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Nortriptyline: Drug information

Nortriptyline: Drug information
(For additional information see "Nortriptyline: Patient drug information" and see "Nortriptyline: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Suicidality in children and adolescents:

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 nortriptyline or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared 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. Appropriately monitor patients of all ages who are started on antidepressant therapy and observe them closely for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the health care provider. Nortriptyline is not approved for use in pediatric patients.

Brand Names: US
  • Pamelor
Brand Names: Canada
  • APO-Nortriptyline;
  • Aventyl;
  • TEVA-Nortriptyline [DSC]
Pharmacologic Category
  • Antidepressant, Tricyclic (Secondary Amine)
Dosing: Adult

Note: In patients sensitive to adverse effects, some experts suggest lower starting doses of 10 mg daily and gradual titration (eg, at intervals ≥1 week) unless otherwise specified (Ref).

Cyclic vomiting syndrome, moderate to severe, prevention

Cyclic vomiting syndrome, moderate to severe, prevention (alternative agent) (off-label use):

Note: May be used as an alternative to amitriptyline to minimize adverse effects. Use and dosing established with amitriptyline; nortriptyline doses are equivalent (Ref).

Oral: Initial: 10 to 25 mg once daily at bedtime; may increase daily dose based on response and tolerability in increments of 10 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).

Functional dyspepsia

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). Use and dosing established with amitriptyline; nortriptyline doses are equivalent (Ref).

Oral: Initial: 10 to 25 mg once daily at bedtime; may increase daily 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. 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

Headache, chronic tension-type, prevention (off-label use):

Note: Use and dosing established with amitriptyline; nortriptyline doses are equivalent (Ref).

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 ≥1 week, up to a maximum of 125 mg/day (Ref). May require up to 12 weeks of treatment at a therapeutic dose to adequately assess efficacy. Once effective, continue for at least 3 to 6 months before attempting gradual tapering (Ref)

Irritable bowel syndrome–associated pain and global symptoms

Irritable bowel syndrome–associated pain and global symptoms (off-label use):

Note: Due to their effect on intestinal transit, tricyclic antidepressants should be used cautiously in patients with constipation (Ref).

Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability to a recommended dose of 25 to 75 mg/day (Ref). Some experts recommend 3 to 4 weeks of therapy before increasing the dose (Ref).

Major depressive disorder

Major depressive disorder (unipolar) (alternative agent): Oral: Initial: 25 to 50 mg once daily at bedtime; increase dose based on response and tolerability in 25 to 50 mg increments at intervals ≥1 week up to a usual dose of 50 to 150 mg/day (Ref). To improve tolerability, some experts suggest an initial dose of 25 mg/day at bedtime for most patients; a higher starting dose of 50 mg/day and more rapid titration (eg, every few days) may be considered in closely supervised (eg, hospitalized) settings (Ref). Maximum: 150 mg/day (Ref); however, some patients tolerate and benefit from doses up to 200 mg/day (Ref).

Migraine, prevention

Migraine, prevention (alternative agent) (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 mg increments at intervals of 1 to 2 weeks, up to 100 mg/day (Ref).

Myofascial pain syndrome and related causes of chronic pain including myofascial pelvic pain, nonradicular neck pain, temporomandibular disorders, and vulvodynia

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 every 1 to 2 weeks 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 doses >50 mg/day (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

Neuropathic pain, chronic, including diabetic neuropathy (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 ≥1 week, up to a usual dosage range of 25 to 100 mg once daily at bedtime. Maximum dose: 150 mg/day (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

Postherpetic neuralgia (alternative agent) (off-label use):

Note: May consider for patients who do not tolerate or respond to a gabapentinoid (Ref).

Oral: Initial: 10 to 20 mg once daily at bedtime; may increase daily dose based on response and tolerability in 10 to 20 mg increments at intervals of ≥3 days (typically weekly) to a maximum dose of 150 mg/day (Ref). May require 6 to 12 weeks of therapy (including 2 weeks at maximum tolerated dose) to adequately assess efficacy (Ref).

Smoking cessation

Smoking cessation (alternative agent) (off-label use):

Note: May consider, in conjunction with behavioral support, for patients who do not tolerate first-line agents or who require an adjunct to first-line therapies (Ref). Initiate ≥2 weeks before planned quit date (Ref).

