duloxetine (Rx)

Brand and Other Names:Cymbalta, Irenka
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

capsule, delayed-release

  • 20mg (Cymbalta, generic)
  • 30mg (Cymbalta, generic)
  • 40mg (Irenka)
  • 60mg (Cymbalta, generic)

Major Depressive Disorder

40-60 mg/day PO initially (in single daily dose or divided q12hr for 1 week if patient needs to adjust to therapy)

For some patients, consider starting at 30 mg qDay for 1 week, to allow patients to adjust to medication before increasing to 60 mg qDay

Diabetic Peripheral Neuropathic Pain

60 mg/day PO initially (in single daily dose or divided q12hr); consider lowering dosage if tolerability is concern

Target dosage: 60 mg/day PO; not to exceed 60 mg/day

Generalized Anxiety Disorder

60 mg/day PO initially (in single daily dose or divided q12hr); may be increased in increments of 30 mg/day if tolerability is concern

Target dosage: 60 mg/day PO; not to exceed 120 mg/day

Fibromyalgia

Cymbalta only

30 mg/day PO initially for 1 week to allow for therapy adjustment

Target dosage: 60 mg/day PO; not to exceed 60 mg/day; no additional benefit shown by doses >60 mg in clinical trials

Chronic Musculoskeletal Pain

Treatment of chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain

30 mg/day PO initially for 1 week to allow for therapy adjustment

Target dosage: 60 mg/day PO; not to exceed 60 mg/day

Dosage Modifications

Renal impairment

  • Mild-to-moderate (CrCl 30-80 mL/min): Population PK analyses suggest that no significant effect on duloxetine apparent clearance
  • Severe (CrCl <30 mL/min): Avoid use
  • End-stage renal disease (ESRD): Limited data; peak plasma concentration and AUC were 100% greater for patients with ESRD receiving chronic hemodialysis

Hepatic impairment

  • Chronic liver disease or cirrhosis: Avoid use

Dosing Considerations

Dosages ≥60 mg/day have not been shown to offer additional benefits; safety and efficacy of doses >120 mg qDay have not been adequately evaluated

Uncontrolled narrow-angle glaucoma: Use not recommended due to increased risk of mydriasis

Discontinuance

  • Gradually reduce dosage
  • Abrupt discontinuance may result in symptoms (eg, dizziness, nausea, headache, paresthesia, fatigue, vomiting, irritability, insomnia, diarrhea, anxiety, hyperhidrosis)
  • Wait ≥14 days after discontinuance of monoamine oxidase inhibitor (MAOI) therapy to initiate duloxetine therapy; wait ≥5 days after discontinuance of duloxetine therapy to initiate MAOI therapy

Other MAO-Is (linezolid or methylene blue)

  • Do not start therapy in a patient who is being treated with linezolid or IV methylene blue due to the potential risk of serotonin syndrome
  • In a patient who requires more urgent treatment of a psychiatric condition, consider other interventions, including hospitalization
  • If linezolid or IV methylene blue must be administered, discontinue duloxetine immediately; monitor for symptoms of serotonin syndrome for 5 days or until 24 hr after the last dose of linezolid or IV methylene blue, whichever comes first
  • Resume duloxetine 24 hr after the last dose of linezolid or IV methylene blue

Dosage Forms & Strengths

capsule, delayed-release

  • 20mg (Cymbalta, generic)
  • 30mg (Cymbalta, generic)
  • 40mg (Irenka)
  • 60mg (Cymbalta, generic)

Generalized Anxiety Disorder

<7 years: Safety and efficacy not established

7-17 years: 30 mg PO qDay initially; after 2 weeks, may consider increasing dose to 60 mg/day

Recommended dosage range: 30-60 mg/day

Some patients may benefit from doses >60 mg/day; if increased beyond 60 mg/day, use increments of 30 mg/day

Maximum dose studied was 120 mg/day; safety of doses >120 mg/day has not been evaluated

Major Depressive Disorder

May initiate at 20 mg PO qDay or divided BID; increase to 40-60 mg qDay or divided doses; alternatively, initiate at 30 mg/day for 1 week, then increase to 60 mg/day as tolerated

Generalized Anxiety Disorder

30 mg/day PO qDay initially; after 2 weeks, consider increasing to target dose of 60 mg/day

Some patients may benefit from doses >60 mg/day; if increased beyond 60 mg/day, use increments of 30 mg/day

Maximum dose studied was 120 mg/day; safety of doses >120 mg/day has not been evaluated

