ATRYLINE

Amitriptyline hydrochloride

USP, a dibenzocycloheptadiene derivative, is a white, or practically white, odorless or practically odorless, crystalline powder or small crystals and freely soluble in water, alcohol, chloroform and methanol and insoluble in ether.

It is designated chemically as 10,11-Dihydro-N,N-dimethyl-5 H -dibenzo[a,d] cycloheptene-Δ 5, γ-propylamine hydrochloride.

It has the following structural formula

Each amitriptyline hydrochloride tablet, USP for oral administration contains 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, or 150 mg amitriptyline hydrochloride, USP.

Inactive ingredients are: croscarmellose sodium, colloidal silicon dioxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch (corn), talc, and titanium dioxide.

Additionally, 25 mg tablets contain: D&C Yellow #10 Aluminum Lake and FD&C Blue #1 Aluminum Lake; 50 mg tablets contain: D&C Yellow #10 Aluminum Lake, iron oxide red and iron oxide yellow; 75 mg tablets contain: FD&C Blue #2 Aluminum Lake and iron oxide yellow; 100 mg tablets contain: D&C Red #27 Aluminum Lake and D&C Yellow #10 Aluminum Lake; 150 mg tablets contain: iron oxide red and iron oxide yellow. structure.

For the relief of symptoms of depression.

Endogenous depression is more likely to be alleviated than are other depressive states.

Amitriptyline hydrochloride is an antidepressant with sedative effects.

Its mechanism of action in man is not known.

It is not a monoamine oxidase inhibitor and it does not act primarily by stimulation of the central nervous system.

Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons.

Pharmacologically, this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity.

This interference with reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline.

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.

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

Coma; seizures; hallucinations; delusions; 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.

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

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

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

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

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.

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

After prolonged administration, abrupt cessation of treatment may produce nausea, headache, and malaise.

Gradual dosage reduction has 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 to 7 days following cessation of chronic therapy with tricyclic antidepressants.

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).

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.

Deaths may occur from overdosage with this class of drugs.

Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose.

As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment.

Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital monitoring is required as soon as possible.

Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma.

Changes in the electrocardiogram particularly in

QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.

In addition, a rightward axis shift in the terminal QRS complex together with a prolonged QT interval and sinus tachycardia are specific and sensitive indicators of first generation tricyclic overdose.

The absence of these findings is not exclusionary.

PR interval, ST-T wave changes, ventricular tachycardia and fibrillation may also occur.

Other signs of overdose may include: impaired myocardial contractility, confusion, disturbed concentration, transient visual hallucinations, dilated pupils, disorders of ocular motility, agitation, hyperactive reflexes polyradiculoneuropathy, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS.

Management General Obtain an

ECG and immediately initiate cardiac monitoring.

Protect the patient's airway, establish an intravenous line and initiate gastric decontamination.

A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary.

If signs of toxicity occur at any time during the period extended monitoring is required.

There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination.

Monitoring of plasma drug levels should not guide management of the patient.

All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination.

This should include, large volume gastric lavage followed by activated charcoal.

If consciousness is impaired, the airway should be secured prior to lavage.

Cardiovascular A maximal limb-lead

QRS duration of ≥0.10 seconds may be the best indication of the severity of the overdose.

Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55.

If the pH response is inadequate, hyperventilation may also be used.

Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring.

A pH >7.60 or a pCO 2 <20 mm Hg is undesirable.

Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin.

Type 1 A and 1 C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity.

However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.

CNS In patients with

CNS depression early intubation is advised because of the potential for abrupt deterioration.

Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).

Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.

Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase.

Psychiatric referral may be appropriate.

The principles of management of pediatric and adult overdosages are similar.

It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages to 24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. $NoTableFooter $FootNote $NoFootNote Age Range Drug.

• Placebo Difference in Number of Cases of Suicidality per 1, 000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for amitriptyline hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that amitriptyline hydrochloride is not approved for use in treating bipolar depression.

Amitriptyline hydrochloride may block the antihypertensive action of guanethidine or similarly acting compounds.

It should be used with caution in patients with a history of seizures and, because of its atropine-like action, in patients with a history of urinary retention or angle-closure glaucoma.

In patients with angle-closure glaucoma, even average doses may precipitate an attack.

Patients with cardiovascular disorders should be watched closely.

Tricyclic antidepressant drugs, including amitriptyline hydrochloride, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time.

Myocardial infarction and stroke have been reported with drugs of this class.

Close supervision is required when amitriptyline hydrochloride is given to hyperthyroid patients or those receiving thyroid medication.

Amitriptyline may enhance the response to alcohol and the effects of barbiturates and other CNS depressants.

In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage.

Delirium has been reported with concurrent administration of amitriptyline and disulfiram.

