Amitriptyline

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as hydrochloride:

Elavil: 25 mg [DSC] [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake]

Generic: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid, well absorbed

Distribution

V_d: ~18 to 22 L/kg (Schulz 1985)

Metabolism

Rapid; hepatic N-demethylation to nortriptyline (active), hydroxy derivatives and conjugated derivatives

Excretion

Urine (glucuronide or sulfate conjugate metabolites; 18% as unchanged drug); Feces (small amounts)

Onset of Action

Individual responses may vary, however 4 to 8 weeks of treatment are needed before determining if a patient with depression is partially or non-responsive; similarly 8 to 12 weeks are required for an adequate migraine prophylaxis trial (APA 2010; Prinsheim 2012); desired therapeutic effect (for analgesia) may take as long as 1 to 3 weeks.

Time to Peak

Serum: ~2 to 5 hours (Schulz 1985)

Half-Life Elimination

~13 to 36 hours (Schulz 1985)

Protein Binding

>90%

Use in Specific Populations

Special Populations: Elderly

May have increased plasma levels and prolonged half-life (Schulz 1985)

Use: Labeled Indications

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder

Use: Off Label

Chronic fatigue syndrome related sleep disturbances and painyes

Based on the NICE guidelines for chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy), amitriptyline is suggested for patients with chronic fatigue syndrome and poor sleep. In addition, based on the Health Canada myalgic encephalomyelitis/chronic fatigue syndrome diagnostic and treatment protocol, amitriptyline is also suggested for chronic fatigue syndrome related pain Carruthers 2003.

Fibromyalgiabyes

Data from network meta-analyses support the use of amitriptyline for improving pain, fatigue, and sleep disturbances in fibromyalgia Hauser 2012, Hauser 2009.

Based on

Functional dyspepsiacyes

Data from a limited number of clinical trials suggest that amitriptyline may be beneficial for the reduction of functional dyspepsia symptoms, particularly in patients with ulcer-like functional dyspepsia Braak 2011, Talley 2015.

Based on the American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) guidelines for the management of dyspepsia, the use of amitriptyline is suggested when dyspepsia symptoms have not responded to proton pump inhibitor therapy or H. pylori eradication therapy in patients <60 years of age or in patients with functional dyspepsia.

Headache, chronic tension-type (prevention)cyes

Data from a limited number of patients studied suggest that amitriptyline may be beneficial for decreasing headache duration and frequency when used for prevention of chronic tension-type headache Bendtsen 1996.

Based on the European Federation of Neurological Societies (EFNS) guidelines for the treatment of tension-type headache, amitriptyline is recommended first-line for the prevention of chronic tension-type headache.

Interstitial cystitis (bladder pain syndrome)byes

Data from 2 double-blind, placebo-controlled studies support the use of amitriptyline in the treatment of interstitial cystitis (bladder pain syndrome) Foster 2010, van Ophoven 2004.

Irritable bowel syndromecyes

Data from a limited number of patients studied suggest that amitriptyline may be beneficial for the treatment of irritable bowel syndrome (IBS) Rajagopalan 1998, Vahedi 2008.

Migraine (prevention)byes

Data from a number of randomized, active-controlled, open-label and blinded studies evaluating the use of amitriptyline (alone or in combination with other agents [eg, topiramate]) support the use of amitriptyline for the prevention of migraine in adult patients Bulut 2004, Dodick 2009, Kalita 2013, Keskinbora 2008.

Based on the American Academy of Neurology and American Headache Society guideline on the pharmacologic treatment for episodic migraine prevention in adults and the EFNS guideline on the drug treatment of migraine, the use of amitriptyline is probably effective and recommended for migraine prophylaxis and may be considered as a therapeutic alternative.

Neuropathic pain, chronic (including diabetic neuropathy)byes

Data from several randomized, double-blind, placebo-controlled trials in patients with chronic pain treated with low-dose amitriptyline support the use of amitriptyline for the treatment of this condition; however, study populations included patients with neuropathic pain as well as nonspecified pain McQuay 1992, Pilowsky 1982, Zitman 1990. Data from a limited number of clinical trials focused on chronic neuropathic pain and diabetic neuropathy suggest that amitriptyline may be beneficial for the treatment of these conditions Boyle 2012, Kalso 1996, Kaur 2011, Max 1992, Mishra 2012, Vrethem 1997.

