Version May 2024
Antidepressants increased the risk compared with 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 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 with placebo in adults older than 24 years; there was a reduction in risk with antidepressants compared with placebo in adults 65 years 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 is not approved for use in pediatric patients.
Chronic fatigue syndrome related sleep disorders and pain (off-label use): Based on limited evidence; recommendations based on expert opinion: Oral: Initial: 10 mg once daily 1 hour before bedtime; may increase dose gradually based on response and tolerability in 10 mg increments up to 50 mg/day at bedtime for sleep disorders; for patients with pain, titrate up to 100 mg/day given once daily at bedtime or in divided doses (Ref).
Cyclic vomiting syndrome, moderate to severe, prevention (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may increase dose based on response and tolerability in increments of 10 to 25 mg at weekly intervals up to 100 mg/day (Ref). Typically requires a trial of 1 to 2 months at a therapeutic dose to adequately assess efficacy (Ref).
Fibromyalgia (off-label use): Oral: Initial: 10 mg once daily, 1 to 3 hours before bedtime; gradually increase dose based on response and tolerability in 5 to 10 mg increments at intervals of ≥2 weeks up to 75 mg/day (Ref). Note: Some experts suggest lower starting doses of 5 mg once daily in patients sensitive to side effects and that a maintenance dose range of 20 to 30 mg/day is often adequate (Ref).
Functional dyspepsia (alternative agent) (off-label use):
Note: May be used to augment or replace proton pump inhibitor therapy in partial and nonresponders who have been tested for H. pylori and treated if positive (Ref).
Oral: Initial: 10 to 25 mg once daily at bedtime; may increase dose based on response and tolerability in increments of 10 to 25 mg at ≥1-week intervals up to a maximum of 50 mg/day (Ref). Some experts suggest a lower maintenance dose range of 20 to 30 mg/day. Typically requires a trial of 8 to 12 weeks at a therapeutic dose to adequately assess efficacy. If effective, reassess at 6 months and consider tapering; may resume if dyspepsia recurs (Ref).
Headache, chronic tension-type (prevention) (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may increase dose based on response and tolerability in 10 to 25 mg increments at intervals of ≥1 week up to 125 mg/day (Ref). A lower starting dose of 10 to 12.5 mg once daily at bedtime and smaller titration increments of 10 to 12.5 mg/day at 2- to 3-week intervals may reduce adverse effects and enhance adherence according to some experts (Ref).
Interstitial cystitis (bladder pain syndrome) (off-label use): Oral: Initial: 10 mg once daily at bedtime; based on response and tolerability, increase dose after 1 week to 25 mg once daily and then at weekly intervals in 25 mg increments to a target dose of 75 to 100 mg/day (Ref). A maximum dose of up to 75 mg/day as tolerated is suggested by some experts (Ref).
Irritable bowel syndrome-associated pain and global symptoms (alternative agent) (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability to a recommended dose of 50 to 100 mg/day (Ref). Some experts recommend 3 to 4 weeks of therapy before increasing the dose (Ref).
Major depressive disorder (unipolar) (alternative agent): Oral: Initial: 25 to 50 mg/day as a single dose at bedtime or in divided doses; increase dose based on response and tolerability in 25 to 50 mg increments at intervals of ≥1 week up to a usual dose of 100 to 300 mg/day (Ref). Some experts suggest an initial dose of 25 mg/day at bedtime for most patients, although higher starting doses of 50 to 100 mg/day and more rapid titration (eg, every few days) may be considered in closely supervised (eg, hospitalized) settings; for patients sensitive to adverse effects, may initiate with 10 mg daily with gradual titration in steps of 10 mg/day every few days or longer (eg, at intervals ≥1 week) (Ref).
Manufacturer's labeling: Dosing in prescribing information may not reflect current clinical practice. Oral: Initial: 75 to 100 mg/day as a single dose at bedtime or in divided doses
Migraine, prevention (off-label use):
Note: An adequate trial for assessment of effect is considered to be at least 2 to 3 months at a therapeutic dose (Ref).
Oral: Initial: 10 to 25 mg once daily at bedtime; increase dose based on response and tolerability in 10 to 25 mg increments at intervals of ≥1 week up to 150 mg/day (Ref). Some experts suggest that a lower maintenance dose range of 10 to 100 mg once daily at bedtime is often adequate and better tolerated (Ref).
Myofascial pain syndrome and related causes of chronic pain including myofascial pelvic pain, nonradicular neck pain, temporomandibular disorders, and vulvodynia (alternative agent) (off-label use):
Note: May consider for patients with persistent symptoms despite multimodal care and treatment with first-line agents (Ref).
Oral: Initial: 10 to 25 mg once daily at bedtime; may increase based on response and tolerability in 10 to 25 mg increments at intervals ≥1 week to a usual dosage range of 25 to 75 mg/day (Ref). Maximum: 150 mg/day (Ref); due to tolerability concerns, some experts avoid or use caution with nortriptyline doses >50 mg/day (nortriptyline and amitriptyline are equipotent) (Ref). May require 6 to 12 weeks of therapy (including 2 weeks at maximum tolerated dose) to adequately assess efficacy (Ref).
Neuropathic pain, chronic (including diabetic neuropathy) (alternative agent) (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability in 10 to 25 mg increments at intervals ≥1 week up to a usual dosage range of 25 to 125 mg/day once daily at bedtime or in 2 divided doses (Ref). Maximum: 150 mg/day given once daily at bedtime or in 2 divided doses (Ref). In patients with diabetic neuropathy, some experts recommend a maximum dose of 100 mg/day (Ref). May require 6 to 12 weeks of therapy (including 2 weeks at maximum tolerated dose) to adequately assess efficacy (Ref).
