Duloxetine

From Wikipedia, the free encyclopedia
  (Redirected from Cymbalta)
Jump to: navigation, search
Duloxetine
Duloxetine.png
Duloxetine3Dan.gif
Systematic (IUPAC) name
(+)-(S)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine
Clinical data
Trade names Cymbalta
AHFS/Drugs.com monograph
MedlinePlus a604030
Licence data EMA:Link, US FDA:link
Pregnancy cat. C (US)
Legal status -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability ~ 50% (32% to 80%)
Protein binding ~ 95%
Metabolism Liver, two P450 isozymes, CYP2D6 and CYP1A2
Half-life 12.1 hours
Excretion 70% in urine, 20% in feces
Identifiers
CAS number 116539-59-4 N (free base)
136434-34-9 (hydrochloride)
ATC code N06AX21
PubChem CID 60835
IUPHAR ligand 202
DrugBank DB00476
ChemSpider 54822 YesY
UNII O5TNM5N07U YesY
KEGG D07880 YesY
ChEBI CHEBI:36795 YesY
ChEMBL CHEMBL1175 YesY
PDB ligand ID 29E (PDBe, RCSB PDB)
Chemical data
Formula C18H19NOS 
Mol. mass 297.41456 g/mol
 N (what is this?)  (verify)

Duloxetine (sold under the brand names Cymbalta, Ariclaim, Xeristar, Yentreve, Duzela, Dulane) is a serotonin-norepinephrine reuptake inhibitor (SNRI) manufactured and marketed by Eli Lilly. It is prescribed for major depressive disorder and generalized anxiety disorder (GAD). Duloxetine also has approval for use in osteoarthiritis and musculoskeletal pain. It can also relieve the symptoms of painful peripheral neuropathy, particularly diabetic neuropathy,[1][2] and it is used to control the symptoms of fibromyalgia. Duloxetine failed the US approval for stress urinary incontinence amidst concerns over liver toxicity and suicidal events; however, it was approved for this indication in Europe, where it is recommended as an add-on medication in stress urinary incontinence instead of surgery.[3]

Medical uses[edit]

The main uses of duloxetine are in major depressive disorder, general anxiety disorder, urinary incontinence, painful peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain associated with osteoarthritis and chronic lower back pain. It is being studied for various other indications.

Major depressive disorder[edit]

Duloxetine was approved for the treatment of major depression in 2004. An 8-week phase two clinical trial found duloxetine superior to placebo in reduction of depressive symptoms, with duloxetine-treated patients showing a statistically significant improvement in scores on the 17-item Hamilton Rating Scale for Depression. [4] A later study evaluating duloxetine's efficacy in the acute and long-term treatment of major depression found that duloxetine-treated patients maintained statistically significant improvements in depressive symptoms over the six-month continuity phase when compared to placebo, indicating that duloxetine is effective in the long-term treatment of major depression.[5] While duloxetine has demonstrated improvement in depression-related symptoms compared to placebo, trials comparing duloxetine to other antidepressant medications have been less successful. A 2012 Cochrane Review evaluating 16 randomized control trials comprising more than 5000 participants failed to demonstrate improved efficacy of duloxetine compared to SSRIs and newer antidepressants. Additionally, the review found evidence that duloxetine has increased side effects and reduced tolerability compared to other antidepressants. The review's authors did not recommend duloxetine as a first line treatment for major depressive disorder, given the high cost of duloxetine compared to off-patent antidepressants and lack of increased efficacy. [6]

Generalized anxiety disorder[edit]

Duloxetine is more effective than placebo in the treatment of generalized anxiety disorder (GAD), as demonstrated in a randomized control trial of adults with GAD.[7] Duloxetine has been shown to be as effective as venlafaxine in the treatment of generalized anxiety disorder, with a daily dose of 60-120 mg duoxetine being non-inferior to venlafaxine XR 75-225 mg/day.[8] Duloxetine has also been shown to be effective in long-term management of generalized anxiety disorder, showing statistically significant improvements in anxiety compared to placebo with up to 6-months of treatment[9][10] Major guidelines such as Maudsley Prescribing Guidelines,[11] Mayo Clinic Health Information[12] and Canadian Psychiatric Association Guidelines[13] do not list duloxetine among the recommended treatment options. However, a recent review from the Annals of Internal Medicine lists duloxetine among the first line drug treatments, along with citalopram, escitalopram, sertraline, paroxetine, and venlafaxine. Cognitive behavioral therapy remains the first line nonpharmacologic treatment for generalized anxiety disorder.[14]

