Duloxetine: Difference between revisions
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==Indications== |
==Indications== |
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The main uses of duloxetine are in [[major depressive disorder]], [[general anxiety disorder]], [[stress urinary incontinence]], painful [[peripheral neuropathy]] and fibromyalgia. In addition, it is being studied for various other indications. |
The main uses of duloxetine are in [[major depressive disorder]], [[general anxiety disorder]], [[stress urinary incontinence]], painful [[peripheral neuropathy]] and fibromyalgia. In addition, it is being studied for various other indications. |
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===Major depressive disorder=== |
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Duloxetine has demostrated efficacy for the treatment of [[major depressive disorder]]. In three out of six well-designed properly controlled pre-marketing trials duloxetine performed better than placebo; the three other trials were inconclusive.<ref name="FDA-1">{{cite web |url=http://www.fda.gov/cder/foi/nda/2004/021427_s000_Cymbalta_Medr_P1.pdf |title=Clinical review for NDA 21-427 Cymbalta (duloxetine). |author= Andreason PJ|date= |format=PDF |work=CDER approval package for application number 21-427. Medical review # 3. |publisher=FDA |page=12|accessdate=2008-05-22}}</ref> A meta-analysis of these trials indicated that the effect size of duloxetine as compared with placebo was weak-to-moderate, and similar to other 11 antidepressants studied.<ref name="pmid18199864">{{cite journal |author=Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R |title=Selective publication of antidepressant trials and its influence on apparent efficacy |journal=N. Engl. J. Med. |volume=358 |issue=3 |pages=252–60 |year=2008 |month=January |pmid=18199864 |doi=10.1056/NEJMsa065779 |url=}}</ref> The rationale behind the development of duloxetine was that inhibition of the reuptake of both serotonin and norepinephrine would make it work better than SSRIs, which inhibit only the reuptake of serotonin. However, in a comparative meta-analysis of clinical trials duloxetine appeared to be insignificantly less effective than SSRIs.<ref name="pmid17588546">{{cite journal |author=Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC |title=Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents |journal=Biol. Psychiatry |volume=62 |issue=11 |pages=1217–27 |year=2007 |month=December |pmid=17588546 |doi=10.1016/j.biopsych.2007.03.027 |url=}}</ref> A head-to-head comparison of duloxetine with an SSRI [[escitalopram]] found duloxetine to be both less tolerable and less effective.<ref name="pmid18545055">{{cite journal |author=Lam RW, Andersen HF, Wade AG |title=Escitalopram and duloxetine in the treatment of major depressive disorder: a pooled analysis of two trials |journal=Int Clin Psychopharmacol |volume=23 |issue=4 |pages=181–7 |year=2008 |month=July |pmid=18545055 |doi=10.1097/YIC.0b013e3282ffdedc |url=}}</ref> |
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===Stress urinary incontinence=== |
===Stress urinary incontinence=== |
Revision as of 02:42, 4 February 2009
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Clinical data | |
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License data |
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Routes of administration | Oral |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | ~ 50% (32% to 80%) |
Protein binding | ~ 95% |
Metabolism | Liver, two P450 isozymes, CYP2D6 and CYP1A2. |
Elimination half-life | 12,1 hours |
Excretion | 70% in urine, 20% in feces |
Identifiers | |
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CAS Number |
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PubChem CID | |
DrugBank | |
ChemSpider | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.116.825 |
Chemical and physical data | |
Formula | C18H19NOS |
Molar mass | 297.41456 g/mol g·mol−1 |
3D model (JSmol) | |
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![](http://upload.wikimedia.org/wikipedia/commons/thumb/d/dd/Cymbalta60mg.png/220px-Cymbalta60mg.png)
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Duloxetine (brand names Cymbalta, Yentreve) is a serotonin-norepinephrine reuptake inhibitor (SNRI) used for major depressive disorder (MDD), generalized anxiety disorder (GAD), pain related to diabetic neuropathy and fibromyalgia and in some countries for stress urinary incontinence (SUI). It is manufactured and marketed by Eli Lilly. Large number of side effects occurring during duloxetine treatment and lack of clear advantage over existing medications prompted several critical reviews concluding that duloxetine "should not be used" for stress urinary incontinence[2] and "currently has no place in the treatment of depression or diabetic neuropathy" as well.[3][4]
History
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.[5] The first publication on the discovery of the racemic form of duloxetine known as LY227942, was made in 1988.[6] The (+)-enantiomer of LY227942, assigned LY248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes two times more potently than (-)-enantiomer. This molecule was subsequently named duloxetine.[7]
Initial trials conducted in patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy [8] and the dose was increased to as high as 120 mg in subsequent clinical trials.[9]
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 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."[10]
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.[11] In 2007 Health Canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.[12]
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.[13]
Indications
The main uses of duloxetine are in major depressive disorder, general anxiety disorder, stress urinary incontinence, painful peripheral neuropathy and fibromyalgia. In addition, it is being studied for various other indications.
