Version July 2025
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.
Chemotherapy-induced peripheral neuropathy (off-label use): Oral: Initial: 30 mg once daily for 1 week, then 60 mg once daily (Ref).
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: 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 after 4 to 6 weeks (Ref). If dose is escalated, increase by 30 mg increments at intervals of ≥1 week as needed and tolerated (Ref). Doses may be increased every 3 to 4 days if warranted in inpatient settings. Maximum: 120 mg/day.
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, limited data support a dose escalation in individual patients who are demonstrating some but not sufficient improvement after ≥4 weeks (Ref). If dose is escalated, increase by 30 mg increments at intervals of ≥3 weeks as needed and tolerated (Ref). Maximum: 120 mg/day.
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). Some experts recommend initiating at 20 mg/day in patients who are sensitive to side effects (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. Some experts recommend initiating at 20 mg/day in patients who are sensitive to side effects (Ref). 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: Oral: Initial: 60 mg once daily; lower initial doses (eg, 20 mg/day) 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 (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 ≥4 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). For brief treatment (eg, 2 to 3 weeks), may taper over 1 to 2 weeks; <2 weeks of treatment generally does not warrant tapering (Ref). Reasons for a slower taper (eg, over 4 weeks) include 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. In general, when switching from an SSRI to duloxetine, it is appropriate to initiate with duloxetine 60 mg/day; however, when switching from fluoxetine or paroxetine, some experts recommend initiating with duloxetine 30 mg/day (Ref). 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.
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).
The liver dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, FAST, FCCP; Jeong Park, PharmD, MS, BCTXP, 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).
Liver impairment prior to treatment initiation:
Initial or dose adjustment 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).
Liver impairment developing in patients already receiving duloxetine:
Chronic disease progression (eg, outpatient):
Baseline to Child-Turcotte-Pugh class A:
If onset of liver impairment temporally related to initiation of duloxetine: Discontinue duloxetine therapy and transition to an alternative agent (Ref).
If onset of liver impairment 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).
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 of liver function (eg, requiring hospitalization): Permanently discontinue therapy for confirmed or suspected duloxetine-induced hepatotoxicity (Ref).
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.
(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: 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 (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 (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.
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.
Children ≥7 years and Adolescents: Avoid use in hepatic impairment; patients with moderate hepatic impairment have shown decreased hepatic metabolism and elimination.
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)
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)
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).
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)
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)
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 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.
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).
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, 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 dose taper) or tapering the antidepressant too quickly (Ref)
• Drugs with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)
• Higher doses (Ref)
• Longer duration of treatment (eg, ≥4 weeks) (Ref)
• Prior history of antidepressant withdrawal symptoms (Ref)
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%)
|
Drug (Duloxetine) |
Placebo |
Population |
Indication |
Number of Patients (Duloxetine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
3% |
1% |
Adults |
MDD and GAD |
4797 |
3303 |
|
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%)
|
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%)
|
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%) (Ref), 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 (Ref), hypersensitivity angiitis, hypertensive crisis (Ref), supraventricular cardiac arrhythmia, syncope
Dermatologic: Erythema multiforme, skin rash, Stevens-Johnson syndrome (Ref), urticaria
Endocrine & metabolic: Galactorrhea not associated with childbirth, hyperglycemia, hyperprolactinemia, hyponatremia (Ref), SIADH (Ref)
Gastrointestinal: Acute pancreatitis, colitis, gingival hemorrhage (Ref)
Genitourinary: Gynecological bleeding, postpartum hemorrhage (Ref), priapism (Ref), urinary retention
Hepatic: Acute hepatic failure (Ref), cholestatic hepatitis (Ref), cholestatic jaundice (Ref), hepatic necrosis (Ref), hepatitis (Ref), hepatocellular hepatitis (Ref), hepatotoxicity (Ref), increased serum transaminases (Ref)
Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction
Nervous system: Aggressive behavior (particularly early in treatment or after treatment discontinuation), altered sense of smell (hyperosmia) (Ref), extrapyramidal reaction, hypomania (Ref), mania (Ref), outbursts of anger (particularly early in treatment or after treatment discontinuation), restless leg syndrome, seizure (with treatment discontinuation), serotonin syndrome (Ref), sleep disorder (rapid eye movement) (Ref), suicidal ideation (Ref), trismus (atraumatic) (Ref), withdrawal syndrome (Ref)
Ophthalmic: Acute angle-closure glaucoma (Ref), cataract (Ref)
Renal: Renal colic (Ref)
Use of monoamine oxidase inhibitors (MAOIs) (concurrently or within 14 days of discontinuing the MAOI); initiation of MAOIs intended to treat psychiatric disorders within 5 days of discontinuing duloxetine; initiation of duloxetine in a patient receiving IV methylene blue.
