DULoxetine

Dosage Forms

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)]

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

Capsule Delayed Release Sprinkle, Oral:

Drizalma Sprinkle: 20 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #10 (quinoline yellow)]

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

Drizalma Sprinkle: 40 mg

Drizalma Sprinkle: 60 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #10 (quinoline yellow)]

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Absorption

Well absorbed, 2-hour delay in absorption after ingestion; food decreases extent of absorption ~10% (no effect on C_max)

Distribution

V_d:

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

Adults: ~1,640 L

Metabolism

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

Excretion

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

Time to Peak

6 hours; 10 hours when ingested with food

Half-Life Elimination

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

Adults: ~12 hours (range: 8 to 17 hours); ~4 hours longer in elderly women

Protein Binding

>90%; primarily to albumin and alpha₁-acid glycoprotein

Use in Specific Populations

Special Populations: Renal Function Impairment

C_max and AUC were ~100% greater in patients with ESRD receiving intermittent hemodialysis.

Special Populations: Hepatic Function Impairment

Metabolism and elimination of duloxetine were decreased in patients with clinically evident hepatic impairment.

Special Populations: Elderly

AUC was ~25% higher in elderly women.

Special Populations Note

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

Use: Labeled Indications

Fibromyalgia: Management of fibromyalgia

Generalized anxiety disorder: Treatment of generalized anxiety disorder (GAD)

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

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

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

Use: Off Label

Chemotherapy-induced peripheral neuropathybyes

Data from a randomized, double-blind, placebo-controlled study support the use of duloxetine in the treatment of pain, numbness, and tingling associated with chemotherapy-induced peripheral neuropathy. Subgroup analyses suggest efficacy may be greater for oxaliplatin-induced neuropathy as opposed to paclitaxel-induced neuropathy Smith 2013.

Based on the American Society of Clinical Oncology clinical practice guidelines for the prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers, duloxetine is suggested in the management of chemotherapy-induced peripheral neuropathy.

Stress urinary incontinence (men)byes

Data from a single-blind randomized study and 2 small open-label studies support the use of duloxetine in the treatment of stress urinary incontinence postprostatectomy in patients unresponsive to nonpharmacologic interventions Filocamo 2007, Fink 2008, Schlenker 2006.

Based on the

Stress urinary incontinence (women)cyes

Data from controlled trials of low and high quality, systematic reviews, and meta-analyses are conflicting.Li 2013, Schagen van Leeuwen 2008, Shamliyan 2012

American College of Physicians (ACP) guidelines on nonsurgical management of urinary incontinence recommend against pharmacologic therapy in women with stress urinary incontinence and note that although low-quality, placebo-controlled studies of duloxetine demonstrate beneficial effects, these effects have not been confirmed by data from high-quality studies.

Contraindications

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

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.

Dosage and Administration

Dosing: Adult

Chemotherapy-induced peripheral neuropathy (off-label use): Oral: Initial: 30 mg once daily for 1 week, then 60 mg once daily (Smith 2013)

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 (Murakami 2017). 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 (Bystritsky 2018; Simon 2010). If dose is escalated, increase by 30 mg increments at intervals of ≥1 week as needed and tolerated (Bystritsky 2018). 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, based upon limited data, individual patients may benefit from dose escalation (Nelson 2018; Shelton 2007). If dose is escalated, increase by 30 mg increments at intervals of ≥1 week as needed and tolerated (Nelson 2018). 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 (ACP [Qaseem 2017]; Chou 2018; Isaac 2019).

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 (Isaac 2019; manufacturer’s labeling).

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 (Deveza 2018; OARSI [McAlindon 2014]).

Oral: Initial: 30 mg once daily for 1 week, then 60 mg once daily. Maximum dose (manufacturer's labeling): 60 mg/day. Doses up to 120 mg/day may provide some additional benefit (Chappell 2009); however, adverse effects may be increased (Micca 2013).

Neuropathic pain associated with diabetes mellitus: Oral: Initial: 60 mg once daily; lower initial doses may be considered in patients when tolerability is a concern; maximum dose: 60 mg/day; doses up to 120 mg/day were studied in clinical trials but did not confer any additional benefit (Ormseth 2011).