Based on the

Postherpetic neuralgiacyes

Data from multiple randomized, double-blind, placebo- and active-controlled studies support the use of amitriptyline for reducing pain in patients with postherpetic neuralgia Graff-Radford 2000, Max 1988, Rowbotham 2005, Watson 1982, Watson 1992, Watson 1998.

Based on the

Sialorrheacyes

No formal studies have evaluated use of amitriptyline for management of sialorrhea in adults. Published data are limited to case reports of clozapine-induced sialorrhea Praharaj 2007, Sinha 2016.

Contraindications

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

Canadian labeling: Additional contraindications (not in the US labeling): Severe liver impairment; acute heart failure

Documentation of allergenic cross-reactivity for tricyclic antidepressants is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Note: In patients sensitive to adverse effects, some experts suggest lower starting doses of 10 mg daily and gradual titration in steps of 10 mg/day every few days or longer (eg, at intervals ≥1 week) unless otherwise specified (Hirsch 2019b).

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 (Carruthers 2003; Gluckman 2019).

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 (Carette 1994; EULAR [Macfarlane 2017]; Goldenberg 2018). 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 (Goldenberg 2018).

Functional dyspepsia (alternative agent) (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability at intervals of ≥2 weeks up to 75 mg/day (Braak 2011; Longstreth 2018; Talley 2015). Some experts suggest a lower maintenance dose range of 20 to 30 mg/day. Allow for an 8- to 12-week trial before discontinuing due to ineffectiveness. If amitriptyline is effective, reassess at 6 months with an attempt to discontinue treatment; may resume if dyspepsia recurs (Longstreth 2018).

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 (Bendtsen 1996; EFNS [Bendtsen 2010]; Taylor 2018). 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 (Taylor 2018).

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 (AUA [Hanno 2014]; Foster 2010; van Ophoven 2004). A maximum dose of up to 75 mg/day as tolerated is suggested by some experts (Clemens 2018).

Irritable bowel syndrome (alternative agent) (off-label use): Oral: Initial: 10 to 25 mg once daily at bedtime; may gradually increase dose based on response and tolerability up to 75 mg/day (Rajagopalan 1998; Vahedi 2008). Some experts recommend 3 to 4 weeks of therapy before increasing the dose (Wald 2018).

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 (Hirsch 2019b; VA/DoD 2016; WFSBP [Bauer 2013]). 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 (Hirsch 2019b).

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): 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 (Dodick 2009; EFNS [Evers 2009]; Keskinbora 2008). Some experts suggest that a lower maintenance dose range of 20 to 50 mg once daily at bedtime is often adequate and better tolerated (Bajwa 2018).

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 150 mg/day given once daily at bedtime or in 2 divided doses (Boyle 2012; Bryson 1996; Moulin 2007).

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 (Graff-Radford 2000; Max 1988; Rowbotham 2005; Watson 1982; Watson 1992; Watson 1998).

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 (EFNS [Andersen 2012]; Praharaj 2007; Sinha 2016, Squires 2012).

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 (APA 2010; WFSBP [Bauer 2015]). Reasons for a slower titration (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 (APA 2010; Hirsch 2019a). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (WFSBP [Bauer 2015]). Evidence supporting ideal taper rates is limited (Shelton 2001; WFSBP [Bauer 2015]).

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 (WFSBP [Bauer 2013]; Hirsch 2019c; Ogle 2013).

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.

Dosing: Geriatric

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 (Hirsch 2019b; VA/DoD 2016; WFSBP [Bauer 2013]). A more rapid titration (eg, every few days) may be considered in closely supervised (eg, hospitalized) settings according to some experts (Hirsch 2019b).

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 (Graff-Radford 2000; Max 1988; Rowbotham 2005; Watson 1982; Watson 1992; Watson 1998).

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants:Refer to adult dosing.