Major depressive disorder
Duloxetine has demostrated efficacy for the treatment of major depressive disorder. In three out of six well-designed properly controlled pre-marketing trials duloxetine performed better than placebo; the three other trials were inconclusive.[14] A meta-analysis of these trials indicated that the effect size of duloxetine as compared with placebo was weak-to-moderate, and similar to other 11 antidepressants studied.[15] The rationale behind the development of duloxetine was that inhibition of the reuptake of both serotonin and norepinephrine would make it work better than SSRIs, which inhibit only the reuptake of serotonin. However, in a comparative meta-analysis of clinical trials duloxetine appeared to be insignificantly less effective than SSRIs.[16] A head-to-head comparison of duloxetine with an SSRI escitalopram found duloxetine to be both less tolerable and less effective.[17]
Stress urinary incontinence
Duloxetine was first reported to improve outcomes in Stress urinary incontinence (SUI) in 1998.[18] Systematic reviews with meta-analysis, conducted in 2005 (Cochrane)[19] and 2008 (University of Minnesota),[20] 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.[19] According to the University of Minnesota review, duloxetine performed worse than oxybutynin or tolterodine 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.[20] 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.[19]
In addition, the full report prepared by Minnesota Evidence-based Practice Center for the US 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. [21] 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.[21]
The only clinical trial, which directly compared duloxetine with the gold standard of the SUI treatment pelvic floor muscle training (PFMT) was conducted by Lilly and gave mixed results. The incontinence episode frequency in duloxetine group decreased by 57% vs 35% in the PFTM group. However, the differences in the pad use and quality of life were not statistically significant. To the contrary, 65% patients doing PFTM 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.[22] In the continuation of this trial more than 91% of the patients on duloxetine experienced side effects.[23]
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's efficacy is "modest and transient, while its adverse effects are numerous and potentially severe."[2]
Painful peripheral neuropathy
At 20mg per day Cymbalta showed no clinical improvement over placebo. At 60mg per day Cymbalta showed modest improvement for diabetic pain over baseline, with 51% of patients treated with Cymbalta reporting at least a 30% sustained reduction in pain. In comparison, 31% of patients treated with placebo reported this magnitude of sustained pain reduction. In one study Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events, another trial had a low dropout rate of 12.1 percent.[24][25] Duloxetine is also used to treat nerve pain in the feet, legs, or hands due to nerve damage caused by poorly controlled diabetes. Duloxetine is thought to enhance the nerve signals within the central nervous system which naturally inhibit pain. Duloxetine is not effective for the numbness or tingling, nor is it effective for the other complications of diabetes. It does not treat the underlying nerve damage, but can help reduce the pain.[26]
Generalized anxiety disorder
On May 11 2006, Eli Lilly and Company announced the recent submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for Cymbalta for the treatment of generalized anxiety disorder (GAD).
Eli Lilly said the FDA has approved Cymbalta for the treatment of GAD in February 2007.[27] Eli Lilly said that in clinical trials patients treated with Cymbalta for GAD experienced a 46% improvement in anxiety symptoms, compared to 32% for those who took placebo, as measured by the Hamilton Anxiety Scale.
Fibromyalgia
On October 19, 2006, Eli Lilly issued a press release saying they had done trials which found that Cymbalta, at 60 mg once or twice daily, significantly reduced pain in more than half of women treated for fibromyalgia (FM), with and without major depression, according to 12-week data presented at the annual meeting of the American College of Rheumatology. Eli Lilly is in Phase III of its FM trials and is expected to submit a sNDA to the FDA for approval of Cymbalta for FM within the next 12 months.
