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Duloxetine: Drug information

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

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Suicidal thoughts and behavior:

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors.

Brand Names: US
  • Cymbalta;
  • Drizalma Sprinkle [DSC]
Brand Names: Canada
  • ACCEL-Duloxetine;
  • AG-Duloxetine;
  • APO-Duloxetine;
  • Auro-Duloxetine;
  • BIO-Duloxetine;
  • Cymbalta;
  • JAMP-Duloxetine;
  • M-Duloxetine;
  • Mar-Duloxetine;
  • MINT-Duloxetine;
  • NRA-Duloxetine;
  • PMS-Duloxetine;
  • PRIVA-Duloxetine [DSC];
  • RAN-Duloxetine;
  • RIVA-Duloxetine [DSC];
  • SANDOZ Duloxetine;
  • TEVA-Duloxetine
Pharmacologic Category
  • Antidepressant, Serotonin/Norepinephrine Reuptake Inhibitor
Dosing: Adult
Chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (off-label use): Oral: Initial: 30 mg once daily for 1 week, then 60 mg once daily (Ref).

Fibromyalgia

Fibromyalgia: Oral: Initial: 30 mg once daily for 1 week, then increase to 60 mg once daily as tolerated. Alternatively, slower titrations have been evaluated: 20 mg once daily, then increase by 20 mg every week up to 60 mg once daily as tolerated (Ref). Maximum dose: 60 mg/day; doses up to 120 mg/day were studied in clinical trials but did not confer any additional benefit.

Generalized anxiety disorder

Generalized anxiety disorder: Oral: Initial: 60 mg once daily; for some patients, it may be desirable to start at 30 mg once daily for 1 week before increasing to 60 mg once daily. Maintenance: 60 mg once daily. Although doses >60 mg/day did not confer additional benefit in clinical trials, some experts consider it reasonable to escalate the dose in individuals who do not respond satisfactorily to 60 mg/day (Ref). If dose is escalated, increase by 30 mg increments at intervals of ≥1 week as needed and tolerated (Ref). Maximum: 120 mg/day.

Major depressive disorder

Major depressive disorder (unipolar): Oral: Initial: 40 to 60 mg/day divided twice daily or given as a single daily dose. For some patients, it may be desirable to start at 30 mg once daily for 1 week before increasing to 60 mg once daily. Maintenance: 60 mg once daily. Although doses >60 mg/day did not confer additional benefit in clinical trials, based upon limited data, individual patients may benefit from dose escalation (Ref). If dose is escalated, increase by 30 mg increments at intervals of ≥1 week as needed and tolerated (Ref). Maximum: 120 mg/day.

Musculoskeletal pain, chronic

Musculoskeletal pain, chronic:

Low back and nonradicular neck pain, chronic (alternative agent): Note: Adjunct for patients with an inadequate response to nonpharmacologic and NSAID therapy (Ref).

Oral: Initial: 30 mg once daily for 1 to 2 weeks, then increase to 60 mg once daily as tolerated; maximum dose: 60 mg/day (Ref).

Osteoarthritis of the knee (alternative agent): Note: For patients with moderate to severe symptoms and an inadequate response to nonpharmacologic interventions and oral NSAIDs or oral NSAIDs are contraindicated (Ref).

Oral: Initial: 30 mg once daily for 1 week, then 60 mg once daily. Maximum dose (Ref): 60 mg/day. Doses up to 120 mg/day may provide some additional benefit (Ref); however, adverse effects may be increased (Ref).

Neuropathic pain associated with diabetes mellitus

Neuropathic pain associated with diabetes mellitus: Oral: Initial: 60 mg once daily; lower initial doses may be considered in patients when tolerability is a concern; maximum dose: 60 mg/day; doses up to 120 mg/day were studied in clinical trials but did not confer any additional benefit (Ref).

Stress urinary incontinence

Stress urinary incontinence (women and men) (off-label use): Note: For patients who are unresponsive to nonpharmacologic interventions or have comorbid depression (Ref).

Oral: 40 mg twice daily (Ref). Lower initial doses have been used in women to reduce adverse effects: 20 mg twice daily for 2 weeks then 40 mg twice daily (Ref).

Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). Reasons for a slower taper (eg, over 4 weeks) include use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), prior history of antidepressant withdrawal symptoms, or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).

Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (Ref).

Switching to or from an MAOI:

Allow 14 days to elapse between discontinuing an MAOI and initiation of duloxetine.

Allow ≥5 days to elapse between discontinuing duloxetine and initiation of an MAOI according to manufacturer labeling; however, some experts recommend a 14-day washout period (Ref).

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 Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, pharmacokinetic studies suggest that mild to moderate renal impairment (CrCl 30 to 80 mL/minute) has no significant effect on duloxetine clearance.

CrCl <30 mL/minute: The manufacturer's labeling recommends to avoid use; duloxetine and inactive metabolites AUC expected to increase significantly (Ref). When necessary, some experts recommend cautious use of lower initial doses (eg, 30 mg daily); titrate slowly, not to exceed 60 mg once daily; monitor closely for adverse effects (Ref).

Hemodialysis: Not dialyzable: The manufacturer's labeling recommends to avoid use; duloxetine AUC approximately doubled and inactive metabolites AUC increased 7- and 9-fold (Ref). When necessary, some experts recommend cautious use of lower initial doses (eg, 30 mg daily); titrate slowly, not to exceed 60 mg once daily; monitor closely for adverse effects (Ref).

Peritoneal dialysis: Unlikely to be dialyzable (expert opinion): The manufacturer's labeling recommends to avoid use; duloxetine and inactive metabolites AUC expected to increase significantly (Ref). When necessary, some experts recommend cautious use of lower initial doses (eg, 30 mg daily); titrate slowly, not to exceed 60 mg once daily; monitor closely for adverse effects (Ref).

CRRT: Unlikely to be significantly removed by CRRT. Dose as for CrCl <30 mL/minute (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be significantly removed by PIRRT. Dose as for CrCl <30 mL/minute (Ref).

Dosing: Hepatic Impairment: Adult

The hepatic dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, FAST, Jeong Park, PharmD, MS, BCPS, FCCP, FAST, Arun Jesudian, MD, Sasan Sakiani, MD

Note: Duloxetine has been associated with severe drug induced liver injury. Underlying chronic liver disease and concurrent alcohol use may predispose patients to duloxetine induced liver injury; hence, use should be avoided in this population (Ref).