Dosing: Pediatric

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 (APS 2008; Freidrichsdorf 2007; Kliegman 2011)

Depressive disorders: 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 patients with comorbid conditions (AACAP [Birmaher 2007]; Dopheide 2006; Wagner 2005)

Children 9 to <12 years: Limited data available: Oral: Initial: 1 mg/kg/day in 3 divided doses; after 3 days, dose may be increased to 1.5 mg/kg/day in 3 divided doses (Kashani 1984; Kliegman 2007); dosing was reported in a small pilot study (n=9) (Kashani 1984)

Children ≥12 years and Adolescents:

Manufacturer's labeling: Usual initial dosage: 10 mg three times daily and 20 mg at bedtime. In general, lower doses are recommended compared to adults; maximum daily dose: 200 mg/day (Kliegman 2007)

Alternate dosing: Usual range: 30 to 100 mg at bedtime or in divided doses twice daily; maximum daily dose: 200 mg/day (Kliegman 2007; Nelson 1996). In adults, therapy is initiated with 25 to 50 mg daily single dose at bedtime or in divided doses (APA 2010; Bauer 2013).

Migraine prophylaxis: Limited data available (Hershey 2000; Lewis 2004): Older children and Adolescents: Oral: Initial: 0.25 mg/kg/day, given at bedtime; increase dose by 0.25 mg/kg/day every 2 weeks to 1 mg/kg/day. Reported dosing range: 0.2 to 1.7 mg/kg/day (Hershey 2000). Dosing based on a large open-label trial in 192 children (mean age 12 ± 3 years) with >3 headaches/month (61% with migraine, 8% with migraine with aura, and 10% with tension-type headaches) used an initial dose of 0.25 mg/kg/day given before bedtime; doses were increased every 2 weeks by 0.25 mg/kg/day to a final dose of 1 mg/kg/day; patients also used appropriate abortive medications and lifestyle adjustments; at initial reevaluation (mean: 67 days after initiation of therapy), the mean number of headaches per month significantly decreased from 17.1 to 9.2; the mean duration of headaches decreased from 11.5 to 6.3 hours; continued improvement was observed at follow-up visits; minimal adverse effects were reported. Note: Mean final dose was 0.99 ± 0.23 mg/kg; range: 0.16-1.7 mg/kg/day; ECGs were obtained on children receiving >1 mg/kg/day or in those describing a cardiac side effect (Hershey 2000).

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).

Monoamine oxidase (MAO) inhibitor recommendations:

Switching to or from an MAO inhibitor antidepressant:

Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat depression and initiation of amitriptyline.

Allow 14 days to elapse between discontinuing amitriptyline and initiation of an MAO inhibitor intended to treat depression.

Administration

Oral: Administer higher doses preferably at late afternoon or as bedtime doses to minimize daytime sedation.

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. 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. 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. 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. 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. 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. Exceptions: Apraclonidine; Brimonidine (Ophthalmic); Lofexidine. Consider therapy modification

Alpha2-Agonists (Ophthalmic): Tricyclic Antidepressants may diminish the therapeutic effect of Alpha2-Agonists (Ophthalmic). Monitor therapy

Altretamine: May enhance the orthostatic hypotensive effect of Tricyclic Antidepressants. Monitor therapy

Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. 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. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. 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. Exceptions: Alosetron; Ondansetron; Ramosetron. 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. Monitor therapy

Aspirin: Tricyclic Antidepressants (Tertiary Amine) may enhance the antiplatelet effect of Aspirin. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Consider therapy modification

Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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. Monitor therapy

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Tricyclic Antidepressants. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. 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. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Cimetidine: May decrease the metabolism of Tricyclic Antidepressants. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

Cinacalcet: May increase the serum concentration of Tricyclic Antidepressants. Management: Seek alternatives when possible. If these combinations are used, monitor closely for increased effects/toxicity and/or elevated serum concentrations (when testing is available) of the tricyclic antidepressant. Consider therapy modification

Cisapride: Amitriptyline may enhance the arrhythmogenic effect of Cisapride. 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. Monitor therapy

CloBAZam: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Cocaine (Topical): May enhance the adverse/toxic effect of Tricyclic Antidepressants. 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. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Consider therapy modification

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. Avoid combination

Darunavir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Desmopressin: Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

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. 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. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. 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. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Dronedarone: Tricyclic Antidepressants may enhance the arrhythmogenic effect of Dronedarone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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. 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. Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. 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. Exceptions: Nicergoline. 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. Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Fexinidazole [INT]: Tricyclic Antidepressants may enhance the QTc-prolonging effect of Fexinidazole [INT]. Avoid combination