Diabetic peripheral neuropathy[edit]

Duloxetine was approved for the pain associated with diabetic peripheral neuropathy (DPN), based on the positive results of two clinical trials. The average daily pain was measured using an 11-point scale, and duloxetine treatment resulted in an additional 1–1.7 points decrease of pain as compared with placebo.[15][16][17] At least 50% pain relief was achieved in 40–45% of the duloxetine patients vs. 20–22% of placebo patients. Pain decreased by more than 90%, in 9–14% of duloxetine patients vs. 2–4% of placebo patients. Most of the response was achieved in the first two weeks on the medication. Duloxetine slightly increased the fasting serum glucose; however this effect was deemed to be of "minimal clinical significance".[15]

Duloxetine was not effective for the numbness or tingling associated with diabetic neuropathy, nor for the other complications of diabetes. It reduced the pain without treating the underlying nerve damage.[18] Only tight glycemic control was unequivocally demonstrated to slow the progression of neuropathy.[19][20] Benfotiamine, alpha-lipoic acid, and ranirestat have also shown some promise.[20]

The comparative efficacy of duloxetine and established pain-relief medications for DPN is unclear. An independent systematic review in BMJ noted that tricyclic antidepressants (imipramine and amitriptyline), traditional anticonvulsants and opioids have better efficacy than duloxetine. Duloxetine, tricyclic antidepressants and anticonvulsants have similar tolerability while the opioids caused more side effects.[19] A review in Drug and Therapeutic Bulletin saw no place for duloxetine in the treatment of DPN, based on its high cost and insufficient evidence of the comparative efficacy with tricyclic antidepressants.[21] Another independent review in Prescrire International, considered the moderate pain relief achieved with duloxetine to be clinically insignificant and the results of the clinical trials—unconvincing. The reviewer saw no reason to prescribe duloxetine in practice.[22] The comparative data collected by reviewers in BMC Neurology indicated that amitriptyline, other tricyclic antidepressants and venlafaxine may be more effective. However, the authors noted that the evidence in favor of duloxetine is much more solid.[23]

Fibromyalgia[edit]

On October 19, 2006, Eli Lilly issued a press release saying they had done trials which found that Cymbalta (duloxetine), at 60 mg once or twice daily, significantly reduced pain in more than half of women treated for fibromyalgia (FM), a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep, with and without major depression, according to 12-week data presented at the annual meeting of the American College of Rheumatology. Eli Lilly has been promoting Cymbalta for FM since 2004.[24]

Duloxetine is superior to many other medications for the treatment of fibromyalgia due to its freedom from muscarinic, histaminergic and adrenergic adverse reactions. Its effectiveness in pain relief is believed to be due to its modulation of the nociception system. A meta-analysis of clinical trials has confirmed its pain relief, fatigue reducing properties as well as its effectiveness in improving physical and mental performance.[25]

In the study testing the efficacy of Duloxetine for FM, participants completed several questionnaires to measure the amount of pain and discomfort the disease caused them at the beginning of the study, and then at the end of each of the first two weeks and every second week for the remaining 12 weeks of the study. Researchers also tested the participants for depression.[24]

Women who took Duloxetine had significantly less pain and discomfort than those who took the placebo. For men, who made up only 11% of the study, there was no effect from taking the medication compared with a placebo. Reportedly, depression played no part in whether or not the drug worked to control pain. The change in the level of women's pain was particularly pronounced after a month of taking the drug, then leveled off a bit before dropping again near the end of the study.[24]

However, in one of the primary measures of pain there was no significant difference between the two groups at the end of the 12-week trial. Also, because the trial lasted only 12 weeks, it is impossible to tell how well the drug would control treatment for a longer period of time.[24]

The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008.[26]

Musculoskeletal pain[edit]