Postherpetic neuralgia (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability in 10 to 25 mg increments at intervals of ≥1 week up to 150 mg/day given once daily at bedtime or in 2 divided doses (Ref).
Sialorrhea (off-label use): Oral: Usual dose: 10 to 25 mg once daily at bedtime. If necessary, may gradually increase dose based on response and tolerability up to 100 mg/day (Ref).
Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). Reasons for a slower taper (eg, over 4 weeks) include use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), prior history of antidepressant withdrawal symptoms, or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (Ref).
Switching to or from an MAOI:
Allow 14 days to elapse between discontinuing an MAOI and initiation of amitriptyline.
Allow 14 days to elapse between discontinuing amitriptyline and initiation of an MAOI.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Mild to severe impairment: No dosage adjustment necessary (Ref); use with caution.
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (large Vd): No supplemental dose or dosage adjustment necessary (Ref); however, dialysis patients have demonstrated increased sensitivity to the anticholinergic side effects of tricyclic antidepressants (TCAs) (potentially due to accumulation of glucuronide metabolites). Use with caution (or avoid use) along with close monitoring for both anticholinergic and QT prolonging effects (Ref).
Peritoneal dialysis: Unlikely to be dialyzed (large Vd): No dosage adjustment necessary (Ref); however, dialysis patients have demonstrated increased sensitivity to the anticholinergic side effects of TCAs (potentially due to accumulation of glucuronide metabolites). Use with caution (or avoid use) along with close monitoring for both anticholinergic and QT prolonging effects (Ref).
CRRT: Unlikely to be dialyzed: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be dialyzed: No dosage adjustment necessary (Ref).
There are no dosage adjustments provided in manufacturer's labeling; however, hepatically metabolized; use with caution. Some experts recommended reducing initial and maintenance doses by 50% in patients with hepatic impairment, with cautious dose adjustments based on response and tolerability; maximum 100 mg/day (Mauri 2014; Mullish 2014).
Note: Avoid use (Ref).
Major depressive disorder (unipolar) (alternative agent): Oral: Initial: 10 to 25 mg once daily at bedtime; increase dose gradually based on response and tolerability in 25 to 50 mg increments at intervals of ≥1 week up to a usual dose of 100 to 300 mg/day (Ref). A more rapid titration (eg, every few days) may be considered in closely supervised (eg, hospitalized) settings according to some experts (Ref); for patients sensitive to adverse effects, may initiate with 10 mg daily with gradual titration in steps of 10 mg/day every few days or longer (eg, at intervals ≥1 week) (Ref).
Manufacturer's labeling: Dosing may not reflect current clinical practice: Oral: 10 mg 3 times daily with an additional 20 mg once daily at bedtime
Postherpetic neuralgia (off-label use): Oral: Initial: 10 to 12.5 mg once daily at bedtime; may gradually increase dose based on response and tolerability in increments of 10 to 25 mg at intervals ≥1 week up to 150 mg/day once daily at bedtime or in 2 divided doses (Ref).
Discontinuation of therapy: Refer to adult dosing.
Switching antidepressants:Refer to adult dosing.
(For additional information see "Amitriptyline: Pediatric drug information")
Chronic pain management: Limited data available: Children and Adolescents: Oral: Initial: 0.1 mg/kg at bedtime; may advance as tolerated over 2 to 3 weeks to 0.5 to 2 mg/kg at bedtime (Ref).
Cyclic vomiting syndrome, prophylaxis: Limited data available:
Note: Prophylaxis is recommended for patients experiencing frequent symptoms (eg, monthly) or severe symptoms (eg, requiring hospitalization, lasting >2 days, resulting in significant school/work absences) (Ref).
Children ≥5 years and Adolescents: Oral: Initial: 0.2 to 0.5 mg/kg/day once daily, administered at bedtime. If needed, may titrate every 1 to 2 weeks (eg, by 5 to 10 mg increments) to a usual dose of 1 to 1.5 mg/kg/day; doses of 2 mg/kg/day or higher have been described; however, should be used with caution with careful titration, ECG monitoring, and therapeutic monitoring; doses may be divided for tolerability (Ref). In adults, the mean effective dose is 75 to 100 mg/day (Ref).
Major depressive disorder (unipolar): Limited data available:
Note: Controlled clinical trials have not shown tricyclic antidepressants to be superior to placebo for the treatment of depression in children and adolescents. Although dosing is included in some manufacturer's labeling for ages ≥12 years, a selective serotonin reuptake inhibitor (SSRI) is recommended first line for treatment of depression in children and adolescents with/without psychotherapeutic interventions. Amitriptyline may be beneficial for patients in whom first- and/or second-line treatment options have failed or with comorbid conditions (eg, migraines, chronic pain) (Ref).
Children ≥12 years and Adolescents: Oral: Usual initial range: 20 to 30 mg/day at bedtime or in divided doses (eg, 10 mg 3 times daily); titrate slowly at weekly intervals; maximum daily dose: 200 mg/day; in general, lower doses are recommended compared to doses in adults (Ref).
Migraine, prophylaxis: Limited data available (Ref):
Note: Pediatric migraine efficacy trials have been observed to have a high placebo response; a meta-analysis has shown that 30% to 61% of subjects receiving placebo report decreased number of migraine attacks or decrease in headache days. Specific to amitriptyline therapy, there is insufficient evidence in pediatric subjects to demonstrate a 50% reduction in headache frequency, headache days, and migraine-related disability compared to placebo. When amitriptyline is combined with cognitive behavioral therapy (CBT), trials have shown a reduction in number of headache days and migraine-related disability compared with amitriptyline plus headache education (Ref).