Fluconazole: Amitriptyline may enhance the QTc-prolonging effect of Fluconazole. Fluconazole may increase the serum concentration of Amitriptyline. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. 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. 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. Monitor therapy

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Guanethidine: Tricyclic Antidepressants may diminish the therapeutic effect of Guanethidine. Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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. 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 anticonvulsants. 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 anticonvulsants. 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 anticonvulsants. Consider therapy modification

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. 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. 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. Consider therapy modification

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Linezolid: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Avoid combination

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. Consider therapy modification

Lorcaserin: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Lorcaserin 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. Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. 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. 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 adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylene Blue: Tricyclic Antidepressants may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Metoclopramide: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with tricyclic antidepressants for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

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

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

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

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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. Monitor therapy

Nicorandil: Tricyclic Antidepressants may enhance the hypotensive effect of Nicorandil. 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. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Tricyclic Antidepressants (Tertiary Amine) may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Nonselective): Tricyclic Antidepressants (Tertiary Amine) may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Monitor therapy

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. 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. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. 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. Monitor therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

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. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. 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. 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). Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pitolisant: Tricyclic Antidepressants may diminish the therapeutic effect of Pitolisant. 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. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Protease Inhibitors: May increase the serum concentration of Tricyclic Antidepressants. 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. Monitor therapy

QuiNIDine: Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may increase the serum concentration of Tricyclic Antidepressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

QuiNINE: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. 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. Monitor therapy

Rasagiline: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Avoid combination

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Avoid combination

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Safinamide: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. 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. Consider therapy modification

Selegiline: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. 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. 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. 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. 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. Exceptions: Almotriptan; Eletriptan. 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. Exceptions: DULoxetine. 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. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Sodium Phosphates: Tricyclic Antidepressants may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure and/or loss of consciousness may be increased in patients with significant sodium phosphate induced fluid/electrolyte abnormalities. 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. Monitor therapy

Sulfonylureas: Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas. 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. 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. Monitor therapy

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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. Consider therapy modification

Terbinafine (Systemic): May increase the serum concentration of Amitriptyline. Management: Monitor for increased effects/toxicity of amitriptyline during concomitant administration with terbinafine. Reduced dosages of amitriptyline may be needed. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thyroid Products: May enhance the arrhythmogenic effect of Tricyclic Antidepressants. Thyroid Products may enhance the stimulatory effect of Tricyclic Antidepressants. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. 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. 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. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Valproate Products: May increase the serum concentration of Tricyclic Antidepressants. 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. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists. 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. Monitor therapy

Yohimbine: Tricyclic Antidepressants may increase the serum concentration of Yohimbine. 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. Consider therapy modification

Adverse Reactions

Anticholinergic effects may be pronounced; moderate to marked sedation can occur (tolerance to these effects usually occurs).

Frequency not defined.

Cardiovascular: Atrioventricular conduction disturbance, cardiac arrhythmia, cardiomyopathy (rare), cerebrovascular accident, ECG changes (nonspecific), edema, facial edema, heart block, hypertension, myocardial infarction, orthostatic hypotension, palpitations, syncope, tachycardia

Central nervous system: Anxiety, ataxia, cognitive dysfunction, coma, confusion, delusions, disorientation, dizziness, drowsiness, drug withdrawal (nausea, headache, malaise, irritability, restlessness, dream and sleep disturbance, mania [rare], and hypomania [rare]), 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, sedation, seizure, tingling of extremities

Dermatologic: Allergic skin rash, alopecia, diaphoresis, skin photosensitivity, urticaria

Endocrine & metabolic: Altered serum glucose, decreased libido, galactorrhea, gynecomastia, increased libido, SIADH, weight gain, weight loss

Gastrointestinal: Ageusia, anorexia, constipation, diarrhea, 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: Bone marrow depression (including agranulocytosis, leukopenia, and thrombocytopenia), eosinophilia, purpura

Hepatic: Hepatic failure, hepatitis (rare; including altered liver function and jaundice)

Hypersensitivity: Tongue edema

Neuromuscular & skeletal: Lupus-like syndrome, tremor, weakness

Ophthalmic: Accommodation disturbance, blurred vision, increased intraocular pressure, mydriasis

