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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/04/03 17:04:51」(JST)

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Duloxetine (Cymbalta, and generics) is a serotonin-norepinephrine reuptake inhibitor (SNRI) created by Eli Lilly. It is mostly prescribed for major depressive disorder and generalized anxiety disorder (GAD) fibromyalgia and neuropathic pain.^[1]

Duloxetine failed to receive US approval for stress urinary incontinence amid concerns over liver toxicity and suicidal events; however, it was approved for this indication in the UK, where it is recommended as an add-on medication in stress urinary incontinence instead of surgery.^[2]

1 Medical uses
- 1.1 Major depressive disorder
- 1.2 Generalized anxiety disorder
- 1.3 Diabetic peripheral neuropathy
- 1.4 Fibromyalgia and chronic pain
- 1.5 Stress urinary incontinence
2 Contraindications
3 Adverse effects
- 3.1 Postmarketing spontaneous reports
- 3.2 Discontinuation syndrome
- 3.3 Suicidality
4 Pharmacology
- 4.1 Mechanism of action
- 4.2 Pharmacokinetics
5 History
6 Brand names
7 References
8 External links

Medical uses

The main uses of duloxetine are in major depressive disorder, general anxiety disorder, urinary incontinence, neuropathic pain, and fibromyalgia.^[1]^[3]^[4]

Duloxetine is recommended as a first line agent for the treatment of chemotherapy-induced neuropathy by the American Society for Clinical Oncology,^[5] as a first-line therapy for fibromyalgia in the presence of mood disorders by the German Interdisciplinary Association for Pain therapy,^[6] as a Grade B recommendation for the treatment of diabetic neuropathy by the American Association for Neurology^[7] and as a level A recommendation in certain neuropathic states by the European Federation of Neurological Societies.^[8]

A 2014 Cochrane review concluded that duloxetine is beneficial in the treatment of diabetic neuropathy and fibromyalgia but that more comparative studies with other medicines are needed.^[9] The medical journal Prescrire (based in France) concluded that duloxetine is no better than other available agents and has a greater risk of side effects.^[10] Thus they recommend against its general use.^[10]

Major depressive disorder

Duloxetine was approved for the treatment of major depression in 2004. While duloxetine has demonstrated improvement in depression-related symptoms compared to placebo, comparisons of duloxetine to other antidepressant medications have been less successful. A 2012 Cochrane Review did not find greater efficacy of duloxetine compared to SSRIs and newer antidepressants. Additionally, the review found evidence that duloxetine has increased side effects and reduced tolerability compared to other antidepressants. It thus did not recommend duloxetine as a first line treatment for major depressive disorder, given the high cost of duloxetine compared to off-patent antidepressants and lack of increased efficacy.^[11] Generic duloxetine became available in 2013.^[12]

Generalized anxiety disorder

Duloxetine is more effective than placebo in the treatment of generalized anxiety disorder (GAD).^[13] Major guidelines such as Maudsley Prescribing Guidelines,^[14] and Canadian Psychiatric Association Guidelines^[15] do not list duloxetine among the recommended treatment options. However, a review from the Annals of Internal Medicine lists duloxetine among the first line drug treatments, along with citalopram, escitalopram, sertraline, paroxetine, and venlafaxine.^[16]

Diabetic peripheral neuropathy

Duloxetine was approved for the pain associated with diabetic peripheral neuropathy (DPN), based on the positive results of two clinical trials. The average daily pain was measured using an 11-point scale, and duloxetine treatment resulted in an additional 1–1.7 points decrease of pain as compared with placebo.^[17]^[18]^[19] At least 50% pain relief was achieved in 40–45% of the duloxetine patients vs. 20–22% of placebo patients. Pain decreased by more than 90%, in 9–14% of duloxetine patients vs. 2–4% of placebo patients. Most of the response was achieved in the first two weeks on the medication. Duloxetine slightly increased the fasting serum glucose; however this effect was deemed to be of "minimal clinical significance".^[17]