Hepatic impairment prior to treatment initiation:

Initial or dose titration in patients with preexisting liver cirrhosis:

Child-Turcotte-Pugh class A: The manufacturer’s labeling recommends avoiding use in patients with chronic liver disease; use of an alternative agent should be considered (Ref). If use of duloxetine is deemed necessary, initiate therapy at a dose of ≤30 mg once daily; may titrate no more frequently than every 2 to 4 weeks with frequent monitoring for adverse effects; maximum dose: 30 mg/day (Ref).

Child-Turcotte-Pugh class B and C: Avoid use (Ref).

Dosage adjustment in patients with chronic, worsening hepatic function during treatment (eg, progression from Child-Turcotte-Pugh Class A to B):

Progression from baseline to new Child-Turcotte-Pugh class A:

If onset of hepatic dysfunction temporally related to initiation of duloxetine: Discontinue duloxetine therapy and transition to an alternative agent (Ref).

If onset of hepatic dysfunction not temporally related to initiation of duloxetine: No dosage adjustment necessary; however, in patients established on >30 mg/day and symptoms for which duloxetine prescribed are well-controlled, then consider dose reduction to a maximum dose of 30 mg once daily (Ref).

Progression to Child-Turcotte-Pugh Class B and C: Discontinue duloxetine therapy and transition to an alternative agent in collaboration with appropriate clinical experts (eg, psychiatrist) (Ref).

Acute worsening hepatic function (eg, requiring hospitalization): Permanently discontinue therapy for confirmed or suspected duloxetine-induced hepatotoxicity (Ref).

Dosing: Older Adult

Generalized anxiety disorder: Oral: Initial: 30 mg once daily; after 2 weeks, may increase to 60 mg once daily; titrate doses >60 mg once daily in increments of 30 mg once daily; maximum dose: 120 mg/day.

Major depressive disorder (unipolar): Based on pharmacokinetic studies, manufacturer labeling suggests dosage adjustment is not necessary; however, lower initial starting doses (eg, 20 mg/day) and lower maintenance doses (eg, 30 to 60 mg/day) have been recommended by some experts for elderly patients with comorbid conditions (Ref). Refer to adult dosing.

Other indications: Refer to adult dosing.

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosing: Pediatric

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

Dosage guidance:

Dosage form information: Duloxetine is available as 2 different capsule formulations: a delayed-release particles capsule (eg, Cymbalta) which is intended to be swallowed whole and delayed-release sprinkle capsule (eg, Drizalma Sprinkle) which is intended to be opened; both have similar dosing; approved indications for formulations in pediatric patients may vary.

Fibromyalgia, juvenile

Fibromyalgia, juvenile: Adolescents ≥13 years: Oral: Delayed-release particles capsule (eg, Cymbalta): Initial: 30 mg once daily; after 1 week, may increase to 60 mg once daily based on tolerability and response. In a multicenter double-blind placebo-controlled trial (n=91 duloxetine, n=93 placebo, 13 weeks duration) and the open-label extension phase that followed (n=106, 26 weeks duration), the endpoint of change in 24-hour average pain severity score (Brief Pain Inventory [BPI]) from baseline to end of the blinded phase of the trial (13 weeks) was not statistically significantly different in duloxetine vs placebo patients; however, significantly more duloxetine-treated patients experienced ≥30% and ≥50% reductions in pain severity (measured by BPI) (Ref).

Generalized anxiety disorder

Generalized anxiety disorder (GAD): Children ≥7 years and Adolescents ≤17 years: Oral: Delayed-release particles and sprinkle capsules (eg, Cymbalta, Drizalma Sprinkle): Initial: 30 mg once daily; after 2 weeks, may increase based on response and tolerability to 60 mg once daily; recommended daily dose range: 30 to 60 mg once daily; if further dose increases are necessary, titrate doses in increments of 30 mg once daily; maximum daily dose: 120 mg/day (Ref).

Major depressive disorder

Major depressive disorder (MDD): Limited data available, efficacy not established: Children ≥7 years and Adolescents ≤17 years: Oral: Initial: 30 mg once daily; may increase based on response and tolerability by 30 mg/dose increments every 2 weeks; maximum daily dose: 120 mg/day. Dosing based on 2 double-blind, placebo-controlled studies (n=800, ages 7 to 17 years) comparing duloxetine (n=341) to fluoxetine (n=234) or placebo (n=225) for the treatment of MDD; treatment with duloxetine or fluoxetine was not shown to improve Children's Depression Rating Scale-Revised (CDRS-R) any better than placebo in either trial; trials were conducted with delayed-released particle capsule formulation (Ref).

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 (Ref). Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of discontinuation syndromes (withdrawal) and allow for the detection of reemerging disease state symptoms (eg, relapse). Evidence supporting ideal taper rates after illness remission is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. After long-term (years) antidepressant treatment, WFSBP guidelines recommend tapering over 4 to 6 months, with close monitoring during and for 6 months after discontinuation. If intolerable discontinuation symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (Ref).

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 a MAO inhibitor intended to treat psychiatric disorders:

Allow at least 14 days to elapse between discontinuing a MAO inhibitor intended to treat psychiatric disorders and initiation of duloxetine.

Allow at least 5 days to elapse between discontinuing duloxetine and initiation of a MAO inhibitor intended to treat psychiatric disorders.

Dosing: Kidney Impairment: Pediatric

Children ≥7 years and Adolescents:

GFR ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, pharmacokinetic studies suggest that mild to moderate renal impairment (CrCl 30 to 80 mL/minute) has no significant effect on duloxetine clearance.

GFR <30 mL/minute: Avoid use.

End-stage renal disease (ESRD): Avoid use; increased concentrations of duloxetine and metabolites may occur.

Dosing: Hepatic Impairment: Pediatric

Children ≥7 years and Adolescents: Avoid use in hepatic impairment; patients with moderate hepatic impairment have shown decreased hepatic metabolism and elimination.

Adverse Reactions (Significant): Considerations
Activation of mania or hypomania

Antidepressants (when used as monotherapy) may precipitate a mixed/manic episode in patients with bipolar disorder. Treatment-emergent mania or hypomania in patients with unipolar major depressive disorder (MDD) has been reported, as many cases of bipolar disorder present in episodes of MDD (Ref).

Mechanism: Non-dose-related; idiosyncratic. Unclear to what extent mood switches represent an uncovering of unrecognized bipolar disorder or a more direct pharmacologic effect independent of diagnosis (Ref).

Onset: Varied; a systematic review observed that the risk of switching increased significantly within the initial 2 years of antidepressant treatment in patients with unipolar MDD receiving an antidepressant as monotherapy, but not thereafter (up to 4.6 years) (Ref).