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Interactions

Interaction Checker

and duloxetine

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      Serious - Use Alternative

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            Adverse Effects

            >10%

            Nausea (23-25%)

            Dry mouth (13-15%)

            Headache (13-14%)

            Somnolence (10-12%)

            Fatigue (10-11%)

            1-10%

            Constipation (10%)

            Dizziness (10%)

            Insomnia (10%)

            Diarrhea (9-10%)

            Anorexia (8%)

            Decreased appetite (7-8%)

            Abdominal pain (6%)

            Hyperhidrosis (6%)

            Increased sweating (6%)

            Agitation (5%)

            Nasopharyngitis (5%)

            Vomiting (3-5%)

            Male sexual dysfunction (2-5%)

            Abdominal pain (4%)

            Decreased libido (4%)

            Musculoskeletal pain (4%)

            Upper respiratory tract infection (URTI) (4%)

            Abnormal orgasm (3%)

            Agitation (3%)

            Anxiety (3%)

            Blurred vision (3%)

            Cough (3%)

            Influenza (3%)

            Muscle spasms (3%)

            Tremor (3%)

            Abnormal dreams (2%)

            Dyspepsia (2%)

            Hot flushes (2%)

            Oropharyngeal pain (2%)

            Palpitations (2%)

            Paresthesia (2%)

            Weight loss (2%)

            Yawning (2%)

            Dysuria (>1%)

            Gastritis (>1%)

            Rash (>1%)

            Postmarketing Reports

            General: Anaphylactic reaction, angioneurotic edema, hypersensitivity

            Cardiovascular: Hypertensive crisis, supraventricular arrhythmia, myocardial infarction, tachycardia, Takotsubo cardiomyopathy

            Endocrine: Galactorrhea, gynecologic bleeding, hyperglycemia, hyperprolactinemia

            Neurologic: Restless legs syndrome, seizures upon treatment discontinuance, extrapyramidal disorders

            Ophthalmic: Glaucoma

            Otic: Tinnitus (upon treatment discontinuance)

            Psychiatric: Aggression and anger (particularly early in treatment or after treatment discontinuance), hallucinations

            Musculoskeletal: Trismus, muscle spasm

            Skin: Serious skin reactions (eg, erythema multiforme and Stevens-Johnson syndrome) necessitating drug discontinuance or hospitalization, urticaria, rash

            Gastrointestinal: Colitis (microscopic or unspecified),cutaneous vasculitis (sometimes associated with systemic involvement), acute pancreatitis

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            Warnings

            Black Box Warnings

            Suicidal thoughts and behaviors

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

            Contraindications

            Concomitant use of duloxetine with MAOIs intended to treat psychiatric disorders

            Initiating duloxetine in patients who are being treated with MAOIs (eg, linezolid or IV methylene blue)

            Cautions

            CYP1A2 inhibitors or thioridazine should not be coadministered

            Use caution in severe renal impairment, ESRD

            Heavy alcohol use

            Suicidality; monitor for clinical worsening and suicide risk, especially in children, adolescents and young adults (18-24 years) during early phases of treatment and alterations in dosage

            Serotonin syndrome or neuroleptic malignant syndrome-like reactions may occur; discontinue and initiate supportive therapy; closely monitor patients concomitantly receiving triptans, antipsychotics and serotonin precursors

            Neonates exposed to serotonin-noreponephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) late in 3rd trimester of pregnancy have developed complications necessitating prolonged hospitalization, respiratory support, and tube feeding

            Screen patients for bipolar disorder; risk of mixed/manic episodes is increased in patients treated with antidepressants

            May cause activation of mania or hypomania

            Increased risk of hepatotoxicity, sometimes fatal; monitor for abdominal pain, hepatomegaly, elevations in hepatic transaminases exceeding 20 times upper limit of normal; jaundice; cholestatic jaundice with minimal elevations of hepatic transaminases have also been reported; use not recommended in patients with substantial alcohol use or chronic liver disease

            SSRIs and SNRIs may impair platelet aggregation and increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and GI hemorrhage to life-threatening hemorrhage; concomitant use of aspirin, NSAIDs, warfarin, other anticoagulants, or other drugs known to affect platelet function may add to this risk

            Severe skin reactions (eg, erythema multiforme and Stevens-Johnson syndrome); discontinue at first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified

            Orthostatic hypotension and syncope, especially during week 1 of therapy; monitor patients taking drugs that increase risk of orthostatic hypotension; consider dose reduction or discontinue therapy in patients who experience symptomatic orthostatic hypotension, falls and/or syncope

