Duloxetine

Structural formula
General
Non-proprietary name	Duloxetine
other names	(+) - ( S ) - N -Methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine ( IUPAC ) (3 S ) - N -Methyl-3- (naphthalen-1-yloxy) -3- (thiophen-2-yl) -propan-1-amine
Molecular formula	C 18 H 19 NOS (duloxetine) C 18 H 19 NOS C 2 H 2 O 4 (duloxetine oxalate ) C 18 H 19 NOS HCl (duloxetine hydrochloride )
External identifiers / databases
CAS number 116539-59-4 (duloxetine) 116817-77-7 (duloxetine oxalate ) 136434-34-9 (duloxetine hydrochloride) EC number 601-438-0 ECHA InfoCard 100.116.825 PubChem 60835 ChemSpider 54822 DrugBank DB00476 Wikidata Q411932
Drug information
ATC code	N06 AX21
Drug class	antidepressant
Mechanism of action	Serotonin norepinephrine reuptake inhibitors
properties
Molar mass	297.42 g mol −1 (duloxetine)
solubility	Duloxetine hydrochloride: slightly soluble in water, slightly soluble in methanol , practically insoluble in hexane
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 351-361 P: ?
Toxicological data	491 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Duloxetine is a drug from the group of selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) and is used in the treatment of depression , generalized anxiety disorders , diabetic polyneuropathy and urinary incontinence .

In addition to the psychological complaints, accompanying physical symptoms ( e.g. pain ) were also alleviated in the studies. The analgesic effect of pain symptoms associated with depression , according to a recent meta-analysis available, but particularly remarkable.

Duloxetine was developed by the Eli Lilly company. Cymbalta is one of the " blockbuster drugs" (over $ 6 billion in sales in 2013).

application areas

Approved areas of application for duloxetine are the treatment of women with moderate to severe stress urinary incontinence ( Yentreve ) and the treatment of depressive disorders, generalized anxiety disorders and pain associated with diabetic polyneuropathy ( Cymbalta , Xeristar , Duloxetine Lilly ).

The remedies can be used orally , various strengths are available. Only the hydrochloride of duloxetine is used pharmaceutically .

Development and marketing

Yentreve

On August 11, 2004, the European Commission granted Eli Lilly Nederland BV a marketing authorization for Yentreve throughout the European Union. Contrary to the expectations of the partners (Eli Lilly and Boehringer Ingelheim ), Yentreve's sales were disappointing, whereupon Boehringer Ingelheim said goodbye to the joint cooperation with Lilly in the area of ​​stress incontinence.

In January 2005, however, the US approval application for Yentreve was withdrawn because the FDA had serious safety concerns. In the US studies, there was a significantly higher number of suicide attempts, the FDA even spoke of twice as high a risk compared to the normal population. Even before that, there were recurring suicides in duloxetine studies, including the particularly tragic case of a healthy test person who hanged herself with a scarf in Eli Lilly's research laboratory. She had recently been switched from duloxetine to placebo, so the reason was suspected to be acute withdrawal syndrome. Both Eli Lilly and the FDA were heavily criticized for their policy of appeasement at the time.

Cymbalta / Xeristar

In December 2004, Cymbalta and Xeristar also received EU-wide approval, initially only for the treatment of depressive episodes. As early as 2005, the indication was expanded to include the treatment of pain associated with diabetic polyneuropathy in adults. In 2008 the treatment of generalized anxiety disorder was added and in 2009 it was expanded to include the treatment of major depressive disorders. The only attempt to add fibromyalgia to the indications failed in 2008. The EMA's Committee for Medicinal Products for Human Use (CHMP) was of the opinion that the effectiveness of Cymbalta / Xeristar in the treatment of fibromyalgia had not been sufficiently proven.

Before opening the market to generic drug manufacturers, Lilly added Duloxetine Lilly in 2014 with approval . Boehringer withdrew its 2004 approval for Ariclaim (the treatment of diabetic polyneuropathy pain) in 2018.

Cost-benefit assessment in Germany

In 2013, the first cost-benefit assessment by the Institute for Quality and Efficiency in Health Care (IQWiG) for the active ingredients venlafaxine , duloxetine, bupropion and mirtazapine found that duloxetine had significantly higher prices in relation to its benefits than other antidepressants.

