DrugindexOnline^{2nd edition}

Generic Name: Amitriptyline hydrochloride
Dosage Form: Tablets

Rx only

Amitriptyline Description

Amitriptyline HCl, a dibenzocycloheptadiene derivative, is a white, or practically white, odorless, crystalline compound which is freely soluble in water and alcohol.

It is designated chemically as 10,11-Dihydro-N,N-dimethyl-5H-dibenzo[a,d] cycloheptene-Δ5, γ-propylamine hydrochloride. It has the following structural formula:

Each tablet for oral administration contains 10, 25, 50, 75, 100, or 150 mg Amitriptyline hydrochloride. Inactive ingredients include colloidal silicon dioxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose (monohydrate), magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch (corn) and titanium dioxide. The 10 mg also includes D&C Red #27 Aluminum Lake, D&C Yellow #10 Aluminum Lake and FD&C Blue #1 Aluminum Lake; 25 mg - D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake and FD&C Red #40 Aluminum Lake; 50 mg - FD&C Blue #2 Aluminum Lake and FD&C Red #40 Aluminum Lake; 75 mg - D&C Red #7 Calcium Lake and FD&C Blue #2 Aluminum Lake; 100 mg - D&C Red #30 Aluminum Lake and D&C Yellow #10 Aluminum Lake; 150 mg - D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake and FD&C Red #40 Aluminum Lake.

Amitriptyline - Clinical Pharmacology

Amitriptyline HCl 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.

Indications and Usage for Amitriptyline

For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than are other depressive states.

Contraindications

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.

Warnings

Clinical Worsening and Suicide Risk

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. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.

Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults.

All pediatric patients being treated with antidepressants for any indication should be 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. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.

Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, 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 pediatric 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 tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.

Screening Patients for Bipolar Disorder

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 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, angle-closure glaucoma or increased intraocular pressure. 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.

Usage In Pregnancy

Pregnancy Category C

Teratogenic effects were not observed in mice, rats, or rabbits when Amitriptyline was given orally at doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose1). Studies in literature have shown Amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of 28 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.

1

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

Nursing Mothers

Amitriptyline is excreted into breast milk. In one report in which a patient received Amitriptyline 100 mg/day while nursing her infant, levels of 83 to 141 ng/mL were detected in the mother's serum. Levels of 135 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.

Usage In Pediatric Patients

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.

Precautions

Schizophrenic patients may develop increased symptoms of psychosis; patients with paranoid symptomatology may have an exaggeration of such symptoms. Depressed patients, particularly those with known manic-depressive illness, may experience a shift to mania or hypomania. In these circumstances the dose of Amitriptyline may be reduced or a major tranquilizer such as perphenazine may be administered concurrently.

The possibility of suicide in depressed patients remains until significant remission occurs. Potentially suicidal patients should not have access to large quantities of this drug. Prescriptions should be written for the smallest amount feasible.

Concurrent administration of Amitriptyline hydrochloride and electroshock therapy may increase the hazards associated with such therapy. Such treatment should be limited to patients for whom it is essential.

When possible, the drug should be discontinued several days before elective surgery.

Both elevation and lowering of blood sugar levels have been reported.

Amitriptyline hydrochloride should be used with caution in patients with impaired liver function.

Drug Interactions

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 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 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 – see CONTRAINDICATIONS section. Guanethidine or similarly acting compounds; thyroid medication; alcohol, barbiturates and other CNS depressants; and disulfiram – see WARNINGS section.

When Amitriptyline 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 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.

Information For Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Amitriptyline and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Amitriptyline. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Amitriptyline.

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

While on therapy with Amitriptyline hydrochloride, patients should be advised as to the possible impairment of mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle.

Geriatric Use

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).

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS – Clinical Worsening and Suicide Risk). Anyone considering the use of Amitriptyline in a child or adolescent must balance the potential risks with the clinical need.

Adverse Reactions

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; 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.

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 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 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.

Overdosage

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.

Manifestations

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. Prolonged 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.

Gastrointestinal Decontamination

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. EMESIS IS CONTRAINDICATED.

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 pCO2< 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.