Note: Although duloxetine is contraindicated per the manufacturer labeling when used in combination with linezolid, new evidence suggests that the combination is unlikely to cause serotonin syndrome (0.06% to 3% risk), and therefore these agents can be administered concomitantly when necessary. Monitor patients on this combination; average duration of serotonin toxicity is ~4 days; however, risks may be greater with longer durations of concurrent therapy. Educate patients on the signs and symptoms of serotonin syndrome (Bai 2022; Butterfield 2012; Karkow 2017; Kufel 2023; Narita 2007; Taylor 2006).
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.
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:
• Bariatric surgery: Presurgical assessment of the indication for use, symptoms, and goals of therapy should be documented to enable postsurgical assessment. Small pharmacokinetic studies showed an alteration in exposure and wide interpatient variability post surgery (Garin 2023; Roerig 2013). Patients who have undergone Roux-en-Y gastric bypass (RYGB) surgery should be closely monitored. Monitor for continued efficacy after bariatric surgery and consider switching to an alternate medication if symptoms worsen.
• 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
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 [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 [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
Drizalma Sprinkle: 40 mg
Drizalma Sprinkle: 60 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]
May be product dependent
Capsule Delayed Release Sprinkle (Drizalma Sprinkle Oral)
20 mg (per each): $8.95
30 mg (per each): $8.95
40 mg (per each): $8.95
60 mg (per each): $8.95
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule Delayed Release Particles, Oral:
Cymbalta: 30 mg [DSC], 60 mg [DSC] [contains fd&c blue #2 (indigotine,indigo carmine)]
Generic: 30 mg, 60 mg
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.
Bariatric surgery: Duloxetine is only available as delayed-release formulations and the release characteristics may be significantly altered in an unknown manner in patients who have undergone bariatric surgery; therefore, it is not recommended to use any capsule formulation (including sprinkle capsules) in this population. Providers should determine if the condition being treated can be safely monitored or if a switch to an alternative is necessary (Ref).
Enteral feeding tube:
The following recommendations are based upon the best available evidence and clinical expertise. Senior editorial team: Joseph I. Boullata, PharmD, RPh, CNS-S, FASPEN, FACN; Peggi A. Guenter PhD, RN, FASPEN; Kathleen Gura, PharmD, BCNSP, FASHP, FASPEN, FPPA, FMSHP; Mark G. Klang MS, RPh, BCNSP, PhD, FASPEN; Linda Lord, NP, ACNP-BC, CNSC, FASPEN.
Oral capsule, delayed-release particles (eg, Cymbalta):
Enteral feeding tube administration utilizing duloxetine delayed-release particle capsules is not recommended. Altering modified-release dosage forms may result in feeding tube occlusion, release of excessive doses, variable serum concentrations, and increased risk of severe adverse effects (Ref).
Oral capsule, delayed-release sprinkle (eg, Drizalma Sprinkle):
Gastric tubes (eg, NG, G-tube ) (≥12 French): Do not crush capsule or contents; open capsule and place contents into an all-plastic enteral dosing syringe; add 50 mL purified water to the syringe. Shake gently for ~10 seconds and administer immediately via feeding tube, ensuring no pellets remain in the syringe (Ref).
General guidance: Hold enteral nutrition (EN) during duloxetine administration (Ref). Flush feeding tube with an appropriate volume of purified water (eg, 15 mL) before administration (Ref). Following administration, rinse syringe used for preparation with purified water (eg, 15 mL); administer contents to ensure no pellets remain and entire dose is delivered (Ref). Flush feeding tube with an appropriate volume of purified water (eg, 15 mL) and restart EN (Ref).