Risk factors:

• Family history of bipolar disorder (Ref)

• Depressive episode with psychotic symptoms (Ref)

• Younger age at onset of depression (Ref)

• Antidepressant resistance (Ref)

• Female sex (Ref)

Bleeding risk

Serotonergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), may increase the risk of bleeding, particularly if used concomitantly with antiplatelets and/or anticoagulants. Multiple observational studies have found an association with SSRI use and a variety of bleeding complications (Ref), although prospective studies have not determined if the cause of the increased risk of bleeding is due to SSRI use alone. For SNRIs, less data exists compared to SSRIs and data supporting an association with bleeding are conflicting (Ref). However, there are case reports of gingival hemorrhage associated with duloxetine and some observational studies have observed an increased risk for postpartum hemorrhage (exposure during late gestation), stroke (cerebrovascular accident), and gastrointestinal hemorrhage in patients receiving SNRIs, predominately with studies using venlafaxine (Ref).

Mechanism: Possibly via inhibition of serotonin-mediated platelet activation (inhibition of the serotonin reuptake transporter) and subsequent platelet dysfunction. SNRIs may also increase gastric acidity, which may increase the risk of GI bleeding (Ref).

Onset: Varied; based on data evaluating SSRIs, it has been suggested that the onset of risk is variable but likely delayed for several weeks until SNRI-induced platelet serotonin depletion becomes clinically significant (Ref), although the onset of bleeding may be more unpredictable if patients are taking concomitant antiplatelets, anticoagulants, or nonsteroidal anti-inflammatory drugs (NSAIDs).

Risk factors:

Concomitant use of antiplatelets and/or anticoagulants (Ref)

Preexisting platelet dysfunction or coagulation disorders (eg, von Willebrand factor) (Ref)

Fragility fractures

Limited data from observational studies involving mostly older adults (≥50 years) suggest serotonin norepinephrine reuptake inhibitors (SNRIs), including duloxetine, may be associated with an increased risk of bone fractures (Ref).

Mechanism: Time-related; mechanism not fully elucidated; postulated to be through a direct effect by serotonergic agents (selective serotonin reuptake inhibitors [SSRIs] or SNRIs) on bone metabolism via interaction with 5-HT and osteoblast, osteocyte, and/or osteoclast activity. Of note, data evaluating the effects of serotonergic agents on bone mineral density primarily involve SSRIs rather than SNRIs (Ref). SNRIs may also contribute to fall risk, contributing to the incidence of fractures (Ref).

Risk factors:

• Long-term use may be a risk factor (Ref).

Hepatotoxicity

Liver test abnormalities may occur with use, but ALT elevations are usually self-limiting. However, postmarketing cases of hepatotoxicity, including hepatitis, cholestatic hepatitis, cholestatic jaundice, acute hepatic necrosis, and fulminant hepatic failure/acute hepatic failure, have been reported rarely, including fatalities and cases occurring in patients without risk factors. The pattern of hepatic injury associated with duloxetine is often hepatocellular hepatitis, but cholestatic and mixed hepatocellular-cholestatic forms have also been described (Ref).

Mechanism: Unknown by which duloxetine may cause liver injury, but likely due to a metabolic byproduct since metabolism occurs in the liver, primarily by CYP1A2 and 2D6 and is susceptible to drug-drug interactions with agents that alter these microsomal enzymes. Idiosyncratic drug-induced liver injury (DILI) is due to either direct cellular injury (metabolic idiosyncratic DILI) or are immune-mediated (immune-allergic idiosyncratic DILI). Both metabolic and immunoallergic mechanisms have been suggested for duloxetine; however, it has been reported that autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia), more indicative of an immune-allergic mechanism, have been uncommon features in cases of duloxetine-associated DILI (Ref).

Onset: Varied; DILI associated with antidepressant use usually occurs within several days to 6 months after initiation. In a case series of DILI associated with duloxetine, a median time to onset of 50 days was observed (Ref).

Risk factors:

• Polypharmacy, particularly with concomitant administration of multiple agents metabolized by the same CYP450 isoenzymes (Ref)

• Higher doses (potential risk factor) (Ref)

Hyponatremia

Duloxetine is associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and/or hyponatremia (including severe cases), predominantly in the elderly. Data evaluating a risk of hyponatremia with serotonin norepinephrine reuptake inhibitors (SNRIs) are more limited compared to selective serotonin reuptake inhibitors (SSRIs) (with the possible exception for venlafaxine), but there are several case reports and a few observational studies involving duloxetine suggesting an association (Ref).

Mechanism: May cause SIADH via release of antidiuretic hormone (ADH) via serotonin effects on 5-HT receptors and norepinephrine effects on alpha-1-adrenergic receptors (Ref) or may cause nephrogenic SIADH by increasing the sensitivity of the kidney to ADH (Ref).

Onset: Intermediate; based on data involving SSRIs, hyponatremia usually develops within the first few weeks of treatment (Ref).

Risk factors:

Based on data involving SSRIs, risk factors include:

• Older age (Ref)

• Females (Ref)

• Concomitant use of diuretics (Ref)

• Low body weight (Ref)

• Lower baseline serum sodium concentration (Ref)

• Volume depletion (Ref)

• History of hyponatremia (potential risk factors) (Ref)

• Symptoms of psychosis (potential risk factors) (Ref)

Ocular effects

Serotonin norepinephrine reuptake inhibitors (SNRIs) are associated with acute angle-closure glaucoma (AACG) in case reports. AACG may cause symptoms including eye pain, changes in vision, swelling, and redness, which can rapidly lead to permanent blindness if not treated (Ref). In addition, SNRIs may be associated with an increased risk of cataract development (Ref).

Mechanism: AACG: Unclear; hypothesized SNRIs may increase the intraocular pressure via serotonergic and adrenergic effects on ciliary body muscle activation and pupil dilation (Ref). In addition, a pseudo-anticholinergic (although debatable for SNRIs) and a dopaminergic effect on ocular tissue cannot be excluded as potential mechanisms (Ref).

Risk factors:

For AACG:

• Females (Ref)

• ≥50 years of age (slight increased risk) (Ref)

• Hyperopia (slight increased risk) (Ref)

• Personal or family history of AACG (Ref)

• Inuit or Asian descent (Ref)

Serotonin syndrome

Serotonin syndrome has been reported and typically occurs with coadministration of multiple serotonergic drugs but can occur following a single serotonergic agent at high therapeutic doses or supratherapeutic doses (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).

