Duloxetine

1. Drug Name

• Generic Name: Duloxetine

• Brand Names: Cymbalta, Irenka, Yentreve, Xeristar.

2. Drug Classification

• Class: Antidepressant

• Subclass: Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)

3. Mechanism of Action

• Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) that works by inhibiting the reuptake of serotonin (5-HT) and norepinephrine (NE) into the presynaptic neuron. This enhances the serotonergic and noradrenergic neurotransmission in the brain.

• Serotonin Effects: Duloxetine increases serotonin levels in synaptic clefts, which is beneficial in treating depression and anxiety disorders.

• Norepinephrine Effects: By also inhibiting norepinephrine reuptake, duloxetine modulates pain transmission pathways, which is useful in treating chronic pain conditions such as fibromyalgia and diabetic neuropathy.

• Receptor Interaction: Duloxetine has a minimal effect on other neurotransmitter systems and has weak activity at dopamine receptors, leading to fewer side effects such as agitation and insomnia compared to other classes of antidepressants.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Duloxetine has an oral bioavailability of approximately 40-60% after a single oral dose. Food may slightly delay but not significantly affect absorption.

  • Peak Plasma Concentration (Tmax): Occurs in 6 hours post-administration, with steady-state concentrations typically achieved within 3 days of daily dosing.

• Distribution:

  • Volume of Distribution (Vd): About 1640 L, indicating extensive distribution into tissues, including the central nervous system.

  • Protein Binding: Duloxetine is highly protein-bound (about 90%), primarily to albumin.

• Metabolism:

  • Liver (CYP450 Enzymes): Duloxetine is primarily metabolized in the liver by CYP1A2 and CYP2D6 enzymes. These enzymes produce active metabolites, which contribute to its therapeutic effects.

  • Polymorphism: Variability in the CYP2D6 enzyme can lead to differences in the drug's metabolism, influencing its efficacy and side effect profile.

• Excretion:

  • Half-life (t½): The terminal half-life of duloxetine is approximately 12 hours, which supports the once-daily dosing regimen.

  • Excretion: Duloxetine is primarily eliminated in the urine, with approximately 70% of the drug excreted as metabolites. A small percentage is excreted unchanged.

• Special Considerations:

  • In patients with liver impairment, duloxetine should be used with caution due to the risk of accumulation and adverse effects. Adjustments are necessary in renal dysfunction (creatinine clearance < 30 mL/min).

5. Indications

• Primary Indications:

  • Major Depressive Disorder (MDD): First-line treatment for major depressive episodes in adults and pediatric patients aged 7 and older.

  • Generalized Anxiety Disorder (GAD): Approved for the treatment of GAD in adults and pediatric patients aged 7–17 years.

  • Neuropathic Pain: For the management of diabetic peripheral neuropathy and chronic musculoskeletal pain.

  • Fibromyalgia: Approved for the treatment of fibromyalgia in adults.

  • Chronic Low Back Pain: Duloxetine is approved for chronic low back pain.

• Off-label Uses:

  • Stress Urinary Incontinence: Used in some cases for treatment of stress urinary incontinence in women.

  • Pain associated with osteoarthritis: Duloxetine may also be used in the management of osteoarthritis pain.

• Special Populations:

  • Elderly: Use cautiously in elderly patients, especially those with liver impairment.

  • Pediatrics: Approved for use in children aged 7 years and older for depression and anxiety.

6. Dosage and Administration

• Adult Dosing:

  • Major Depressive Disorder (MDD): Initial dose is 40–60 mg/day, which may be increased to a maximum dose of 120 mg/day depending on the response.

  • Generalized Anxiety Disorder (GAD): Start at 30 mg/day, increasing to 60 mg/day after 1 week if needed. Maximum dose is 120 mg/day.

  • Diabetic Peripheral Neuropathy: Initial dose is 60 mg/day, which may be increased based on response.

  • Fibromyalgia: Typically started at 30 mg/day, increasing to 60 mg/day.

  • Chronic Pain: 60 mg/day, with potential increases to 120 mg/day.

• Pediatric Dosing:

  • For children aged 7 years and older, dosing typically starts at 30 mg/day for depression or anxiety, with a maximum dose of 120 mg/day.

• Renal/Hepatic Impairment:

  • Adjust dose in hepatic impairment (e.g., cirrhosis). The drug is contraindicated in patients with severe hepatic impairment.

  • Renal impairment (creatinine clearance <30 mL/min) requires dose reduction or avoidance.

• Route of Administration: Oral (capsule, delayed-release).

• Max Safe Dose: 120 mg/day for most indications.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to duloxetine or any of its components.