Children ≥8 years and Adolescents: Oral: Initial: 0.25 mg/kg/day once daily at bedtime; increase dose by 0.25 mg/kg/day every 2 weeks to 1 mg/kg/day; maximum daily dose: 100 mg/day; combining amitriptyline with CBT may also be effective at reducing headache days and migraine-related disability (Ref).
Discontinuation of therapy: Depression: Consider planning antidepressant discontinuation for lower-stress times, recognizing non–illness-related factors could cause stress or anxiety and be misattributed to antidepressant discontinuation (Ref). Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of discontinuation syndromes (withdrawal) and allow for the detection of reemerging disease state symptoms (eg, relapse). Evidence supporting ideal taper rates after illness remission is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively, avoiding abrupt discontinuation of the medication to prevent withdrawal effects. After long-term (years) antidepressant treatment, WFSBP guidelines recommend tapering over 4 to 6 months, with close monitoring during and for 6 months after discontinuation. If intolerable discontinuation symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies in pediatric patients is sparse; strategies described in pediatric guidelines include a conservative approach (tapering and discontinuing the antidepressant before adding the second) and cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant). While consensus does not exist regarding which approach to utilize, it is important to note that the conservative approach runs the risk for exacerbation of symptoms or discontinuation syndrome; cross-titration may avoid these risks but may increase the risk for the development of adverse effects or serotonin syndrome (Ref). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches but is contraindicated when switching to or from a monoamine oxidase inhibitor. While not as common of a strategy, a direct switch may be considered when switching to another agent in the same or similar class (eg, when switching between 2 SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects such as increased suicidal thoughts and behaviors or worsening depression or mania. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, pharmacodynamics), and the degree of symptom control desired (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥12 years and Adolescents: There are no dosage adjustments provided in manufacturer's labeling; however, renally eliminated; use with caution.
Children ≥12 years and Adolescents: There are no dosage adjustments provided in manufacturer's labeling; however, hepatically metabolized; use with caution.
Amitriptyline may cause anticholinergic effects, such as constipation (including fecal impaction), xerostomia, blurred vision, and urinary retention.
Mechanism: Binding affinity to the muscarinic receptor(s), permeability of the blood-brain barrier, and serum and tissue concentrations all influence the risk of anticholinergic effects (Ref). Amitriptyline is considered to have high anticholinergic activity at typical doses (Ref).
Risk factors:
• Older age (Ref)
• Higher doses (Ref)
• Concomitant use of drugs with anticholinergic properties (Ref)
• Specific tricyclic antidepressants: Amitriptyline has the highest degree of anticholinergic effects, while desipramine and nortriptyline have modest effects (Ref).
Amitriptyline may increase the risk of bleeding, particularly if used concomitantly with antiplatelets and/anticoagulants. Multiple observational studies with other drugs that interfere with serotonin reuptake (eg, selective serotonin reuptake inhibitors [SSRIs]) have found an association with use and a variety of bleeding complications. Similar to these agents, amitriptyline may increase the risk of bleeding (Ref).
Mechanism: Possibly via inhibition of serotonin-mediated platelet activation and subsequent platelet dysfunction. Amitriptyline is considered to display intermediate affinity for the serotonin reuptake receptor (Ref).
Onset: Varied; per SSRI-derived literature (ie, amitriptyline not included), bleeding risk is likely delayed for several weeks until SSRI-induced platelet serotonin depletion becomes clinically significant (Ref).
Risk factors:
• Concomitant use of antiplatelet agents and/or anticoagulants (based on SSRI-derived literature) (Ref)
• Preexisting platelet dysfunction or coagulation disorders (eg, von Willebrand factor) (Ref)
Amitriptyline may cause dose-dependent ECG changes (nonspecific), most commonly QRS prolongation (Ref), atrioventricular conduction disturbance, and cardiac arrhythmias, including sinus tachycardia. QT prolongation and ventricular arrhythmias may also occur. May precipitate heart block in patients with preexisting conduction system disease.
Mechanism: Inhibits cardiovascular sodium, calcium, and potassium channels (Ref). Sinus tachycardia is attributed to the inhibition of norepinephrine and anticholinergic action (Ref).
Risk factors:
• Increased age (Ref)
• Females (Ref)
• Presence of metabolic disease (Ref)
• Hypokalemia (Ref)
• Coadministration of drugs independently associated with QT interval prolongation or further increase risk of arrhythmia (amitriptyline shares electrophysiologic properties of type Ia antiarrhythmics such as quinidine, procainamide, and disopyramide) (Ref)
• Family history of congenital long QT syndrome (Ref). Note: Use is relatively contraindicated in patients with conduction abnormalities
Amitriptyline may cause dose-dependent CNS depression, including dizziness, drowsiness, a sedated state, ataxia, cognitive dysfunction, confusion, disorientation, and fatigue (Ref).
Mechanism: Dose related; alpha-adrenergic and histamine receptor blockade may cause dizziness (via orthostatic hypotension) and a high degree of sedation (Ref).
Onset: Varied; difficult to define; some symptoms may occur with first dose. A meta-analysis in inpatients treated with a tricyclic antidepressant (TCA), including amitriptyline, suggested that CNS toxicity (defined primarily as delirium or its prodromal symptoms) may have an insidious onset over 1 to 3 weeks following initiation or dose increase (Ref).