Critics argue that randomized controlled trials of FM are difficult due to factors such as a lack of understanding of the pathophysiology and a heterogeneous FM patient population. Although there is a lack of understanding of what causes FM, it is estimated that approximately 5-7% of the U.S. population has FM,[28] representing a large patient clientele. Eli Lilly hopes Cymbalta will be the first FDA approved medication for FM and had been promoting Cymbalta for FM since 2004.[29]
In the study testing the efficacy of Cymbalta 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.[29]
Women who took Cymbalta 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.[29]
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.[29]
The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008. [30]
Chronic fatigue syndrome
As of January 11 2007, Eli Lilly is currently enrolling patients for double blind Phase II and Phase III trials of Cymbalta for the use of Chronic Fatigue Syndrome (CFS) in conjunction with the University of Cincinnati.[31] CFS is characterized by severe disabling fatigue of at least six months' duration which cannot be fully explained by an identifiable medical condition. Eli Lilly has not publicly stated their hypothesis for use of Cymbalta for CFS.[citation needed]
Contraindications
The following contraindications are listed by the manufacturer:[citation needed]
- 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.
- Cymbalta and thioridazine should not be co-administered.
Adverse effects
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Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% of patients.[32]
In a trial for mild 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:[33]
Other side-effects include:
- Orthostatic hypotension
- Fatigue
- Vivid nightmares
- Increased sweating
- Decreased appetite and weight loss
- Blurred vision
- Paresthesia
- Disturbances of the gastrointestinal tract, such as nausea, constipation, diarrhea, indigestion, vomiting and profuse bleeding
- Tremor
- Anxiety, nervousness, agitation
- Palpitations
- Decreased sex drive or difficulty achieving orgasm
- Impotence or delayed ejaculation
- Hot flashes
- Taste disturbances
- Difficulty passing urine
- Increase in blood pressure or heart rate
- Cold hands or feet
- Jaundice
- Inflammation of the liver or hepatitis leading to cirrhosis if left unchecked.
- Depersonalization
- Hypomania
- Weight gain or loss
Duloxetine and SSRIs have been shown to cause sexual side effects in some patients, both males and females. Although usually reversible, these sexual side effects can sometimes last for months, years, or longer, even after the drug has been completely withdrawn.[citation needed] This disorder is known as post-SSRI sexual dysfunction.
Postmarketing spontaneous reports
Reported adverse events which were temporally correlated to Cymbalta 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.[34]
A number of more serious complications, in which duloxetine may have played a role, has been published in the form of case reports:
- The Los Angeles County Department of Coroner released a report of the first post mortem studies of duloxetine; they identified twelve cases in which duloxetine was present on toxicologic analysis, but in no case was it deemed to be the ultimate cause of death. Five cases were declared multiple drug intoxication, and two were declared suicide.[35]
- A case of hyponatremia induced by duloxetine was reported by doctors at Weill Cornell Medical College in New York. This is common to all SSRIs.[36]
- A case of dyskinesia during treatment with duloxetine was reported in Germany.[37]
- Two episodes of serotonin syndrome have been documented in the use of duloxetine in conjunction with other medications.[38][39]
- A case of fulminant hepatic failure involving duloxetine which resulted in death was reported by the Department of Internal Medicine, Ohio State University, Columbus, Ohio.[40]
- An attack of acute porphyria in a patient with known variegate porphyria who had been commenced on duloxetine.[41]
Discontinuation syndrome
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. Although these events are generally self-limiting, some have been reported to be severe. This withdrawal phenomenon is known as the SSRI discontinuation syndrome. For those experiencing extreme and unusual difficulty discontinuing duloxetine, it is recommended by medical professionals that an SSRI with a longer half-life, such as fluoxetine, be administered for approximately four weeks, then discontinued, to lessen symptoms.[citation needed]
When discontinuing treatment with Cymbalta, 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."[42] This tapering process may be ineffective for some patients.[citation needed]
In MDD placebo-controlled clinical trials of up to nine weeks' duration, systematically evaluating 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 Cymbalta-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.[43]
Suicidality
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.[44][45][46]
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. In line with the general results, duloxetine use in depressed adults insignificantly decreased the odds of suicidality by 12%[45] or 20%[46] depending of the statistical technique used. However, in the subgroup of young adults (18–24 years old) duloxetine increased the odds of suicidality 5-fold, close to statistical significance.[45] There have been no trials of duloxetine in minors.
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."[47] 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.[48][49] 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.[49] 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.[50]
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.[51]
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 with her scarf from a shower rod in the bathroom of Lilly Laboratory for Clinical Research.[52][53] The New York Times article mentioned a withdrawal syndrome as a possible reason for this suicide.[53]
Pharmacology
Pharmacodynamics
Although the exact mechanisms of the antidepressant and central pain inhibitory action of duloxetine in humans are unknown, they are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical studies demonstrate that duloxetine potently inhibits neuronal serotonin and norepinephrine reuptake [54], and it has been demonstrated that this inhibition is balanced throughout the dosing range (when compared to venlafaxine in which the inhibition of noradrenaline is low at low doses and raises as the dose escalates).