Stress urinary incontinence (women and men) (off-label use): Note: For patients who are unresponsive to nonpharmacologic interventions or have comorbid depression (ACP [Qaseem 2014]; EAU [Burkhard 2018]; NICE 2013).

Oral: 40 mg twice daily (Filocamo 2007; Li 2013). Lower initial doses have been used in women to reduce adverse effects: 20 mg twice daily for 2 weeks then 40 mg twice daily (Castro-Diaz 2007; Schagen van Leeuwen 2008).

Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (APA 2010; WFSBP [Bauer 2015]). Reasons for a slower titration (eg, over 4 weeks) include use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), prior history of antidepressant withdrawal symptoms, or high doses of antidepressants (APA 2010; Hirsch 2019). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (WFSBP [Bauer 2015]). Evidence supporting ideal taper rates is limited (Shelton 2001; WFSBP [Bauer 2015]).

Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (Hirsch 2018; Ogle 2013; WFSBP [Bauer 2013]).

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 (APA 2010).

Dosing: Geriatric

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 (Kennedy 2005). Refer to adult dosing.

Other indications: Refer to adult dosing.

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosing: Pediatric

Generalized anxiety disorder (GAD): Children ≥7 years and Adolescents ≤17 years: Oral: Initial: 30 mg once daily; after 2 weeks, may increase based on response and tolerability 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 (Strawn 2015)

Major depressive disorder (MDD): Children ≥7 years and Adolescents ≤17 years: Limited data available, efficacy not established: 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 (Atkinson 2014; Emslie 2014).

Discontinuation of therapy: Consider planning antidepressant discontinuation for lower-stress times, recognizing non-illness-related factors could cause stress or anxiety and be misattributed to antidepressant discontinuation (Hathaway 2018). Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of discontinuation syndromes (withdrawal) and allow for the detection of reemerging disease state symptoms (eg, relapse). Evidence supporting ideal taper rates after illness remission is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. After long-term (years) antidepressant treatment, WFSBP guidelines recommend tapering over 4 to 6 months, with close monitoring during and for 6 months after discontinuation. If intolerable discontinuation symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (APA 2010; Bauer 2002; Fenske 2009; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

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.

Administration

Oral: 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 (Wells 2008). 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 (FDA 2007). Administer without regard to meals.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

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

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

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

Alcohol (Ethyl): May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Specifically, risks of psychomotor impairment may be enhanced. Alcohol (Ethyl) may enhance the hepatotoxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Particularly duloxetine and milnacipran. Management: Patients receiving serotonin/norepinephrine reuptake inhibitors (SNRIs) should be advised to avoid alcohol. Monitor for increased psychomotor impairment and hepatotoxicity in patients who consume alcohol during treatment with SNRIs. Consider therapy modification

Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Alpha-/Beta-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Consider therapy modification

Alpha2-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine. Monitor therapy

Amphetamines: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amphetamines. Monitor therapy

Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Exceptions: Bemiparin; Enoxaparin; Heparin. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Alosetron; Ondansetron; Ramosetron. Monitor therapy

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

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

ARIPiprazole: May enhance the adverse/toxic effect of DULoxetine. ARIPiprazole may enhance the serotonergic effect of DULoxetine. This could result in serotonin syndrome. DULoxetine may increase the serum concentration of ARIPiprazole. Monitor therapy

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

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

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

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

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

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

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

BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

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

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

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

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

Cyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

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

CYP2D6 Inhibitors (Strong): May increase the serum concentration of DULoxetine. Exceptions: FLUoxetine; PARoxetine. Monitor therapy

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

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

Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

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

Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

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

Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Eliglustat: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

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

Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Nicergoline. Monitor therapy

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

FentaNYL: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Monitor therapy

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

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

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Management: Avoid combination when possible. If used, monitor more closely for evidence of bleeding. Discontinue herbal products with anticoagulant or antiplatelet actions 2 weeks prior to surgical, dental, or invasive procedures. Consider therapy modification

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

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

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

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

Iobenguane Radiopharmaceutical Products: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Avoid combination

Ioflupane I 123: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

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

Lorcaserin: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Meperidine: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

Metoclopramide: May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with serotonin/norepinephrine reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