On November 4, 2010, the U.S. Food and Drug Administration approved duloxetine to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain.[27]

Stress urinary incontinence[edit]

Duloxetine was first reported to improve outcomes in stress urinary incontinence (SUI) in 1998.[28] Systematic reviews with meta-analysis, conducted in 2005 by Cochrane Collaboration[29] and in 2008 by University of Minnesota,[30] concluded that duloxetine failed to cure SUI better than placebo. According to the Cochrane review, some studies showed that episodes of incontinence were reduced by about 50%. This was associated with an improvement in quality of life measurements.[29] According to the University of Minnesota review, duloxetine performed worse than oxybutynin (Ditropan) or tolterodine (Detrol) that cured 18% of the cases, or than pelvic floor muscle training + bladder training, which cured 13% of the cases. In terms of "improvement", that is incomplete cure, duloxetine showed improvement in 11% of patients while pelvic floor muscle training + bladder training showed improvement in 36% of the cases.[30] Significant side effects were common with duloxetine; they were reported as acceptable and about a fifth had to discontinue the medication because of poor tolerance.[29]

In addition, the full report prepared by Minnesota Evidence-based Practice Center for the U.S. government, on which the University of Minnesota review is based, notes that weight reduction would result in improved SUI in 990 adults per 1,000 treated.[31] In the light of the cited data, the report does not mention duloxetine in its policy recommendations. The only recommended interventions are early behavioral changes in weight, physical activity, and pelvic floor muscle training.[31]

The only clinical trial, which directly compared duloxetine with the gold standard of the SUI treatment pelvic floor muscle training (PFMT) was conducted by Eli Lilly and gave mixed results. The incontinence episode frequency in duloxetine group decreased by 57% vs. 35% in the PFMT group. However, the differences in the pad use and quality of life were not statistically significant. To the contrary, 65% patients doing PFMT reported feeling better vs 54% of the patients on duloxetine. 31% of the patients on duloxetine discontinued the trial due to the side effects during the first 12 weeks.[32] In the continuation of this trial more than 91% of the patients on duloxetine experienced side effects.[33]

Summing up the existing evidence, a review in Prescrire International recommends pelvic floor exercises, which are "risk-free and effective in two-thirds to three-quarters of cases", as the first line treatment of SUI. Duloxetine use reduced the frequency of stress incontinence by one episode a day as compared with placebo. "The tangible effect of duloxetine on the quality of life is doubtful, with a maximum gain of five points on a 100-point scale." The review notes that, at best, duloxetine efficacy is "modest and transient, while its adverse effects are numerous and potentially severe."[34]

Interstitial cystitis[edit]

There is a U.S. Patent 6150396 for the use of duloxetine for treatment of interstitial cystitis although one study found positive outcomes in only a small proportion of cases.[35] Interstitial cystitis is a bladder and urinary tract disorder which presents as chronic pelvic and perineal pain. It is speculated that duloxetine suppresses neural impulses related to pain below a threshold level sufficient to alleviate some or all neurological pain symptoms. Duloxedtine is not FDA-approved for the treatment of interstitial cystitis.

Contraindications[edit]

The following contraindications are listed by the manufacturer:[36]

  • Hypersensitivity - duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
  • MAOIs - concomitant use in patients taking MAOIs is contraindicated.
  • Uncontrolled narrow-angle glaucoma - in clinical trials, Cymbalta use was associated with an increased risk of mydriasis (dilation of the pupil); therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma, in which mydriasis can cause sudden worsening.
  • CNS acting drugs - given the primary central nervous system (CNS) effects of duloxetine, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.
  • Duloxetine and thioridazine should not be co-administered.