Note: Recommendations may not account for differences in inactive ingredients, osmolality, or other formulation properties that may vary among products from different manufacturers.
The following recommendations are based upon the best available evidence and clinical expertise. Senior editorial team: Joseph I. Boullata, PharmD, RPh, CNS-S, FASPEN, FACN; Peggi A. Guenter, PhD, RN, FASPEN; Kathleen Gura, PharmD, BCNSP, FASHP, FASPEN, FPPA, FMSHP; Mark G. Klang, MS, RPh, BCNSP, PhD, FASPEN; Linda Lord, NP, ACNP-BC, CNSC, FASPEN.
Note: Recommendations may not account for differences in inactive ingredients, osmolality, or other formulation properties that may vary among products from different manufacturers.
Oral: Administer without regard to meals.
Capsule, delayed-release particles (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).
Administration via feeding tube: NOT recommended: Altering modified-release dosage forms may result in feeding tube occlusion, release of excessive doses, variable serum concentrations, and increased risk of severe adverse effects (Ref).
Capsule, delayed-release sprinkle (eg, Drizalma Sprinkle): 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.
Administration via feeding tube:
Gastric (eg, NG, G-tube) tubes ( ≥ 12 French): Do not crush capsule or contents; open capsule and place contents into an all-plastic enteral dosing syringe; add 50 mL purified water to the syringe. Shake gently for ~10 seconds and administer immediately via feeding tube, ensuring no pellets remain in the syringe; rinse with additional water if needed (eg, 15 mL) (Ref).
General guidance: Hold enteral nutrition during duloxetine administration (Ref). Flush feeding tube with the lowest volume of purified water necessary to clear the tube prior to administration based on size of patient and/or feeding tube (eg, neonates: 1 to 3 mL; infants and children: 2 to 5 mL; adolescents: 15 mL); refer to institutional policies and procedures (Ref). Following administration process above, flush feeding tube with an appropriate volume of purified water and restart enteral nutrition (Ref).
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/2023/021427s055s057lbl.pdf#page=38
Drizalma Sprinkle: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212516s005lbl.pdf#page=45
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.
Chemotherapy-induced peripheral neuropathy; Stress urinary incontinence (men); Stress urinary incontinence (women)
Cymbalta may be confused with Symbyax.
Drizalma may be confused with Drisdol, Drisdan.
DULoxetine may be confused with Dexilant, FLUoxetine, PARoxetine, vortioxetine.
Beers Criteria: Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) (duloxetine) are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to their 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 2023]).
Duloxetine is identified in the Screening Tool of Older Person's Prescriptions (STOPP) criteria as a potentially inappropriate medication in older adults (≥65 years of age) with urinary urgency, urge incontinence, severe hypertension, or recurrent falls (O’Mahony 2023).
Substrate of CYP1A2 (Major), CYP2D6 (Major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (Moderate);
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 drug interactions program by clicking on the “Launch drug interactions program” link above.
