DEPRESTAT LP

Amitriptyline is a tricyclic antidepressant that has been used to treat depression for decades.

ELAVIL, a previously approved branded product of amitriptyline, was first approved by the FDA in 1961.

Amitriptyline has been investigated in the treatment of pain-related conditions, attributed to its analgesic properties.

This drug in indicated for the following conditions Label: Major depressive disorder in adults 12 Management of neuropathic pain in adults Prophylactic treatment of chronic tension-type headache (CTTH) in adults Prophylactic treatment of migraine in adults Treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, have been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products.

This product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis Label Off-label uses: irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation, fibromyalgia, and insomnia

Effects in pain and depression

Amitriptyline is a tricyclic antidepressant and an analgesic.

It has anticholinergic and sedative properties

Clinical studies have shown that oral amitriptyline achieves, at a minimum, good to moderate response in up to 2/3 of patients diagnosed with post-herpetic neuralgia and 3/4 of patients diagnosed with diabetic neuropathic pain, and neurogenic pain syndromes that are frequently unresponsive to narcotic analgesics.

Amitriptyline has also shown efficacy in diverse groups of patients with chronic non-malignant pain.

There have also been some studies showing efficacy in managing fibromyalgia (an off-label use of this drug) 5, 8.

Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart 13.

Amitriptyline may inhibit ion channels, which are necessary for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations.

Therefore, amitriptyline may increase the risk for cardiac arrhythmia Label.

Orthostatic hypotension and tachycardia can be a problem in elderly patients receiving this drug at normal doses for depression.

There is evidence in the literature that these effects may occur, rarely, at the lower dosages utilized in the treatment of pain.

As with any other tricyclic antidepressant agent, increased glucose levels can occur with amitriptyline 6.

Effects on seizure threshold

This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns 13.

Sodium-dependent noradrenaline transporter Inhibitor

Sodium-dependent serotonin transporter Inhibitor 5-hydroxytryptamine receptor 2A Antagonist.

Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism).

Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration Label.

Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences 13.

The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg) Label.

It is found widely distributed throughout the body 6.

Amitriptyline and the main metabolite nortriptyline pass across the placental barrier and small amounts are present in breast milk Label.

In vitro, the metabolism of amitriptyline occurs mainly by demethylation (CYP2C19, CYP3A4) as well as hydroxylation (CYP2D6) followed by conjugation with glucuronic acid.

Other isozymes involved in amitriptyline metabolism are CYP1A2 and CYP2C9.

The metabolism of this drug is subject to genetic polymorphisms.

The main active metabolite is the secondary amine, nortriptyline Label.

Nortriptyline is a stronger inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin with equal efficacy.

Other metabolites such as cis.

• and trans-10-hydroxyamitriptyline and cis.

• and trans-10-hydroxynortriptyline have the same pharmacologic profile as nortriptyline but are significantly weaker.

Demethylnortriptyline and amitriptyline

N oxide are only present in plasma in negligible amounts; the latter is mostly inactive Label.

Hover over products below to view reaction partners Amitriptyline Nortriptyline Desmethylnortriptyline E-10-Hydroxydesmethylnortriptyline E-10-Hydroxynortriptyline E-10-Hydroxyamitriptyline E-10-Hydroxynortriptyline E-10-Hydroxydesmethylnortriptyline E-10-Hydroxyamitriptyline.

Amitriptyline and its metabolites are mainly excreted in the urine.

Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine Label. 25-50% of a single Oral administered dose is excreted in urine as inactive metabolites within 24 hours Label.

Small amounts are excreted in feces via biliary elimination 13.

The elimination half-life (t1⁄2 β) amitriptyline after peroral administration is about 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 hours) Label.

The mean systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h) Label.

No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased 6.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg 13.

Ingestion of 750 mg or more by an adult may result in severe toxicity.

The effects in overdose are further increased by simultaneous ingestion of alcohol and another psychotropic agent Label.

Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma, among others Label, 13.

Use in pregnancy

For amitriptyline, only limited clinical data are available regarding its use in pregnancy.

Amitriptyline is not recommended during pregnancy unless clearly required and only after careful consideration of both risks and benefits Label.

Use in breastfeeding

Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % - 1 % of the maternal dose).

A risk to the suckling child must be considered.

A decision should be made as to whether it is appropriate to discontinue breastfeeding or to discontinue/abstain from the therapy of this medicinal product, considering the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Effects on fertility

Animal studies have shown reproductive toxicity.

No data on the effects of amitriptyline on human fertility are available Label.

Mutagenesis and carcinogenesis

The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. some contradictory results, a potential of amitriptyline to lead to chromosome abnormalities cannot be excluded.

Long-term carcinogenicity studies have not been performed to this date Label.

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.