Mechanism: Dose-related; overstimulation of serotonin receptors (5-HT2A) by serotonergic agents (Ref).

Onset: Rapid; onset is typically within hours of an exposure (but delays of 24 hours or longer have been reported) (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, are contraindicated.

Sexual dysfunction

Serotonin norepinephrine reuptake inhibitors (SNRIs) (data primarily involves venlafaxine) have been associated with sexual disorder in both men and women. The following adverse reactions have been associated with duloxetine: orgasm abnormal, erectile dysfunction, decreased libido (Ref). Priapism has also been reported with duloxetine (Ref).

Mechanism: Based on data involving selective serotonin reuptake inhibitors (SSRIs), it has been postulated that increases in serotonin may affect other hormones and neurotransmitters involved in sexual function; in particular, testosterone's effect on sexual arousal and dopamine's role in achieving orgasm (Ref).

Suicidal thinking and behavior

Antidepressants are associated with an increased risk of suicidal ideation and suicidal tendencies in pediatric and young adult patients (18 to 24 years) in short-term studies. In adults >24 years, short-term studies did not show an increased risk of suicidal thinking and behavior; in older adults ≥65 years of age, a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, collective evidence shows a trend of an elevated risk of suicidality in younger age groups (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.

Mechanism: Not established; one of several postulated mechanisms is that antidepressants may energize suicidal patients to act on impulses; another suggests that antidepressants may produce a worsening of depressive symptoms leading to the emergence of suicidal thoughts and actions (Ref).

Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to long-term use (ie, >4 months).

Risk factors:

• Children and adolescents (Ref)

• Depression (risk of suicide is associated with major depression and may persist until remission occurs)

Withdrawal syndrome

Withdrawal syndrome, consisting of both somatic symptoms (eg, dizziness, chills, light-headedness, vertigo, shock-like sensations, paresthesia, fatigue, headache, nausea, tremor, diarrhea, visual disturbances) and psychological symptoms (eg, anxiety, agitation, confusion, insomnia, irritability, mania), have been reported with serotonin norepinephrine reuptake inhibitors (SNRIs), primarily following abrupt discontinuation. One case describes a duloxetine withdrawal seizure (Ref). 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).

Onset: Rapid; withdrawal symptoms typically occur within a few days of discontinuation (Ref).

Risk factors:

• Abrupt discontinuation (rather than gradual dosage 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.

>10%:

Endocrine & metabolic: Weight loss (children and adolescents: 14% to 15%; adults: ≥1%)

Gastrointestinal: Abdominal pain (children and adolescents: 13%; adults: 5%), decreased appetite (6% to 15%; dose related), nausea (18% to 25%; dose related), vomiting (children and adolescents: 9% to 15%; adults: 3% to 4%), xerostomia (adults: 11% to 14%, dose related; children and adolescents: 2%)

Nervous system: Drowsiness (9% to 11%; dose related), fatigue (5% to 11%; dose related), headache (13% to 18%)

1% to 10%:

Cardiovascular: Flushing (3%), increased blood pressure (2%), palpitations (2%)

Dermatologic: Diaphoresis (6%), pruritus (≥1%)

Endocrine & metabolic: Decreased libido (3%) (table 1), hot flash (≥1%), orgasm abnormal (2%) (table 2), weight gain (≥1%)

Duloxetine: Adverse Reaction: Decreased Libido

Drug (Duloxetine)

Placebo

Population

Indication

Number of Patients (Duloxetine)

Number of Patients (Placebo)

3%

1%

Adults

MDD and GAD

4797

3303

Duloxetine: Adverse Reaction: Orgasm Abnormal

Drug (Duloxetine)

Placebo

Population

Indication

Number of Patients (Duloxetine)

Number of Patients (Placebo)

2%

<1%

Adults

MDD and GAD

4797

3303

Gastrointestinal: Constipation (9% to 10%; dose related), diarrhea (6% to 9%), dysgeusia (≥1%), dyspepsia (2%), flatulence (≥1%), viral gastroenteritis (adolescents: 5%)

Genitourinary: Ejaculatory disorder (2%), erectile dysfunction (4%) (table 3), urinary frequency (≥1%)

Duloxetine: Adverse Reaction: Erectile Dysfunction

Drug (Duloxetine)

Placebo

Population

Indication

Number of Patients (Duloxetine)

Number of Patients (Placebo)

4%

<1%

Males

DPNP, FM, OA, and CLBP

3303

2352

4%

1%

Males

MDD and GAD

4797

3303

Hepatic: Increased serum alanine aminotransferase (>3 x ULN: 1%)

Nervous system: Abnormal dreams (≥1%), agitation (3% to 4%), anorgasmia (≥1%), anxiety (3%), chills (≥1%), delayed ejaculation (2%; dose related) (table 4), dizziness (8% to 9%), hypoesthesia (≥1%), insomnia (7% to 10%), lethargy (≥1%), paresthesia (≥1%), rigors (≥1%), sleep disorder (≥1%), vertigo (≥1%), yawning (2%)

Duloxetine: Adverse Reaction: Delayed Ejaculation

Drug (Duloxetine)

Placebo

Population

Indication

Number of Patients (Duloxetine)

Number of Patients (Placebo)

2%

<1%

Males

DPNP, FM, OA, and CLBP

3303

2352

2%

1%

Males

MDD and GAD

4797

3303

Neuromuscular & skeletal: Musculoskeletal pain (≥1%), tremor (2% to 3%)

Ophthalmic: Blurred vision (3%)

Respiratory: Cough (children and adolescents: 3%), nasopharyngitis (adolescents: 9%), oropharyngeal pain (children and adolescents: 4%; adults: ≥1%), upper respiratory tract infection (adolescents: 7%)

<1%:

Cardiovascular: Acute myocardial infarction, cardiomyopathy (Takotsubo), cold extremity, orthostatic hypotension, tachycardia

Dermatologic: Contact dermatitis, ecchymoses, erythema of skin, night sweats, skin photosensitivity

Endocrine & metabolic: Dehydration, dyslipidemia, hyperlipidemia, hypothyroidism, increased serum cholesterol, increased thirst, menstrual disease

Gastrointestinal: Bruxism, dysphagia, eructation, gastric ulcer, gastritis, gastroenteritis, gastrointestinal hemorrhage, halitosis, stomatitis

Genitourinary: Dysuria, malodorous urine, menopausal symptoms, nocturia, sexual disorder (literature suggests an incidence of 46%) (Lahon 2011), urinary urgency