In addition, the FDA has reported on life threatening drug interactions that may be possible when co-administered with any CNS stimulant, such as phentermine, diethylpropion, amphetamine, sibutramine, methylphenidate, methamphetamine, or cocaine, leading to increased risk for serotonin syndrome.[37]

Adverse effects[edit]

Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% of patients.[38]

In a trial for major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group.[39]

Sexual dysfunction is often a side effect of drugs that inhibit serotonin reuptake. Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and anorgasmia (trouble achieving orgasm). Loss of or decreased response to sexual stimuli and ejaculatory anhedonia are also possible. Frequency of treatment-emergent sexual dysfuction in long-term treatment has been found to be similar for duloxetine and SSRIs when compared in clinical trials,[40][41] while there is some evidence that duloxetine is associated with less sexual dysfunction than escitalopram when measured at 4 and 8 weeks of treatment.[42]

Postmarketing spontaneous reports[edit]

Reported adverse events which 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, hepatitis, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens–Johnson syndrome, syncope (especially at initiation of treatment), and urticaria.[43]

Discontinuation syndrome[edit]

During marketing of other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. The withdrawal syndrome from duloxetine resembles the SSRI discontinuation syndrome.

When discontinuing treatment with duloxetine, the manufacturer recommends a gradual reduction in the dose, rather than abrupt cessation, whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. The use of a liquid form of the drug may facilitate more gradual tapering."[44]

In placebo-controlled clinical trials of up to nine weeks' duration of patients with MDD,a systematic evaluation of discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring at a rate greater than or equal to 2% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.[45]

Suicidality[edit]

The FDA requires all antidepressants, including duloxetine, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.[46][47][48]

To obtain statistically significant results the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications. As suicidal ideation and behavior in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance.

Several commentators noted that the data FDA used in their analysis of duloxetine-associated suicidality may have been incomplete. According to Arif Khan, the Summary Basis of Approval used by the FDA to approve duloxetine for depression contained only the mention of two completed suicides out of 3490 patients, and the rest of the data was not sufficient to "conduct any meaningful analysis."[49] Jeanne Lenzer wrote in The Independent and Slate Magazine, and this fact was also confirmed by a Lilly spokesman, that another two completed suicides, which occurred in the depression studies ran by the Lilly's Japanese partner Shionogi, have not been reported to the FDA.[50][51] According to Lenzer, four completed suicides also occurred in the trials of duloxetine for stress urinary incontinence (SUI). As these trials failed, the FDA initially insisted that any information about them is a commercial secret and cannot be released.[51] Later, in a short statement the FDA acknowledged that in SUI trials eleven suicide attempts occurred in persons taking duloxetine vs none in the placebo group.[52]

A series of four cases of duloxetine-associated suicidality has been reported. In all four cases depressed patients began having suicidal thoughts after starting on duloxetine or increasing its dose. These thoughts stopped, and the patients returned to normal after duloxetine was discontinued, and they were switched to another antidepressant.[53]

A suicide of 19-year-old Traci Johnson, a healthy volunteer in a duloxetine clinical pharmacology study, was highly publicized. For about a month she had been given high doses of duloxetine, and then she was switched to placebo. Four days after the switch, she hanged herself in the bathroom of Lilly Laboratory for Clinical Research.[54][55] The New York Times article mentioned a withdrawal syndrome as a possible reason for this suicide.[55]

Pharmacology[edit]

Mechanism of Action[edit]

Duloxetine inhibits the reuptake of serotonin and norepinephrine in the central nervous system. Duloxetine is also considered a less potent inhibitor of dopamine reuptake. However, duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NA transporters. Duloxetine undergoes extensive metabolism, but the major circulating metabolites do not contribute significantly to the pharmacologic activity.[56][57]

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.[58]

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.[59]

Pharmacokinetics[edit]

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.[60]

Distribution: Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. Volume of distribution is 1640L.[61]

Metabolism: Duloxetime undergoes predominately hepatic metabolism via two cytochrome P450 isozymes, CYP2D6 and CYP1A2. Circulating metabolites are pharmacologically inactive.[62]

Elimination: Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 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.[63]

History[edit]

Cymbalta (duloxetine) 60mg

Duloxetine was created by Lilly 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.[64] The first publication on the discovery of the racemic form of duloxetine known as LY227942, was made in 1988.[65] The (+)-enantiomer of LY227942, assigned LY248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes to twice the degreee as the (–)-enantiomer. This molecule was subsequently named duloxetine.[66]

Initial trials conducted in patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy[67] and the dose was increased to as high as 120 mg in subsequent clinical trials.[68]

In 2001 Lilly filed a New Drug Application (NDA) for duloxetine with the US Food and Drug Administration (FDA). However, in 2003 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" at the new highest recommended dose of 120 mg, "where 24% patients had one or more blood pressure readings of 140/90 vs. 9% of placebo patients."[69]

