Cymbalta - Drug Monograph

Introduction

Cymbalta (duloxetine hydrochloride) is a prescription medication classified as a serotonin-norepinephrine reuptake inhibitor (SNRI). Developed by Eli Lilly and Company, it was first approved by the FDA in 2004. Cymbalta represents an important therapeutic option for multiple neuropsychiatric and pain conditions, offering dual neurotransmitter modulation that distinguishes it from selective serotonin reuptake inhibitors (SSRIs).

Mechanism of Action

Duloxetine exerts its therapeutic effects by potently inhibiting the reuptake of both serotonin (5-HT) and norepinephrine (NE) in the central nervous system. It achieves this by binding to the serotonin transporter (SERT) and norepinephrine transporter (NET), increasing the availability of these neurotransmitters in the synaptic cleft. This dual mechanism is believed to underlie its efficacy in both mood disorders and chronic pain conditions. Duloxetine has minimal affinity for muscarinic, histaminergic, or adrenergic receptors, resulting in a more favorable side effect profile compared to tricyclic antidepressants.

Indications

FDA-approved indications include:

• Major depressive disorder (MDD)
• Generalized anxiety disorder (GAD)
• Diabetic peripheral neuropathic pain (DPNP)
• Fibromyalgia
• Chronic musculoskeletal pain

Additionally, duloxetine is used off-label for:

• Stress urinary incontinence
• Chemotherapy-induced peripheral neuropathy
• Osteoarthritis pain
• Low back pain

Dosage and Administration

• Depression: 40-60 mg/day (initiate at 30 mg/day for one week, then increase to 60 mg/day)
• Anxiety: 60 mg/day (may initiate at 30 mg/day for one week)
• Neuropathic pain: 60 mg/day
• Fibromyalgia: 30-60 mg/day
• Chronic musculoskeletal pain: 60 mg/day

• Administer whole capsule orally, with or without food
• Do not crush, chew, or open capsules (contents may cause irritation)
• Swallow capsule whole to avoid taste irritation

• Hepatic impairment: Avoid use in chronic liver disease
• Renal impairment: Not recommended in severe renal impairment (CrCl <30 mL/min)
• Elderly: Initiate at lower doses; monitor closely
• Pediatrics: Safety and effectiveness not established under age 7

Pharmacokinetics

Contraindications

• Concomitant use with MAOIs or within 14 days of MAOI discontinuation
• Uncontrolled narrow-angle glaucoma
• Known hypersensitivity to duloxetine or product components
• Severe hepatic impairment
• Concomitant use with thioridazine

Warnings and Precautions

• Increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults
• Not approved for use in pediatric patients except for certain conditions

• Hepatotoxicity: Cases of liver injury reported
• Orthostatic hypotension and syncope: Monitor blood pressure
• Serotonin syndrome: Risk increased with other serotonergic drugs
• Abnormal bleeding: Increased risk of bleeding events
• Activation of mania/hypomania: Screen for bipolar disorder
• Discontinuation syndrome: Taper gradually when discontinuing
• Seizures: Use cautiously in patients with seizure history
• Hyponatremia: Monitor sodium levels in elderly patients

Drug Interactions

• MAOIs: Contraindicated (risk of serotonin syndrome)
• Other serotonergic drugs: Increased serotonin syndrome risk (tramadol, triptans, other antidepressants)
• CYP1A2 inhibitors: Increased duloxetine levels (fluvoxamine, ciprofloxacin)
• CYP2D6 inhibitors: May increase duloxetine levels (paroxetine, fluoxetine)
• Anticoagulants/antiplatelets: Increased bleeding risk (warfarin, NSAIDs)
• CNS depressants: Additive sedation (alcohol, benzodiazepines)

Adverse Effects

• Nausea (20-30%)
• Dry mouth (15-20%)
• Fatigue (10-15%)
• Constipation (10-15%)
• Dizziness (10-15%)
• Insomnia (10-15%)
• Decreased appetite (5-10%)

• Hepatotoxicity
• Serotonin syndrome
• Suicidal ideation
• Severe discontinuation symptoms
• Orthostatic hypotension
• Hyponatremia
• Abnormal bleeding
• Angle-closure glaucoma

Monitoring Parameters

• Comprehensive metabolic panel (including LFTs)
• Blood pressure and heart rate
• Screening for bipolar disorder
• Assessment of suicide risk
• Renal function assessment

• Therapeutic response assessment (PHQ-9, GAD-7 scales)
• Blood pressure (especially during dose titration)
• Signs of hepatotoxicity (monitor LFTs if symptoms develop)
• Emergence of suicidal thoughts (especially first few months)
• Signs of serotonin syndrome
• Weight changes
• Sodium levels in elderly patients

Patient Education

• Take medication exactly as prescribed; do not stop abruptly
• Therapeutic effect may take 2-4 weeks for full benefit
• Report any worsening depression or suicidal thoughts immediately
• Avoid alcohol consumption during treatment
• Rise slowly from sitting/lying position to prevent dizziness
• Inform all healthcare providers about duloxetine use
• Use effective contraception; notify if pregnancy is planned or suspected
• Do not crush or chew capsules
• Report any unusual bleeding or bruising
• Be aware of potential discontinuation symptoms if stopping treatment

• Store at room temperature (15-30°C/59-86°F)
• Keep in original container with lid tightly closed
• Keep out of reach of children and pets

References

1. FDA Prescribing Information: Cymbalta (duloxetine) capsules. Revised 2023. 2. Sansone RA, Sansone LA. Duloxetine: patient safety. Psychiatry (Edgmont). 2009;6(7):24-29. 3. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115. 4. Carter NJ, McCormack PL. Duloxetine: a review of its use in the treatment of generalized anxiety disorder. CNS Drugs. 2009;23(6):523-541. 5. Wernicke J, Lledó A, Raskin J, et al. An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies. Drug Saf. 2007;30(5):437-455. 6. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010. 7. Product Monograph: Cymbalta (duloxetine hydrochloride). Eli Lilly Canada Inc. Revised 2023.