Duloxetine: Difference between revisions

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{{drugbox
{{DrugProjectFormSinglePage
| IUPAC_name = (+)-(''S'')-''N''-methyl-3-(1-naphthyloxy)- 3-(thiophen-2-yl)-propan-1-amine
|authorTag=
| image = Duloxetine.png
 
| image2 =  
 
| width =  
<!--Overview-->
| CAS_number = 116539-59-4
 
| CAS_supplemental = {{CAS|136434-34-9}} ([[hydrochloride]])
|genericName=
| ATC_prefix = N06
 
| ATC_suffix = AX21
 
| ATC_supplemental =  
 
| PubChem = 60835
|aOrAn=
| DrugBank = APRD00060
 
| C=18 | H=19 | N=1 | O=1 | S=1
a
| molecular_weight = 297.416 g/mol
 
| bioavailability =  
|drugClass=
| protein_bound = >90%
 
| metabolism = Liver, two P450 isozymes, CYP2D6 and CYP1A2.
 
| elimination_half-life =8-17 hours
 
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
|indication=
| pregnancy_US      = C
 
| pregnancy_category=
 
| legal_AU          =  <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
 
| legal_CA          =  <!--             / Schedule I, II, III, IV, V, VI, VII, VIII -->
|hasBlackBoxWarning=
| legal_UK          = <!-- GSL        / P      / POM / CD / Class A, B, C -->
 
| legal_US          = Rx-only
Yes
| legal_status      =  
 
| routes_of_administration = Oral
|adverseReactions=
| excretion = 70% in urine, 20% in feces
 
| licence_EU =Ariclaim
 
| licence_US =duloxetine
 
}}
<!--Black Box Warning-->
 
|blackBoxWarningTitle=
Title
 
|blackBoxWarningBody=
<i><span style="color:#FF0000;">ConditionName: </span></i>
 
* Content
 
<!--Adult Indications and Dosage-->
 
<!--FDA-Labeled Indications and Dosage (Adult)-->
 
|fdaLIADAdult=
 
=====Condition1=====
 
* Dosing Information
 
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* Dosing Information
 
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=====Condition3=====
 
* Dosing Information
 
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* Dosing Information
 
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=====Condition1=====
 
* Developed by:
 
* Class of Recommendation:
 
* Strength of Evidence:
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
 
<!--Non–Guideline-Supported Use (Adult)-->
 
|offLabelAdultNoGuideSupport=
 
=====Condition1=====
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
 
<!--Pediatric Indications and Dosage-->
 
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
 
|fdaLIADPed=
 
=====Condition1=====
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Off-Label Use and Dosage (Pediatric)-->
 
<!--Guideline-Supported Use (Pediatric)-->
 
|offLabelPedGuideSupport=
 
=====Condition1=====
 
* Developed by:
 
* Class of Recommendation:
 
* Strength of Evidence:
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Non–Guideline-Supported Use (Pediatric)-->
 
|offLabelPedNoGuideSupport=
 
=====Condition1=====
 
* Dosing Information
 
:* Dosage
 
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There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
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|contraindications=
 
* Condition1
 
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|warnings=
 
* Description
 
====Precautions====
 
* Description
 
<!--Adverse Reactions-->
 
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|clinicalTrials=
 
There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
 
=====Body as a Whole=====
 
 
 
 
=====Cardiovascular=====
 
 
 
 
=====Digestive=====
 
 
 
 
=====Endocrine=====
 
 
 
 
=====Hematologic and Lymphatic=====
 
 
 
 
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|postmarketing=
 
There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
 
=====Body as a Whole=====
 
 
 
=====Cardiovascular=====
 
 
 
=====Digestive=====
 
 
 
=====Endocrine=====
 
 
 
=====Hematologic and Lymphatic=====
 
 
 
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* Drug
:* Description
 
<!--Use in Specific Populations-->
 
|useInPregnancyFDA=
* '''Pregnancy Category'''
 
|useInPregnancyAUS=
* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''


There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.


'''Duloxetine''' (brand names ''Cymbalta'', ''Yentreve'', and in parts of Europe, ''Xeristar'' or ''Ariclaim'') is a drug which primarily targets [[major depressive disorder]] (MDD), [[general anxiety disorder|generalized anxiety disorder]] (GAD), pain related to diabetic [[peripheral neuropathy]] and in some countries [[Urinary incontinence#Stress incontinence|stress urinary incontinence]] (SUI). It is manufactured and marketed by [[Eli Lilly and Company]].  
|useInLaborDelivery=
There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.