Risk factors:
• Concomitant alcohol
• Concomitant CNS depressants (eg, anticholinergics, antihistamines) (Ref)
• Females (Ref)
• Increased age (>55 years) (Ref)
• Increased TCA plasma levels, especially levels >300 ng/mL (Ref)
• Specific TCA: Amitriptyline has the highest risk of sedation among the TCAs (Ref)
Antidepressants (primarily selective serotonin reuptake inhibitors [SSRIs]) have been associated with an increased risk of bone fractures in observational studies (Ref). Tricyclic antidepressants, including amitriptyline, have also been associated with increased fracture risk (Ref).
Mechanism: Not fully elucidated; per SSRI-derived literature, may be related to a direct effect on bone metabolism via interaction with 5-HT and osteoblast, osteocyte, and/or osteoclast activity (Ref). Fall risk may be attributed to sedation, syncope, orthostatic hypotension, and/or confusion (Ref).
Onset: Varied; in a large, population-based case-controlled study, the increase risk of fracture with amitriptyline was more pronounced within the first 6 months of initiating therapy and declined with increasing duration of use (Ref).
Risk factors:
• Dose; amitriptyline is associated with fractures at low doses and a dose-dependent increase in risk has been observed (Ref)
• Concomitant use with other agents that may further affect physical balance and contribute to falls (eg, anxiolytics) (Ref).
Tricyclic antidepressants (TCAs) have been rarely associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and/or hyponatremia, predominately in the elderly (Ref).
Mechanism: May cause SIADH via release of antidiuretic hormone (ADH) (Ref) or may cause nephrogenic SIADH by increasing the sensitivity of the kidney to ADH (Ref).
Onset: Varied; overall, hyponatremia risk is much higher within 2 to 4 weeks of initiating therapy and the risk seems to diminish over time. By 3 to 6 months, the hyponatremia risk is the same as for patients who do not take antidepressants (Ref).
Risk factors:
• Older age (Ref)
• Females (Ref)
• Concomitant use of diuretics (Ref)
• Low body weight (Ref)
• Lower baseline serum sodium concentration (Ref)
• Volume depletion (potential risk factor) (Ref)
• History of hyponatremia (potential risk factor) (Ref)
• Symptoms of psychosis (potential risk factor) (Ref)
• Specific antidepressant: TCAs have a lower risk for hyponatremia in comparison to selective serotonin reuptake inhibitors (SSRIs) (Ref)
Amitriptyline is associated with acute angle-closure glaucoma (AACG) in a case report (Ref). May cause mild pupillary dilation, which, in susceptible individuals, can result in physical obstruction of the outflow of intraocular fluid. AACG may cause symptoms including eye pain, changes in vision, swelling, and redness, which can rapidly lead to permanent blindness if not treated (Ref).
Mechanism: May occur due to anticholinergic activity and mydriasis (Ref). May also be related to effects on serotonin or norepinephrine receptors in the iris and ciliary body of the eye (Ref).
Risk factors:
For AACG:
• Females (Ref)
• ≥50 years of age (slight increase) (Ref)
• Hyperopia (slight increase) (Ref)
• Personal or family history of AACG (Ref)
• Inuit or Asian descent (Ref)
Amitriptyline may cause orthostatic hypotension, which may lead to syncope and subsequent falls (Ref).
Mechanism: Alpha-adrenergic receptor blockade may lower systemic vascular resistance and result in hypotension, including orthostatic hypotension (Ref).
Onset: Varied; unclear; in a small study of elderly patients treated with amitriptyline 100 mg, orthostatic hypotension remained throughout the entire 5-week study period (Ref).
Risk factors:
• Cerebrovascular disease
• Cardiovascular disease
• Hypovolemia/dehydration (Ref)
• Concurrent medication use that may predispose to hypotension/bradycardia (Ref)
• Older adults, especially in those with preexisting heart conditions (Ref)
• Specific TCA: Amitriptyline is usually associated with a high risk for significant orthostatic hypotension (Ref)
Serotonin syndrome has been reported and typically occurs with coadministration of multiple serotonergic drugs (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).
Mechanism: Dose related; overstimulation of serotonin receptors by serotonergic agents (Ref).
Onset: Rapid; in the majority of cases (74%), onset occurred within 24 hours of treatment initiation, overdose, or change in dose (Ref).
Risk factors:
• Concurrent use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism
Antidepressants are associated with an increased risk of suicidal thinking and suicidal behavior in pediatric and young adult patients (18 to 24 years) in short-term studies. In adults >24 years, short-term studies did not show an increased risk of suicidal thinking and behavior, and in older adults ≥65 years of age, a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, collective evidence shows a trend of an elevated risk of suicidality in younger age groups (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.
Mechanism: Not established; one of several postulated mechanisms is antidepressants may energize suicidal patients to act on impulses; another suggests that antidepressants may produce a worsening of depressive symptoms leading to the emergence of suicidal thoughts and actions (Ref).
Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to long-term use (ie, >4 months).
Risk factors:
• Children and adolescents (Ref)
• Depression (risk of suicide is associated with major depression and may persist until remission occurs)
Withdrawal syndrome, consisting of both somatic symptoms (eg, dizziness, chills, light-headedness, vertigo, shock-like sensations, paresthesia, fatigue, headache, nausea, tremor, diarrhea, visual disturbances) and psychological symptoms (eg, anxiety, agitation, confusion, insomnia, irritability) has been reported, primarily following abrupt discontinuation of selective serotonin reuptake inhibitors (SSRIs). Withdrawal symptoms may also occur following gradual tapering (Ref).
Mechanism: Withdrawal; due to reduced availability of serotonin in the CNS with decreasing levels of the serotonergic agent. Other neurotransmission systems, including increased glutamine and dopamine, may also be affected, as well as the hypothalamic-pituitary-adrenal axis (Ref). May also be related in part to an adaptive hypersensitivity of muscarinic cholinergic receptors called cholinergic rebound or cholinergic overdrive (Ref).