Initial:

Days 1 to 3: Oral: 25 mg once daily at bedtime (Ref).

Days 4 to 7: Oral: 50 mg once daily at bedtime (Ref).

Maintenance (day 8 and later): Oral: 75 mg once daily at bedtime (Ref). Some patients may experience improved tolerability by administering in 2 or 3 divided doses. Further titration up to 125 mg/day may be needed to adequately decrease cravings in some patients (Ref).

Duration: Continue for a total of at least 12 weeks of treatment (Ref). May consider extended maintenance therapy (eg, up to 1 year) based on individualized risk-benefit assessment (Ref).

Discontinuation of therapy: In general, 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 a 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 a monoamine oxidase inhibitor (MAOI). A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between 2 selective serotonin reuptake inhibitors), 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, 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 nortriptyline.

Allow 14 days to elapse between discontinuing nortriptyline 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.

Dosing: Kidney Impairment: Adult

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: No dosage adjustment necessary for any degree of kidney dysfunction (Dawling 1981; Nagler 2012); however, interindividual variability in clearance and half-life is high (Dawling 1981); use with caution.

Hemodialysis, intermittent (thrice weekly): Not dialyzed: No supplemental dose or dosage adjustment necessary (Dawling 1982); however, dialysis patients have demonstrated increased sensitivity to the anticholinergic effects of tricyclic antidepressants (TCAs). Use with caution along with close monitoring for both anticholinergic and QT-prolonging effects (Eyler 2015; Lieberman 1985; expert opinion).

Peritoneal dialysis: Unlikely to be dialyzed (large Vd): No dosage adjustment necessary (expert opinion); however, dialysis patients have demonstrated increased sensitivity to the anticholinergic effects of TCAs. Use with caution along with close monitoring for both anticholinergic and QT-prolonging effects (Eyler 2015; Lieberman 1985; expert opinion).

CRRT: Unlikely to be dialyzed: No dosage adjustment necessary (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be dialyzed: No dosage adjustment necessary (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling. Nortriptyline is metabolized hepatically; 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 (Mauri 2014; Mullish 2014).

Dosing: Pediatric

(For additional information see "Nortriptyline: Pediatric drug information")

Attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD): Limited data available: Note: Should not be used first-line; use should be reserved for cases where other therapies have failed or not tolerated (AACAP [Pliszka 2007]; Dopheide 2005).

Children ≥6 years and Adolescents: Oral: Initial: 0.5 mg/kg/day; may increase by 0.5 mg/kg/day increments at weekly intervals; maximum daily dose: 2 mg/kg/day up to 100 mg/day (AACAP [Pliszka 2007]; Prince 2000; Spencer 1996; Wilens 1993); in one trial, the daily dose was divided twice daily with a dose administered before school and a dose after dinner; reported mean effective dose: 1.8 mg/kg/day (Prince 2000).

Enuresis

Enuresis: Limited data available: Note: Due to the risk of serious side effects (eg, arrhythmias, heart block, seizures), TCAs are considered third line treatment for enuresis; may consider use in patients who have failed all other therapies; high relapse rate when discontinued (Deshpande 2012; Gal 2007). Administer dose 30 minutes before bedtime; usual treatment duration: ≤3 months.

Children ≥6 years and Adolescents: Oral: General dosing: Initial: 10 to 20 mg/day; titrate up to maximum daily dose of 40 mg/day (Gal 2007).

Depression

Depression: Oral: Note: Controlled clinical trials have not shown tricyclic antidepressants to be superior to placebo for the treatment of depression in children and adolescents; not recommended as first line medication; may be beneficial for patient with comorbid conditions (ADHD enuresis) (AACAP [Birmaher 2007]; Dopheide 2006; Wagner 2005).

Children 6 to 12 years: Limited data available: 1 to 3 mg/kg/day in 4 divided doses; maximum daily dose: 150 mg/day (Gal 2007).

Adolescents: 30 to 50 mg/day in 3 to 4 divided doses or as a single daily dose; maximum daily dose: 150 mg/day.

Neuropathic pain

Neuropathic pain: Limited data available: Children and Adolescents: Oral: Usual range: 0.05 to 1 mg/kg/dose at bedtime; begin at the lower end of dosing range and titrate every 3 days to effect; the analgesic effects of TCA's are typically observed at a lower dose compared to TCA doses for depression; maximum daily dose: 3 mg/kg/day or 150 mg/day, whichever is less (APS 2016; Kliegman 2011).