Duloxetine has not yet been FDA approved for stress urinary incontinence or for [[fibromyalgia]].
|useInNursing=
There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.


Duloxetine is a selective SNRI (selective [[serotonin-norepinephrine reuptake inhibitor]]).  Duloxetine is a [[systemic]] drug therapy which affects the body as a whole. Known also under the code name LY248686, it is a potent dual reuptake inhibitor of [[serotonin]] (5-hydroxytryptamine, 5-HT) and [[norepinephrine]] (NE), possessing comparable affinities in binding to [[Norepinephrine transporter|NE-]] and [[Serotonin transporter|5-HT transporter]] sites.  It is a less potent inhibitor of [[dopamine]] reuptake.
|useInPed=
There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.


==History==
|useInGeri=
Duloxetine was created by Lilly researchers. The first publication of the discovery of the novel drug, then known as LY227942, was made in [[1988]] by David T. Wong and Frank P. Bymaster, two of the researchers behind Eli Lilly's [[fluoxetine]] ([[Prozac]]). Researchers reported: "These findings suggest that LY227942 has the pharmacological profile of an antidepressant drug and is useful to study the pharmacological responses of concerted enhancement of [[serotonergic]] and [[norepinephrine]] neurotransmission."<ref>Wong DT, Robertosn DW, Bymaster FP, Krushinski JH, Reid LR. "LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant drug." Life Sci. 1988;43(24):2049-57.</ref>
There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.


Eli Lilly and Company had the formula for duloxetine hydrochloride patented in 1991.  They began research on human subjects at 20mg by [[1997]]. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11282251&query_hl=28&itool=pubmed_DocSum]Turcotte JE, Debonnel G, de Montigny C, Hebert C, Blier P. "Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects." Neuropsychopharmacology. 2001 May;24(5):511-21.</ref> and the dose was increased to as high as 120mg in subsequent clinical trials done by Eli Lilly.
|useInGender=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.


In [[November 2001]], Lilly filed a New Drug Application (NDA) for duloxetine for depression with the US [[Food and Drug Administration]] (FDA). The launch of duloxetine was planned for the second half of [[2002]].  However, at the time, analysts predicted that the drug would actually be launched in the first quarter of 2003.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12211418&query_hl=24&itool=pubmed_docsum]Antilla S, Leinonen "Duloxetine Eli Lilly". Curr Opin Investig Drugs. 2002 Aug;3(8):1217-21</ref> 
|useInRace=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.


On [[July 18]], [[2002]], Eli Lilly made an agreement with [[Quintiles]] Transnational Corporation (a pharmaceutical research and marketing company) jointly to commercialize Cymbalta in the United States.<ref>[http://www.novaquest.com/NewsEvents/NovaQuestNews/2002/PressRelease-2002-52.htm] NovaQuest Press Release 2002</ref> [[PharmaBio]], the investment arm of Quintiles, invested $100 million to help develop Cymbalta.
|useInRenalImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.


Lilly received an approval letter from the FDA for Cymbalta (for depression) in [[September 2002]]. In [[October 2003]], the FDA issued duloxetine a second approval letter saying it did not need to see any more test results before the drug got the final approval for depression.  The agency said it would approve the drug once "manufacturing issues" had been resolved, as Lilly had quality control problems at two plants at the time.  
|useInHepaticImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.


Duloxetine (as Cymbalta) was approved by the FDA for MDD in [[August 2004]], and for diabetic neuropathy in September of [[2004]]. Lilly and Quintiles immediately began co-promoting Cymbalta. Through its contract sales organization, [[Innovex]], Quintiles has provided more than 500 sales representatives to help Lilly's substantial sales force promote Cymbalta in the United States for five years. In exchange, Quintiles stands to earn 8.5 percent of royalties from net sales of Cymbalta for depression and other neuroscience indications for eight years.<ref>[http://www.bizjournals.com/triangle/stories/2004/02/23/story1.html] Triangle Business Journal February 20, 2004</ref>
|useInReproPotential=
There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.


