Skip to Content
Could you or a loved one be experiencing depression?

DULoxetine

Pronunciation

Pronunciation

(doo LOX e teen)

Index Terms

  • (+)-(S)-N-Methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine Hydrochloride
  • Duloxetine HCl
  • Duloxetine Hydrochloride
  • LY248686

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)]

Irenka: 40 mg

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

Brand Names: U.S.

  • Cymbalta
  • Irenka

Pharmacologic Category

  • Antidepressant, Serotonin/Norepinephrine Reuptake Inhibitor

Pharmacology

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.

Absorption

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

Distribution

~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

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

Protein Binding

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

Special Populations: Renal Function Impairment

Cmax and AUC were approximately 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 approximately 33% in smokers.

Use: Labeled Indications

Chronic musculoskeletal pain: Management of chronic musculoskeletal pain.

Diabetic peripheral neuropathic pain: Management of diabetic peripheral neuropathy.

Fibromyalgia (except Irenka): Management of fibromyalgia.

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

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

Use: Unlabeled

Treatment of stress incontinence

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 CYP1A2 inhibitors.

Dosing: Adult

Major depressive disorder: Oral:

US labeling: Initial: 40 to 60 mg daily; dose may be divided (ie, 20 or 30 mg twice daily) or given as a single daily dose of 60 mg. 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; maximum dose: 120 mg daily.

Canadian labeling: Initial: 60 mg once daily. Based on tolerability, it may be desirable to start at 30 mg once daily for 1 to 2 weeks before increasing to maintenance dose of 60 mg once daily; maximum dose: 60 mg daily.

Note: Doses >60 mg daily have not been demonstrated to be more effective than 60 mg daily.

Diabetic neuropathy: Oral:

US labeling: Initial: 60 mg once daily; lower initial doses may be considered in patients where tolerability is a concern and/or renal impairment is present; maximum dose: 60 mg once daily.

Canadian labeling: Initial: 60 mg daily. Based on tolerability, it may be desirable to start at 30 mg once daily for 1 to 2 weeks before increasing to 60 mg once daily; maximum dose: 120 mg daily.

Note: Doses >60 mg/day administered in clinical trials offered no additional benefit and were less well tolerated than dose of 60 mg daily.

Fibromyalgia (excluding Irenka): Oral:

US labeling: Initial: 30 mg once daily for 1 week, then increase to 60 mg once daily as tolerated; maximum dose: 60 mg daily.

Canadian labeling: Initial: 30 to 60 mg once daily (based on tolerability) for 1 to 2 weeks; then increase to 60 mg once daily as tolerated; maximum dose: 60 mg daily.

Note: Doses >60 mg daily administered in clinical trials offered no additional benefit and were less well tolerated than dose of 60 mg daily.

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. For doses >60 mg once daily, titrate dose in increments of 30 mg once daily over 1 week (US labeling) or 1 to 2 weeks (Canadian labeling) as tolerated; maximum dose: 120 mg once daily. Note: Doses >60 mg once daily have not been demonstrated to be more effective than 60 mg once daily.

Chronic musculoskeletal pain: Oral: 30 mg once daily for 1 week (US labeling) or 1 to 2 weeks (Canadian labeling), then increase to 60 mg once daily as tolerated; maximum dose: 60 mg once daily. Note: Doses >60 mg once daily administered in clinical trials offered no additional benefit and were less well tolerated than dose of 60 mg once daily. The Canadian labeling indicates that a maximum dose of 120 mg daily may be considered for patients with chronic pain associated with osteoarthritis of the knee.

Stress urinary incontinence (women) (off-label use): Oral: 40 mg twice daily (Li, 2013). Lower initial doses have been used to reduce adverse effects: 20 mg twice daily for 2 weeks titrated to or followed by 40 mg twice daily (Castro-Diaz, 2007; Schagen van Leeuwen, 2008).

Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms. Evidence supporting ideal taper rates 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. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4-6 months. If intolerable withdrawal 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; Haddad, 2001; NCCMH, 2010; Schatzberg, 2006; Shelton, 2001; Warner, 2006).

MAO inhibitor recommendations:

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

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

Allow ≥5 to 14 days to elapse between discontinuing duloxetine and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Use with other MAO inhibitors (such as linezolid or IV methylene blue):

Do not initiate duloxetine in patients receiving linezolid or IV methylene blue; consider other interventions for psychiatric condition.

If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving duloxetine and potential benefits outweigh potential risks, discontinue duloxetine promptly and administer linezolid or IV methylene blue. Monitor for serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first. May resume duloxetine 24 hours after the last dose of linezolid or IV methylene blue.

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 once daily.

Other indications: Refer to adult dosing.