Psychiatric Follow-up

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

Pediatric Management

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.

Amitriptyline Dosage and Administration

Oral Dosage

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

Initial Dosage For Adults

For outpatients, 75 mg of Amitriptyline HCl 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 50 to 100 mg Amitriptyline HCl 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.

Maintenance

The usual maintenance dosage of Amitriptyline HCl is 50 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.

Usage In Pediatric Patients

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.

Plasma Levels

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(23):2530-2533.

How is Amitriptyline Supplied

Amitriptyline hydrochloride tablets, USP for oral administration are available as:

10 mg: Round, film-coated pink tablets, debossed GG 40 on one side and plain on the reverse side, and supplied as:
  NDC 0781-1486-01 bottles of 100
  NDC 0781-1486-10 bottles of 1000

25 mg: Round, film-coated light green tablets, debossed GG 44 on one side and plain on the reverse side, and supplied as:
  NDC 0781-1487-01 bottles of 100
  NDC 0781-1487-10 bottles of 1000

50 mg: Round, film-coated brown tablets, debossed GG 431 on one side and plain on the reverse side, and supplied as:
  NDC 0781-1488-01 bottles of 100
  NDC 0781-1488-10 bottles of 1000

75 mg: Round, film-coated purple tablets, debossed GG 451 on one side and plain on the reverse side, and supplied as:
  NDC 0781-1489-01 bottles of 100
  NDC 0781-1489-10 bottles of 1000

100 mg: Round, film-coated orange tablets, debossed GG 461 on one side and plain on the reverse side, and supplied as:
  NDC 0781-1490-01 bottles of 100
  NDC 0781-1490-10 bottles of 1000

150 mg: Capsule shaped, film-coated light green tablets, debossed GG 450 on one side and plain on the reverse side, and supplied as:
  NDC 0781-1491-01 bottles of 100
  NDC 0781-1491-10 bottles of 1000

Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature).

Dispense in a tight, light-resistant container.

METABOLISM

Studies in man following oral administration of 14C-labeled drug indicated that Amitriptyline is rapidly absorbed and metabolized. Radioactivity of the plasma was practically negligible, although significant amounts of radioactivity appeared in the urine by 4 to 6 hours and one-half to one-third of the drug was excreted within 24 hours.

Amitriptyline is metabolized by N-demethylation and bridge hydroxylation in man, rabbit, and rat. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with little unchanged drug appearing in the urine. Other metabolic pathways may be involved.

REFERENCES

Ayd, F.J., Jr.: Amitriptyline therapy for depressive reactions, Psychosom. 1:
  320-325, Nov.-Dec. 1960.

Diamond, S.: Human metabolization of Amitriptyline tagged with carbon 14,
  Curr. Therap. Res. 7: 170-175, Mar. 1965.

Dorfman, W.: Clinical experiences with Amitriptyline (A preliminary report),
  Psychosom. 1: 153-155, May-June 1960.

Fallette, J.M.; Stasney, C.R.; Mintz, A.A.: Amitriptyline poisoning treated with
  physostigmine, S. Med. J. 63: 1492-1493, Dec. 1970 (in Soc. Proc.).

Hollister, L.E.; Overall, J.E.; Johnson, M.; Pennington, V.; Katz, G.; Shelton,
  J.: Controlled comparison of Amitriptyline, imipramine and placebo in hospitalized
  depressed patients, J. Nerv. and Ment. Dis. 139: 370-375, Oct. 1964.

Hordern, A.; Burt, C.G.; Holt, N.F.: Depressive states. A pharmacotherapeutic
  study, Springfield, Ill., Charles C. Thomas, 1965.

Jenike, M.A.: Treatment of Affective Illness in the Elderly with Drugs and
  Electroconvulsive Therapy, J. Geriatr. Psychiatry 1989;22(1).77-112.

Klerman, G.L.; Cole, J.O.: Clinical pharmacology of imipramine and related
  antidepressant compounds, Int. J. Psychiat. 3: 267-304, Apr. 1976.