Cymbalta has not been approved for stress urinary incontinence (SUI) in the US, but Yentreve and Ariclaim have been approved for SUI in the [[European Union]] since [[August 2004]]. Yentreve, Xeristar and Ariclaim are produced by [[Boehringer Ingelheim]] and Eli Lilly and Company in a joint licensing agreement made in [[2002]].
|useInImmunocomp=
There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.


In Japan, duloxetine has been jointly developed with the pharmaceutical company [[Shionogi]] Ltd. for depression since 1992, after signing a license agreement with Eli Lilly. As of [[January 2007]], Shionogi had already received approval for the indication of depression, but is still conducting additional [[Phase III]] trials. For the treatment of pain related to diabetic peripheral neuropathy, Shionogi said it and Eli Lilly Japan K.K. will work together on the development as well as marketing. For this use, the drug is now going through [[Phase II]] clinical trials.
<!--Administration and Monitoring-->


==Delivery==
|administration=
[[Image:cymbalta60mg.png|thumb|Cymbalta 60mg]]


Each capsule of duloxetine contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride, equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach.
* Oral


==Mechanism of Action==
* Intravenous
{{see|Serotonin|Norepinephrine}}
When [[serotonin]] and [[norepinephrine]] are released from nerve cells in the brain they act to "lighten mood". When they are reabsorbed into the nerve cells, they no longer have an effect on mood. It is thought that when depression occurs, there may be a decreased amount of serotonin and norepinephrine released from nerve cells in the brain.


Duloxetine works by preventing serotonin, norepinephrine, and to a lesser extent [[dopamine]] from being reabsorbed into the nerve cells in the brain, specifically on the [[5-HT]] and [[Norepinephrine|NE]] and [[dopamine|D2]] receptors respectively. This helps prolong the "mood lightening" effect of any released serotonin and norepinephrine. In this way, duloxetine is thought to help relieve depression.
|monitoring=


Serotonin and norepinephrine in the [[brain]] and [[spinal cord]] are believed to mediate core depression symptoms and to help regulate the perception of pain. Disturbances of serotonin and/or norepinephrine may explain the presence of both the emotional and physical symptoms, including painful physical symptoms, of depression. Based on pre-clinical studies, duloxetine is a balanced and potent reuptake inhibitor of serotonin and norepinephrine.  While the mechanism of action of duloxetine is not fully known, scientists believe its effect on both emotional symptoms and pain perception is due to increasing the activity of serotonin and norepinephrine in the central nervous system (CNS).
There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.


It may take between two and four weeks of treatment for the benefits of this medicine to appear, so it is very important for a patient to keep taking it even if it doesn't seem have much effect at first. If the patient feels that the depression has become worse, has any of the listed side effects, or has any distressing thoughts or feelings in the first few weeks, he/she should talk to the prescribing doctor.
* Description


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.<ref>[http://www.esi-topics.com/fbp/2006/june06-MichaelJDetke.html Essential Science Indicators]</ref>
<!--IV Compatibility-->


==Contraindications==
|IVCompat=


*Hypersensitivity
There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
Cymbalta is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.


*Monoamine Oxidase Inhibitors
<!--Overdosage-->
Concomitant use in patients taking [[monoamine oxidase inhibitor]]s is contraindicated.


*Uncontrolled Narrow-Angle Glaucoma
|overdose=
In clinical trials, Cymbalta use was associated with an increased risk of [[mydriasis]]; therefore, its use should be avoided in patients with uncontrolled narrow-angle [[glaucoma]].


*CNS Acting Drugs
===Acute Overdose===
Given the primary CNS effects of Cymbalta, 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.


==Precautions==
====Signs and Symptoms====


* Cymbalta and [[thioridazine]] should not be co-administered.
* Description


==Side effects==
====Management====


Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects which are known to be associated with this medicine.  Simply being listed here does not mean that all people using this medicine will experience these (or any other) side effects.
* Description


Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10 to 20 percent of patients.<ref>Cymbalta® package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.</ref>
===Chronic Overdose===


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<ref>D. G. S. Perahia1, D. K. Kajdasz, D. J. Walker, J. Raskin, A. Tylee. "Duloxetine 60 mg once daily in the treatment of milder major depressive disorder". International Journal of Clinical Practice (Vol, 60 Issue 5 Pg 613 - May 2006)</ref>
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.