Abciximab: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Abrocitinib: Agents with Antiplatelet Effects may increase antiplatelet effects of Abrocitinib. Risk X: Avoid
Acalabrutinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Ajmaline: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Ajmaline. Risk C: Monitor
Ajmaline: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Alcohol (Ethyl): May increase hepatotoxic effects of Serotonin/Norepinephrine Reuptake Inhibitor. 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 increase serotonergic effects 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
Alosetron: May increase serotonergic effects 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
Alpha-/Beta-Agonists: Serotonin/Norepinephrine Reuptake Inhibitor may increase tachycardic effects of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitor may increase vasopressor effects 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 Inhibitor may decrease therapeutic effects of Alpha2-Agonists. Risk C: Monitor
Amphetamines: CYP2D6 Inhibitors (Moderate) may increase 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
Amphetamines: May increase serotonergic effects 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
Anagrelide: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Anticoagulants (Miscellaneous Agents): Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Anticoagulants (Miscellaneous Agents). Risk C: Monitor
Antiemetics (5HT3 Antagonists): May increase serotonergic effects 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
Antiplatelet Agents (P2Y12 Inhibitors): Agents with Antiplatelet Effects may increase antiplatelet effects of Antiplatelet Agents (P2Y12 Inhibitors). Risk C: Monitor
Antipsychotic Agents: Serotonergic Agents (High Risk) may increase adverse/toxic effects of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Moderate) may increase active metabolite exposure of ARIPiprazole Lauroxil. Risk C: Monitor
ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase 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
Artemether and Lumefantrine: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Aspirin: Serotonin/Norepinephrine Reuptake Inhibitor may increase antiplatelet effects of Aspirin. Risk C: Monitor
Atomoxetine: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Atomoxetine. Risk C: Monitor
Blood Pressure Lowering Agents: May increase hypotensive effects of DULoxetine. Risk C: Monitor
Brexanolone: Serotonin/Norepinephrine Reuptake Inhibitor may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase 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
Broccoli: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor
Bromopride: May increase adverse/toxic effects of Serotonin/Norepinephrine Reuptake Inhibitor. Risk X: Avoid
BusPIRone: May increase serotonergic effects 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
Cannabis: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor
Caplacizumab: Agents with Antiplatelet Effects may increase adverse/toxic effects of Caplacizumab. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Carvedilol: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Carvedilol. Risk C: Monitor
CloZAPine: CYP2D6 Inhibitors (Moderate) may increase serum concentration of CloZAPine. Risk C: Monitor
Codeine: CYP2D6 Inhibitors (Moderate) may decrease therapeutic effects of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor
Collagenase (Systemic): Agents with Antiplatelet Effects may increase adverse/toxic effects of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor
Cyclobenzaprine: May increase serotonergic effects 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
CYP1A2 Inducers (Moderate): May decrease serum concentration of DULoxetine. Risk C: Monitor
CYP1A2 Inhibitors (Moderate): May increase serum concentration of DULoxetine. Risk C: Monitor
CYP1A2 Inhibitors (Strong): May increase serum concentration of DULoxetine. Risk X: Avoid
CYP2D6 Inhibitors (Strong): May increase serum concentration of DULoxetine. Risk C: Monitor
Dapoxetine: May increase serotonergic effects 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
Dasatinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Deoxycholic Acid: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Desmopressin: Hyponatremia-Associated Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor
Deutetrabenazine: CYP2D6 Inhibitors (Moderate) may increase active metabolite exposure of Deutetrabenazine. Risk C: Monitor
Dexmethylphenidate-Methylphenidate: May increase serotonergic effects 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
Dextromethorphan: May increase serotonergic effects 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
Diazoxide Choline: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk X: Avoid
Direct Oral Anticoagulants (DOACs): Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Direct Oral Anticoagulants (DOACs). Risk C: Monitor
DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase serum concentration of DOXOrubicin (Conventional). Risk X: Avoid
Eletriptan: May increase serotonergic effects 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
Eliglustat: CYP2D6 Inhibitors (Moderate) may increase 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
Epinephrine (Racemic): Serotonin/Norepinephrine Reuptake Inhibitor may increase adverse/toxic effects of Epinephrine (Racemic). Risk X: Avoid
Ergot Derivatives: May increase serotonergic effects 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
Fenfluramine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
FentaNYL: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. 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
Flecainide: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Flecainide. Risk C: Monitor
FluvoxaMINE: DULoxetine may increase serotonergic effects of FluvoxaMINE. This could result in serotonin syndrome. DULoxetine may increase antiplatelet effects of FluvoxaMINE. FluvoxaMINE may increase serum concentration of DULoxetine. Risk X: Avoid
Fondaparinux: Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Fondaparinux. Risk C: Monitor
