reductions have been reported to produce, within two 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.

Causal Relationship Unknown: Other reactions, reported under circumstances where a causal relationship could not be established, are listed to serve as alerting information to physicians.

Body as a Whole: Lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor).

Digestive: Hepatic failure, ageusia.

Postmarketing Adverse Events

A syndrome resembling neuroleptic malignant syndrome (NMS) has been very rarely reported after starting or increasing the dose of amitriptyline hydrochloride, 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 (SS) have been reported with amitriptyline hydrochloride in combination with other drugs that have a recognized association with SS.

Very rare cases of cardiomyopathy have been reported with amitriptyline.

Drugs Metabolized By P450 2D6

• The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) 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 P450 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 inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs 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 P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide).
• While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 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 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 P450 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 co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.

Monoamine Oxidase Inhibitors

• Guanethidine or similarly acting compounds; thyroid medication; alcohol, barbiturates and other CNS depressants; and disulfiram.
• When amitriptyline hydrochloride is given with anticholinergic agents or sympathomimetic drugs, including epinephrine combined with local anesthetics, close supervision and careful adjustment of dosages are required.
• Hyperpyrexia has been reported when amitriptyline hydrochloride is administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather.
• Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs.
• Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants, thereby delaying elimination and increasing steady-state concentrations of these drugs.
• Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine. Increases in plasma levels of tricyclic antidepressants, and in the frequency and severity of side effects, particularly anticholinergic, have been reported when cimetidine was added to the drug regimen.
• Discontinuation of cimetidine in well-controlled patients receiving tricyclic antidepressants and cimetidine may decrease the plasma levels and efficacy of the antidepressants.
• Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients who were treated with one gram of ethchlorvynol and 75 to 150 mg of amitriptyline hydrochloride.