Otic: Tinnitus

Postmarketing and/or case reports: Angle-closure glaucoma, neuroleptic malignant syndrome (rare; Stevens, 2008), serotonin syndrome (rare)

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Amitriptyline is not FDA-approved for use in children.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse effects:

• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, increased intraocular pressure (IOP), narrow-angle glaucoma, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is high relative to other antidepressants.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).
• Hematologic effects: TCAs may rarely cause bone marrow suppression; monitor for any signs of infection and obtain CBC if symptoms (eg, fever, sore throat) evident.
• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.
• Orthostatic hypotension: May cause orthostatic hypotension (risk is very high relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia). Therapy is relatively contraindicated in patients with symptomatic hypotension.
• Syndrome of inappropriate antidiuretic hormone secretion and hyponatremia: Antidepressant agents have been associated with the development of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia, predominately in the elderly. Other risk factors include volume depletion, concurrent use of diuretics, female gender, low body weight, and severe physical illness. TCAs have a lower risk for hyponatremia in comparison to SSRIs (De Picker 2014).

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk of conduction abnormalities with this agent is high relative to other antidepressants. Heart block may be precipitated in patients with preexisting conduction system disease and use is relatively contraindicated in patients with conduction abnormalities. In a scientific statement from the American Heart Association, amitriptyline has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: moderate) (AHA [Page 2016]).
• Diabetes: Use with caution in patients with diabetes mellitus; may alter glucose regulation.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Patients presenting with depressive symptoms should be screened for bipolar disorder, including details regarding family history of suicide, bipolar disorder, and depression. Amitriptyline is not FDA approved for the treatment of bipolar depression.
• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, light-headedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).
• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
• 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.

Monitoring Parameters

Serum sodium in at-risk populations (as clinically indicated); evaluate mental status, suicide ideation (especially at the beginning of therapy or when doses are increased or decreased); anxiety, social functioning, mania, panic attacks or other unusual changes in behavior; heart rate, blood pressure and ECG in older adults and patients with preexisting 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).

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Amitriptyline crosses the human placenta; CNS effects, limb deformities, and developmental delay have been noted in case reports (causal relationship not established). Tricyclic antidepressants may be associated with irritability, jitteriness, and convulsions (rare) in the neonate (Yonkers 2009). Crying, constipation, problems with urinating, and nausea may also occur in neonates exposed during pregnancy (Larsen 2015).

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 women 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 women prior to conception and during pregnancy (Yonkers 2009). Tricyclic antidepressants are not the preferred therapy for depression in pregnant women but may be helpful when agitation is also present. If a TCA is needed, amitriptyline is one of the preferred agents. Maternal serum concentrations should be monitored during pregnancy (Larsen 2015; Yonkers 2009). Migraine prophylaxis should be avoided during pregnancy; if needed, amitriptyline may be used if other agents are ineffective or contraindicated (Pringsheim 2012).

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 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.

Patient Education

What is this drug used for?

• It is used to treat low mood (depression).
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Fatigue
• Dry mouth
• Nausea
• Vomiting
• Lack of appetite
• Change in taste
• Anxiety
• Weight gain
• Weight loss
• Diarrhea
• Mouth sores

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression like thoughts of suicide, anxiety, emotional instability, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion
• Confusion
• Trouble focusing
• Behavioral changes
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes
• Fast heartbeat
• Abnormal heartbeat
• Severe dizziness
• Passing out
• Severe headache
• Unable to pass urine
• Severe loss of strength and energy
• Bruising
• Bleeding
• Swelling
• Tremors
• Seizures
• Sensing things that seem real but are not
• Burning or numbness feeling
• Chest pain
• Sexual dysfunction
• Decreased sex drive
• Testicle swelling
• Eye swelling or redness
• Enlarged breasts
• Nipple discharge
• Chills
• Sore throat
• Severe abdominal pain
• Severe constipation
• Lack of sweating
• Vision changes
• Trouble sleeping
• Nightmares
• Noise or ringing in the ears
• Tongue discoloration
• Sweating a lot
• Eye pain
• Tardive dyskinesia like unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; and puffing cheeks
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.