Gepirone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Glycoprotein IIb/IIIa Inhibitors: Agents with Antiplatelet Effects may increase antiplatelet effects of Glycoprotein IIb/IIIa Inhibitors. Risk C: Monitor
Haloperidol: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Haloperidol. Risk C: Monitor
Heparin: Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Heparin. Risk C: Monitor
Heparins (Low Molecular Weight): Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Heparins (Low Molecular Weight). Risk C: Monitor
Herbal Products with Anticoagulant/Antiplatelet Effects: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Iboga: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Iboga. Risk C: Monitor
Ibritumomab Tiuxetan: Agents with Antiplatelet Effects may increase antiplatelet effects of Ibritumomab Tiuxetan. Risk C: Monitor
Ibrutinib: Agents with Antiplatelet Effects may increase adverse/toxic effects of Ibrutinib. Specifically, the risk of bleeding and hemorrhage may be increased. Risk C: Monitor
Iloperidone: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Iloperidone. CYP2D6 Inhibitors (Moderate) may decrease active metabolite exposure of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Moderate) may increase active metabolite exposure of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. Risk C: Monitor
Indoramin: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Indoramin. Risk C: Monitor
Inotersen: Agents with Antiplatelet Effects may increase adverse/toxic effects of Inotersen. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Iobenguane Radiopharmaceutical Products: Serotonin/Norepinephrine Reuptake Inhibitor may decrease therapeutic effects 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
Lasmiditan: May increase serotonergic effects 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
Levomethadone: May increase serotonergic effects 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
Limaprost: May increase adverse/toxic effects of Agents with Antiplatelet Effects. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Linezolid: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. This could result in serotonin syndrome. Risk X: Avoid
Mavorixafor: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid
Meperidine: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. 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
Mequitazine: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Mequitazine. Risk X: Avoid
Metaxalone: May increase serotonergic effects 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
Methadone: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Methadone. Risk C: Monitor
Methadone: May increase serotonergic effects 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
Methylene Blue: Serotonin/Norepinephrine Reuptake Inhibitor may increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid
Metoclopramide: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Metoclopramide. Risk C: Monitor
Metoprolol: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Metoprolol. Risk C: Monitor
Mirtazapine: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. 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
Miscellaneous Antiplatelets: Agents with Antiplatelet Effects may increase antiplatelet effects of Miscellaneous Antiplatelets. Risk C: Monitor
Monoamine Oxidase Inhibitors (Antidepressant): May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. This could result in serotonin syndrome. Risk X: Avoid
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Nebivolol. Risk C: Monitor
Nefazodone: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. 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
Nonsteroidal Anti-Inflammatory Agents (Nonselective): Serotonin/Norepinephrine Reuptake Inhibitor may increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents (Topical): Serotonin/Norepinephrine Reuptake Inhibitor may increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents (Topical). Risk C: Monitor
Obinutuzumab: Agents with Antiplatelet Effects may increase adverse/toxic effects of Obinutuzumab. Specifically, the risk of bleeding may be increased. Management: Consider avoiding coadministration of obinutuzumab and agents with antiplatelet effects, especially during the first cycle of obinutuzumab therapy. Risk D: Consider Therapy Modification
Oliceridine: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Oliceridine. Risk C: Monitor
Olmutinib: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Olmutinib. Risk C: Monitor
Ondansetron: May increase serotonergic effects 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
Opioid Agonists (metabolized by CYP3A4 and CYP2D6): May increase serotonergic effects 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
Opioid Agonists (metabolized by CYP3A4): May increase serotonergic effects 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
Opioid Agonists: May increase serotonergic effects 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
Opipramol: May increase serotonergic effects 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
Oxitriptan: Serotonergic Agents (High Risk) may increase serotonergic effects 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
OxyCODONE: May increase serotonergic effects 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
Peginterferon Alfa-2b: May decrease serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Pentosan Polysulfate Sodium: Agents with Antiplatelet Effects may increase adverse/toxic effects of Pentosan Polysulfate Sodium. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor
Perhexiline: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Perhexiline. Risk C: Monitor
Perphenazine: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Perphenazine. Risk C: Monitor
Pimozide: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Pimozide. Risk C: Monitor
Pirtobrutinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Pitolisant: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Pitolisant. Risk C: Monitor
Primaquine: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor
Propafenone: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Propafenone. Risk C: Monitor
Propranolol: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Propranolol. Risk C: Monitor
Psilocybin: Antidepressants may decrease therapeutic effects of Psilocybin. Risk C: Monitor
Ramosetron: May increase serotonergic effects 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
Rasagiline: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. This could result in serotonin syndrome. Risk X: Avoid
RisperiDONE: CYP2D6 Inhibitors (Moderate) may increase serum concentration of RisperiDONE. Risk C: Monitor
Safinamide: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. This could result in serotonin syndrome. Risk X: Avoid
Selective Serotonin Reuptake Inhibitor: May increase serotonergic effects of DULoxetine. This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitor may increase antiplatelet effects of DULoxetine. 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
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): DULoxetine may increase serotonergic effects of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. DULoxetine may increase antiplatelet effects of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase 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
Selegiline: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. This could result in serotonin syndrome. Risk X: Avoid
Selumetinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Serotonergic Agents (High Risk, Miscellaneous): Serotonin/Norepinephrine Reuptake Inhibitor may increase serotonergic effects 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
Serotonin 5-HT1D Receptor Agonists (Triptans): May increase serotonergic effects 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
Serotonin/Norepinephrine Reuptake Inhibitor: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. This could result in serotonin syndrome. Serotonin/Norepinephrine Reuptake Inhibitor may increase antiplatelet effects of Serotonin/Norepinephrine Reuptake Inhibitor. 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
Sertindole: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Sertindole. Risk C: Monitor
Sofpironium: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Sofpironium. Risk C: Monitor
St John's Wort: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease 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
Syrian Rue: May increase serotonergic effects 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
Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease active metabolite exposure 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 serum concentration of Tamsulosin. Risk C: Monitor
Tetrabenazine: CYP2D6 Inhibitors (Moderate) may increase active metabolite exposure of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Risk C: Monitor
Thioridazine: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Thioridazine. Risk X: Avoid
Thrombolytic Agents: Agents with Antiplatelet Effects may increase adverse/toxic effects of Thrombolytic Agents. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Tilidine: May increase serotonergic effects 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
Timolol (Systemic): CYP2D6 Inhibitors (Moderate) may increase serum concentration of Timolol (Systemic). Risk C: Monitor
Tipranavir: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Tobacco (Smoked): May decrease serum concentration of DULoxetine. Risk C: Monitor
TraMADol: DULoxetine may increase adverse/toxic effects of TraMADol. The risk for serotonin syndrome/serotonin toxicity and seizures may be increased with this combination. DULoxetine may decrease therapeutic effects 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
TraZODone: May increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. 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
Tricyclic Antidepressants: DULoxetine may increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may increase 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
Valbenazine: CYP2D6 Inhibitors (Moderate) may increase active metabolite exposure of Valbenazine. Risk C: Monitor
Vitamin E (Systemic): May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Vitamin K Antagonists: Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Vitamin K Antagonists. Risk C: Monitor
Volanesorsen: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Zanubrutinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Ziprasidone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Zuclopenthixol: CYP2D6 Inhibitors (Moderate) may increase serum concentration of Zuclopenthixol. Risk C: Monitor
When treating depression, evaluate pregnancy status prior to initiating treatment in patients who could become pregnant. Treatment should not be withheld, but pharmacologic management may vary based on reproductive status, severity of illness, and history of antidepressant response (ACOG 2023; WFSBP [Dodd 2018]). When treating depression or anxiety, serotonin-norepinephrine reuptake inhibitors are not a first-line medication for use prior to conception in patients who are treatment naive or who do not have a history of effective treatment. Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist (BAP [McAllister-Williams 2017]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).
When treating fibromyalgia, guidelines recommend an individualized multidisciplinary team approach to treatment. A combination of pharmacological and nonpharmacologic therapies may be required to treat features such as pain and associated features such as depression (EULAR [Macfarlane 2017]). Nonmedication therapies should be maximized prior to conception in patients planning to become pregnant. When planning a pregnancy, pharmacologic treatment including antidepressants should be reserved for patients with significant symptoms and reproductive safety of the medication should be evaluated (Marcus 2011).
Product labeling notes menstrual disorders have been reported following use of duloxetine. Depression is also associated with menstrual changes (Padda 2021).
