What is the recommended dosing regimen for Cymbalta (duloxetine) in patients with major depressive disorder, generalized anxiety disorder, or fibromyalgia, particularly those with impaired renal function or liver disease?

Cymbalta (Duloxetine) Dosing

Major Depressive Disorder

For adults with major depressive disorder, start duloxetine at 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). 1

• For some patients, it may be desirable to start at 30 mg once daily for 1 week to allow adjustment before increasing to 60 mg once daily 1
• While 120 mg/day has been shown effective, there is no evidence that doses greater than 60 mg/day confer additional benefits 1
• The recommended dosage range is 40-120 mg/day, with 60 mg once daily being the highest recommended dosage that shows improvements in efficacy measures after 1-2 weeks of treatment 2

Generalized Anxiety Disorder

Adults Less Than 65 Years of Age

Initiate duloxetine at 60 mg once daily for most adults with generalized anxiety disorder. 1

• For some patients, start at 30 mg once daily for 1 week before increasing to 60 mg once daily 1
• While 120 mg once daily was shown effective, there is no evidence that doses greater than 60 mg/day confer additional benefit 1
• If increasing beyond 60 mg once daily, use increments of 30 mg once daily 1
• Duloxetine 60-120 mg once daily demonstrated significant improvements in Hamilton Anxiety Rating Scale scores compared to placebo in 9-10 week trials 3

Geriatric Patients (≥65 Years)

In geriatric patients with generalized anxiety disorder, initiate duloxetine at 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg/day. 1

• Patients may benefit from doses above 60 mg once daily 1
• If increasing beyond 60 mg once daily, use increments of 30 mg once daily, with a maximum studied dose of 120 mg per day 1

Pediatric Patients (7-17 Years)

Initiate duloxetine in pediatric patients 7-17 years of age at 30 mg once daily for 2 weeks before considering an increase to 60 mg once daily. 1

• The recommended dosage range is 30-60 mg once daily 1
• Some patients may benefit from dosages above 60 mg once daily 1
• If increasing beyond 60 mg once daily, use increments of 30 mg once daily, with a maximum studied dose of 120 mg per day 1

Fibromyalgia

The recommended duloxetine dosage for fibromyalgia is 60 mg once daily in adults. 1

• Begin treatment at 30 mg once daily for 1 week to allow adjustment before increasing to 60 mg once daily 1
• Some patients may respond to the 30 mg starting dosage 1
• There is no evidence that dosages greater than 60 mg/day confer additional benefit, even in patients who do not respond to 60 mg/day, and higher dosages are associated with higher rates of adverse reactions 1
• Both duloxetine 60 mg once daily and 60 mg twice daily (120 mg/day) were effective and safe in treating fibromyalgia in female patients with or without major depressive disorder, with treatment effects on pain reduction independent of effects on mood 4
• The EULAR guidelines note that duloxetine at 20-120 mg/day for 12-28 weeks has moderate quality evidence, with dropout rates due to side effects higher than placebo but no difference in serious adverse events 5

Important Administration Instructions

• Administer duloxetine delayed-release capsules orally with or without meals and swallow whole 1
• Do not chew, crush, open the capsule, or sprinkle contents on food or mix with liquids, as these actions might affect the enteric coating 1
• If a dose is missed, take it as soon as remembered; if it is almost time for the next dose, skip the missed dose and take the next dose at the regular time 1
• Never take two doses at the same time 1

Special Populations

Hepatic Impairment

Avoid use in patients with chronic liver disease or cirrhosis. 1

Severe Renal Impairment

Avoid use in patients with severe renal impairment (GFR <30 mL/minute). 1

• Since diabetes is frequently complicated by renal disease, consider a lower starting dosage and gradual increase for patients with renal impairment 1

Discontinuation

A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible. 1

• Adverse reactions after discontinuation include dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue 1
• Discontinuation-emergent adverse events, most commonly nausea and dizziness, occurred in up to one-third of duloxetine recipients in short-term trials 3

Pharmacokinetic Considerations

• Duloxetine achieves maximum plasma concentration approximately 6 hours after dosing, with an elimination half-life of approximately 10-12 hours 6
• Steady state is typically reached by day 3 of administration 3
• Duloxetine is metabolized by CYP1A2 and CYP2D6; concomitant use with potent CYP1A2 inhibitors (such as fluvoxamine) should be avoided, as this increases duloxetine exposure by 460% 6
• Smoking is associated with a 30% decrease in duloxetine concentration 6
• CYP2D6 inhibitors or poor metabolizer status increases duloxetine exposure to a lesser extent than CYP1A2 inhibition and does not require dose adjustment 6

Common Pitfalls to Avoid

• Never initiate treatment at 120 mg/day, as higher starting doses are associated with increased discontinuation rates due to adverse events without clear evidence of superior efficacy 2
• Avoid combining duloxetine with potent CYP1A2 inhibitors like fluvoxamine, as this dramatically increases duloxetine levels and risk of toxicity 6
• Do not abruptly discontinue duloxetine, as this increases risk of withdrawal symptoms; always taper gradually 1
• Avoid use in patients with hepatic impairment or severe renal impairment, as duloxetine clearance is significantly reduced in these populations 1