Generic Name: AMITRIPTYLINE HYDROCHLORIDE
Brand Name: Amitriptyline Hydrochloride
- Substance Name(s):
- AMITRIPTYLINE HYDROCHLORIDE
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. 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 18–24) 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 65 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 4400 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 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 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. 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 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. 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 hydrochloride tablets are 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 hydrochloride 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 dose*). 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 the 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. 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.
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 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 section. Guanethidine or similarly acting compounds; thyroid medication; alcohol, barbiturates and other CNS depressants; and disulfiram – see section. CONTRAINDICATIONS WARNINGS 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.
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 pCO < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). 2 In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with the 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 HCl is 3-(10,11-dihydro-5H-dibenzo [a, ] cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Its empirical formula is C H N•HCl, and its structural formula is: d 20 23 Amitriptyline HCl, a dibenzocycloheptadiene derivative, has a molecular weight of 313.87. It is a white, odorless, crystalline compound which is freely soluble in water. Amitriptyline HCl is supplied as 10 mg, 25 mg, 50 mg, 75 mg, 100 mg or 150 mg tablets. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate, sodium starch glycolate and titanium dioxide. The 10 mg tablets also contain FD&C blue #1 lake. The 25 mg tablets also contain D&C yellow #10 lake and FD&C blue #2 lake. The 50 mg tablets also contain synthetic black iron oxide, synthetic red iron oxide and synthetic yellow iron oxide. The 75 mg tablets also contain FD&C yellow #6 lake. The 100 mg tablets also contain D&C red #33 lake and FD&C red #40 lake. The 150 mg tablets also contain FD&C blue #2 lake and FD&C yellow #6 lake. This is an image of the sturctural formula of Amitriptyline HCl.
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
INDICATIONS AND USAGE
For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than are other depressive states.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see and ). Anyone considering the use of amitriptyline hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need. BOX WARNING WARNINGS- Clinical Worsening and Suicide Risk
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 dose*). 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 the 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.
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.
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of amitriptyline hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Amitriptyline hydrochloride tablets are not approved for use in pediatric patients (see , , and .) Warnings: Clinical Worsening and Suicide Risk Precautions: Information for Patients Precautions: Pediatric Use
INFORMATION FOR PATIENTS
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 hydrochloride tablets and should counsel them in its appropriate use. A patient about is available for amitriptyline hydrochloride tablets. 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. Medication Guide “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking amitriptyline hydrochloride tablets. 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.
DOSAGE AND ADMINISTRATION
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. Adjustment in dosage should be made according to the patient’s clinical response and not on the basis of plasma levels.**