Duloxetine 60 mg once daily for 5 weeks followed by 30 mg once daily for 1 week was not found to impair semen parameters in otherwise healthy participants (Punjani 2021). Product labeling notes sexual dysfunction has been reported with duloxetine. Depression is also associated with sexual dysfunction (Padda 2021).
Duloxetine crosses the placenta (Schoretsanitis 2021).
Outcome data following maternal use of duloxetine during pregnancy are available (Anderson 2020; Ankarfeldt 2021a; Ankarfeldt 2021b; Ankarfeldt 2023; Bellantuono 2015; Huybrechts 2020; Lassen 2016; Marks 2021). An increased risk of preeclampsia and spontaneous abortion may be associated with serotonin-norepinephrine reuptake inhibitor (SNRI) use; however, the quality of evidence for these outcomes is low (ACOG 2023).
Adverse effects in the newborn following SNRI exposure in the third trimester include neonatal adaptation syndrome and persistent pulmonary hypertension of the newborn. Neonatal adaptation syndrome can occur shortly after birth and typically resolves within 2 weeks. Mechanisms of neonatal adaptation syndrome are not well understood but may be due to either SNRI toxicity or withdrawal. Reducing the dose or discontinuing the SNRI prior to delivery to reduce the risk of neonatal adaptation syndrome is not recommended (ACOG 2023). Symptoms can include apnea, constant crying, cyanosis, feeding difficulty, hyperreflexia, hypo- or hypertonia, hypoglycemia, irritability, jitteriness, respiratory distress, seizures, temperature instability, tremor, and vomiting. Prolonged hospitalization, respiratory support, or tube feedings may be required.
Persistent pulmonary hypertension of the newborn is a rare complication of SNRI use during pregnancy with symptoms of respiratory distress within the first hours of life and an increased risk of neonatal mortality (ACOG 2023). Monitoring of infants exposed to SNRIs late in pregnancy is recommended (Masarwa 2019).
SNRIs may increase the risk of bleeding; exposure during the month prior to delivery may increase the risk of postpartum hemorrhage. The clinical significance of this is uncertain (BAP [McAllister-Williams 2017]).
Data from one patient suggest pregnancy-induced physiologic changes may decrease duloxetine serum concentrations during the third trimester (Leutritz 2023; Yue 2023).
Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Untreated or undertreated depression is associated with preterm birth, low birth weight (LBW), preeclampsia, postpartum depression, and impaired infant attachment (associated with long-term developmental effects). Anxiety disorders during pregnancy are associated with LBW, preterm birth, and adverse behavioral outcomes in the offspring. Discontinuing effective medications during pregnancy increases the risk of relapse. Management should be made as part of a shared decision-making process (ACOG 2023).
Patients effectively treated for depression or anxiety pre-pregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]). Treatment should not be withheld or discontinued based only on pregnancy status (ACOG 2023). SNRIs are not first-line medications for pregnant patients who are treatment naive or who do not have a history of effective treatment with another medication (ACOG 2023; BAP [McAllister-Williams 2017]); however, duloxetine may be considered as an alternative (CANMAT [MacQueen 2016]). SNRI dosing should be initiated with half the lowest recommended dose and titrated gradually over 4 to 10 days. Dose adjustments may be required as pregnancy progresses to keep symptoms in remission. When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Monthly monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).
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 patients with severe forms of FMS complicated by depressive symptoms which worsen during pregnancy. Close monitoring is recommended (Gentile 2019). Nonmedication therapies should be maximized in pregnant patients treated for fibromyalgia (Marcus 2011).
Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Pregnant patients 45 years of age and younger with a history of psychiatric illness are encouraged to enroll in the National Pregnancy Registry for Antidepressants (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants).
Duloxetine is present in breast milk.
Multiple reports summarize data related to the presence of duloxetine in breast milk:
• The presence of duloxetine in breast milk was evaluated in one patient 18 days postpartum. The patient had initiated duloxetine 60 mg prior to pregnancy and continued postpartum. Breast milk was sampled over one dosing interval. Peak breast milk concentrations (~120 mcg/L) occurred ~8 hours after the maternal dose. The infant duloxetine serum concentration was 0.82% of the maternal serum concentration. Using the average breast milk concentration (51 mcg/L) authors of the study calculated the estimated infant dose of duloxetine via breast milk to be 7.6 mcg/kg/day providing a relative infant dose (RID) of 0.81% compared to the weight adjusted maternal dose (Boyce 2011).