Hematologic & oncologic: Nonthrombocytopenic purpura

Nervous system: Abnormal gait, apathy, confusion, disorientation, disturbance in attention, dysarthria, falling, feeling abnormal, irritability, malaise, myoclonus, sensation of cold, suicidal tendencies

Neuromuscular & skeletal: Asthenia, dyskinesia, muscle spasm, muscle twitching

Ophthalmic: Diplopia, dry eye syndrome, visual impairment

Otic: Otalgia, tinnitus

Renal: Polyuria

Respiratory: Laryngitis, pharyngeal edema

Frequency not defined:

Endocrine & metabolic: Decreased serum potassium, increased serum bicarbonate, increased serum potassium

Hepatic: Increased serum alkaline phosphatase, increased serum aspartate aminotransferase

Neuromuscular & skeletal: Bone fracture, increased creatinine phosphokinase in blood specimen

Postmarketing:

Cardiovascular: Cerebrovascular accident (Leong 2017), hypersensitivity angiitis, hypertensive crisis (Shukla 2020), supraventricular cardiac arrhythmia, syncope

Dermatologic: Erythema multiforme, skin rash, Stevens-Johnson syndrome (Strawn 2011), urticaria

Endocrine & metabolic: Galactorrhea not associated with childbirth, hyperglycemia, hyperprolactinemia, hyponatremia (Hu 2018), SIADH (Mori 2014)

Gastrointestinal: Acute pancreatitis, colitis, gingival hemorrhage (Balhara 2007; Gicquel 2017)

Genitourinary: Gynecological bleeding, postpartum hemorrhage (Huybrechts 2020), priapism (Wilkening 2016), urinary retention

Hepatic: Acute hepatic failure (Hanje 2006), cholestatic hepatitis (Vuppalanchi 2010), cholestatic jaundice (Park 2010), hepatic necrosis (Vuppalanchi 2010), hepatitis (Vuppalanchi 2010), hepatocellular hepatitis (Vuppalanchi 2010), hepatotoxicity (Park 2013), increased serum transaminases (Kang 2011)

Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction

Nervous system: Aggressive behavior (particularly early in treatment or after treatment discontinuation), altered sense of smell (hyperosmia) (Gundogmus 2020), extrapyramidal reaction, hypomania (Peritogiannis 2009), mania (Dunner 2005), outbursts of anger (particularly early in treatment or after treatment discontinuation), restless leg syndrome, seizure (with treatment discontinuation), serotonin syndrome (Gelener 2011), sleep disorder (rapid eye movement) (Tan 2017), suicidal ideation (Parikh 2008), trismus (atraumatic) (Ohn 2021), withdrawal syndrome (Perahia 2005)

Ophthalmic: Acute angle-closure glaucoma (Mahmut 2017), cataract (Erie 2014)

Renal: Renal colic (Wilkening 2016)

Contraindications

Use of monoamine oxidase (MAO) inhibitors intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing the MAO inhibitor); initiation of MAO inhibitor intended to treat psychiatric disorders within 5 days of discontinuing duloxetine; initiation of duloxetine in a patient receiving linezolid or intravenous methylene blue.

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

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to duloxetine or any component of the formulation; hepatic impairment; severe renal impairment (eg, CrCl <30 mL/minute) or end-stage renal disease (ESRD); uncontrolled narrow-angle glaucoma; concomitant use with thioridazine or with potent CYP1A2 inhibitors.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May impair cognitive or motor performance; caution operating hazardous machinery or driving.

• Hyperglycemia: Modest increases in serum glucose and HbA1c levels have been observed in some diabetic patients receiving duloxetine for diabetic peripheral neuropathic pain (DPNP).

• Orthostatic hypotension/syncope: May cause orthostatic hypotension/syncope, especially within the first week of therapy and after dose increases. Carefully monitor blood pressure with initiation of therapy, dose increases (especially in patients receiving >60 mg/day), or when using concomitant vasodilators or CYP1A2 inhibitors. Consider dose reduction or discontinuation of duloxetine if orthostatic hypotension or syncope occurs.

Disease-related concerns:

• Cardiovascular disease: Use caution in patients with cardiovascular conditions or cerebrovascular disease.

• Gastroparesis: Use caution in patients with impaired gastric motility (eg, some diabetics); may affect stability of the capsule's enteric coating.

• Hepatic impairment: Use should generally be avoided in patients with chronic liver disease or cirrhosis. Limited data is available in patients with hepatic impairment. In a single dose pharmacokinetic study in patients with moderate liver impairment, clearance was decreased, and half-life and plasma concentrations were increased; patients were also more likely than controls to experience adverse effects (eg, nausea, vomiting, diarrhea, and dizziness) (Suri 2005).

• Hypertension: Use caution in patients with hypertension; preexisting hypertension should be treated prior to initiating therapy. Although no statistically significant differences in the frequency of sustained elevations of BP were observed in clinical trials when compared with placebo, modest increases in BP have been reported with use. Additionally, rare cases of hypertensive crisis have been reported; BP should be evaluated prior to initiating therapy and periodically thereafter; consider dose reduction or gradual discontinuation of therapy in individuals with sustained hypertension during therapy.

• Renal impairment: Use with caution; dose reduction may be required.

• Seizure disorders: Use caution in patients with a previous seizure disorder or condition predisposing to seizures, such as brain damage or alcohol use disorder (Montgomery 2005).

Special populations:

• Fall risk: Falls with serious consequences, including bone fractures and hospitalization, have been reported in patients receiving therapeutic doses of duloxetine. The risk of falling appears related to the degree of orthostatic decrease in BP. Risks may also be greater in elderly patients, patients taking concomitant medications that induce orthostatic hypotension or are potent CYP1A2 inhibitors, and in patients taking doses >60 mg/day. Consider dose reduction or discontinuation of duloxetine if falls occur.

• Sucrose intolerance: Some formulations may contain sucrose; patients with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should avoid use.

Dosage Forms: US

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

Capsule Delayed Release Particles, Oral:

Cymbalta: 20 mg, 30 mg, 60 mg [contains fd&c blue #2 (indigotine,indigo carmine)]

Generic: 20 mg, 30 mg, 40 mg, 60 mg

Capsule Delayed Release Sprinkle, Oral:

Drizalma Sprinkle: 20 mg [DSC] [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]

Drizalma Sprinkle: 30 mg [DSC] [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]

Drizalma Sprinkle: 40 mg [DSC]

Drizalma Sprinkle: 60 mg [DSC] [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]

Generic Equivalent Available: US

May be product dependent

Pricing: US

Capsule, enteric pellets (Cymbalta Oral)

20 mg (per each): $10.01

30 mg (per each): $11.22

60 mg (per each): $11.22

Capsule, enteric pellets (DULoxetine HCl Oral)

20 mg (per each): $0.16 - $7.00

30 mg (per each): $0.23 - $7.85

40 mg (per each): $7.85

60 mg (per each): $0.40 - $7.85

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.