The comparative efficacy of duloxetine and established pain-relief medications for DPN is unclear. A systematic review noted that tricyclic antidepressants (imipramine and amitriptyline), traditional anticonvulsants and opioids have better efficacy than duloxetine. Duloxetine, tricyclic antidepressants and anticonvulsants have similar tolerability while the opioids caused more side effects.^[20] Another review in Prescrire International considered the moderate pain relief achieved with duloxetine to be clinically insignificant and the results of the clinical trials unconvincing. The reviewer saw no reason to prescribe duloxetine in practice.^[21] The comparative data collected by reviewers in BMC Neurology indicated that amitriptyline, other tricyclic antidepressants and venlafaxine may be more effective. However, the authors noted that the evidence in favor of duloxetine is much more solid.^[22] A Cochrane review concluded that the evidence in support of duloxetine's efficacy in treating painful diabetic neuropathy was adequate, and that further trials should focus on comparisons with other medications.^[23]

Fibromyalgia and chronic pain

A review of duloxetine found that it reduced pain and fatigue, and improved physical and mental performance compared to placebo.^[24]

The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008.^[25]

It may be useful for chronic pain from osteoarthritis.^[26]^[27]

On November 4, 2010, the U.S. Food and Drug Administration approved duloxetine to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain.^[28]

Stress urinary incontinence

Duloxetine was first reported to improve outcomes in stress urinary incontinence (SUI) in 1998.^[29] The safety and utility of duloxetine in the treatment of incontinence has been evaluated in a series of meta analyses and practice guidelines.

A 2013 meta analysis concluded that duloxetine decreased incontinence episodes more than placebo with people about 56% more likely than placebo to experience a 50% decrease in episodes. Adverse effects were experienced by 83% of duloxetine-treated subjects and by 45% of placebo-treated subjects.^[30]

A 2012 review and practice guideline published by the European Association of Urology concluded that the clinical trial data provides Grade 1a evidence that duloxetine improves but does not cure urinary incontinence, but that it causes a high rate of gastrointestinal side effects (mainly nausea and vomiting) leading to a high rate of treatment discontiuation.^[31]

The National Institute for Clinical and Health Excellence recommends (as of September 2013) that duloxetine not be routinely offered as first line treatment, and that it only be offered as second line therapy in women wishing to avoid therapy. The guideline further states that women should be counseled regarding the drug's side effects.^[32]

Contraindications

The following contraindications are listed by the manufacturer:^[33]

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

In addition, the FDA has reported on life-threatening drug interactions that may be possible when co-administered with triptans and other drugs acting on serotonin pathways leading to increased risk for serotonin syndrome.^[34]

Adverse effects

Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% of patients.^[35]

In a trial for major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group.^[36] In a long-term study of fibromyalgia patients receiving duloxetine, frequency and type of adverse effects was similar to that reported in the MDD above. Side effects tended to be mild-to-moderate, and tended to decrease in intensity over time.^[37]

Sexual dysfunction is often a side effect of drugs that inhibit serotonin reuptake. Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and anorgasmia (trouble achieving orgasm). Loss of or decreased response to sexual stimuli and ejaculatory anhedonia are also possible. Frequency of treatment-emergent sexual dysfunction in long-term treatment has been found to be similar for duloxetine and SSRIs when compared in clinical trials,^[38]^[39] while there is some evidence that duloxetine is associated with less sexual dysfunction than escitalopram when measured at 4 and 8 weeks of treatment.^[39]

Postmarketing spontaneous reports

Reported adverse events which were temporally correlated to duloxetine therapy include rash, reported rarely, and the following adverse events, reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatitis, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens–Johnson syndrome, syncope (especially at initiation of treatment), and urticaria.^[40]

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. The withdrawal syndrome from duloxetine resembles the SSRI discontinuation syndrome.