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.[70] In 2007 Health Canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.[71]

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.[72][73]

The FDA approved duloxetine for the treatment of generalized anxiety disorder in February 2007.[74]

Cymbalta is Eli Lilly's top selling drug. It brought in just shy of $5 billion in 2012 with $4 billion of that in the U.S., but its patent protection terminated January 1, 2014. Lilly received a six month extension beyond June 30, 2013 after testing for the treatment of depression in adolescents, which may produce $1.5 billion in added sales.[75][76]

The first generic duloxetine was marketed by Dr. Reddy.[77]

References[edit]

  1. ^ National Institute for Health and Clinical Excellence. Clinical guideline 96: Neuropathic pain - pharmacological management. London, 2010.
  2. ^ Bril V, England J, Franklin GM et al (2011). "Evidence-based guideline: Treatment of painful diabetic neuropathy". Neurology. Online. doi:10.1212/WNL.0b013e3182166ebe. PMID 21482920. 
  3. ^ National Institute for Health and Clinical Excellence. Clinical guideline 40: Urinary incontinence. London, 2006.
  4. ^ Goldstein, David J; Mallinckrodt, Lu, Demitrack (March 2002). "Duloxetine in the Treatment of Major Depressive Disorder: A Double-Blind Clinical Trial". Journal of Clinical Psychiatry 63 (3): 225-231. 
  5. ^ Detke, MJ; Wiltse, Mallinckrodt, McNamara, Demitrack, Bitter (Dec 2004). "Duloxetine in the acute and long-term treatment of depressive disorder: a placebo- and paroxetine-controlled trial". European Neuropsychopharmacoloy 14 (6): 457-470. 
  6. ^ Cipriani, A; Koesters, Furukawa, Nose, Purgato, Omori, Trespidi, Barbui (Oct 2012). "Duloxetine versus other anti-depressive agents for depression". The Cochrane Databse of Systematic Reviews (10). 
  7. ^ Hartford, J; Kornstein, Liebowitz, Pigott, Russell, Detke, Walker, Ball, Dunayevich, Dinkel, Erickson (May 2007). "Duloxetine as an SNRI treatment for generalized anxiety disorder: results from a placebo and active-controlled trial". International Clinical Psychopharmacology 22 (3): 167-74. 
  8. ^ Allqullander, C; Nutt, Detke, Erickson, Spann, Walker, Ball, Russell (June 2008). "A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder". Journal of Psychopharmacology 22 (4): 417-425. 
  9. ^ Piero, A; Locati (Jan 2011). "An open, non-randomised comparison of escitalopram and duloxetine for the treatment of subjects with Generalized Anxiety Disorder". Human Psychopharmacology 26 (1): 63-71. 
  10. ^ Davidson, JR; Wittchen, Llorca, Erickson, Detke, Ball, Russell (Sep 2008). "Duloxetine treatment for relapse prevention in adults with generalized anxiety disorder: a double-blind placebo-controlled trial". European Neuropsychopharmacology 18 (9): 673-681. 
  11. ^ Kerwin, Robert; Taylor, David H.; Carol Paton (2007). Maudsley Prescribing Guidelines. Informa Healthcare. p. 254. ISBN 0-415-42416-X. 
  12. ^ "Generalized anxiety disorder: Treatments and drugs - MayoClinic.com". Retrieved 2009-11-28. 
  13. ^ Canadian Psychiatric, Association (July 2006). "Clinical practice guidelines. Management of anxiety disorders". Can J Psychiatry 51 (8 Suppl 2): 52S–55S. PMID 16933543. 
  14. ^ Patel, Gavatri; Fancher (December 3 2013). "Generalized Anxiety Disorder". Annals of Internal Medicine 159 (11). 
  15. ^ a b Josefberg H (2004-09-03). "Application number 21-733. Medical review(s)." (PDF). FDA. Retrieved 2009-04-14. [dead link]