Onset: Intermediate; based on data of withdrawal syndrome following SSRI discontinuation, expected onset is 1 to 10 days (following either abrupt or tapered discontinuation) (Ref).
Risk factors:
• Abrupt discontinuation (rather than gradual dose reduction) of an antidepressant treatment that has lasted for >3 weeks, particularly a drug with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)
• Prior history of antidepressant withdrawal symptoms (Ref)
• High dose (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Anticholinergic effects may be pronounced; moderate to marked sedation can occur (tolerance to these effects usually occurs).
Frequency not defined:
Cardiovascular: Acute myocardial infarction, atrioventricular conduction disturbance, cardiac arrhythmia, cardiomyopathy (rare) (Briec 2006), cerebrovascular accident, ECG changes (nonspecific) (Boehnerr 1985), edema, exacerbation of cardiac disease (AHA [Page 2016]), facial edema, heart block, hypertension, orthostatic hypotension, palpitations, sinus tachycardia, syncope
Dermatologic: Allergic skin rash, alopecia, diaphoresis, skin photosensitivity, urticaria
Endocrine & metabolic: Altered serum glucose (inconclusive, but increased weight gain may increase insulin resistance) (Gagnon 2018), decreased libido, galactorrhea not associated with childbirth, gynecomastia, increased libido, SIADH, weight gain, weight loss
Gastrointestinal: Ageusia, anorexia, constipation, melanoglossia, nausea, paralytic ileus, parotid gland enlargement, stomatitis, unpleasant taste, vomiting, xerostomia
Genitourinary: Breast hypertrophy, impotence, testicular swelling, urinary frequency, urinary retention, urinary tract dilation
Hematologic & oncologic: Eosinophilia, purpuric disease
Hepatic: Hepatic failure, hepatitis (rare; including altered liver function and jaundice)
Hypersensitivity: Tongue edema
Nervous system: Anxiety, ataxia, cognitive dysfunction, coma, confusion, delusion, disorientation, dizziness, drowsiness, dysarthria, EEG pattern changes, excitement, extrapyramidal reaction (including abnormal involuntary movements and tardive dyskinesia), fatigue, hallucination, headache, hyperpyrexia, insomnia, lack of concentration, nightmares, numbness, paresthesia, peripheral neuropathy, restlessness, sedated state, seizure, suicidal ideation, suicidal tendencies, tingling of extremities
Neuromuscular & skeletal: Asthenia, lupus-like syndrome, tremor
Ophthalmic: Accommodation disturbance, blurred vision, increased intraocular pressure, mydriasis
Otic: Tinnitus
Postmarketing:
Hematologic & oncologic: Agranulocytosis (Azadeh 2014), thrombocytopenia (Taniguchi 1996)
Nervous system: Neuroleptic malignant syndrome (rare) (Corrigan 1988; Janati 2012; Stevens 2008), serotonin syndrome (rare) (Dougherty 2002; Perry 2000), withdrawal syndrome (rare: <1%) (Davison 1993; Dilsaver 1984)
Ophthalmic: Angle-closure glaucoma (rare: <1%) (Lowe 1966)
Hypersensitivity to amitriptyline or any component of the formulation; coadministration with or within 14 days of MAOIs; coadministration with cisapride; acute recovery phase following myocardial infarction
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Canadian labeling: Additional contraindications (not in the US labeling): Severe liver impairment; acute heart failure
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities).
• GI motility: Use with caution in patients with decreased GI motility (eg, paralytic ileus) as anticholinergic effects may exacerbate underlying condition.
• Hepatic impairment: Use with caution in patients with hepatic impairment; clearance is decreased, and plasma concentrations are increased. Due to the narrow therapeutic index, use lower initial and maintenance doses of tricyclic antidepressants. Use caution in patients with hepatic encephalopathy due to the risk of neurocognitive effects (Mullish 2014).
• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer should also be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder. Amitriptyline is not FDA approved for the treatment of bipolar depression.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Mehrizi 2012).
• Ophthalmic conditions: Use with caution in patients with certain ophthalmic conditions (eg, increased intraocular pressure, narrow angle glaucoma, visual problems) as anticholinergic effects may exacerbate underlying condition.
• Renal impairment: Use with caution in patients with renal impairment.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
• Urinary retention (eg, benign prostatic hyperplasia): Use with caution in patients with urinary retention as anticholinergic effects may exacerbate underlying condition.
Other warnings/precautions:
• Surgery: Recommended by the manufacturer to discontinue prior to elective surgery; risks exist for drug interactions with anesthesia and for cardiac arrhythmias. However, definitive drug interactions have not been widely reported in the literature and continuation of tricyclic antidepressants is generally recommended as long as precautions are taken to reduce the significance of any adverse events that may occur. Norepinephrine should be considered the vasopressor of choice for TCA-related hypotension (Pass 2004). Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Generic: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg
Yes
Tablets (Amitriptyline HCl Oral)
10 mg (per each): $0.18 - $0.32
25 mg (per each): $0.36 - $0.64
50 mg (per each): $0.71 - $1.27
75 mg (per each): $1.07 - $1.91
100 mg (per each): $1.43 - $2.54
150 mg (per each): $2.14 - $3.81
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Elavil: 10 mg, 25 mg, 50 mg, 75 mg
Generic: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg
Oral: Administer higher doses preferably at late afternoon or as bedtime doses to minimize daytime sedation.
Oral: May administer with food to decrease GI upset.