When discontinuing treatment with duloxetine, the manufacturer recommends a gradual reduction in the dose, rather than abrupt cessation, whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. The use of a liquid form of the drug may facilitate more gradual tapering."^[41]

In placebo-controlled clinical trials of up to nine weeks' duration of patients with MDD, a systematic evaluation of discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring at a rate greater than or equal to 2% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.^[42]

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.^[43]^[44]^[45]

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 2005 the United States FDA released a public health advisory noting that there had been 11 reports of suicide attempts and 3 reports of suicidialty within the mostly middle-aged women participating in the open label extension trials of duloxetine for the treatment of stress urinary incontinence. The FDA described the potential role of confounding social stressors "unclear". The suicide attempt rate in the SUI study population (based on 9,400 patients) was calculated to be 400 per 100,000 person years. This rate is greater than the suicide attempt rate among middle-aged U.S. women that has been reported in published studies, i.e., 150 to 160 per 100,000 person years. In addition, one death from suicide was reported in a Cymbalta clinical pharmacology study in a healthy female volunteer without SUI. No increase in suicidality was reported in controlled trials of Cymbalta for depression or diabetic neuropathic pain.^[46]

Pharmacology

Mechanism of action

Duloxetine inhibits the reuptake of serotonin and norepinephrine (NE) in the central nervous system. Duloxetine increases dopamine (DA) specifically in the prefrontal cortex where there are few DA reuptake pumps via the inhibition of NE reuptake pumps (NET) thus allowing greater diffusion of DA in this brain region.^[47] However, duloxetine has no significant affinity for dopaminergic, cholinergic, histaminergic, opioid, glutamate, and GABA reuptake transporters and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NE transporters. Duloxetine undergoes extensive metabolism, but the major circulating metabolites do not contribute significantly to the pharmacologic activity.^[48]^[49]

Major depressive disorder is believed to be due in part to an increase in pro-inflammatory cytokines within the central nervous system. Antidepressants including ones with a similar mechanism of action as duloxetine, i.e. serotonin metabolism inhibition, cause a decrease in proinflammatory cytokine activity and an increase in anti-inflammatory cytokines; this mechanism may apply to duloxetine in its effect on depression but research on cytokines specific to duloxetine therapy is lacking.^[50]

The analgesic properties of duloxetine in the treatment of diabetic neuropathy and central pain syndromes such as fibromyalgia are believed to be due to sodium ion channel blockade.^[51]

Pharmacokinetics

Absorption: Duloxetine is acid labile, and is formulated with enteric coating to prevent degradation in the stomach. Duloxetine has good oral bioavailability, averaging 50% after one 60 mg dose. There is an average 2-hour lag until absorption begins with maximum plasma concentrations occurring about 6 hours post dose. Food does not affect the C_max of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours.^[49]

Distribution: Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. Volume of distribution is 1640L.^[52]

Metabolism: Duloxetine undergoes predominately hepatic metabolism via two cytochrome P450 isozymes, CYP2D6 and CYP1A2. Circulating metabolites are pharmacologically inactive.^[52]

Elimination: Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state is usually achieved after 3 days. Only trace amounts (<1%) of unchanged duloxetine are present in the urine and most of the dose (approx. 70%) appears in the urine as metabolites of duloxetine with about 20% excreted in the feces.^[52]

History

Cymbalta (duloxetine) 60mg

Duloxetine was created by Lilly researchers. David Robertson; David Wong, a co-discoverer of fluoxetine; and Joseph Krushinski are listed as inventors on the patent application filed in 1986 and granted in 1990.^[53] The first publication on the discovery of the racemic form of duloxetine known as LY227942, was made in 1988.^[54] The (+)-enantiomer of LY227942, assigned LY248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes to twice the degree of the (–)-enantiomer. This molecule was subsequently named duloxetine.^[55]

