An Expert Monograph on Duloxetine (DB00476)

Executive Summary

Duloxetine is a potent and selective Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) developed by Eli Lilly and Company and first approved by the U.S. Food and Drug Administration (FDA) in 2004.[1] Marketed under various brand names, including Cymbalta®, Drizalma Sprinkle®, and Yentreve®, it has become a widely prescribed medication for a range of psychiatric and pain-related disorders.[1] The therapeutic efficacy of duloxetine is derived from its dual inhibition of the serotonin (5-HT) and norepinephrine (NE) transporters, which underpins its broad spectrum of FDA-approved indications. These include Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), Diabetic Peripheral Neuropathic Pain (DPNP), Fibromyalgia (FM), and Chronic Musculoskeletal Pain.[1]

Pharmacokinetically, duloxetine is administered orally as an enteric-coated, delayed-release capsule to protect the acid-labile molecule from degradation in the stomach. It exhibits a mean oral bioavailability of approximately 50% and is extensively metabolized in the liver, primarily by the cytochrome P450 enzymes CYP1A2 and CYP2D6.[1] This metabolic pathway is a key determinant of its drug-drug interaction profile and is subject to genetic polymorphisms. From a safety perspective, duloxetine carries an FDA-mandated boxed warning for an increased risk of suicidal ideation and behavior in children, adolescents, and young adults.[7] Common adverse effects include nausea, dry mouth, constipation, and somnolence. The primary patents protecting the drug expired between 2013 and 2015, which has since led to the widespread availability of numerous generic formulations, significantly altering its market landscape.[2]

Chemical Identity, Synthesis, and Properties

Identification and Nomenclature