Dosage Forms: Canada

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

Capsule Delayed Release Particles, Oral:

Cymbalta: 30 mg, 60 mg [contains fd&c blue #2 (indigotine,indigo carmine)]

Generic: 30 mg, 60 mg

Administration: Adult

Oral: Administer without regard to meals. Swallow capsule whole; do not crush or chew.

Delayed-release particles capsule: Although the manufacturer does not recommend opening the capsule to facilitate administration, duloxetine has been found to be stable for up to 2 hours after sprinkling the contents of capsule on applesauce or in apple juice (not chocolate pudding) taking care not to crush the pellets and damage the enteric coating (Ref). Tolerability studies of this administration technique have not been conducted. Adverse effects have been reported to the FDA when patients opened the capsules, however, reports do not detail if pellets were crushed (Ref).

Delayed-release sprinkle capsule: Capsule can be opened and contents sprinkled over small amount of applesauce; instruct patient to swallow drug/food mixture immediately after mixing. Contents of capsule can also be added to a plastic catheter tip syringe with 50 mL of water and shaken for 10 seconds before administering through a 12 French or larger nasogastric tube.

Administration: Pediatric

Oral: Administer without regard to meals.

Delayed-release particles capsule (eg, Cymbalta): Swallow capsule whole; do not crush or chew. Although the manufacturer does not recommend opening the capsule to facilitate administration, duloxetine has been found to be stable for up to 2 hours after sprinkling the contents of capsule on applesauce or in apple juice (not chocolate pudding) taking care not to crush the pellets and damage the enteric coating (Ref). Tolerability studies of this administration technique have not been conducted. Adverse effects have been reported to the FDA when patients opened the capsules; however, reports do not detail if pellets were crushed (Ref).

Delayed-release sprinkle capsule (eg, Drizalma Sprinkle):

Oral: Swallow capsule whole; do not crush or chew. For patients with difficulty swallowing, capsules may be opened and contents sprinkled over small amount of applesauce; instruct patient to swallow drug/food mixture immediately after mixing.

Nasogastric tube: Contents of capsule can be added to a plastic catheter tip syringe with 50 mL of water and gently shaken for 10 seconds before administering through a 12 French or larger nasogastric tube. Ensure no pellets are left in the syringe; if present, rinse syringe with an additional 15 mL of water.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Cymbalta: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021427s056lbl.pdf#page=38

Drizalma Sprinkle: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212516s002lbl.pdf#page=46

Use: Labeled Indications

Fibromyalgia: Management of fibromyalgia in adult (all formulations) and pediatric patients ≥13 years of age (delayed-release particles capsule).

Generalized anxiety disorder: Treatment of generalized anxiety disorder in adult and pediatric patients ≥7 years of age.

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder in adults.

Musculoskeletal pain, chronic: Management of chronic musculoskeletal pain including osteoarthritis of the knee and low back pain in adults.

Neuropathic pain associated with diabetes mellitus: Management of pain associated with diabetic peripheral neuropathy in adults.

Use: Off-Label: Adult

Chemotherapy-induced peripheral neuropathy; Stress urinary incontinence (men); Stress urinary incontinence (women)

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

Cymbalta may be confused with Symbyax.

Drizalma may be confused with Drisdol, Drisdan.

DULoxetine may be confused with Dexilant, FLUoxetine, PARoxetine, vortioxetine.

Older Adult: High-Risk Medication:

Beers Criteria: Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to its potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2019]). Note: Updates for the American Geriatrics Society 2023 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults are in process.

Metabolism/Transport Effects

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

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.

Abrocitinib: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Abrocitinib. Risk X: Avoid combination

Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: Monitor therapy

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

Ajmaline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Ajmaline. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the hepatotoxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Particularly duloxetine and milnacipran. Management: Consider advising patients to avoid concomitant use of alcohol with SNRIs, particularly those using extended-release SNRI formulations, due to the risk of accelerated drug release. Heavy alcohol use has been associated with overdose and hepatotoxicity. Risk D: Consider therapy modification

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: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Management: If possible, avoid coadministration of direct-acting alpha-/beta-agonists and serotonin/norepinephrine reuptake inhibitors. If coadministered, monitor for increased sympathomimetic effects (eg, increased blood pressure, chest pain, headache). Risk D: Consider therapy modification

Alpha2-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Alpha2-Agonists. Risk C: Monitor therapy

Amphetamines: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amphetamines. Management: Monitor for amphetamine toxicities (including serotonin syndrome) if used with a moderate CYP2D6 inhibitor. Initiate amphetamine therapy at lower doses, monitor frequently, and adjust doses as needed. Discontinue amphetamines if serotoinin syndrome occurs Risk C: Monitor therapy

Amphetamines: 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). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapy

Anagrelide: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. 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

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Risk C: Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy, indication, or dosage form. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Risk C: Monitor therapy

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

Aspirin: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Atomoxetine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Atomoxetine. Risk C: Monitor therapy

Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

Brexanolone: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose when treating indications other than major depressive disorder. Risk C: Monitor therapy

Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Risk X: Avoid combination

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

Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Caplacizumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Caplacizumab. Specifically, the risk of bleeding may be increased. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification

Carvedilol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Risk C: Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

CloZAPine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. 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

CYP1A2 Inducers (Moderate): May decrease the serum concentration of DULoxetine. Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May increase the serum concentration of DULoxetine. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May increase the serum concentration of DULoxetine. Risk X: Avoid combination

CYP2D6 Inhibitors (Strong): May increase the serum concentration of DULoxetine. Risk C: Monitor therapy

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. 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

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

Deutetrabenazine: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deutetrabenazine. Risk C: 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. 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

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. 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

Eliglustat: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs. Risk D: Consider therapy modification

Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

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

Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

FentaNYL: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. 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

Flecainide: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Flecainide. Risk C: Monitor therapy

FluvoxaMINE: DULoxetine may enhance the antiplatelet effect of FluvoxaMINE. DULoxetine may enhance the serotonergic effect of FluvoxaMINE. This could result in serotonin syndrome. FluvoxaMINE may increase the serum concentration of DULoxetine. Risk X: Avoid combination

Haloperidol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Haloperidol. Risk C: Monitor therapy

Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Risk D: Consider therapy modification

Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk C: Monitor therapy

Iboga: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Iboga. Risk C: Monitor therapy

Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Iloperidone: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Iloperidone. Risk C: Monitor therapy

Indoramin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Indoramin. Risk C: Monitor therapy

Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Iobenguane Radiopharmaceutical Products: Serotonin/Norepinephrine Reuptake Inhibitors 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

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

Lecanemab: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor therapy

Levomethadone: 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

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Linezolid: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

Lipid Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Lorcaserin (Withdrawn From US Market): 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

Meperidine: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. 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

Mequitazine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Mequitazine. Risk X: Avoid combination

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

Methadone: 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

Methylene Blue: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination

Metoclopramide: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Metoclopramide. Risk C: Monitor therapy

Metoprolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Metoprolol. Risk C: Monitor therapy

Mirtazapine: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. 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

Monoamine Oxidase Inhibitors (Antidepressant): May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy

Nefazodone: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. 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

Nonsteroidal Anti-Inflammatory Agents (Nonselective): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Topical): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Topical). Risk C: Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy

Oliceridine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Oliceridine. Risk C: Monitor therapy

Olmutinib: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Olmutinib. Risk C: Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: 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. Risk C: Monitor therapy

Opioid Agonists: 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 (metabolized by CYP3A4 and CYP2D6): 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 (metabolized by CYP3A4): 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

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

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy

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

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Perhexiline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Perhexiline. Risk C: Monitor therapy

Perphenazine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Perphenazine. Risk C: Monitor therapy

Pimozide: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Risk C: Monitor therapy

Pirtobrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Pitolisant: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Pitolisant. Risk C: Monitor therapy

Propafenone: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Risk C: Monitor therapy

Propranolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Propranolol. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. 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 Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

RisperiDONE: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of RisperiDONE. Risk C: Monitor therapy

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy

Safinamide: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of DULoxetine. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of DULoxetine. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): DULoxetine may enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). DULoxetine may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of DULoxetine. Management: Monitor for increased duloxetine effects/toxicities and signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperthermia, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor therapy

Selegiline: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Serotonergic Agents (High Risk, Miscellaneous): Serotonin/Norepinephrine Reuptake Inhibitors 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

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 antiplatelet effect of other Serotonin/Norepinephrine Reuptake Inhibitors. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of other Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor therapy

Sertindole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Sertindole. 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

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

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives to the use of moderate CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with reduced clinical effectiveness of tamoxifen. Risk D: Consider therapy modification

Tamsulosin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Risk C: Monitor therapy

Tetrabenazine: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Risk C: Monitor therapy

Thioridazine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Thioridazine. Risk X: Avoid combination

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy

Timolol (Systemic): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Timolol (Systemic). Risk C: Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

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

TraMADol: DULoxetine may enhance the adverse/toxic effect of TraMADol. The risk for serotonin syndrome/serotonin toxicity and seizures may be increased with this combination. DULoxetine may diminish the therapeutic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), reduced tramadol effectiveness and seizures if these agents are combined. Risk C: Monitor therapy

TraZODone: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. 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

Tricyclic Antidepressants: 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

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Risk X: Avoid combination

Valbenazine: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Valbenazine. Risk C: Monitor therapy

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Zuclopenthixol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Risk C: Monitor therapy

Reproductive Considerations

If treatment for major depressive disorder is initiated for the first time in females planning a pregnancy, agents other than duloxetine are preferred (Larsen 2015).

Pregnancy Considerations

Duloxetine crosses the placenta (Boyce 2011; Briggs 2009; Collin-Lévesque 2018).

Nonteratogenic adverse events have been observed with venlafaxine or other SNRIs/SSRIs when used during pregnancy. Cyanosis, apnea, respiratory distress, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor have been reported in the neonate immediately following delivery after exposure to venlafaxine, SSRIs, or other SNRIs late in the third trimester. Prolonged hospitalization, respiratory support, or tube feedings may be required. Some symptoms may be due to the toxicity of the SNRIs/SSRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with treatment.

Duloxetine may impair platelet aggregation, resulting in an increased risk of bleeding; the risk of postpartum hemorrhage may be increased when used within the month prior to delivery.

Untreated or inadequately treated mental illness may lead to poor compliance with prenatal care. The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized. Use of a single agent is preferred. According to their recommendations, treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary care provider, and pediatrician (ACOG 2008). If treatment for major depressive disorder is initiated for the first time during pregnancy, agents other than duloxetine are preferred (Larsen 2015; MacQueen 2016).

Untreated fibromyalgia may be associated with adverse pregnancy outcomes, including placental abruption, venous thrombosis, premature rupture of membranes, preterm birth, and intrauterine growth restriction/small for gestational age. It is not known if these outcomes are due specifically to fibromyalgia or comorbid conditions. Due to limited data, use of duloxetine for the treatment of fibromyalgia syndrome (FMS) in pregnancy should be reserved for women with severe forms of FMS complicated by depressive symptoms which worsen during pregnancy. Close monitoring is recommended (Gentile 2019).

Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Health care providers are encouraged to enroll patients in the National Pregnancy Registry for Antidepressants (1-844-405-6185).

Breastfeeding Considerations

Duloxetine is present in breast milk.

The relative infant dose (RID) of duloxetine is 2.3% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 60 mg/day.

In general, breastfeeding is considered acceptable when the RID 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 duloxetine was calculated using a milk concentration of ~120 mcg/L, providing an estimated daily infant dose via breast milk of 0.02 mg/kg/day. This milk concentration was obtained following maternal administration of duloxetine 60 mg/day (Briggs 2009). Duloxetine has also been detected in the serum of a breastfeeding infant (Boyce 2011).

Information related to the use of duloxetine in breastfeeding women is limited. 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 (Sachs 2013; Sriraman 2015).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. When first initiating an antidepressant in a breastfeeding woman, agents other than duloxetine are preferred. Women successfully treated with duloxetine during pregnancy may continue use while breastfeeding if there are no other contraindications (Berle 2011).

Monitoring Parameters

BP (baseline, then periodically, especially in patients with high baseline BP); renal function tests (baseline; as clinically indicated); liver function tests (baseline then as clinically indicated in patients with no underlying liver dysfunction; in patients with underlying liver dysfunction, repeat liver function tests during the first 2 months of therapy then as clinically indicated [expert opinion; Vuppalanchi 2010]); closely monitor patients for depression, clinical worsening, suicidality, or unusual changes in behavior (eg. 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 (increases or decreases); serum sodium in at-risk populations (as clinically indicated); blood glucose and HbA1c in diabetic patients (baseline and as clinically indicated); signs/symptoms of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, delirium), seizures, autonomic instability (eg, tachycardia, dizziness, diaphoresis), neuromuscular symptoms (eg, tremor, rigidity, myoclonus), or GI symptoms (eg, nausea, vomiting, diarrhea).