It 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 receptors. Duloxetine undergoes extensive metabolism, but the major circulating metabolites do not contribute significantly to the pharmacologic activity.
Pharmacokinetics
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.
Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.
When orally administered it is well absorbed. There is an average 2-hour lag until absorption begins with maximal 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. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein.
Metabolism and Elimination — Only trace amounts (<1%) of unchanged duloxetine are present in the urine and most of the dose (aprox 70%) appears in the urine as metabolites of duloxetine with about 20% excreted in the feces.
See also
- Serotonin-norepinephrine reuptake inhibitor (SNRI)
- Neuropsychopharmacology
- Neuropharmacology
- Pharmacology
- Psychoactive drug
References
- ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
- ^ a b "Duloxetine: new drug. For stress urinary incontinence: too much risk, too little benefit". Prescrire Int. 14 (80): 218–20. 2005. PMID 16400743.
{{cite journal}}
: Unknown parameter|month=
ignored (help) - ^ "Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects". Prescrire Int. 15 (85): 168–72. 2006. PMID 17121211.
{{cite journal}}
: Unknown parameter|month=
ignored (help) - ^ Drug and Therapeutics Bulletin concurs: "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." "Is there a place for duloxetine?". Drug Ther Bull. 45 (4): 29–32. 2007. PMID 17451072.
{{cite journal}}
: Unknown parameter|month=
ignored (help) - ^ Robertson DW, Wong DT, Krushinski JH (1990-09-11). "United States Patent 4,956,388: 3-Aryloxy-3-substituted propanamines" (htm). USPTO. Retrieved 2008-05-17.
{{cite web}}
: CS1 maint: multiple names: authors list (link) - ^ 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.
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: CS1 maint: multiple names: authors list (link) - ^ Bymaster FP, Beedle EE, Findlay J; et al. (2003). "Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake". Bioorg. Med. Chem. Lett. 13 (24): 4477–80. PMID 14643350.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Turcotte JE, Debonnel G, de Montigny C, Hébert C, Blier P (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.
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: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ For example, see: Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA (2002). "Duloxetine in the treatment a double-blind clinical trial". J Clin Psychiatry. 63 (3): 225–31. PMID 11926722.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ "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.
- ^ FDA news
- ^ Health Canada Notice of Compliance Database - duloxetine. November 1, 2007, retrieved November 24, 2007.
- ^ Steyer R (2006-02-15). "Lilly Won't Pursue Yentreve for U.S." (htm). TheStreet.com. Retrieved 2008-05-18.
- ^ Andreason PJ. "Clinical review for NDA 21-427 Cymbalta (duloxetine)" (PDF). CDER approval package for application number 21-427. Medical review # 3. FDA. p. 12. Retrieved 2008-05-22.
- ^ Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (2008). "Selective publication of antidepressant trials and its influence on apparent efficacy". N. Engl. J. Med. 358 (3): 252–60. doi:10.1056/NEJMsa065779. PMID 18199864.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC (2007). "Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents". Biol. Psychiatry. 62 (11): 1217–27. doi:10.1016/j.biopsych.2007.03.027. PMID 17588546.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ Lam RW, Andersen HF, Wade AG (2008). "Escitalopram and duloxetine in the treatment of major depressive disorder: a pooled analysis of two trials". Int Clin Psychopharmacol. 23 (4): 181–7. doi:10.1097/YIC.0b013e3282ffdedc. PMID 18545055.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ Voelker R (1998). "International group seeks to dispel incontinence "taboo"". JAMA. 280 (11): 951–3. PMID 9749464.
{{cite journal}}
: Unknown parameter|month=
ignored (help) - ^ 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". Cochrane Database Syst Rev (3): CD004742. doi:10.1002/14651858.CD004742.pub2. PMID 16034945.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ a b Shamliyan TA, Kane RL, Wyman J, Wilt TJ (2008). "Systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women". Ann. Intern. Med. 148 (6): 459–73. PMID 18268288.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b http://www.ahrq.gov/downloads/pub/evidence/pdf/fuiad/fuiad.pdf
- ^ "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.
{{cite web}}
: Check date values in:|accessdate=
(help); Cite has empty unknown parameter:|coauthors=
(help) - ^ "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.
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