  16. ^ Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S (July 2005). "Duloxetine vs. placebo in patients with painful diabetic neuropathy". Pain 116 (1-2): 109–18. doi:10.1016/j.pain.2005.03.029. PMID 15927394. 
  17. ^ Raskin J, Pritchett YL, Wang F, et al. (2005). "A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain". Pain Med 6 (5): 346–56. doi:10.1111/j.1526-4637.2005.00061.x. PMID 16266355. 
  18. ^ Goldstein, DJ; Lu, Detke, Lee, Iyengar (July 2005). "Duloxetine vs placebo in patients with painful diabetic neuropathy". Pain 116 (1-2): 109-118. 
  19. ^ a b Wong MC, Chung JW, Wong TK (July 2007). "Effects of treatments for symptoms of painful diabetic neuropathy: systematic review". BMJ 335 (7610): 87. doi:10.1136/bmj.39213.565972.AE. PMC 1914460. PMID 17562735. 
  20. ^ a b Várkonyi T, Kempler P (February 2008). "Diabetic neuropathy: new strategies for treatment". Diabetes Obes Metab 10 (2): 99–108. doi:10.1111/j.1463-1326.2007.00741.x. PMID 17593238. 
  21. ^ "Is there a place for duloxetine?". Drug Ther Bull 45 (4): 29–32. April 2007. doi:10.1136/dtb.2007.45429. PMID 17451072. "There is insufficient published evidence of its comparative efficacy to judge its duloxetine place in depression among many other longer-established antidepressant drugs, or how it compares with other therapy for diabetic peripheral neuropathic pain. Therefore we can see no place for it in either indication." 
  22. ^ "Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects". Prescrire Int 15 (85): 168–72. October 2006. PMID 17121211. 
  23. ^ Sultan A, Gaskell H, Derry S, Moore RA (2008). "Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials". BMC Neurol 8: 29. doi:10.1186/1471-2377-8-29. PMC 2529342. PMID 18673529. 
  24. ^ a b c d Arnold LM, Lu Y, Crofford LJ, et al. (September 2004). "A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder". Arthritis Rheum. 50 (9): 2974–84. doi:10.1002/art.20485. PMID 15457467. 
  25. ^ Acuna C (October 2008). "Duloxetine for the treatment of fibromyalgia". Drugs Today 44 (10): 725–34. doi:10.1358/dot.2008.44.10.1269675. PMID 19137126. 
  26. ^ "FDA Approves Cymbalta for the Management of Fibromyalgia". Eli Lilly Co. 2008-06-16. Retrieved 2008-06-17. 
  27. ^ "FDA clears Cymbalta to treat chronic musculoskeletal pain". FDA Press Announcements. Food and Drug Administration. 4 November 2010. Retrieved 19 August 2013. 
  28. ^ Voelker R (September 1998). "International group seeks to dispel incontinence "taboo"". JAMA 280 (11): 951–3. doi:10.1001/jama.280.11.951. PMID 9749464. 
  29. ^ a b c Mariappan P, Ballantyne Z, N'Dow JM, Alhasso AA (2005). "Serotonin and noradrenaline reuptake inhibitors (SNRI) for stress urinary incontinence in adults". In Mariappan, Paramananthan. Cochrane Database Syst Rev (3): CD004742. doi:10.1002/14651858.CD004742.pub2. PMID 16034945. 
  30. ^ a b Shamliyan TA, Kane RL, Wyman J, Wilt TJ (March 2008). "Systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women". Ann. Intern. Med. 148 (6): 459–73. PMID 18268288. 
  31. ^ a b http://www.ahrq.gov/downloads/pub/evidence/pdf/fuiad/fuiad.pdf
  32. ^ "Trial 2615a Efficacy and Safety of Duloxetine compared with Placebo, Pelvic Floor Muscle Training, and Combined Duloxetine/Pelvic Floor Muscle Training in Subjects with Moderate to Severe Stress Urinary Incontinence" (PDF). www.clinicalstudyresults.org. Retrieved 02-03-09. 
  33. ^ "Trial 2615b. Efficacy and Safety of Duloxetine compared with Placebo, Pelvic Floor Muscle Training, and Combined Duloxetine/Pelvic Floor Muscle Training in Subjects with Moderate to Severe Stress Urinary Incontinence" (PDF). www.clinicalstudyresults.org. Retrieved 02-03-09. 