An FDA-approved patient medication guide, which is available with the product information and at the following website, must be dispensed with this medication:
Antidepressant medications: https://www.fda.gov/downloads/drugs/drugsafety/ucm088660.pdf
Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder
Chronic fatigue syndrome–related sleep disturbances and pain; Cyclic vomiting syndrome, moderate to severe, prevention; Fibromyalgia; Functional dyspepsia; Headache, chronic tension-type (prevention); Interstitial cystitis (bladder pain syndrome); Irritable bowel syndrome-associated pain and global symptoms; Migraine, prevention; Myofascial pain syndrome and related causes of chronic pain including myofascial pelvic pain, nonradicular neck pain, temporomandibular disorders, and vulvodynia; Neuropathic pain, chronic (including diabetic neuropathy); Postherpetic neuralgia; Sialorrhea
Amitriptyline may be confused with aminophylline, imipramine, nortriptyline
Elavil may be confused with Aldoril, Eldepryl, enalapril, Equanil, Plavix
Elavil may be confused with Elavil OTC (an over-the-counter sleep aid containing melatonin, valerian root, and vitamins).
Beers Criteria: Amitriptyline (alone or in combination) is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to its strong anticholinergic properties and potential for sedation and orthostatic hypotension. In addition, use TCAs with caution due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2023]).
Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Alpha-/Beta-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists. Management: Avoid, if possible, the use of alpha-/beta-agonists in patients receiving tricyclic antidepressants. If combined, monitor for evidence of increased pressor effects and consider reductions in initial dosages of the alpha-/beta-agonist. Risk D: Consider therapy modification
Alpha1-Agonists: Tricyclic Antidepressants may enhance the therapeutic effect of Alpha1-Agonists. Tricyclic Antidepressants may diminish the therapeutic effect of Alpha1-Agonists. Risk C: Monitor therapy
Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding this combination. If used, monitor for decreased effects of the alpha2-agonist. Exercise great caution if discontinuing an alpha2-agonist in a patient receiving a TCA. Risk D: Consider therapy modification
Alpha2-Agonists (Ophthalmic): Tricyclic Antidepressants may diminish the therapeutic effect of Alpha2-Agonists (Ophthalmic). Risk C: Monitor therapy
Altretamine: May enhance the orthostatic hypotensive effect of Tricyclic Antidepressants. Risk C: Monitor therapy
Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy
Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Amphetamines: Tricyclic Antidepressants may enhance the adverse/toxic effect of Amphetamines. Tricyclic Antidepressants may potentiate the cardiovascular effects of Amphetamines. Amphetamines may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased cardiovascular effects when these agents are combined. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy
Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
ARIPiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Asenapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Management: Monitor for decreased efficacy of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. Tricyclic antidepressant dose adjustments are likely required. Risk D: Consider therapy modification
Benperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brexpiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Risk X: Avoid combination
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
BuPROPion: Tricyclic Antidepressants may enhance the neuroexcitatory and/or seizure-potentiating effect of BuPROPion. BuPROPion may increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Cannabinoid-Containing Products: Tricyclic Antidepressants may enhance the tachycardic effect of Cannabinoid-Containing Products. Blood pressure raising effects and drowsiness may also be enhanced. Risk C: Monitor therapy
Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
CarBAMazepine: May decrease the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Cariprazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Chlorprothixene: Anticholinergic Agents may enhance the anticholinergic effect of Chlorprothixene. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Risk X: Avoid combination
Cisapride: Amitriptyline may enhance the arrhythmogenic effect of Cisapride. Risk X: Avoid combination
Citalopram: Tricyclic Antidepressants may enhance the serotonergic effect of Citalopram. Tricyclic Antidepressants may increase the serum concentration of Citalopram. Citalopram may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA and citalopram concentrations/effects. Risk C: Monitor therapy
Clothiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Cocaine (Topical): May enhance the adverse/toxic effect of Tricyclic Antidepressants. Risk C: Monitor therapy
Cyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of Amitriptyline. CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amitriptyline. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Amitriptyline. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Amitriptyline. Risk C: Monitor therapy
Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combination
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Desmopressin: Tricyclic Antidepressants may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: Monitor therapy
Dronedarone: Tricyclic Antidepressants may enhance the arrhythmogenic effect of Dronedarone. Risk X: Avoid combination
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
DULoxetine: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations and effects if these agents are combined. Risk C: Monitor therapy
Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Escitalopram: Tricyclic Antidepressants may enhance the serotonergic effect of Escitalopram. Escitalopram may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk C: Monitor therapy
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Fluconazole: Amitriptyline may enhance the QTc-prolonging effect of Fluconazole. Fluconazole may increase the serum concentration of Amitriptyline. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
FLUoxetine: May enhance the serotonergic effect of Tricyclic Antidepressants. FLUoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk D: Consider therapy modification
Flupentixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
FluvoxaMINE: May enhance the serotonergic effect of Tricyclic Antidepressants. FluvoxaMINE may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk C: Monitor therapy
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
Gepirone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor therapy
Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid combination
Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Guanethidine: Tricyclic Antidepressants may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Haloperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Iloperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Iobenguane Radiopharmaceutical Products: Tricyclic Antidepressants may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid combination
Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Risk C: Monitor therapy
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Landiolol: Tricyclic Antidepressants may enhance the hypotensive effect of Landiolol. Risk C: Monitor therapy
Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination
Linezolid: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: Tricyclic Antidepressants may diminish the therapeutic effect of Lofexidine. Management: Consider avoiding this drug combination when possible. If concurrent administration is required, monitor blood pressure carefully at the beginning of the combined therapy and when either drug is stopped. Adjust the dosage accordingly. Risk D: Consider therapy modification
Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Lorcaserin (Withdrawn From US Market) may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations and effects if these agents are combined. Risk C: Monitor therapy
Loxapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lumateperone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lurasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Methylene Blue: Tricyclic Antidepressants may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Metoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Risk C: Monitor therapy
