fda released a public health advisory noting that there had been eleven reports of suicide attempts and three reports of suicidality within the mostly middle-aged women participating in the open label extension trials of duloxetine for the treatment of stress urinary incontinence (sui). the fda described the potential role of confounding social stressors "unclear". the suicide attempt rate in the sui study population (based on 9,400 patients) was calculated to be 400 per 100,000 person years. this rate is greater than the suicide attempt rate among middle-aged u.s. women that has been reported in published studies, i.e., 150 to 160 per 100,000 person years. in addition, one death from suicide was reported in a cymbalta clinical pharmacology study in a healthy female volunteer without sui. no increase in suicidality was reported in controlled trials of cymbalta for depression or diabetic neuropathic pain. postmarketing reports reported adverse events that were temporally correlated to duloxetine therapy include rash, reported rarely, and the following adverse events, reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatotoxicity, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), stevens–johnson syndrome, syncope (especially at initiation of treatment), and urticaria. pharmacology mechanism of action binding profile receptorki (nm) sert0.7~0.8 net7.5 dat240 5-ht2a504 5-ht2c916 5-ht6419 duloxetine inhibits the reuptake of serotonin and norepinephrine (ne) in the central nervous system. duloxetine increases dopamine (da) specifically in the prefrontal cortex, where there are few da reuptake pumps, via the inhibition of ne reuptake pumps (net), which is believed to mediate reuptake of da and ne. duloxetine has no significant affinity for dopaminergic, cholinergic, histaminergic, opioid, glutamate, and gaba reuptake transporters, however, and can therefore be considered to be a selective reuptake inhibitor at the 5-ht and ne transporters. duloxetine undergoes extensive metabolism, but the major circulating metabolites do not contribute significantly to the pharmacologic activity. in vitro binding studies using synaptosomal preparations isolated from rat cerebral cortex indicated that duloxetine was approximately 3 fold more potent at inhibiting serotonin uptake than norepinephrine uptake. major depressive disorder is believed to be due in part to an increase in pro-inflammatory cytokines within the central nervous system. antidepressants including ones with a similar mechanism of action as duloxetine, i.e. serotonin metabolism inhibition, cause a decrease in proinflammatory cytokine activity and an increase in anti-inflammatory cytokines; this mechanism may apply to duloxetine in its effect on depression but research on cytokines specific to duloxetine therapy is lacking. the analgesic properties of duloxetine in the treatment of diabetic neuropathy and central pain syndromes such as fibromyalgia are believed to be due to sodium ion channel blockade. pharmacokinetics absorption: duloxetine is acid labile, and is formulated with enteric coating to prevent degradation in the stomach. duloxetine has good oral bioavailability, averaging 50% after one 60 mg dose. there is an average 2-hour lag until absorption begins with maximum plasma concentrations occurring about 6 hours post dose. food does not affect the cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours. distribution: duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. volume of distribution is 1640l. metabolism: duloxetine undergoes predominately hepatic metabolism via two cytochrome p450 isozymes, cyp2d6 and cyp1a2. circulating metabolites are pharmacologically inactive. duloxetine is a moderate cyp2d6 inhibitor. elimination: administered in healthy young male subjects at doses between 20 and 40 mg twice a day, had a half-life of 12.5 hours and its pharmacokinetics are dose proportional over the therapeutic range. steady-state is usually achieved after 3 days. only trace amounts (<1%) of unchanged duloxetine are present in the urine and most of the dose (approx. 70%) appears in the urine as metabolites of duloxetine with about 20% excreted in the feces. smoking is associated with a decrease in duloxetine concentration. history cymbalta (duloxetine) 60mg duloxetine was created by eli lilly and company researchers. david robertson; david wong, a co-discoverer of fluoxetine; and joseph krushinski are listed as inventors on the patent application filed in 1986 and granted in 1990. the first publication on the discovery of the racemic form of duloxetine known as ly227942, was made in 1988. the (+)-enantiomer, assigned ly248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes to twice the degree of the (–)-enantiomer. this molecule was subsequently named duloxetine. in 2001, lilly filed a new drug application (nda) for duloxetine with the us food and drug administration. in 2003, however, the fda "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cgmp (current good manufacturing practice) violations at the finished product manufacturing facility" of eli lilly in indianapolis. additionally, "potential liver toxicity" and qtc interval prolongation appeared as a concern. the fda experts concluded that "duloxetine can cause hepatotoxicity in the form of transaminase elevations. it may also be a factor in causing more severe liver injury, but there are no cases in the nda database that clearly demonstrate this. use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver." the fda also recommended "routine blood pressure monitoring", since there was a dose-dependant increase in elevated blood pressure readings, including at the new highest recommended dose of 120 mg "where 24% of patients had one or more blood pressure readings of 140/90 vs. 9% of placebo patients." after the manufacturing issues were resolved, the liver toxicity warning included in the prescribing information, and the follow-up studies showed that duloxetine does not cause qtc interval prolongation, duloxetine was approved by the fda for depression and diabetic neuropathy in 2004. in 2007, health canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain. duloxetine was approved for use of stress urinary incontinence (sui) in the eu in 2004. in 2005, lilly withdrew the duloxetine application for stress urinary incontinence (sui) in the u.s., stating that discussions with the fda indicated "the agency is not prepared at this time to grant approval ... based on the data package submitted." a year later lilly abandoned the pursuit of this indication in the u.s. market. the fda approved duloxetine for the treatment of generalized anxiety disorder in february 2007. cymbalta generated sales of nearly us$5 billion in 2012, with us$4 billion of that in the u.s., but its patent protection terminated 1 january 2014. lilly received a six-month extension beyond 30 june 2013, after testing for the treatment of depression in adolescents, which may produce us$1.5 billion in added sales. the first generic duloxetine was marketed by indian pharmaceutical company dr. reddy's laboratories. explanatory notes duloxetine moderately inhibits cyp2d6, decreasing the rate of metabolism and thereby increasing the concentration of thioridazine. this raises the patient's risk of lethal ventricular arrythmias.