* [[Dry mouth]]
<!--Pharmacology-->
* [[Headache]]
* [[Insomnia]]
* [[Sleepiness]] or [[somnolence]]
* [[Dizziness]] or [[Orthostatic hypotension]]
* [[Fatigue (physical)|Fatigue]]
* Vivid nightmares
* Increased sweating
* Decreased appetite and weight loss
* Blurred vision
* [[Paresthesia]] (relates to "[[brain shivers]] or brain zaps")
* Disturbances of the gut, such as nausea, constipation, diarrhea, indigestion, vomiting
* [[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]]
* [[Depersonalization]]
* [[Hypomania]]


Duloxetine and other 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. This disorder is known as [[Post SSRI Sexual Dysfunction]].
<!--Drug box 2-->


Antidepressants may cause the amount of sodium in the blood to drop &mdash; a condition called [[hyponatraemia]]. This can cause symptoms such as drowsiness, confusion, muscle twitching, and convulsions. Elderly people may be particularly susceptible to this effect. There may also be an increased risk in people with [[cirrhosis]] and those who are dehydrated or taking diuretic medicines. Anyone who develops any of these symptoms while taking this medicine should consult their doctor so that their blood sodium level can be checked if necessary.
|drugBox=


Duloxetine as Cymbalta comes with suicide risk warning for children and adolescents under 18.


==Serious Adverse Effects==


Since duloxetine is a newer drug (FDA approved in 2004), few peer-reviewed articles have been published on its adverse effects, and effects of long-term use are still unknown. More than 40 different types of adverse effects have been reported, including completed suicide attempts and severe hepatic disorders.
<!--Mechanism of Action-->


*Journalists Jeanne Lenzer and Nicholas Pyke, writing for [[The Independent]] newspaper, uncovered 41 deaths and 13 suicides for patients taking duloxetine as of June 19, 2005.<ref>[http://news.independent.co.uk/uk/health_medical/article226432.ece The Independent 19 June 2005]</ref> 
|mechAction=


*The French journal ''Prescrire International'' published this opinion: "In practice, duloxetine currently has no place in the treatment of depression or diabetic neuropathy. Its efficacy has not yet been demonstrated to be even equivalent to that of other available drugs, and it has too many adverse effects, given this degree of uncertainty."<ref>"Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects." Prescrire International. (2006 Oct;15(85):168-72)</ref>
*  


*The [[Los Angeles County, California|Los Angeles County]] Department of Coroner released a report of the first ''[[Post-mortem examination|post mortem]]'' studies of duloxetine; they identified twelve cases in which duloxetine was the ultimate cause of death.  Five cases were declared multiple drug intoxication, and two were declared suicide.<ref>Anderson D, Reed S, Lintemoot J, Kegler S, DeQuintana S, Sandberg M, Muto J. "A first look at duloxetine (Cymbalta) in a postmortem laboratory. Journal of Annual Toxicology. (2006 Oct;30(8):576-480)</ref>  
<!--Structure-->


*A case of [[hyponatremia]] induced by duloxetine was reported by doctors at [[Weill Cornell Medical College of Cornell University|Weill Cornell Medical College]] in New York.<ref>Safdieh JE, Rudominer R. "A case of hyponatremia induced by duloxetine". J Clin Psychopharmacol. 2006 Dec;26(6):675-6.</ref> 
|structure=


*A case of [[dyskinesia]] during treatment with duloxetine was reported in Germany.<ref>Deuschle M, Mase E, Zink M. "Dyskinesia during treatment with duloxetine". Pharmacopsychiatry. 2006 Nov;39(6):237-8.</ref>
*  


*Two episodes of [[serotonin syndrome]] have been documented in the use of duloxetine in conjunction with other medications.<ref>J Clin Psychopharmacol. 2006 Dec;26(6):681-683, Anesth Analg. 2006 Dec;103(6):1466-8.</ref>
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]


*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]].<ref>Hanje AJ, Pell LJ, Votolato NA, Frankel WL, Kirkpatrick RB. "Case report: fulminant hepatic failure involving duloxetine hydrochloride". Clin Gastroenterol Hepatol. 2006 Jul;4(7):912-7. Epub 2006 Jun 22. </ref>
<!--Pharmacodynamics-->


*An acute attack of [[porphyria]] in a patient taking duloxetine.<ref>Loper T, Touchet B. Psychosomatics. 2007 Mar-Apr;48(2):179-80</ref>
|PD=


===Postmarketing Spontaneous Reports===
There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.