Molindone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors (Antidepressant): May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Nefazodone: Tricyclic Antidepressants may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Nicorandil: Tricyclic Antidepressants may enhance the hypotensive effect of Nicorandil. Risk C: Monitor therapy
Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Tricyclic Antidepressants may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of major adverse cardiac events (MACE), hemorrhagic stroke, ischemic stroke, and heart failure may be increased. Tricyclic Antidepressants may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
OLANZapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy
Paliperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
PARoxetine: May enhance the serotonergic effect of Tricyclic Antidepressants. PARoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk D: Consider therapy modification
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Periciazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Perphenazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Pimozide: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pimozide. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Pipamperone [INT]: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pipamperone [INT]. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pitolisant: Tricyclic Antidepressants may diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor therapy
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid combination
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid combination
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Promazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QUEtiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Rasagiline: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination
Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination
RifAMPin: May decrease serum concentrations of the active metabolite(s) of Amitriptyline. Specifically, concentrations of nortriptyline may be reduced. RifAMPin may decrease the serum concentration of Amitriptyline. Risk C: Monitor therapy
Rifapentine: May decrease serum concentrations of the active metabolite(s) of Amitriptyline. Specifically, concentrations of nortriptyline may be reduced. Rifapentine may decrease the serum concentration of Amitriptyline. Risk C: Monitor therapy
RisperiDONE: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Rivastigmine: Anticholinergic Agents may diminish the therapeutic effect of Rivastigmine. Rivastigmine may diminish the therapeutic effect of Anticholinergic Agents. Management: Use of rivastigmine with an anticholinergic agent is not recommended unless clinically necessary. If the combination is necessary, monitor for reduced anticholinergic effects. Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Safinamide: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider therapy modification
Selegiline: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination
Serotonergic Agents (High Risk, Miscellaneous): Tricyclic Antidepressants may enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Serotonergic Non-Opioid CNS Depressants: Tricyclic Antidepressants may enhance the CNS depressant effect of Serotonergic Non-Opioid CNS Depressants. Tricyclic Antidepressants may enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and CNS depression when these agents are combined. Risk C: Monitor therapy
Serotonergic Opioids (High Risk): Tricyclic Antidepressants may enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification
Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes when these agents are combined. Risk C: Monitor therapy
Sertindole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Sertraline: May enhance the serotonergic effect of Tricyclic Antidepressants. Sertraline may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk C: Monitor therapy
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy
St John's Wort: May enhance the serotonergic effect of Amitriptyline. This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Amitriptyline. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and reduced amitriptyline concentrations when these agents are combined. Risk C: Monitor therapy
Sulpiride: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sulpiride. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Thioridazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thioridazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Thiothixene: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Thyroid Products: May enhance the arrhythmogenic effect of Tricyclic Antidepressants. Thyroid Products may enhance the stimulatory effect of Tricyclic Antidepressants. Risk C: Monitor therapy
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination
Topiramate: May enhance the CNS depressant effect of Amitriptyline. Topiramate may increase serum concentrations of the active metabolite(s) of Amitriptyline. Topiramate may increase the serum concentration of Amitriptyline. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the anticholinergic effect of other Tricyclic Antidepressants. Tricyclic Antidepressants may enhance the CNS depressant effect of other Tricyclic Antidepressants. Tricyclic Antidepressants may enhance the serotonergic effect of other Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor closely for increased TCA adverse effects, including serotonin syndrome/serotonin toxicity, CNS depression, and anticholinergic effects. Risk C: Monitor therapy
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valproate Products: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy
Vilazodone: Tricyclic Antidepressants may enhance the serotonergic effect of Vilazodone. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Amitriptyline may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Vortioxetine: Tricyclic Antidepressants may enhance the serotonergic effect of Vortioxetine. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy
Ziprasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Tricyclic antidepressants (TCAs) are not preferred for the treatment of depression. However, if a TCA is needed in a patient planning to become pregnant, use of amitriptyline may be considered (Larsen 2015).
Amitriptyline may be effective for prevention of migraines. In general, preventive treatment for migraine in patients trying to become pregnant should be avoided. Options for patients planning a pregnancy should be considered as part of a shared decision-making process. Nonpharmacologic interventions should be considered initially. When needed, preventive treatment should be individualized considering the available safety data and needs of the patient should pregnancy occur. A gradual discontinuation of preventive medications is generally preferred when the decision is made to stop treatment prior to conception (ACOG 2022; AHS [Ailani 2021]).
Amitriptyline crosses the human placenta.
CNS effects, limb deformities, and developmental delay have been noted in case reports (causal relationship not established). Tricyclic antidepressants (TCAs) may be associated with irritability, jitteriness, and convulsions (rare) in the neonate (Yonkers 2009). Increased crying, constipation, problems with urinating, respiratory distress, and nausea may also occur in neonates exposed during pregnancy (ACOG 2022; Larsen 2015).
Untreated or inadequately treated psychiatric illness may lead to poor adherence with prenatal care and adverse pregnancy outcomes. Therapy with antidepressants during pregnancy should be individualized; treatment with antidepressant medication is recommended for pregnant patients with severe major depressive disorder (ACOG 2008; CANMAT [MacQueen 2016]). Patients treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued (68%) as compared to pregnant patients who continue taking antidepressant medications (26%) (Cohen 2006). In general, TCAs are not preferred for the treatment of depression and agents other than amitriptyline are preferred if treatment is initiated for the first time during pregnancy (CANMAT [MacQueen 2016]; Larsen 2015). If pregnancy occurs during amitriptyline therapy, close plasma monitoring is recommended to avoid toxicity (Larsen 2015).