• Breast milk was sampled from one lactating patient taking duloxetine 60 mg once daily since the second half of pregnancy. Sampling occurred on postpartum day 32, ~6 hours after the morning dose. Duloxetine concentrations were 64 mcg/L (breast milk) and 53 mcg/L (maternal plasma). Duloxetine was not detected in the infant plasma. Authors of the study calculated the estimated infant dose of duloxetine via breast milk to be 7.1 mcg/kg/day providing a RID of 0.82% compared to the weight adjusted maternal dose (Briggs 2009).
• Data are available from a report of 2 patients. The first patient was taking duloxetine 90 mg prior to and during pregnancy; breast milk was sampled 6.5 hours after the maternal dose on postpartum day 29. The breast milk concentration of duloxetine was 32.8 mcg/L. Authors of the study calculated the RID to be 0.3% of the weight adjusted maternal dose. The second patient was taking duloxetine 60 mg daily. Samples were obtained twice, once on postpartum day 6 and again at 6 weeks postpartum. Duloxetine breast milk concentrations were 23.6 mcg/L (foremilk, 21.6 hours after the maternal dose) and 14.3 mcg/L (hindmilk, 23.3 hours after the maternal dose) on postpartum day 6. At 6 weeks postpartum, duloxetine breast milk concentrations were 25.2 mcg/L (foremilk, 5.2 hours after the maternal dose) and 29.3 mcg/L (hindmilk, 29.3 hours after the maternal dose). Authors of the study calculated the RID of duloxetine to be 0.2% to 0.4% of the weight adjusted maternal dose (the RID was calculated based on a maternal weight of 60kg, as the actual weight of either patient was not known) (Collin-Lévesque 2018).
• Additional data are available from 6 lactating patients ≥12 weeks postpartum administered duloxetine 40 mg every 12 hours for 3 days and the morning of day 4. Breast milk was sampled at intervals over 12 hours on the fourth day. Duloxetine concentrations in breast milk ranged from 3.63 to 15.3 mcg/day (Lobo 2008).
• In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Anderson 2021).
Infants exposed to duloxetine via breast milk should be monitored for over sedation, poor feeding, and poor weight gain.
Maternal use of a serotonin reuptake inhibitor (SRI) during pregnancy may delay lactogenesis (Marshall 2010); however, the underlying maternal illness and various other factors may also influence this outcome. Patients who wish to breastfeed during treatment with an SRI may need additional assistance to initiate and maintain breastfeeding (Anderson 2021).
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 the benefits of treatment to the mother.
Patients effectively treated for depression or anxiety during pregnancy may continue their medication postpartum unless contraindications to breastfeeding exist. The presence and concentration of the drug in breast milk, efficacy of maternal treatment, and infant age should be considered when initiating a medication for the first time postpartum (ABM [Sriraman 2015]; BAP [McAllister-Williams 2017]). When first initiating an antidepressant in a patient who is treatment naive and breastfeeding, agents other than serotonin-norepinephrine reuptake inhibitors are preferred (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]); however, duloxetine may be considered as an alternative (CANMAT [MacQueen 2016]). Breastfeeding may be continued in patients treated with an SNRI during pregnancy (ABM [Sriraman 2015]; ACOG 2023). Treatment should not be withheld or discontinued based only on breastfeeding status (ACOG 2023).
Nonmedication therapies should be maximized in lactating patients treated for fibromyalgia; pharmacologic treatment including antidepressants should be reserved for breastfeeding patients with significant symptoms and safety of the medication should be evaluated (Marcus 2011).
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).
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.
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 2023]); some experts suggest up to 12 weeks of treatment may be necessary for response (BAP [Baldwin 2014]; Katzman 2014; WFSBP [Bandelow 2023]).
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%).
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 AUC is reduced by ~33% in smokers.