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]].<ref>[http://www.rxlist.com/cgi/generic/cymbalta_ad.htm] Cymbalta Side Effects, and Drug Interactions - RxList Monographs</ref>
<!--Pharmacokinetics-->


==Discontinuing Duloxetine==
|PK=
{{see |SSRI 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]].
There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.


Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose, rather than abrupt cessation, is recommended 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."<ref>Cymbalta® patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006</ref> This tapering process may be ineffective for some patients.
<!--Nonclinical Toxicology-->


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.<ref>Perahia DG, Kajdasz DK, Desaiah D, Haddad PM. "Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder". J Affect Disord. 2005 Dec;89(1-3):207-12. Epub 2005 Nov 2.</ref> 
|nonClinToxic=


Many patients on the drug longer than the nine weeks of Lilly's discontinuation test trials anecdotally report evidence of serious withdrawals from Cymbalta, lasting from weeks to many months.
There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.


===Clinical Worsening and Suicide Risk===
<!--Clinical Studies-->


All adult and pediatric patients being treated with duloxetine for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially when decreasing the dose.<ref>Cymbalta® patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006</ref>
|clinicalStudies=


==Efficacy of Duloxetine (Cymbalta) versus Venlafaxine (Effexor)==
There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.


A study by Bymaster and colleagues found that duloxetine inhibited binding to the human norephinepherine (NE) and serotonin (5-HT) transporters with K(i) values of 7.5 and 0.8 nM, respectively, and with a K(i) ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K(i) values of 2480 and 82 nM, respectively, and with a K(i) ratio of 30. Duloxetine inhibited ''ex vivo'' binding to rat 5-HT transporters and NE transporters with ED(50) values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED(50) values of 2 and 54 mg/kg, respectively.
<!--How Supplied-->


Thus, duloxetine more potently blocks serotonin and norephinepherine transporters ''in vitro'' and ''in vivo'' than [[venlafaxine]],<ref>Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT. "Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors". Neuropsychopharmacology. 2001 Dec;25(6):871-80</ref> arguably making it the most potent of all commercially available SNRIs.  Duloxetine and venlafaxine  have not been measured against [[milnacipran]].  Milnacipran is not yet available in the United States.
|howSupplied=


==Controversy==
*
===Diabetic Neuropathy===
Duloxetine received a second FDA approval a month after it was approved for depression when it also became the first FDA-approved treatment for pain caused by diabetic peripheral neuropathy on September 7, 2004.<ref>[http://www.fda.gov/bbs/topics/news/2004/NEW01113.html] FDA News</ref> The approval was based on two clinical trials done by Eli Lilly between June 2001 and August 2003. At 20mg per day Cymbalta showed no clinical improvement over placebo. At 60mg per day Cymblata showed modest improvement for diabetic pain over baseline, with 51 percent of patients treated with Cymbalta reporting at least a 30 percent sustained reduction in pain. In comparison, 31 percent of patients treated with placebo reported this magnitude of sustained pain reduction. At 60mg per day 89.5% of patients had some marked treatment adverse effects in one trial, and 87% in the other trial.<ref>Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. "Duloxetine vs. placebo in patients with painful diabetic neuropathy". Pain. 2005 Jul;116(1-2):109-18.</ref><ref>Raskin J, Pritchett YL, Wang F, D'Souza DN, Waninger AL, Iyengar S, Wernicke JF. "A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain". Pain Med. 2005 Sep-Oct;6(5):346-56.</ref>


===Stress Urinary Incontinence and Suicidality===
<!--Patient Counseling Information-->


Duloxetine as Yentreve and Ariclaim was approved for use of stress urinary incontinence (SUI) in the EU on August 13, 2004.  In November 2002, Eli Lilly and Company and [[Boehringer Ingelheim]], a German pharmaceutical company, signed a long-term agreement jointly to develop and commercialize duloxetine hydrochloride.
|fdaPatientInfo=


Although the FDA approved Cymbalta for MDD and diabetic neuropathy, and Yentreve was approved for use of SUI in the [[European Union]], Eli Lilly rescinded their request for FDA approval for SUI use in the United States.  In a 9,400-person trial of duloxetine for the treatment of SUI in women, eleven suicide attempts and three cases of suicidal ideation were reported.<ref>[http://www.fda.gov/cder/drug/infopage/duloxetine/historical.htm FDA Historical Information on Duloxetine]</ref> Withdrawal of an application from FDA approval process is usually the result of the manufacturer's failure to demonstrate in clinical trials that the drug's risk-benefit ratio is positive.  
There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.