Mechanism of Action

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a weak inhibitor of dopamine reuptake. Duloxetine has no significant activity for muscarinic cholinergic, H1-histaminergic, or alpha2-adrenergic receptors. Duloxetine does not possess MAO-inhibitory activity.

Pharmacokinetics (Adult Data Unless Noted)

Onset of action:

Anxiety disorders (generalized anxiety disorder): Initial effects may be observed within 2 weeks of treatment, with continued improvements through 4 to 6 weeks (WFSBP [Bandelow 2012]); some experts suggest up to 12 weeks of treatment may be necessary for response (BAP [Baldwin 2014]; Katzman 2014; WFSBP [Bandelow 2012]).

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: Well absorbed; food has no effect on Cmax, but decreases AUC by 10%.

Distribution: Vd:

Children ≥7 years and Adolescents: 1,200 L (Lobo 2014).

Adults: ~1,640 L.

Protein binding: >90%; primarily to albumin and alpha1-acid glycoprotein.

Metabolism: Hepatic, via CYP1A2 and CYP2D6; forms multiple metabolites (inactive).

Half-life elimination:

Children ≥7 years and Adolescents: 10.4 hours (Lobo 2014).

Adults: ~12 hours (range: 8 to 22 hours); ~4 hours longer in elderly women.

Time to peak: 5 to 6 hours; food delays by 1.7 to 4 hours.

Excretion: Urine (~70%; <1% of total dose as unchanged drug); feces (~20%).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: Cmax and AUC were ~100% greater in patients with ESRD receiving intermittent hemodialysis.

Hepatic function impairment: Six patients with cirrhosis and moderate hepatic impairment had a 5-fold higher exposure (AUC) and a 3-fold longer half-life compared to patients with normal hepatic function (Suri 2005).

Older adult: AUC was ~25% higher in elderly women.

Cigarette smoking: Duloxetine bioavailability is reduced by ~33% in smokers.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AR) Argentina: Duxetin | Nitidex;
  • (AU) Australia: Andepra | Apo duloxetine | Cm Duloxetine | Cymbalta | Deotine | Depreta | Drulox | Duloxetine | Duloxetine drla | Duloxetine gh | Dytrex | Pharmacor duloxetine | Tixol;
  • (BD) Bangladesh: Deloxi | Diliner | Duzela;
  • (BG) Bulgaria: Nexetin;
  • (BR) Brazil: Cloridrato de duloxetina | Cymbalta | Velija;
  • (CH) Switzerland: Cymbalta;
  • (CL) Chile: Duceten | Lervitan | Nitexol | Realta;
  • (CN) China: Cymbalta;
  • (CO) Colombia: Cimal | Duxetina | Duzela | Nitexol;
  • (DE) Germany: Ariclaim | Cymbalta | Xeristar | Yentreve;
  • (DO) Dominican Republic: Duloxvitae | Durotine;
  • (EC) Ecuador: Cymbalta | Nitexol;
  • (EE) Estonia: Cymbalta;
  • (EG) Egypt: Cymbatex | Duloxeprin;
  • (ES) Spain: Cymbalta | Dulotex | Duloxetina apotex | Duloxetina bexal | Duloxetina mylan | Duloxetina normon | Duloxetina qualigen | Duloxetina ratiopharm | Duloxetina stada genericos | Xeristar;
  • (FI) Finland: Yentreve;
  • (GB) United Kingdom: Duloxetine neuraxpharm | Dutor;
  • (GR) Greece: Ariclaim | Yentreve;
  • (HK) Hong Kong: Apo duloxetine | Duloxetine alvogen;
  • (HR) Croatia: Cymbalta | Duloksetin Pliva | Duloksetin Stada | Onelar;
  • (IE) Ireland: Cymbalta | Duloxetine zentiva | Yentreve;
  • (IN) India: Cendu | Dell | Delok | Detine | Dureep | Nudep;
  • (IT) Italy: Ariclaim | Xeristar | Yentreve;
  • (KE) Kenya: C yalta;
  • (KR) Korea, Republic of: Cymbalta | Ducetine | Duloxta | Duroxetine | Julotin | Teva dulosequal | Tobalta;
  • (MX) Mexico: Cymbalta | Devixdol | Dharma seis | Duax r | Duloxetina | Dulpicap | Duxiauro | Lenno vaxyn | Limbaxia | Magax | Qalih | Rimalix | Splypax | Xeronora;
  • (NL) Netherlands: Cymbalta;
  • (NO) Norway: Cymbalta | Yentreve;
  • (PE) Peru: Duzela;
  • (PH) Philippines: Cymbalta;
  • (PK) Pakistan: Aurolox | C yalta | Cymanta | D lox | D pram | Detine | Dextine dr | Diliner | Dobalta | Dulact | Dulocap | Duloxe | Duloxepil | Duloxet | Dultix dr | Dumore | Duron | Duzac | Dwist | Dyloxia | Hepretin | Hi ser | Hilux | Ilario | Koxetine | Loxivant | Medlux | Mexetin | Neuxil | Oxcym dr | Rexa | Sprain | Sympta | Xilenka | Zenbar;
  • (PR) Puerto Rico: Cymbalta;
  • (PT) Portugal: Duloxetina kipa | Duloxetina mylan | Duloxetina ratiopharm | Duloxetina tolife;
  • (PY) Paraguay: Duxetin;
  • (RU) Russian Federation: Cymbalta | Duloxetine canon;
  • (SE) Sweden: Duloxetine zentiva;
  • (SI) Slovenia: Duloksetin mylan | Duloksetin sandoz | Duloksetin teva;
  • (TR) Turkey: Cymbalta | Dulaxat | Duloxx | Duxet | Dyloxia | Komox | Lodux | Nexetin | Zedulox;
  • (TW) Taiwan: Cymta | Durotine | Duxetine;
  • (UA) Ukraine: Nexetin;
  • (UY) Uruguay: Duxetin | Duzac;
  • (VE) Venezuela, Bolivarian Republic of: Duzela;
  • (ZA) South Africa: Cymbalta | Davix | Dueloks | Dulocap | Duloxetine mr 30 unicorn | Duloxetine mr 60 unicorn
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