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Pediatric

Generalized anxiety disorder: Children and Adolescents 7 to 17 years: Oral: Initial: 30 mg once daily; after 2 weeks may increase based on response and tolerability to 60 mg once daily; titrate doses >60 mg once daily in increments of 30 mg once daily; maximum dose: 120 mg once daily. Note: Use in patients <18 years of age is not approved in the Canadian labeling.

Dosing: Renal Impairment

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: Avoid use (contraindicated in Canadian labeling)

End-stage renal disease (ESRD): Avoid use (contraindicated in Canadian labeling)

Dosing: Hepatic Impairment

Avoid use in hepatic impairment (contraindicated in Canadian labeling).

Administration

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

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. 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

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

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

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

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. 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

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

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. 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

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

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

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

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

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

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. 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 adverse/toxic effect of Serotonin Modulators. Avoid combination

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

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. 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

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

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

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

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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. 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

Iobenguane I 123: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

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

MAO Inhibitors: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Avoid combination

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

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

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. 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 may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification

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

NSAID (Nonselective): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. 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

PARoxetine: DULoxetine may enhance the serotonergic effect of PARoxetine. This could result in serotonin syndrome. PARoxetine may increase the serum concentration of DULoxetine. Management: Coadminister with caution. If duloxetine and paroxetine are used in combination, monitor for signs and symptoms of serotonin toxicity/serotonin syndrome, as well as other toxic effects of duloxetine. Consider therapy modification

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. 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

Propafenone: May increase the serum concentration of CYP2D6 Inhibitors (Moderate). Monitor therapy

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

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

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

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. 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

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. 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

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Tricyclic Antidepressants: DULoxetine may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may decrease the metabolism of Tricyclic Antidepressants. Management: Use these drugs in combination with caution. Monitor closely for signs and symptoms of serotonin toxicity/serotonin syndrome. Consider therapy modification

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

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Vitamin E (Systemic): 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), diarrhea (6% to 9%), vomiting (adults: 3% to 4%; children and adolescents: 9%), decreased appetite (6% to 10%; dose related), 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% (Limited to important or life-threatening): Alopecia, angle-closure glaucoma, apathy, bruxism, cardiac failure (exacerbation), cardiomyopathy, cholestatic jaundice, disorientation, dysarthria, dysphagia, dysuria, emotional lability, erythema multiforme, extrapyramidal reaction, falling, gastroenteritis, gastrointestinal hemorrhage, glaucoma, hallucination, hematoma, hepatic failure, hepatic injury, hyperglycemia, hyperkalemia, hyperlipidemia, hypersensitivity angiitis, hypersensitivity reaction, hypokalemia, hypothyroidism, impulsivity, increased serum bicarbonate, jaundice, lymphocytic colitis, menopausal symptoms, menstrual disease, muscle spasm, myocardial infarction, night sweats, orthostatic hypotension, outbursts of anger (particularly early in treatment or after treatment discontinuation), panic attack, restless leg syndrome, seizure, sensation of cold, serotonin syndrome, SIADH, skin photosensitivity, Stevens-Johnson syndrome, suicidal ideation, supraventricular cardiac arrhythmia, syncope, tachycardia, testicular pain, thrombocytopenia, trismus, urinary retention, urinary urgency

ALERT: U.S. Boxed Warning

Suicidal thoughts and behavior:

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. The studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients older than 24 years; there was a reduction in risk with antidepressant use in patients 65 years and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.

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 healthcare provider. A medication guide concerning the use of antidepressants in children and teenagers should be dispensed with each prescription. Duloxetine is not FDA approved for use in children.

• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.

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 (contraindicated in Canadian labeling). 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 A1c (HbA1c) 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 worsen psychosis in some patients or 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 (contraindicated in Canadian labeling).

• 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 should be checked prior to initiating therapy and then regularly monitored, especially in patients with a high baseline blood pressure; mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks or other unusual changes in behavior; glucose levels and HbA1c levels in diabetic patients, creatinine, BUN, transaminases

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Nonteratogenic effects in the newborn following SSRI/SNRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hyper- or hypotonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Symptoms may be due to the toxicity of the SNRIs/SSRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. The long-term effects of in utero SNRI/SSRI exposure on infant development and behavior are not known.

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

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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, constipation, diarrhea, dry mouth, loss of strength and energy, insomnia, fatigue, lack of appetite, or sweating a lot. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of low sodium (headache, difficulty focusing, memory problems, illogical thinking, weakness, seizures, or change in balance), signs of bleeding (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 bleeding or persistent bleeding, severe headache, dizziness, passing out, memory impairment, tinnitus, urinary retention, change in amount of urine passed, excessive weight gain or loss, sexual dysfunction, vision changes, eye pain, eye irritation, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, severe diarrhea), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Hide