indication

For the acute and maintenance treatment of major depressive disorder (MDD), as well as acute management of generalized anxiety disorder. Also used for the management of neuropathic pain associated with diabetic peripheral neuropathy, and fibromyalgia. Has been used in the management of moderate to severe stress urinary incontinence (SUI) in women.

pharmacology

Duloxetine is in a class of medications called selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) and primarily targets major depressive disorders (MDD) and stress urinary incontinence (SUI). Duloxetine is also used to treat pain and tingling caused by diabetic neuropathy (damage to nerves that can develop in people who have diabetes). Known also as LY248686, it is a potent dual inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake, possessing comparable affinities in binding to NE and 5-HT transport sites. Interestingly, its behavior contrasts to most other dual-reuptake inhibitors. Furthermore, duloxentine lacks affinity for monoamine receptors within the central nervous system.

mechanism of action

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. The antidepressant and pain inhibitory actions of duloxetine are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. The mechanism of action of duloxetine in SUI has not been determined, but is thought to be associated with the potentiation of serotonin and norepinephrine activity in the spinal cord, which increases urethral closure forces and thereby reduces involuntary urine loss.

toxicity

Oral, rat LD₅₀: 491 mg/kg for males and 279 mg/kg for females. Symptoms of overdose include tremors, convulsions, reduced activity, slow pupillary response, intermittent tremors, and rigidity.

biotransformation

The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. The major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.

absorption

Orally administered duloxetine hydrochloride is well absorbed.

half life

12 hours (range 8-17 hours)

route of elimination

Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces.

drug interactions

Amitriptyline: Possible increase in the levels of this agent when used with duloxetine

Ciprofloxacin: Ciprofloxacin, a strong CYP1A2 inhibitor, may decrease the metabolism of duloxetine. Monitor for changes in the therapeutic and adverse effects of duloxetine if ciprofloxacin is initiated or discontinued.

Desipramine: Possible increase in the levels of this agent when used with duloxetine

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Flecainide: Possible increase in the levels of this agent when used with duloxetine

Fluvoxamine: Fluvoxamine increases the effect and toxicity of duloxetine

Imipramine: Possible increase in the levels of this agent when used with duloxetine

Isocarboxazid: Possible severe adverse reaction with this combination

Nortriptyline: Possible increase in the levels of this agent when used with duloxetine

Phenelzine: Possible severe adverse reaction with this combination

Propafenone: Possible increase in the levels of this agent when used with duloxetine

Rasagiline: Possible severe adverse reaction with this combination

Tamoxifen: Duloxetine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Duloxetine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Duloxetine is initiated, discontinued, or dose changed.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Duloxetine. Consider alternate therapy or monitor for therapeutic/adverse effects of Duloxetine if Terbinafine is initiated, discontinued or dose changed.

Thiabendazole: The strong CYP1A2 inhibitor, Thiabendazole, may increase the effects and toxicity of Duloxetine by decreasing Duloxetine metabolism and clearance. Monitor for changes in the therapeutic and adverse effects of Duloxetine if Thiabendazole is initiated, discontinued or dose changed.

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

Tramadol: Duloxetine may decrease the effect of Tramadol by decreasing active metabolite production. Increased risk of serotonin syndrome. Monitor for Tramadol efficacy and symptoms of serotonin syndrome.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Triprolidine: The CNS depressants, Triprolidine and Duloxetine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and duloxetine, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.