The pupillary dilation that occurs following use of many antidepressant drugs including amitriptyline hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of to 40 mg/kg/day (up to 13 times the maximum recommended human dose 1 ).

Studies in literature have shown amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of to 100 mg/kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations.

Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies without other signs of embryotoxicity.

In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of cranial bones.

Amitriptyline has been shown to cross the placenta.

Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy.

There are no adequate and well-controlled studies in pregnant women.

Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Based on a maximum recommended amitriptyline dose of 150 mg/day or 3 mg/kg/day for a 50 kg patient.

Amitriptyline is excreted into breast milk.

In one report in which a patient received amitriptyline 100 mg/day while nursing her infant, levels of to 141 ng/mL were detected in the mother's serum.

Levels of to 151 ng/mL were found in the breast milk, but no trace of the drug could be detected in the infant's serum.

Because of the potential for serious adverse reactions in nursing infants from amitriptyline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age.

Amitriptyline hydrochloride is contraindicated in patients who have shown prior hypersensitivity to it.

It should not be given concomitantly with monoamine oxidase inhibitors.

Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressant and monoamine oxidase inhibiting drugs simultaneously.

When it is desired to replace a monoamine oxidase inhibitor with amitriptyline hydrochloride, a minimum of 14 days should be allowed to elapse after the former is discontinued.

Amitriptyline hydrochloride should then be initiated cautiously with gradual increase in dosage until optimum response is achieved.

Amitriptyline hydrochloride should not be given with cisapride due to the potential for increased QT interval and increased risk for arrhythmia.

This drug is not recommended for use during the acute recovery phase following myocardial infarction.

Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.

For outpatients, 75 mg of amitriptyline hydrochloride a day in divided doses is usually satisfactory.

If necessary, this may be increased to a total of 150 mg per day. Increases are made preferably in the late afternoon and/or bedtime doses.

A sedative effect may be apparent before the antidepressant effect is noted, but an adequate therapeutic effect may take as long as 30 days to develop.

An alternate method of initiating therapy in outpatients is to begin with to 100 mg amitriptyline hydrochloride at bedtime.

This may be increased by 25 or 50 mg as necessary in the bedtime dose to a total of 150 mg per day. Hospitalized patients may require 100 mg a day initially.

This can be increased gradually to 200 mg a day if necessary.

A small number of hospitalized patients may need as much as 300 mg a day. Adolescent and Elderly Patients In general, lower dosages are recommended for these patients.

Ten mg 3 times a day with 20 mg at bedtime may be satisfactory in adolescent and elderly patients who do not tolerate higher dosages.

The usual maintenance dosage of amitriptyline hydrochloride is to 100 mg per day. In some patients, 40 mg per day is sufficient.

For maintenance therapy, the total daily dosage may be given in a single dose, preferably at bedtime.

When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms.

It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse.

In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age.

Because of the wide variation in the absorption and distribution of tricyclic antidepressants in body fluids, it is difficult to directly correlate plasma levels and therapeutic effect.

However, determination of plasma levels may be useful in identifying patients who appear to have toxic effects and may have excessively high levels, or those in whom lack of absorption or noncompliance is suspected.

Because of increased intestinal transit time and decreased hepatic metabolism in elderly patients, plasma levels are generally higher for a given oral dose of amitriptyline hydrochloride than in younger patients.

Elderly patients should be monitored carefully and quantitative serum levels obtained as clinically appropriate.

Adjustments in dosage should be made according to the patient's clinical response and not on the basis of plasma levels. 2 2 Hollister, L.E.; Monitoring Tricyclic Antidepressant Plasma Concentrations.

JAMA 1979; 241:2,530-2,533.

50090-4005 NDC: 50090-4005-0 30 TABLET, FILM COATED in a BOTTLE NDC: 50090-4005-4 60 TABLET, FILM COATED in a BOTTLE NDC: 50090-4005-1 100 TABLET, FILM COATED in a BOTTLE, PLASTIC NDC: 50090-4005-8 90 TABLET, FILM COATED in a BOTTLE, PLASTIC.

Amitriptyline is excreted into breast milk.

In one report in which a patient received amitriptyline 100 mg/day while nursing her infant, levels of to 141 ng/mL were detected in the mother's serum.

Levels of to 151 ng/mL were found in the breast milk, but no trace of the drug could be detected in the infant's serum.

Because of the potential for serious adverse reactions in nursing infants from amitriptyline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in the pediatric population have not been established.

Anyone considering the use of amitriptyline in a child or adolescent must balance the potential risks with the clinical need.

Clinical experience has not identified differences in responses between elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic function, concomitant disease and other drug therapy in elderly patients.

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 hydrochloride and observed closely See DOSAGE AND ADMINISTRATION.