The trials &mdash; including 19-year-old Traci Johnson<ref>[http://www.ahrp.org/infomail/04/02/11.php] Alliance for Human Research Protection. "19 year old volunteer suicided in Eili Lilly laboratory". February 11, 2004.</ref> and four other patients who committed suicide during Lilly trials for duloxetine &mdash; were cleared by the FDA, stating that underlying depression &mdash; not the drug &mdash; causes sufferers to become suicidal.  Ms. Johnson was in a Lilly trial testing duloxetine as Yentreve, a urinary stress incontinence medication, and not in an anti-depressant trial.  In light of suicide risks, some critics claim that the FDA approval of duloxetine for MDD and diabetic neuropathy is irresponsible.  On the other hand, the number of participants in the SUI studies was large, and trials of duloxetine for MDD and diabetic neuropathy showed no increase in suicidality.
<!--Precautions with Alcohol-->


|alcohol=


* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.


==Recent News==
<!--Brand Names-->
===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). Approximately 6.8 million American adults, or about 3.1 percent of people age 18 and over, have GAD in a given year.<ref>[http://www.nimh.nih.gov/publicat/numbers.cfm] NIMH: The Numbers Count</ref> 


Eli Lilly said the FDA has approved Cymbalta for the treatment of GAD in February 2007.<ref>[http://www.news-medical.net/?id=22194] News-Medical.Net February 26, 2007</ref> 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.
|brandNames=


===Fibromyalgia===
* ®<ref>{{Cite web | title = | url =  }}</ref>
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,<ref>[http://www.fmaware.org/fminfo/brochure.htm] National Fibromyalgia Association Brochure</ref> 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.<ref>[http://doctor.medscape.com/viewarticle/488994] Duloxetine Effective in Fibromyalgia Arthritis Rheum. 2004;50:2974-2984</ref>
<!--Look-Alike Drug Names-->


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.
|lookAlike=


Women who took Cymbalta had significantly less pain and discomfort than those who took the placebo. For men, who made up only 11 percent 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.  
* A® — B®<ref name="www.ismp.org">{{Cite web  | last =  | first =  | title = http://www.ismp.org | url = http://www.ismp.org | publisher =  | date =  }}</ref>


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. Lastly, the primary researcher on the project has received more than $10,000 in consulting fees from Eli Lilly, the manufacturer of Cymbalta, all other researchers also had ties to the company, reflecting a conflict of interest.
<!--Drug Shortage Status-->


===Chronic Fatigue Syndrome===
|drugShortage=
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]].<ref>[http://clinicaltrials.gov/ct/show/NCT00375973?order=1] Clinicaltrials.gov</ref>  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.
}}


==See also==
<!--Pill Image-->
*[[Selective Serotonin Reuptake Inhibitor]]
*[[Neuropsychopharmacology]]
*[[Neuropharmacology]]
*[[Neurotoxicology]]
*[[Neuropsychotoxicology]]
*[[Pharmacology]]
*[[Psychoactive drug]]