Discontinuation of therapy: Consider planning antidepressant discontinuation for lower-stress times, recognizing non-illness-related factors could cause stress or anxiety and be misattributed to antidepressant discontinuation (Hathaway 2018). 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. 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 (APA 2010; Bauer 2002; Fenske 2009; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

MAO inhibitor recommendations:

Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of nortriptyline.

Allow 14 days to elapse between discontinuing nortriptyline and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Dosing: Kidney Impairment: Pediatric

Not dialyzable. There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Pediatric

Adolescents: Use lower doses and slower titration; individualization of dosage is recommended.

Dosing: Older Adult

Depression: Oral: Initial: 30 to 50 mg/day, given as a single daily dose or in divided doses.

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Pamelor: 10 mg, 25 mg [contains fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]

Pamelor: 50 mg

Pamelor: 75 mg [contains fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]

Generic: 10 mg, 25 mg, 50 mg, 75 mg

Solution, Oral:

Generic: 10 mg/5 mL (473 mL)

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Aventyl: 10 mg, 25 mg

Generic: 10 mg, 25 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088671.pdf, must be dispensed with this medication.

Administration: Pediatric

Oral: May administer without regards to food; in pediatric patients, the timing of doses dependent upon use; for nocturnal enuresis and neuropathic pain, doses administered at bedtime; for ADHD, daily doses may be administered once daily in the morning or some have divided doses twice daily with a morning dose and a dose at dinner.

Use: Labeled Indications

Major depressive disorder, unipolar: Treatment of symptoms of unipolar major depressive disorder.

Use: Off-Label: Adult

Cyclic vomiting syndrome, moderate to severe, prevention; Functional dyspepsia; Headache, chronic tension-type, prevention; 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; Smoking cessation

Medication Safety Issues
Sound-alike/look-alike issues:

Aventyl HCl may be confused with Bentyl

Nortriptyline may be confused with amitriptyline, desipramine, Norpramin

Pamelor may be confused with Demerol, Tambocor [DSC]

Older Adult: High-Risk Medication:

Beers Criteria: Nortriptyline (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 2019]).

Pharmacy Quality Alliance (PQA): Nortriptyline (alone or in combination) is identified as a high-risk medication in patients 65 years and older on the PQA’s Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (Ref).

Adverse Reactions (Significant): Considerations
Anticholinergic effects

Nortriptyline may cause anticholinergic effects, such as constipation, xerostomia, blurred vision, palpitations, tachycardia, and urinary retention (Ref). Drugs with anticholinergic effects may increase the risk of falls in older adults (Ref).

Mechanism: Dose-related; 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).

Risk factors:

• Older age (Ref)

• Higher doses (Ref)

• Concomitant use of drugs with anticholinergic properties (Ref)

• Specific tricyclic antidepressants: Nortriptyline is considered to display modest to moderate anticholinergic activity at typical doses compared to agents with high anticholinergic effects, such as amitriptyline (Ref)

Cardiac conduction abnormalities

Tricyclic antidepressants (TCAs), including nortriptyline, are associated with cardiotoxicity, particularly at supratherapeutic doses. At therapeutic doses, TCAs can cause slowing of intraventricular conduction, manifested by prolonged PR, QRS, and QT intervals on ECG in children, adolescents, and adults (Ref). Sinus tachycardia and potentially life-threatening ventricular arrhythmias, or heart block leading to sudden cardiac death are associated with supratherapeutic doses or therapeutic doses in select patients with severe heart disease or preexisting conduction disorders (eg, Brugada syndrome or bundle branch block, long QT syndrome) (Ref).

Mechanism: Dose-related (some mechanisms); at therapeutic doses, TCAs inhibit sodium channel conduction, potentially delaying cardiac depolarization and causing prolongation of the QRS complex on ECG. Multiple other mechanisms contribute to the cardiac effects associated with TCAs, including inhibition of central cholinergic neurotransmission (potentially causing tachycardia), norepinephrine reuptake inhibition (potentially exacerbating tachycardia), and blockade of alpha-adrenergic receptors (potentially lowering systemic vascular resistance and causing hypotension or orthostatic hypotension). In addition, high doses increase sympathetic and decrease parasympathetic effects on heart rate (Ref). Sinus tachycardia is attributed to the inhibition of norepinephrine and nortriptyline's anticholinergic action (Ref).