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

Mirtazapine: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

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

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

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

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

Nefazodone: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

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

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

Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Opioid Agonists: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: FentaNYL; Meperidine; TraMADol. Monitor therapy

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

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

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification

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

Propafenone: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

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

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

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

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

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

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

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

Serotonergic Agents (High Risk, Miscellaneous): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Almotriptan; Eletriptan. Monitor therapy

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

St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

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

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

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

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

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

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

TraZODone: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Tricyclic Antidepressants: DULoxetine may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations and effects if these agents are combined. Monitor therapy

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

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

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

Adverse Reactions

>10%:

Central nervous system: Headache (13% to 14%), drowsiness (9% to 11%; dose related), fatigue (7% to 11%; dose related)

Gastrointestinal: Nausea (18% to 23%), xerostomia (adults: 11% to 14%; dose related, children and adolescents: 2%), abdominal pain (children and adolescents: 13%, adults: 5%)

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

Neuromuscular & skeletal: Weakness (≤7% to ≤11%; dose related)

1% to 10%:

Cardiovascular: Flushing (3%), increased blood pressure (2%), palpitations (≥1% to 2%)

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

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

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

Gastrointestinal: Constipation (9% to 10%; dose related), decreased appetite (6% to 10%; dose related), vomiting (children and adolescents: 9%; adults: 3% to 4%), diarrhea (6% to 9%), dyspepsia (2%), dysgeusia (≥1%), flatulence (≥1%)

Genitourinary: Erectile dysfunction (4%), ejaculatory disorder (2%), urinary frequency (≥1%)

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

Neuromuscular & skeletal: Tremor (2% to 3%; dose related), musculoskeletal pain (≥1%)

Ophthalmic: Blurred vision (≥1% to 3%)

Respiratory: Oropharyngeal pain (children and adolescents: 4%; adults: ≥1%), cough (children and adolescents: 3%)

<1%, postmarketing, and/or case reports: Abnormal gait, acute pancreatitis, aggressive behavior (particularly early in treatment or after treatment discontinuation), akathisia, anaphylaxis, angioedema, angle-closure glaucoma, apathy, bruxism, cardiomyopathy (takotsubo), cholestatic jaundice, cold extremities, confusion, contact dermatitis, dehydration, diplopia, disorientation, disturbance in attention, dry eye syndrome, dysarthria, dyskinesia, dyslipidemia, dysphagia, dysuria, ecchymoses, elevated glycosylated hemoglobin (diabetic neuropathic pain), emotional lability, epistaxis, eructation, erythema, erythema multiforme, extrapyramidal reaction, falling, feeling abnormal, galactorrhea, gastric ulcer, gastritis, gastroenteritis, gastrointestinal hemorrhage, gynecological bleeding, halitosis, hallucination, hematoma, hepatic failure, hepatitis, hepatomegaly, hostility, hyperbilirubinemia, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hyperprolactinemia, hypersensitivity angiitis, hypersensitivity reaction, hypertensive crisis, hypertonia, hypokalemia, hypomania, hyponatremia, hypothyroidism, impulsivity, increased blood pressure, increased creatine phosphokinase, increased diastolic blood pressure, increased serum alkaline phosphatase, increased serum AST, increased serum bicarbonate, increased serum transaminases, increased thirst, irritability, jaundice, laryngitis, lymphocytic colitis, malaise, malodorous urine, mania, menopausal symptoms, menstrual disease, myocardial infarction, muscle spasm, muscle twitching, myoclonus, night sweats, nocturia, orthostatic hypotension, otalgia, outbursts of anger (particularly early in treatment or after treatment discontinuation), panic attack, petechia, pharyngeal edema, polyuria, restless leg syndrome, seizure, sensation of cold, serotonin syndrome, sexual disorder, SIADH, skin photosensitivity, skin rash, Stevens-Johnson syndrome, stomatitis, suicidal ideation, supraventricular cardiac arrhythmia, syncope, tachycardia, testicular pain, tinnitus, trismus, urinary retention, urinary urgency, urticaria, visual disturbance

Warnings/Precautions

Major psychiatric warnings:

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

Concerns related to adverse effects:

• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin or NSAIDs due to ulcerogenic potential. Bleeding related to SNRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.
• CNS depression: Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.
• Dermatologic: Severe skin reactions (including Stevens-Johnson syndrome and erythema multiforme) have been reported; discontinue immediately if blisters, peeling rash, mucosal erosions, or any other signs of hypersensitivity reactions are suspected.
• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).
• Hepatotoxicity: Avoid use in patients with substantial ethanol intake, evidence of liver disease or hepatic impairment. Rare cases of hepatic failure (including fatalities) have been reported with use. Hepatitis with abdominal pain, hepatomegaly, elevated transaminase levels >20 times the upper limit of normal (ULN) with and without jaundice have all been observed. Discontinue therapy with the presentation of jaundice or other signs of hepatic dysfunction and do not reinitiate therapy unless another source or cause is identified.
• Hyperglycemia: Modest increases in serum glucose and hemoglobin A_1c (HbA_1c) levels have been observed in some diabetic patients receiving duloxetine for diabetic peripheral neuropathic pain (DPNP).
• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.
• Orthostatic hypotension/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.
• Serotonin syndrome (SS) reactions: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St John's wort) or drugs that impair serotonin metabolism (eg, MAO inhibitors, specifically linezolid, methylene blue, and others used for psychiatric disorders). Monitor patients closely for signs/symptoms of SS which may include mental status changes (eg, agitation, hallucinations, delirium), seizures, autonomic instability (eg, tachycardia, dizziness, diaphoresis), neuromuscular symptoms (eg, tremor, rigidity, myoclonus), or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Discontinue treatment (and any concomitant serotonergic agents) immediately if signs/symptoms arise.
• Sexual dysfunction: May cause or exacerbate sexual dysfunction.
• SIADH and hyponatremia: SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L), predominately in the elderly. Volume depletion and/or concurrent use of diuretics likely increases risk.
• Urinary hesitancy: May cause increased urinary resistance; advise patient to report symptoms of urinary hesitation/difficulty.

Disease-related concerns:

• Gastroparesis: Use caution in patients with impaired gastric motility (eg, some diabetics); may affect stability of the capsule's enteric coating.
• Hepatic impairment: Avoid use in patients with chronic liver disease or cirrhosis.
• Hypertension: Use caution in patients with hypertension. Although no statistically significant differences in the frequency of sustained elevations of blood pressure were observed in clinical trials when compared with placebo, modest increases in blood pressure have been reported with use. Additionally, rare cases of hypertensive crisis have been reported; blood pressure 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.
• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Duloxetine is not FDA approved for the treatment of bipolar depression.
• Renal impairment: Use with caution; clearance is decreased and plasma concentrations are increased; avoid use in patients with CrCl <30 mL/minute or ESRD.
• Seizure disorders: Use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage or alcoholism (Montgomery 2005).

Concurrent drug therapy issues:

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

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 blood pressure. 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.

Other warnings/precautions:

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

Monitoring Parameters

Blood pressure (baseline, then periodically, especially in patients with high baseline blood pressure); liver and renal function tests (baseline; as clinically indicated); suicidal ideation (baseline and with dose changes); serum sodium in at-risk populations (as clinically indicated); blood glucose and HbA_1c in diabetic patients (baseline and as clinically indicated)

Pregnancy

Pregnancy Considerations

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

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

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

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

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

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

Health care providers are encouraged to enroll women exposed to duloxetine during pregnancy in the Cymbalta Pregnancy Registry (866-814-6975 or http://cymbaltapregnancyregistry.com).

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Patient Education

What is this drug used for?

• It is used to treat low mood (depression), anxiety, and some products are used to treat fibromyalgia. It is used to help painful nerve diseases and diabetic nerve problems. It is used to ease long-term pain problems. It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Constipation
• Diarrhea
• Abdominal pain
• Dry mouth
• Weakness
• Weight loss
• Trouble sleeping
• Fatigue
• Lack of appetite
• Sweating a lot

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

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion
• Agitation
• Panic attacks
• Mood changes
• Low sodium like headache, difficulty focusing, trouble with memory, confusion, weakness, seizures, or change in balance
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Severe headache
• Dizziness
• Passing out
• Unable to pass urine
• Sexual dysfunction
• Vision changes
• Decreased sex drive
• Eye pain
• Eye redness
• Eye edema
• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

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

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