In 2001, Lilly filed a New Drug Application (NDA) for duloxetine with the US Food and Drug Administration (FDA). However, in 2003, the FDA "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cGMP (current Good Manufacturing Practice) violations at the finished product manufacturing facility" of Eli Lilly in Indianapolis. Additionally, "potential liver toxicity" and QTc interval prolongation appeared as a concern. The FDA experts concluded that "duloxetine can cause hepatotoxicity in the form of transaminase elevations. It may also be a factor in causing more severe liver injury, but there are no cases in the NDA database that clearly demonstrate this. Use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver." The FDA also recommended "routine blood pressure monitoring" at the new highest recommended dose of 120 mg, "where 24% patients had one or more blood pressure readings of 140/90 vs. 9% of placebo patients."^[56]

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.^[57] In 2007, Health Canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.^[58]

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.^[59]^[60]

The FDA approved duloxetine for the treatment of generalized anxiety disorder in February 2007.^[61]

Cymbalta generated sales of nearly $5 billion in 2012 with $4 billion of that in the U.S., but its patent protection terminated January 1, 2014. Lilly received a six month extension beyond June 30, 2013 after testing for the treatment of depression in adolescents, which may produce $1.5 billion in added sales.^[62]^[63]

The first generic duloxetine was marketed by Dr. Reddy.^[64]

Brand names

Brand names include: Ariclaim, Xeristar, Yentreve, Duzela, Dulane, Cymbalta, and Cymgen (in South Africa).

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^ "Summary Basis of Decision (SBD): Cymbalta". Health Canada. 2008-05-05.
^ Steyer R (2006-02-15). "Lilly Won't Pursue Yentreve for U.S.". TheStreet.com. Retrieved 2008-05-18.
^ Lenzer J (2005). "FDA warns that antidepressants may increase suicidality in adults". BMJ 331 (7508): 70. doi:10.1136/bmj.331.7508.70-b. PMC 558648. PMID 16002878. edit
^ "FDA approves antidepressant Cymbalta (duloxetine HCl) for treatment of generalized anxiety disorder". News-Medical.Net. Retrieved 25 December 2013. |first1= missing |last1= in Authors list (help)
^ Staton, Tracy (July 9, 2012). "Lilly could net $1.5B-plus from Cymbalta extension". FiercePharma. Retrieved 25 December 2013.
^ Palmer, Eric (April 11, 2013). "Eli Lilly to lay off hundreds in sales as Cymbalta nears edge of patent cliff". FiercePharma. Retrieved 25 December 2013.
^ Anson, Pat (December 12, 2013). "Generic Cheaper Versions of Cymbalta Approved". National Pain Report. Retrieved January 2, 2014.

External links

Eli Lilly Cymbalta Prescribing Guide
U.S. National Library of Medicine: Drug Information Portal - Duloxetine

English Journal

Prescribing patterns and safety monitoring of duloxetine using the Danish Register of Medicinal Product Statistics as a source.

Johansen AN1, Stenzhorn AA, Rosenzweig M, Thirstrup S, Gazerani P.
Scandinavian journal of public health.Scand J Public Health.2013 Dec;41(8):866-73. doi: 10.1177/1403494813496599. Epub 2013 Jul 24.
BACKGROUND: The safety and pattern of use of a medicinal product cannot be fully studied prior to its marketing. In Denmark, the Danish Health and Medicines Authority (DHMA) monitors marketed drugs. An available source is the Register of Medicinal Product Statistics (RMPS), which can possibly be use
PMID 23885111

Is there a place for duloxetine?

[No authors listed]
Drug and therapeutics bulletin.Drug Ther Bull.2007 Apr;45(4):29-32.
Duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, is licensed in the UK under two brand names for a total of three different indications. It is available as Cymbalta (jointly promoted by Boehringer Ingelheim and Lilly) for the treatment of patients with major depression, or wit
PMID 17451072

[News in the pharmacological treatment of female urinary incontinence].