  • MAOIs: Concurrent use with or within 14 days of stopping a monoamine oxidase inhibitor (MAOI) is contraindicated due to the risk of serotonin syndrome.

  • Severe Hepatic Impairment: Duloxetine is contraindicated in patients with liver failure (e.g., cirrhosis).

• Relative Contraindications:

  • Uncontrolled narrow-angle glaucoma.

  • Severe renal impairment (creatinine clearance <30 mL/min).

  • History of seizures: Duloxetine may lower the seizure threshold.

8. Warnings and Precautions

• Black Box Warning:

  • Suicidal Thoughts: Like all antidepressants, duloxetine carries a black box warning about the increased risk of suicidality in children, adolescents, and young adults, particularly during the early stages of treatment.

• Other Warnings:

  • Serotonin Syndrome: Risk when used with other serotonergic drugs (e.g., MAOIs, triptans).

  • Liver Toxicity: Caution is needed in patients with liver disease, and hepatic function should be monitored.

  • Hypertension: Duloxetine can increase blood pressure. Monitor blood pressure regularly, particularly in patients with hypertension.

  • Bleeding Risk: Increased risk of bleeding when used with anticoagulants or NSAIDs.

9. Adverse Effects

• Common Adverse Effects:

  • Gastrointestinal: Nausea, constipation, dry mouth, loss of appetite, diarrhea.

  • Central Nervous System: Drowsiness, dizziness, insomnia, headache.

• Less Common but Clinically Significant:

  • Hypertension: Especially at higher doses (≥ 120 mg/day).

  • Sexual Dysfunction: Decreased libido, erectile dysfunction.

  • Sweating: Increased perspiration, particularly at higher doses.

• Rare/Serious:

  • Serotonin Syndrome: Symptoms include fever, muscle rigidity, tremors, delirium, and tachycardia.

  • Liver Toxicity: Elevation in liver enzymes, jaundice.

  • Seizures: Rare, but possible in patients with a seizure history or when used with other drugs lowering the seizure threshold.

10. Drug Interactions

• Major Drug Interactions:

  • MAOIs: Serious interaction causing serotonin syndrome.

  • Other SSRIs or SNRIs: Increased risk of serotonin syndrome.

  • CYP1A2 and CYP2D6 inhibitors (e.g., quinidine): May increase duloxetine plasma concentrations.

  • Anticoagulants/Antiplatelets: Increased bleeding risk.

• Food-Drug Interactions: No significant food interactions.

• Lab Test Interactions: Duloxetine may interfere with liver function tests (LFTs), showing elevated AST and ALT levels.

11. Clinical Pharmacology

• Pharmacodynamics: Duloxetine is a potent reuptake inhibitor of serotonin and norepinephrine. It primarily enhances the action of these neurotransmitters, providing therapeutic effects in mood disorders and pain conditions.

• Additional Effects: Duloxetine's role in pain modulation is due to its effects on the descending pain pathways in the central nervous system, particularly via norepinephrine reuptake inhibition.

12. Special Populations

• Pregnancy Category: Category C (US FDA). Duloxetine should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

• Lactation: Excreted in breast milk. Caution is advised if used during lactation.

• Geriatrics/Pediatrics: Careful monitoring required in older adults due to increased sensitivity to adverse effects, particularly hyponatremia and GI upset.

13. Therapeutic Uses

• First-line treatments for MDD, GAD, and fibromyalgia.

• Effective as second-line therapy for chronic pain and neuropathic pain, including diabetic neuropathy.

• Combination therapy with other antidepressants or pain relievers may be used in treatment-resistant cases.

14. Monitoring and Follow-Up

• Before Treatment: Baseline LFTs, blood pressure, and serum sodium.

• During Treatment: Regular monitoring of blood pressure, weight, serum sodium, and LFTs.

• Therapeutic Levels: No routine drug level monitoring is required.

15. Overdose Management

• Symptoms of Overdose: Somnolence, nausea, vomiting, tachycardia, serotonin syndrome.

• Treatment:

  • Activated charcoal if within 1 hour of ingestion.

  • Symptomatic treatment: IV fluids, respiratory support, and cardiovascular monitoring.

• Antidote: There is no specific antidote for duloxetine overdose.

16. Patient Counseling Information

• Key Points:

  • Take duloxetine once daily, with or without food.

  • Do not abruptly discontinue the medication to avoid discontinuation syndrome (e.g., dizziness, headache).

• Signs for Immediate Medical Attention:

  • Serotonin syndrome: Hyperthermia, rigidity, altered mental status.

  • Signs of liver damage: Jaundice, dark urine, or upper-right abdominal pain.