Risk factors:

• Increased age (Ref)

• Females (Ref)

• Hypokalemia (Ref)

• Coronary artery disease (Ref)

• Coadministration of drugs independently associated with QT interval prolongation or further increase risk of arrhythmia (nortriptyline shares electrophysiologic properties of type IA antiarrhythmics such as quinidine, procainamide, and disopyramide) (Ref)

• Preexisting conduction disease, particularly bundle branch block or Brugada syndrome, or family history of congenital long QT syndrome (Ref). Note: Use is relatively contraindicated in patients with conduction abnormalities.

• Higher doses, particularly in children (Ref)

CNS depression

Tricyclic antidepressants (TCAs), including nortriptyline, may cause dose-dependent CNS depression, including dizziness, drowsiness, ataxia, cognitive dysfunction (particularly in older adults), confusion, disorientation, fatigue, and psychomotor impairment (Ref).

Mechanism: Dose-related; drowsiness and psychomotor effects are due to anticholinergic and antihistaminergic properties of TCAs, with varying degrees of effects depending on the specific agent. TCAs also produce alpha-adrenergic blockade which can contribute to sedation and dizziness (from orthostatic hypotension) (Ref).

Onset: Varied; difficult to define; some symptoms may occur with first dose.

Risk factors (TCAs in general):

• Concomitant alcohol

• Concomitant CNS depressants (eg, anticholinergics, antihistamines) (Ref)

• Females (Ref)

• Older adults (Ref)

• Increased TCA plasma levels (Ref)

• Specific TCA: Nortriptyline is associated with a low propensity for causing sedation relative to TCAs associated with high levels of sedation, such as amitriptyline (Ref). Nortriptyline is associated with a modest to moderate propensity for producing anticholinergic effects (Ref)

Fractures

Antidepressants have been associated with an increased risk of falls and bone fractures in observational studies (Ref). Tricyclic antidepressants (TCAs) have also been associated with an increased fracture risk; however, risk varies by agent and the evidence is conflicting, particularly with nortriptyline (Ref).

Mechanism: Not fully elucidated; per selective serotonin reuptake inhibitor-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). Of note, nortriptyline is associated with low 5-HT (serotonin) transporter inhibition compared to its effect on norepinephrine inhibition (Ref). Fall risk with TCAs may also be attributed to sedation, syncope, orthostatic hypotension, and/or confusion (Ref).

Onset: Intermediate; observational studies suggest the increased fracture risk observed with TCAs occurs early and reaches a peak within 1 month of initiation of therapy (Ref)

Risk factors (TCAs in general):

• Concomitant use with other agents that may further affect physical balance and contribute to falls (eg, anxiolytics) (Ref)

Hyponatremia

Tricyclic antidepressants (TCAs), including nortriptyline, 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 antidepressant 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)

Severe physical illness (Ref)

Lower baseline serum sodium concentration (selective serotonin reuptake inhibitor [SSRI]–derived literature) (Ref)

Volume depletion (potential risk factor; SSRI-derived literature) (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 SSRIs (Ref)

Ocular effects

Tricyclic antidepressants (TCAs) may cause mydriasis (pupillary dilation) and cycloplegia (affected eyes cannot focus on nearby objects), resulting in transient accommodation disturbances and blurred vision (Ref). Mydriasis and cycloplegia usually improve over time as patients develop a tolerance to these effects (Ref). In susceptible individuals, TCA-induced mydriasis may result in the exacerbation of chronic angle-closure glaucoma and/or induction of acute angle-closure glaucoma (AACG). 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: Mydriasis and cycloplegia are likely due to the anticholinergic effect of TCAs (Ref). TCA-induced effects on norepinephrine and serotonin receptors in the iris and ciliary body of the eye, as well as alpha-adrenergic receptors may also play a role (Ref). In susceptible individuals, mydriasis can lead to AACG, which is caused by the physical obstruction of the outflow of intraocular fluid.