Since 2015, duloxetine generics have also been approved for the German market .

pharmacology

Binding profile

receptor	K (nM) i
SERT	0.8
NET	7.5
DAT	240
5-HT 6	419
5-HT 2A	504
5-HT 2C	916
Histamine H 1	2300
α 1	8300
α 2	8600

Duloxetine is chiral and is considered stereochemically more uniform (= purer ). Drug used in the ( S ) configuration. The active substance is a combined serotonin and noradrenaline reuptake inhibitor. He shows little reuptake inhibition of dopamine , but has no significant affinity for histamine , dopamine and acetylcholine receptors and adrenoceptors . The pain-relieving effect of duloxetine is likely to be due to a strengthening of the descending inhibitory pain pathways in the central nervous system. The antidepressant effect only occurs with a latency and is - as with all antidepressants - probably due to the higher availability of neurotransmitters due to the adaptation of the receptors and similar structures.

Compared to other serotonin-norepinephrine reuptake inhibitors , duloxetine has a 10-fold greater selectivity for serotonin than for norepinephrine. While Milnacipran blocks serotonin and norepinephrine reuptake approximately equally, venlafaxine has a 30-fold greater selectivity for serotonin.

Metabolism ( pharmacokinetics )

The absolute oral bioavailability of duloxetine fluctuates widely and can be between 32% and 80% depending on the patient. This is due to the strong first-pass effect , which is subject to large inter-individual differences, due to a. Gender, age, smoking status ( compared to nonsmokers a plasma concentration reduced by almost 50% ), food consumption and enzyme activity of the cytochrome P450 2D6 (CYP2D6). Liver and kidney diseases also affect the pharmacokinetics of duloxetine. The degradation occurs simultaneously via the cytochromes P450 1A2 and 2D6 (whereby duloxetine probably only causes a moderate inhibition of 2D6 and the other isoenzymes are not inhibited). Inhibition of one of these enzymes by other drugs can lead to dangerous overdoses (see Interactions). The two main metabolites formed, 4-hydroxy-duloxetine and 5-hydroxy-6-methoxy-duloxetine, are both inactive.

unwanted effects

The observed side effects include:

• Nausea , dry mouth , sore throat, and constipation (constipation)
• Diarrhea , vomiting , loss or decrease in appetite
• Headache, blurred vision, dizziness, drowsiness, and tremors
• Sleep disorders, anxiety and nervousness
• increased sweating , night sweats and hot flashes
• Freeze
• Tiredness, frequent yawning
• Sexual disorders (e.g. inability to orgasm or erectile dysfunction)
• High blood pressure and heart problems
• delayed micturition and urinary retention
• Liver damage has been reported - particularly with alcohol.

The undesirable effects occur particularly in the first few days after starting the intake, but can last for several weeks. In a direct comparison, duloxetine is inferior to venlafaxine : more patients discontinued therapy because of side effects. Both duloxetine and venlafaxine performed worse than serotonin reuptake inhibitors on this criterion .

Withdrawal symptoms may occur if duloxetine is stopped suddenly . You may experience dizziness, hyperhidrosis , nausea, vomiting, diarrhea , insomnia, headache, sensory disturbances, irritability and anxiety. It is therefore recommended to end the treatment gradually .

Interactions and contraindications

Caution should be exercised when using duloxetine with other antidepressants. Simultaneous use of duloxetine and irreversible monoamine oxidase inhibitors (MAO-B inhibitors) such as selegiline and tranylcypromine is contraindicated . The combination with CYP1A2 inhibitors, such as fluvoxamine , ciprofloxacin or enoxacin , is also contraindicated , as increased plasma levels of duloxetine result. The combination of duloxetine with reversible MAOIs such as moclobemide is not recommended. Duloxetine should not be taken with St. John's wort .

Pregnancy risks

The potential risk to humans is unknown. Although no data are available on the use of duloxetine, it should be noted that withdrawal symptoms have occurred in newborns when the mother has used other serotonergic drugs shortly before the due date. Duloxetine should not be used during pregnancy. However, taking duloxetine is not a reason for an abortion. Women who become pregnant or are planning to become pregnant during treatment should tell their doctor. In animal experiments, duloxetine caused damage in the offspring of pregnant animals to which it was administered (see below). However, it is unclear whether this can be carried over to humans.

