Dosing and uses of Cymbalta (duloxetine)
Adult dosage forms and strengths
capsule, delayed-release
- 20mg
- 30mg
- 40mg
- 60mg
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)
Titrate dose in increments of 30 mg/day over 1 week as tolerated
Target dosage: 60 mg/day PO (in single daily dose or divided q12hr); not to exceed 120 mg/day (safety of dosages >120 mg/day has not been evaluated)
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
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 mig 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
Dosing Modifications
Severe renal impairment (CrCl <30 mL/min) or end-stage renal disease (ESRD): Use not recommended
Hepatic impairment: Use not recommended, because of risk of hepatic injury
Dosing Considerations
Dosages ≥60 mg/day have not been shown to offer additional benefits
Major depressive disorder and generalized anxiety disorder: Acute episodes often necessitate several months of sustained therapy
Diabetic peripheral neuropathic pain: Efficacy for >12 weeks has not been studied; if diabetes is complicated by renal disease, consider lower starting dosage with gradual increase to effective dosage
Fibromyalgia: Efficacy for ≥12 weeks has not been studied; continue treatment on basis of individual patient response
Chronic musculoskeletal pain: Efficacy for ≥13 weeks has not been studied
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
Renal Impairment
Avoid use in patients with severe renal impairment (GFR <30 mL/min)
Hepatic Impairment
Avoid use in patients with chronic liver disease or cirrhosis
Administration
Because of enteric coating, must be swallowed whole; do not chew, crush, or open capsule and sprinkle contents in food or liquid
Can be taken without regard to meals
Pediatric dosage forms and strengths
capsule, delayed-release
- 20mg
- 30mg
- 40mg
- 60mg
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
Geriatric dosage forms and strengths
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
Cymbalta (duloxetine) adverse (side) 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%)
Nausea (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
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
Warnings
Black box warnings
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
Coadministration with serotonergic drugs
- Wait ≥14 days between discontinuance of MAOI and initiation of duloxetine; wait ≥5 days between discontinuance of duloxetine and initiation of MAOI
- Starting duloxetine in patient being treated with linezolid or IV methylene blue is contraindicated because of increased risk of serotonin syndrome
- If linezolid or IV methylene blue must be administered, discontinue duloxetine immediately and monitor for central nervous system (CNS) toxicity; duloxetine may be resumed 24 hours after last linezolid or methylene blue dose or after 2 weeks of monitoring, whichever comes first
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
Pregnancy and lactation
Pregnancy category: C
Lactation: Drug enters breast milk; use not recommended unless benefits greatly outweigh risks
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.
Pharmacology of Cymbalta (duloxetine)
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%)