            Hyponatremia due to syndrome of inappropriate antidiuretic hormone (SIADH); cases of serum sodium <110 mmol/L have been reported to be reversible upon discontinuance

            Diabetes due to worsening of glycemic control in some patients; monitor increases in fasting blood glucose and hemoglobin A1c

            Monitor weight and growth in adolescents and children; decrease in appetite and weight loss reported

            Urinary hesitation and retention

            Cognitive or motor function impairment; use with caution when operating heavy machinery

            Bone fractures reported with antidepressant treatment; consider possibility of bone fracture if patient complains of unexplained bone pain or joint tenderness or experiences bruising or swelling

            May cause or exacerbate sexual dysfunction

            Use caution in gastroparesis, hypertension, controlled narrow angle glaucoma, renal impairment, or seizure disorders

            May lower seizure threshold when administered oncurrently with other drugs that lower seizure threshold

            Use caution when administering concomitantly with CNS depressants

            Risk of mydriasis; may trigger angle closure attack in patients with angle closure glaucoma with anatomically narrow angles without a patent iridectomy

            Headache, dizziness, nausea, diarrhea, paresthesia, vomiting, irritability, insomnia, hyperhidrosis, anxiety, and fatigue reported in patients following abrupt discontinuation of duloxetine

            Therapy may increase blood pressure; measure blood prior to initiating treatment and periodically throughout treatment

            Abnormal bleeding reported when used in combination with aspirin, NSAIDs, or other drugs that affect coagulation

            Angle closure glaucoma reported in patients with untreated anatomically narrow angles that do not have a patent iridectomy and are being treated with antidepressants

            Use with caution in patients with conditions that slow gastric emptying

            Drug interaction overview

            • Development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including duloxetine, when administered concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)
            • If concomitant use with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort is clinically warranted, patients should be made aware of potential risk for serotonin syndrome, particularly during treatment initiation and dose increases; treatment with concomitant serotonergic agents, should be discontinued immediately if above events occur and supportive symptomatic treatment should be initiated
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            Pregnancy & Lactation

            Pregnancy

            There are no adequate and well-controlled studies administration in pregnant women

            Animal data

            • In animal studies with duloxetine, fetal weights were decreased but there was no evidence of teratogenicity in pregnant rats and rabbits at oral doses administered during organogenesis up to 4 and 7 times the maximum recommended human dose (MRHD) of 120 mg/day
            • When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD
            • At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed
            • Postweaning growth was not adversely affected
            • Use in pregnancy only if the potential benefit justifies the potential risk to the fetus

            Pregnancy registry

            • Pregnancy registry monitors the pregnancy outcomes in women exposed during pregnancy
            • Contact pregnancy registry at 1-866-814-6975 or www.cymbaltapregnancyregistry.com

            Clinical considerations

            • Neonates exposed during pregnancy to serotonin - norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding which can arise immediately upon delivery
            • Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying
            • These features are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome
            • In some cases, the clinical picture is consistent with serotonin syndrome

            Lactation

            Drug present in human milk In a published study, lactating women who were weaning their infants were given duloxetine

            At steady state, duloxetine concentration in breast milk was ~25% that of maternal plasma

            Estimated daily infant dose was ~0.14% of the maternal dose

            Exercise caution when administering to a nursing woman

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Exact mechanism of action unknown; inhibits reuptake of serotonin and norepinephrine; weakly inhibits reuptake of dopamine; has no MAOI activity; has no significant activity for histaminergic H1 receptor or alpha2-adrenergic receptor

            Absorption

            Well absorbed

            Peak plasma time: 6 hr (Empty stomach); 10 hr (with food)

            Distribution

            Vd: 3.4 L/kg

            Protein bound: >90%

            Metabolism

            Metabolized in liver by CYP2D6 and CYP1A2

            Metabolites: 4-Hydroxy duloxetine glucuronide; 5-hydroxy, 6-methoxy duloxetine sulfate

            Enzymes inhibited: CYP2D6

            Elimination

            Half-life: 12 hr

            Excretion: Urine (70% as metabolites; <1% unchanged), feces (20%)

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            Administration

            Oral Administration

            Swallow capsule whole; do not chew or crush

            Do not open capsule and sprinkle its contents on food or mix with liquids

            All of these might affect the enteric coating

            May be administer without regard to meals

            Missed dose

            • If a dose is missed, take missed dose as soon as it is remembered
            • If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time; do not take 2 doses at the same time

            Storage

            Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.