Onset: Blurred vision occurs in the initial stages of treatment with a TCA (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)

Narrow-angle glaucoma (avoid or use with extreme caution in these patients) (Ref)

Specific tricyclic antidepressants: Nortriptyline is considered to display modest to moderate anticholinergic activity at typical doses (Ref)

Orthostatic hypotension

Tricyclic antidepressants (TCAs), including nortriptyline, may cause orthostatic hypotension, which may lead to syncope and subsequent falls, particularly in older adults (Ref).

Mechanism: Alpha-adrenergic receptor blockade may lower systemic vascular resistance and result in hypotension, including orthostatic hypotension (Ref).

Onset: In a small study of older adults ≥55 years of age treated with nortriptyline (mean dose: 79 mg/day), orthostatic hypotension appeared during the first week and generally persisted throughout the 7-week study period (Ref).

Risk factors:

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: Nortriptyline is associated with a lower risk of significant orthostatic hypotension compared to other TCAs (Ref)

Serotonin syndrome

Serotonin syndrome has been reported and typically occurs with coadministration of multiple drugs with serotonin activity (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, hypertension, mydriasis, diaphoresis, 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:

• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism (eg, monoamine oxidase inhibitors [MAOIs]). Of note, concomitant use of some serotonergic agents, such as MAOIs, is contraindicated.

Suicidal thinking and behavior

Antidepressants have been 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, per product labeling. In adults >24 years of age, 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, some evidence shows a trend of an elevated risk of suicidality in younger age groups with certain antidepressants (Ref). Additionally, an observational study suggested an association with decreased rate of antidepressant prescribing and an increase in suicide rates in children and adolescents after the labeling was updated with the warnings (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 (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

Withdrawal syndrome has been reported in children and adults, primarily following abrupt discontinuation of tricyclic antidepressants (TCAs). Common symptoms include somatic symptoms (eg, lethargy, headache, tremor, sweating, anorexia); affective symptoms (eg, irritability, anxiety, agitation, low mood); sleep disorders (insomnia, excessive dreaming); and gastrointestinal disturbances (eg, nausea/vomiting, abdominal pain, anorexia). Rarely, movement disorders, such as akathisia or parkinsonism, hypomania/mania, psychosis, and/or cardiac arrhythmias may also occur. Of note, sensory abnormalities (eg, shock-like sensations, numbness), which are commonly reported with selective serotonin reuptake inhibitor withdrawal, are rarely seen with TCA withdrawal. 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). TCA-associated withdrawal symptoms may also be related in part to an adaptive hypersensitivity of muscarinic cholinergic receptors called cholinergic rebound or cholinergic overdrive and to involve noradrenergic mechanisms (Ref).

Onset: Symptoms generally appear within a few days of stopping or reducing the dosage of the antidepressant. Onset >1 week later is unusual (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)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Some reactions listed are based on reports for other agents in this same pharmacologic class and may not be specifically reported for nortriptyline.

<1%: Gastrointestinal: Sublingual adenitis

Frequency not defined:

Cardiovascular: Acute myocardial infarction, cardiac arrhythmia (Bardai 2013), cerebrovascular accident, edema, flushing, heart block, hypertension, hypotension, orthostatic hypotension (Chandra 2006), palpitations, tachycardia

Dermatologic: Alopecia, diaphoresis (excessive), pruritus, skin photosensitivity, skin rash, urticaria

Endocrine & metabolic: Decreased libido, galactorrhea not associated with childbirth, gynecomastia, increased libido, increased serum glucose, SIADH, weight gain, weight loss

Gastrointestinal: Abdominal cramps, anorexia, constipation, diarrhea, epigastric discomfort, melanoglossia, nausea, paralytic ileus, parotid gland enlargement, stomatitis, unpleasant taste, vomiting, xerostomia

Genitourinary: Breast hypertrophy, impotence, nocturia, testicular swelling, urinary frequency, urinary hesitancy, urinary retention, urinary tract dilation

Hematologic & oncologic: Agranulocytosis, bone marrow depression, eosinophilia, petechia, purpuric disease, thrombocytopenia

Hepatic: Abnormal liver function, cholestatic jaundice

Hypersensitivity: Drug-induced hypersensitivity reaction (tricyclic class)

Nervous system: Agitation, anxiety, ataxia, confusion, delusion, disorientation, dizziness, drowsiness, drug fever, EEG pattern changes, exacerbation of depression, extrapyramidal reaction, fatigue, hallucination, headache, hypomania, insomnia, nightmares, numbness, panic, peripheral neuropathy, restlessness, seizure, tingling of extremities, tingling sensation, withdrawal syndrome (Geller 1987)