In general, preventive treatment for migraine should be avoided during pregnancy. Options for pregnant patients should be considered as part of a shared decision-making process. Nonpharmacologic interventions should be considered initially. When needed, preventive treatment should be individualized considering the available safety data, the potential for adverse maternal and fetal events, and needs of the patient (ACOG 2022; AHS [Ailani 2021]). Efficacy data of amitriptyline for migraine prevention in pregnancy are limited and use is not recommended (ACOG 2022). Amitriptyline may be used if other agents are ineffective or contraindicated, considering the risks and benefits of use (ACOG 2022; CHS [Pringsheim 2012]).
Patients exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Patients 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.
Amitriptyline and the metabolite nortriptyline are present in breast milk.
Data related to the presence of amitriptyline in breast milk are available from multiple sources (Bader 1980; Breyer-Pfaff 1995; Brixen-Rasmussen 1982; Fortinguerra 2009; Pittard 1986; Yoshida 1997).
• In a review article which included 6 mother/infant pairs, following maternal use of amitriptyline 75 to 175 mg/day, the estimated exposure to the breastfeeding infant was calculated as 0.2% to 1.9% of the weight-adjusted maternal dose (additional detail not provided) (Fortinguerra 2009).
• The relative infant dose (RID) of amitriptyline is reported to be ~1% to 3% (Larsen 2015). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).
• Very small amounts of amitriptyline can be detected in the plasma and urine of breastfeeding infants. Actual milk concentrations of tricyclic antidepressants (TCAs) are generally related to maternal serum concentration and vary by fat content of breast milk; the level of detection varies greatly by assay method (Yoshida 1997).
Most sources have not reported adverse events in infants exposed to amitriptyline via breast milk (Fortinguerra 2009; Larsen 2015; Yoshida 1997). However, in a case report, severe sedation with associated poor feeding was observed in a breastfed infant (~15 days old) following the initiation of amitriptyline 10 mg/day in the mother. Symptoms in the infant decreased within 24 hours and resolved within 48 hours after the maternal dose was discontinued. Once amitriptyline was reinitiated in the mother, symptoms in the infant returned (Uguz 2017).
Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (WFSBP [Bauer 2013]) as well as infant growth and neurodevelopment (ABM [Sriraman 2015]).
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother. The World Health Organization considers amitriptyline to be compatible with breastfeeding in doses ≤150 mg/day (WHO 2002).
Psychotherapy or other nonmedication therapies are recommended for the initial treatment of mild depression in breastfeeding patients; antidepressant medication is recommended when psychotherapy is not an option or symptoms are moderate to severe. When first initiating an antidepressant in a breastfeeding patient, agents other than amitriptyline are preferred (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]; Larsen 2015). A patient already stabilized on a TCA during pregnancy may continue that medication while breastfeeding (ABM [Sriraman 2015]).
In general, preventive treatment for migraine in lactating patients should be avoided. When needed, therapy should be individualized considering the available safety data and needs of the patient (AHS [Ailani 2021]). Amitriptyline may be used if other agents are ineffective or contraindicated (CHS [Pringsheim 2012]).
Serum sodium in at-risk populations (as clinically indicated); mental status and alertness; closely monitor all patients for depression, clinical worsening, suicidality, psychosis, or unusual changes in behavior (such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, and social functioning), particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increased or decreases); heart rate, BP, and ECG in older adults and patients with pre-existing cardiac disease; electrolyte panel (to assess risk of conduction abnormalities); blood glucose; weight and BMI; blood levels are useful for therapeutic monitoring (APA 2010; De Picker 2014). Monitor for signs/symptoms of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, diaphoresis), neuromuscular changes (eg, tremor, rigidity, myoclonus), GI symptoms (eg, nausea, vomiting, diarrhea), and/or seizures.
Timing of serum samples: Draw trough just before next dose (Hiemke 2018); with once daily bedtime dosing draw level 12 to 16 hours after dose (Ziegler 1977).
Therapeutic reference range: Amitriptyline plus nortriptyline 80 to 200 ng/mL (SI: 288.8 to 722 nmol/L).
Laboratory alert level: Amitriptyline plus nortriptyline levels >300 ng/mL (SI: >1,083 nmol/L) (Hiemke 2018).
Increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane pump.
Onset of action: Depression: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).
Absorption: Rapid, well absorbed.
Distribution: Vd: ~18 to 22 L/kg (Schulz 1985).
Protein binding: >90%.
Metabolism: Rapid; hepatic N to demethylation to nortriptyline (active), hydroxy derivatives and conjugated derivatives.
Bioavailability: ~43% to 46% (Schulz 1985).
Half-life elimination: ~13 to 36 hours (Schulz 1985).
Time to peak, serum: ~2 to 5 hours (Schulz 1985).
Excretion: Urine (glucuronide or sulfate conjugate metabolites; little as unchanged drug); Feces (small amounts).
Special Populations: Older adults: May have increased plasma levels (Schulz 1985).
Older adult: May have increased plasma levels and prolonged half-life (Schulz 1985).
Sex: In women over 50 years of age, plasma amitriptyline concentrations were higher than males in the same age group (Preskorn 1985).
Hepatic function impairment: Plasma levels and AUC approximately tripled in a patient with portocaval anastomosis and liver cirrhosis (Hrdina 1985).
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