==References==
{{PillImage
<div class="references-small" style="-moz-column-count:2; column-count:2;">
|fileName=No image.jpg|This image is provided by the National Library of Medicine.
{{reflist|2}}
|drugName=
*Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA. "Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial". J Clin Psychiatry 2002;63(3):225-31.
|NDC=
*Detke MJ, Lu Y, Goldstein DJ, McNamara RK, Demitrack MA. "Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression". J Psychiatr Res 2002;36:383-90.
|drugAuthor=
*Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. "Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial". J Clin Psychiatry 2002;63(4):308-15.
|ingredients=
*Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. "Duloxetine in the long-term treatment of major depressive disorder". J Clin Psychiatry 2003;64(10):1237-44.
|pillImprint=
*Bailey KP. Yale University School of Nursing, New Haven, Connecticut, USA. "Physical symptoms comorbid with depression and the new antidepressant duloxetine". J Psychosoc Nurs Ment Health Serv. 2003 Dec;41(12):13-8. 
|dosageValue=
*Gutman DA, Owens MJ.Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA. "Serotonin and norepinephrine transporter binding profile of SSRIs". Essent Psychopharmacol. 2006;7(1):35-41. 
|dosageUnit=
*Raskin J, Wang F, Pritchett YL, Goldstein DJ. "Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study". Pain Med. 2006 Sep-Oct;7(5):373-85.
|pillColor=
</div>
|pillShape=
|pillSize=
|pillScore=
}}


==External links==
<!--Label Display Image-->
* [http://www.cymbalta.com/ Manufacturer website]
* [http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500549.html Duloxetine] - medlineplus.org
* [http://pi.lilly.com/us/cymbalta-pi.pdf Eli Lilly Cymbalta Prescribing Guide]
* [http://www.fda.gov/cder/drug/InfoSheets/HCP/duloxetineHCP.htm FDA Alert for Healthcare Professionals - Cymbalta Serotonin Syndrome]
* [http://www.fda.gov/cder/drug/infosheets/patient/duloxetinePIS.pdf FDA Patient Information Sheet on Cymbalta]
* [http://www.rxlist.com/drugs/drug-91491-Cymbalta+Oral.aspx?drugid=91491&drugname=Cymbalta+Oral&pagenumber=6 Cymbalta List of Side Effects] - rxlist.com
*[http://www.askapatient.com/viewratings.asp?drug=21427&name=CYMBALTA&sort=DateAdded Cymbalta User Ratings] - askapatient.com
*[http://newsroom.lilly.com/ReleaseDetail.cfm?ReleaseID=231196 Eli Lilly Press Release for Cymbalta for GAD]
*[http://drugs.healthdiaries.com/cymbalta-side-effects.html Patient Stories about Cymbalta Side Effects]


{{Antidepressants}}
{{LabelImage
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
}}


[[Category:Lilly]]
{{LabelImage
[[Category:Serotonin-norepinephrine reuptake inhibitors]]
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
[[Category:Thiophenes]]
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[[de:Duloxetin]]
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[[it:Duloxetina]]
[[pt:Duloxetina]]
[[sv:Cymbalta]]


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Revision as of 13:38, 30 July 2014

Duloxetine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Black Box Warning

Title
See full prescribing information for complete Boxed Warning.
ConditionName:
  • Content

Overview

Duloxetine is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition1
  • Dosing Information
  • Dosage
Condition2
  • Dosing Information
  • Dosage
Condition3
  • Dosing Information
  • Dosage
Condition4
  • Dosing Information
  • Dosage

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Duloxetine in adult patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Duloxetine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding FDA-Labeled Use of Duloxetine in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Duloxetine in pediatric patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Duloxetine in pediatric patients.

Contraindications

  • Condition1

Warnings

Title
See full prescribing information for complete Boxed Warning.
ConditionName:
  • Content
  • Description

Precautions

  • Description

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Duloxetine in the drug label.

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Duloxetine in the drug label.

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Drug Interactions

  • Drug
  • Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Duloxetine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Duloxetine during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Duloxetine with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Duloxetine with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Duloxetine with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Duloxetine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Duloxetine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Duloxetine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Duloxetine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Duloxetine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Duloxetine in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • Intravenous

Monitoring

There is limited information regarding Monitoring of Duloxetine in the drug label.

  • Description

IV Compatibility

There is limited information regarding IV Compatibility of Duloxetine in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

  • Description

Management

  • Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Duloxetine in the drug label.

Pharmacology

There is limited information regarding Duloxetine Pharmacology in the drug label.

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Duloxetine in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Duloxetine in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Duloxetine in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Duloxetine in the drug label.

How Supplied

Storage

There is limited information regarding Duloxetine Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Duloxetine |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Duloxetine |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Patient Counseling Information of Duloxetine in the drug label.

Precautions with Alcohol

  • Alcohol-Duloxetine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ Empty citation (help)
  2. ↑ "http://www.ismp.org". External link in |title= (help)


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