Neuromuscular & skeletal: Asthenia, tremor

Ophthalmic: Accommodation disturbance, blurred vision, mydriasis

Otic: Tinnitus

Renal: Polyuria

Postmarketing:

Cardiovascular: Cardiac conduction disorder (Brugada syndrome exacerbation) (Alampay 2014), prolonged QT interval on ECG (Funai 2014), sinus tachycardia (Wilens 2006), widened QRS complex on ECG (Bardai 2013)

Dermatologic: Pityriasis rosea (pityriasis rosea-like drug eruption) (Bangash 2013)

Nervous system: Cognitive dysfunction (Hoff 1990, Knegtering 1994), psychomotor impairment (Khade 2010), psychosis (including exacerbation of and associated with withdrawal syndrome) (Patterson 1984), serotonin syndrome (Hinds 2000), suicidal ideation, suicidal tendencies

Ophthalmic: Angle-closure glaucoma

Contraindications

Hypersensitivity to nortriptyline and similar chemical class dibenzazepines, or any component of the formulation; use in a patient during the acute recovery phase of myocardial infarction; use of monoamine oxidase (MAO) inhibitors (concurrently or within 14 days of discontinuing either nortriptyline or the MAO inhibitor); initiation of nortriptyline in a patient receiving linezolid or IV methylene blue.

Warnings/Precautions

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia).

• Diabetes: Use with caution in patients with diabetes mellitus; a causal relationship of tricyclic antidepressants with poor glycemic control has not been established, although some evidence of association exists. In addition, depression may reduce adherence to diabetic therapies (APA 2010).

• 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 of TCAs is decreased. Due to the narrow therapeutic index, use lower initial and maintenance doses of TCAs. 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 may be effective for acute treatment of bipolar major depressive episodes, but should 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. Nortriptyline is not FDA approved for the treatment of bipolar depression.

• Ophthalmic conditions: Use with caution in patients with certain ophthalmic conditions as anticholinergic effects may exacerbate underlying condition.

• Renal impairment: Use with caution in patients with renal impairment.

• Seizure disorder: Use with caution in patients with a history of seizures.

• Urinary retention (eg, benign prostatic hyperplasia): Use with caution in patients with urinary retention as anticholinergic effects may exacerbate underlying condition.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

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.

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2D6 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

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

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

Antipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Antipsychotic Agents: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Antipsychotic Agents. 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

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

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

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

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

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

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

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 the serum concentration of Nortriptyline. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Nortriptyline. 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: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. 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

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

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

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

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

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

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

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

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

MetyroSINE: May enhance the adverse/toxic effect of Tricyclic Antidepressants. 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

Monoamine Oxidase Inhibitors (Antidepressant): May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. 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

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

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

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

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. 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

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

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 the serum concentration of Nortriptyline. Risk C: Monitor therapy

Rifapentine: May decrease the serum concentration of Nortriptyline. Risk C: Monitor therapy

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

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 Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). 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

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

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

Tobacco (Smoked): May decrease the serum concentration of Nortriptyline. Risk C: Monitor therapy

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. 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

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

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

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

Pregnancy Considerations

Nortriptyline and its metabolites cross the human placenta and can be detected in cord blood (Loughhead 2006). Tricyclic antidepressants may be associated with irritability, jitteriness, and convulsions (rare) in the neonate (Yonkers 2009).

The ACOG recommends that therapy for depression during pregnancy be individualized; treatment should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician (ACOG 2008). According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For patients who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery (APA 2010). Treatment algorithms have been developed by the ACOG and the APA for the management of depression in patients prior to conception and during pregnancy (Yonkers 2009).

Pregnant 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.

Breastfeeding Considerations

Nortriptyline is present in breast milk.

The relative infant dose (RID) of nortriptyline is 3.4% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 125 mg/day.

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).

The RID of nortriptyline was calculated using a milk concentration of 0.404 mcg/mL, providing an estimated daily infant dose via breast milk of 60.6 mcg/kg/day. This milk concentration was obtained following maternal administration of nortriptyline 125 mg daily, starting at delivery, and sampling occurred 6 days postpartum (Matheson 1988). It should be noted that actual milk concentrations of tricyclic antidepressants 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).