Growth retardation of the pups has been observed in the offspring of pregnant mice that received duloxetine. In the offspring of pregnant rabbits, one study found an increased incidence of cardiovascular and skeletal malformations, but not another study. When duloxetine was administered to pregnant rats, behavioral problems occurred in their pups.

Trade names

Cymbalta (EU, CH, USA, J), Yentreve (EU), Xeristar (EU), various generics

Web links

• FDA Warning on Duloxetine , FDA ALERT, 7/2006
• Duloxetine (Cymbalta) . In: Active substance NEWS , 03/2009, as of: February 20, 2009, (PDF 72 kB)
• European Public Assessment Reports (EPAR) for duloxetine on the European Medicines Agency website
• Critical evaluation

Individual evidence

1. ↑ European Pharmacopoeia. 8th edition. Basic work 2014, p. 3150.
2. ↑ There is not yet a harmonized classification for this substance . A labeling of N-methyl-gama- (1-naphthalenyloxy) -2-thiophenepropanamine in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on January 16, 2020, is reproduced from a self-classification by the distributor .
3. ^ Entry on duloxetine in the DrugBank of the University of Alberta .
4. ↑ Psychother Psychosom. Volume 77, No. 1, 2008, pp. 12-16, doi: 10.1159 / 000110055 . PMID 18087203 .
5. ↑ ROTE LISTE 2008. Verlag Rote Liste Service, Frankfurt am Main 2008, ISBN 978-3-939192-20-6 .
6. ↑ Amendment of the agreement regarding Yentreve / Ariclaim company report 2005 ( Memento of December 20, 2013 in the Internet Archive ) (PDF; 3.1 MB).
7. ↑ J Lenzer FDA warns that antidepressants may increase suicidality in adults. In: BMJ. Volume 331, 2005, p. 70. PMID 16002878 .
8. ^ G. Harris: Student, 19, in Trial of New Antidepressant Commits Suicide. In: The New York Times. February 12, 2004.
9. ↑ J. Lenzer: What the FDA isn't telling. In: Slate Magazine. September 27, 2005.
10. ↑ Public Assessment Report (EPAR) of the European Medicines Agency (EMA) on: Cymbalta
11. ↑ Cost-benefit assessment of venlafaxine, duloxetine, bupropion and mirtazapine compared to other drug treatments that can be prescribed. (PDF) Institute for Quality and Efficiency in Health Care, October 30, 2013, accessed on January 1, 2014 . 
12. ↑ Specialist information on corresponding preparations, accessible e.g. B. on the Red List online ( memento of January 25, 2019 in the Internet Archive ) and the website of the European Medicines Agency , accessed on March 10, 2019.
13. ↑ FP Bymaster, LJ Dreshfield-Ahmad, PG Threlkeld, JL Shaw, L. Thompson: Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors . In: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology . tape 25 , no. 6 , December 2001, p. 871-880 , doi : 10.1016 / S0893-133X (01) 00298-6 , PMID 11750180 .
14. ↑ C. Moret, M. Charveron, JP Finberg, JP Couzinier, M. Briley: Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug . In: Neuropharmacology . tape 24 , no. 12 , 1985, pp. 1211-9 , doi : 10.1016 / 0028-3908 (85) 90157-1 , PMID 3005901 .
15. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f, July 22, 2019, pp. 508-517, p. 509.
16. ↑ Duloxetine (Cymbalta®). (PDF 77 kB) In: AktUELL - Issue 03/2009. National Association of Statutory Health Insurance Physicians; Drug Commission of the German Medical Association, February 20, 2009, accessed on June 22, 2010 (content may be copied): "Duloxetine is not the first choice for the acute treatment of depressive disorders" 
17. ↑ arznei-telegramm.de
18. ↑ Antidepressants: Benefits of SNRI Proven. Institute for Quality and Efficiency in Health Care, August 18, 2009, accessed on January 1, 2014 . 
19. ↑ SNRI in patients with depression, p. 3, table 2, final report A05-20A, abstract, version 1.0, June 17, 2009, IQWiG 111 kB, accessed on March 21, 2010.
20. ↑ ^{a b c} Specialist information of the Swiss Medicines Compendium: Cymbalta; Status: February 2008.
21. ^ Specialist information Yentreve, as of July 2004.
22. ^ Technical information "Cymbalta"; Status: April 2009.

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