  34. ^ "Duloxetine: new drug. For stress urinary incontinence: too much risk, too little benefit". Prescrire Int 14 (80): 218–20. December 2005. PMID 16400743. 
  35. ^ van Ophoven A, Hertle L (February 2007). "The dual serotonin and noradrenaline reuptake inhibitor duloxetine for the treatment of interstitial cystitis: results of an observational study". J. Urol. 177 (2): 552–5. doi:10.1016/j.juro.2006.09.055. PMID 17222632. 
  36. ^ http://www.cymbalta.com/learnaboutcymbalta/importantsafetyinformation.jsp?type=print>
  37. ^ Report a Serious Problem (2013-08-14). "Information for Healthcare Professionals: Duloxetine (marketed as Cymbalta) - Selective Serotonin Reuptake Inhibitors (SSRIs) or Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and 5-Hydroxytryptamine Receptor Agonists (Triptans)". Fda.gov. Retrieved 2013-09-18. 
  38. ^ Cymbalta package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.
  39. ^ Perahia DG, Kajdasz DK, Walker DJ, Raskin J, Tylee A (May 2006). "Duloxetine 60 mg once daily in the treatment of milder major depressive disorder". Int. J. Clin. Pract. 60 (5): 613–20. doi:10.1111/j.1368-5031.2006.00956.x. PMC 1473178. PMID 16700869. 
  40. ^ Duenas, H; Brnabic, Lee, Montejo, Prakash, Casimiro-Querubin, Khaled, Dossenbach, Raskin (Nov 2011). "Treatment-emergent sexual dysfunction with SSRIs and duloxetine: efferctiveness and functional outcomes over a 6-month observational period". International Journal of Psychiatry in Clinical Practice 15 (4): 242-254. 
  41. ^ Clayton, A; Kornstein, Prakash, Mallinckrodt, Wohlreich (July 2007). "Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder". Journal of Sexual Medicine 4: 917-929. 
  42. ^ Clayton, A; Kornstein, Prakash, Mallinckrodt, Wohlreich (July 2007). "Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder". Journal of Sexual Medicine 4: 917-929. 
  43. ^ [1] Duloxetine Side Effects, and Drug Interactions - RxList Monographs
  44. ^ duloxetine patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006
  45. ^ Perahia DG, Kajdasz DK, Desaiah D, Haddad PM (December 2005). "Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder". J Affect Disord 89 (1-3): 207–12. doi:10.1016/j.jad.2005.09.003. PMID 16266753. 
  46. ^ Levenson M, Holland C. "Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)". Retrieved 2007-05-13. 
  47. ^ Stone MB, Jones ML (2006-11-17). "Clinical review: relationship between antidepressant drugs and suicidality in adults" (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 11–74. Retrieved 2007-09-22. 
  48. ^ Levenson M, Holland C (2006-11-17). "Statistical Evaluation of Suicidality in Adults Treated with Antidepressants" (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 75–140. Retrieved 2007-09-22. 
  49. ^ Khan A, Schwartz K (2007). "Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports". Ann Clin Psychiatry 19 (1): 31–6. doi:10.1080/10401230601163550. PMID 17453659. 
  50. ^ Lenzer J (2005-09-27). "What the FDA isn't telling". Slate Magazine. Retrieved 2008-01-20. 
  51. ^ a b Jeanne Lenzer and Nicholas Pyke (2005-06-05). "Was Traci Johnson driven to suicide by anti-depressants? That's a trade secret, say US officials". Independent Online Edition. Retrieved 2008-01-20. 
  52. ^ "Historical Information on Duloxetine hydrochloride (marketed as Cymbalta)". FDA. June 2005. Archived from the original on 2007-09-29. Retrieved 2008-01-20. 
  53. ^ Parikh AR, Thatcher BT, Tamano EA, Liskow BI (February 2008). "Suicidal ideation associated with duloxetine use: a case series". J Clin Psychopharmacol 28 (1): 101–2. doi:10.1097/jcp.0b013e318160d5c3. PMID 18204351. 