The majority of available studies have measured infant serum concentrations rather than breast milk concentrations of nortriptyline. Nortriptyline and the E-10-hydroxynortriptyline and Z-10-hydroxynortriptyline metabolites have been detected in the serum of some infants exposed to nortriptyline via breast milk. Adverse events have not been observed (Lanza di Scalea 2009; Weissman 2004).

Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (Bauer 2013), as well as infant growth and neurodevelopment (Sriraman 2015).

Tricyclic antidepressants are not the preferred therapy for depression (Larsen 2015). However, when a TCA is needed, nortriptyline is one of the agents with the most available information in breastfeeding women (Gjerdingen 2003; Lanza di Scalea 2009). A patient already stabilized on a TCA during pregnancy may continue that medication while breastfeeding (Sriraman 2015). Due to pregnancy-induced pharmacokinetic changes, the clearance of nortriptyline may be altered; maternal serum concentrations should be monitored closely immediately postpartum to prevent toxicity (Wisner 1997).

Monitoring Parameters

Serum sodium in at-risk populations (as clinically indicated), blood pressure, heart pulse rate and ECG in older adults and patients with preexisting cardiac disease; blood glucose; weight and BMI; therapeutic blood levels (as clinically indicated); mental 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, and mania), particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increased or decreases). 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.

Reference Range

Timing of serum samples: Draw trough just before next dose.

Therapeutic reference range: 70 to 170 ng/mL (SI: 266 to 646 nmol/L)

Laboratory alert level: 300 ng/mL (SI: 1,140 nmol/L) (Hiemke 2018)

Mechanism of Action

Traditionally believed to increase the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane. Inhibits the activity of histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine. However, additional receptor effects have been found including desensitization of adenyl cyclase, down regulation of beta-adrenergic receptors, and down regulation of serotonin receptors.

Pharmacokinetics

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: Oral: Rapid (Alexanderson 1972)

Distribution: Vd: 21.1 to 31.1 L/kg (Alexanderson 1972)

Protein binding: Extensively bound to plasma proteins (Alexanderson 1972)

Metabolism: Primarily hepatic; extensive first-pass effect (Rubin 1985)

Bioavailability: 46% to 70% (Rubin 1985)

Half-life elimination:

Adults: 14 to 51 hours (mean: 26 hours) (Dawling 1980)

Elderly: 23.5 to 79 hours (mean 45 hours) (Dawling 1980)

Time to peak, serum: 4 to 9 hours (Alexanderson 1972)

Excretion: Urine (as metabolites and small amounts of unchanged drug) (Alexanderson 1972)

Pricing: US

Capsules (Nortriptyline HCl Oral)

10 mg (per each): $0.73 - $0.74

25 mg (per each): $1.47

50 mg (per each): $2.77

75 mg (per each): $4.22

Capsules (Pamelor Oral)

10 mg (per each): $47.15

25 mg (per each): $48.10

50 mg (per each): $49.04

75 mg (per each): $49.98

Solution (Nortriptyline HCl Oral)

10 mg/5 mL (per mL): $0.48

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.

Brand Names: International
  • Allegron (AU, GB, IE);
  • Altilev (UY);
  • Ateben (AR);
  • Avelin (BD);
  • Aventyl (MY);
  • N-Trip (TH);
  • Norfenazin (ES);
  • Noritren (DK, EE, FI, IS, IT, LT, NO);
  • Norline (TH);
  • Norpress (NZ);
  • Norterol (PT);
  • Nortilin (BD);
  • Nortip (BD);
  • Nortrilen (AE, AT, BE, BF, BH, BJ, CH, CI, CY, CZ, DE, EG, ET, GH, GM, GN, GR, HK, ID, IQ, IR, JO, KE, LB, LR, LU, LY, MA, ML, MR, MT, MU, MW, NE, NG, NL, OM, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZA, ZM, ZW);
  • Nortrilin (PK);
  • Nortrip (BR);
  • Nortyl (BD);
  • Nortylin (IL);
  • Nortyline (TH);
  • NotriTABS (AU);
  • Ortrip (TH);
  • Pamelor (BR);
  • Paxtibi (ES);
  • Qualinortin (HK);
  • Sensaval (SE);
  • Sensival (IN, KR);
  • Vividyl (IT)


For country code abbreviations (show table)
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