Duloxetine Flavio Guzman, MD

Overview SNRI approved for depression, GAD and pain conditions Metabolized by CYP1A2 and CYP2D6 Avoid in patients with hepatic impairment 40-60 mg/day in depression 60 mg/day in GAD

Pharmacodynamics

Duloxetine – Pharmacodynamics High affinity for: SERT NET In vitro: more “balanced” SNRI: Greater SERT and NET affinity than venlafaxine Clinical significance unclear Frampton, James E.. Plosker G. "Duloxetine." CNS drugs 21.7 (2007): 581-609.

Indications

Duloxetine: FDA-Approved Indications Major depressive disorder Generalized Anxiety Disorder (GAD) Pain conditions: Diabetic Peripheral Neuropathic Pain (DPNP) Fibromyalgia (FM) Chronic Musculoskeletal Pain Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

First-line agents for generalized anxiety disorder SSRIs Escitalopram Sertraline Paroxetine Paroxetine CR SNRIs Duloxetine Venlafaxine XR Other Agomelatine Pregabalin Katzman, Martin A., et al. "Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders." BMC psychiatry 14.Suppl 1 (2014): S1.

Duloxetine: Off-Label Uses Can significantly improve the quality of life of patients with SUI Unclear whether or not benefits are sustainable. Stress Urinary Incontinence Mariappan, Paramananthan, et al. "Duloxetine, a serotonin and noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence: a systematic review." European urology 51.1 (2007): 67-74.

Pharmacokinetics

Duloxetine Pharmacokinetics CYP2D6 inhibitors Paroxetine Fluoxetine CYP1A2 inhibitors Fluvoxamine Quinolone antibiotics Inactive metabolites Knadler MP, et al. Duloxetine: clinical pharmacokinetics and drug interactions. Clinical pharmacokinetics. 2011;50(5):281-94.

Duloxetine Pharmacokinetics moderate inhibitor CYP2D6 substrates Tricyclic antidepressants Knadler MP, Lobo E, Chappell J, Bergstrom R. Duloxetine: clinical pharmacokinetics and drug interactions. Clinical pharmacokinetics. 2011;50(5):281-94.

Duloxetine Adverse Effects Common side effects: Nausea (similar to fluoxetine and paroxetine) Insomnia Serotonergic adverse effects: Sexual dysfunction Discontinuation syndrome: Should be tapered Gupta S et al. Duloxetine: review of its pharmacology, and therapeutic use in depression and other psychiatric disorders. Annals of Clin Psych. 2007;19(2):125-32.

Duloxetine and hypertension Placebo Systolic BP 0.5 mmHg 0.6 mmHg Diastolic BP 0.8 mmHg 0.3 mmHg Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

Duloxetine and hypertension “BP should be measured prior to initiating treatment and periodically measured throughout treatment” Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

Duloxetine – Adverse Effects Hepatic adverse effects: Patients with Hep C and severe alcoholism Might exacerbate abnormal liver functions Avoid in this population Urinary hesitation Rare event NE: increase in urethral resistance Gupta S et al. Duloxetine: review of its pharmacology, and therapeutic use in depression and other psychiatric disorders. Annals of Clin Psych. 2007;19(2):125-32.

Prescribing information

Dosage forms and strengths 20 mg Delayed-release capsules 20 mg 30 mg 60 mg 30 mg 60 mg Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

Duloxetine dose range 60 mg/day 60 mg/day GAD Diabetic neuropathy Fibromyalgia Chronic musculoskeletal pain Depression 40 mg/day Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

Depression dosing 30 mg 60 mg 30 mg 20 mg 20 mg 60 mg/day Depression Maximum dose: 120 mg/day Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

Generalized anxiety disorder dosing 60 mg/day 60 mg GAD Maximum dose: 120 mg/day Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

End of presentation