Liu, B.; Anderson, C.; Mittman, N. et al: Use of selective serotonin-reuptake
  inhibitors or tricyclic antidepressants and risk of hip fractures in elderly
  people. Lancet 1998; 351 (91 12):1303-1307.

McConaghy, N.; Joffe, A.D.; Kingston, W.R.; Stevenson, H.G.; Atkinson, I.;
  Cole, E.; Fennessy, L.A.; Correlation of clinical features of depressed outpatients
  with response to Amitriptyline and protriptyline, Brit. J. Psychiat. 114:
  103-106, Jan. 1968.

McDonald, I.M.; Perkins, M.; Marjerrison, G.; Podilsky, M.: A controlled comparison
  of Amitriptyline and electroconvulsive therapy in the treatment of
  depression, Amer. J. Psychiat. 122: 1427-1431. June 1966 (in Brief Communications).

Slovis, T.; Ott, J.; Teitelbaum, D.; Lipscomb, W.: Physostigmine therapy in
  acute tricyclic antidepressant poisoning, Clin. Toxicol. 4: 451-459, Sept. 1971.

Symposium on depression with special studies of a new antidepressant,
  Amitriptyline, Dis. Nerv. Syst. 22: 5-56, May 1961 (Sect. 2).

MEDICATION GUIDE
About Using Antidepressants in
Children and Teenagers

What is the most important information I should know if my child is being prescribed an antidepressant?

Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant:

1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants

1. There is a Risk of Suicidal Thoughts or Actions

Children and teenagers sometimes think about suicide, and many report trying to kill themselves.

Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal.

A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal.

For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with

• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide

If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant.

2. How to Try to Prevent Suicidal Thoughts and Actions

To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for.

Whenever an antidepressant is started or its dose is changed, pay close attention to your child.

After starting an antidepressant, your child should generally see his or her healthcare provider:

• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider's advice about how often to come back
• More often if problems or questions arise (see Section 3)

You should call your child's healthcare provider between visits if needed.

3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant

Contact your child's healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher:

• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood

Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms.

4. There are Benefits and Risks When Using Antidepressants

Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants.

Other side effects can occur with antidepressants (see section below).

Of all the antidepressants, only fluoxetine (Prozac®)3 has been FDA approved to treat pediatric depression.

For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac®)3, sertraline (Zoloft®)4, fluvoxamine, and clomipramine (Anafranil®)5.

Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members.

Is this all I need to know if my child is being prescribed an antidepressant?

No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

3

Prozac® is a registered trademark of Eli Lilly and Company

4

Zoloft® is a registered trademark of Pfizer Pharmaceuticals

5

Anafranil® is a registered trademark of Mallinckrodt Inc.

Rev. 03-2006M
1005

Sandoz Inc.
Princeton, NJ 08540

Amitriptyline Hydrochloride (Amitriptyline Hydrochloride)

PRODUCT INFO Product Code 0781-1486 Dosage Form TABLET Route Of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength Amitriptyline Hydrochloride (Amitriptyline) Active 10 MILLIGRAM  In 1 TABLET Microcrystalline Cellulose Inactive   Pregelatinized Starch Inactive   Colloidal Silicon Dioxide Inactive   Lactose Monohydrate Inactive   Magnesium Stearate Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color PINK Score 1 Shape ROUND Symbol false Imprint Code GG;40 Coating true Size 6mm

PACKAGING # NDC Package Description Multilevel Packaging 1 0781-1486-01 100 TABLET In 1 BOTTLE None 2 0781-1486-10 1000 TABLET In 1 BOTTLE None

Amitriptyline Hydrochloride (Amitriptyline Hydrochloride)

PRODUCT INFO Product Code 0781-1487 Dosage Form TABLET Route Of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength Amitriptyline Hydrochloride (Amitriptyline) Active 25 MILLIGRAM  In 1 TABLET Microcrystalline Cellulose Inactive   Pregelatinized Starch Inactive   Colloidal Silicon Dioxide Inactive   Lactose Monohydrate Inactive   Magnesium Stearate Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color GREEN (light green) Score 1 Shape ROUND Symbol false Imprint Code GG;44 Coating true Size 6mm

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