  54. ^ Naedele WF (2004-02-12). "Drug test altered in wake of suicide". Philadelphia Inquirer. Retrieved 2008-01-20. [dead link]
  55. ^ a b Harris G (2004-02-12). "Student, 19, in Trial of New Antidepressant Commits Suicide". New York Times. Retrieved 2008-01-20. 
  56. ^ Stahl, SM; Grady, Moret, Briley (Sep 2005). "SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants". CNS Spectrums 10 (9): 732-747. 
  57. ^ Bymaster, FP; Lee, Knadler (2005). "The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression". Curr Pharm Des 11 (12). 
  58. ^ De Berardis D, Conti CM, Serroni N, Moschetta FS, Olivieri L, Carano A, Salerno RM, Cavuto M, Farina B, Alessandrini M, Janiri L, Pozzi G, Di Giannantonio M (2010). "The effect of newer serotonin-noradrenalin antidepressants on cytokine production: a review of the current literature". Int J Immunopathol Pharmacol 23 (2): 417–22. PMID 20646337. 
  59. ^ Wang SY, Calderon J, Kuo Wang G (September 2010). "Block of neuronal Na+ channels by antidepressant duloxetine in a state-dependent manner". Anesthesiology 113 (3): 655–65. doi:10.1097/ALN.0b013e3181e89a93. PMID 20693878. 
  60. ^ Bymaster, FP; Lee, Knadler (2005). "The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression". Curr Pharm Des 11 (12). 
  61. ^ "Cymbalta product insert". 
  62. ^ "Cymbalta product insert". 
  63. ^ "Cymbalta product insert". 
  64. ^ Robertson DW, Wong DT, Krushinski JH (1990-09-11). "United States Patent 4,956,388: 3-Aryloxy-3-substituted propanamines". USPTO. Retrieved 2008-05-17. 
  65. ^ Wong DT, Robertson DW, Bymaster FP, Krushinski JH, Reid LR (1988). "LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant drug". Life Sci. 43 (24): 2049–57. doi:10.1016/0024-3205(88)90579-6. PMID 2850421. 
  66. ^ Bymaster FP, Beedle EE, Findlay J, et al. (December 2003). "Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake". Bioorg. Med. Chem. Lett. 13 (24): 4477–80. doi:10.1016/j.bmcl.2003.08.079. PMID 14643350. 
  67. ^ Turcotte JE, Debonnel G, de Montigny C, Hébert C, Blier P (May 2001). "Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects". Neuropsychopharmacology 24 (5): 511–21. doi:10.1016/S0893-133X(00)00220-7. PMID 11282251. 
  68. ^ For example, see: Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA (March 2002). "Duloxetine in the treatment a double-blind clinical trial". J Clin Psychiatry 63 (3): 225–31. PMID 11926722. 
  69. ^ "Approval package for: application number NDA 721-427. Administrative/Correspondence #2" (PDF). The FDA Center for Drug Evaluation and Research. 2003. Retrieved 2008-05-18. [dead link]
  70. ^ FDA news
  71. ^ Health Canada Notice of Compliance Database - duloxetine. November 1, 2007, retrieved November 24, 2007.
  72. ^ Steyer R (2006-02-15). "Lilly Won't Pursue Yentreve for U.S.". TheStreet.com. Retrieved 2008-05-18. 
  73. ^ Lenzer J (2005). "FDA warns that antidepressants may increase suicidality in adults". BMJ 331 (7508): 70. doi:10.1136/bmj.331.7508.70-b. PMC 558648. PMID 16002878.  edit
  74. ^ "FDA approves antidepressant Cymbalta (duloxetine HCl) for treatment of generalized anxiety disorder". News-Medical.Net. Retrieved 25 December 2013. 
  75. ^ Staton, Tracy (July 9, 2012). "Lilly could net $1.5B-plus from Cymbalta extension". FiercePharma. Retrieved 25 December 2013. 
  76. ^ Palmer, Eric (April 11, 2013). "Eli Lilly to lay off hundreds in sales as Cymbalta nears edge of patent cliff". FiercePharma. Retrieved 25 December 2013. 
  77. ^ Anson, Pat (December 12, 2013). "Generic Cheaper Versions of Cymbalta Approved". National Pain Report. Retrieved January 2, 2014. 

External links[edit]