Martan A.
Casopís lékar̆ů c̆eských.Cas Lek Cesk.2006;145(7):549-53.
The article addresses the issue of pharmacological treatment of female urinary incontinence. It summarizes the two types of incontinence, i.e. stress urinary incontinence (SUI) and urgency incontinence, or even just urgency symptoms (overactive bladder--OAB). It focuses on the role of urethra in mai
PMID 16921783

Related Pictures

YENTREVE 20 MG 56 CAPS (Geneesmiddel) Yentreve | Duloxetine | Inkontinenz YENTREVE® 40 mg magensaftresistente Home > Incontinence > Yentreve (Duloxetine Yentreve 20mg gastro-resistant capsules delayed release) capsules, analog Yentreve YENTREVE 20mg magensaftresistente Yentreve 20mg Duloxetine 28 capsules

★リンクテーブル★

リンク元

「デュロキセチン」

Duloxetine
Systematic (IUPAC) name
	(+)-(S)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine
Clinical data
Trade names	Cymbalta
AHFS/Drugs.com	monograph
MedlinePlus	a604030
Licence data	EMA:Link, US FDA:link
Pregnancy; category	AU: B3; US: C;
Legal status	AU: Prescription Only (S4); CA: ℞-only; UK: POM; US: ℞-only;
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	~ 50% (32% to 80%)
Protein binding	~ 95%
Metabolism	Liver, two P450 isozymes, CYP2D6 and CYP1A2
Half-life	12.1 hours
Excretion	70% in urine, 20% in feces
Identifiers
CAS Registry Number	116539-59-4 (free base); 136434-34-9 (hydrochloride)
ATC code	N06AX21
PubChem	CID 60835
IUPHAR ligand	202
DrugBank	DB00476
ChemSpider	54822
UNII	O5TNM5N07U
KEGG	D07880
ChEBI	CHEBI:36795
ChEMBL	CHEMBL1175
PDB ligand ID	29E (PDBe, RCSB PDB)
Chemical data
Formula	C18H19NOS
Molecular mass	297.41456 g/mol
	SMILES CNCC[C@@H](C1=CC=CS1)OC2=CC=CC3=CC=CC=C32;
	InChI InChI=1S/C18H19NOS/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16/h2-10,13,17,19H,11-12H2,1H3/t17-/m0/s1 ; Key:ZEUITGRIYCTCEM-KRWDZBQOSA-N ;
(what is this?) (verify)

　　[★]

英: duloxetine
化: 塩酸デュロキセチン duloxetine hydrochloride
商: サインバルタ Cymbalta, Yentreve
関: 抗精神病薬、抗うつ薬、セロトニン・ノルアドレナリン再取り込み阻害薬 SNRI

特徴

構造

作用機序

薬理作用

抗菌スペクトル

動態

適応

うつ病・うつ状態
下記疾患に伴う疼痛：糖尿病性神経障害、線維筋痛症、慢性腰痛症、変形性関節症

用法・用量

通常、成人には1日1回朝食後、デュロキセチンとして40mgを経口投与する。投与は1日20mgより開始し、1週間以上の間隔を空けて1日用量として20mgずつ増量する。
なお、効果不十分な場合には、1日60mgまで増量することができる。
減量する場合には1-2週で20mgずつ減量しする。20mgまで到達したら、隔日投与、2日おき投与、3日おき投与と投与間隔を長くしていく。離脱症状（身体症状：しびれ・耳鳴り・めまい・頭痛・吐き気・だるさ。精神症状：イライラ・ソワソワ感・不安・不眠。特徴的な症状：シャンピリ感・ビリビリする）に注意する。

注意

禁忌

1.　本剤の成分に対し過敏症の既往歴のある患者
2.　モノアミン酸化酵素阻害剤(MAOI)を投与中あるいは投与中止後2週間以内の患者
3.　高度の肝障害のある患者［肝障害が悪化することがある。また、消失半減期が延長し、本剤の血中濃度が上昇することがある。
4.　高度の腎障害のある患者［本剤の血中濃度が上昇することがある。
5.　コントロール不良の閉塞隅角緑内障の患者［症状が悪化することがある。］

副作用

副作用等発現状況の概要

うつ病・うつ状態の患者を対象とした国内臨床試験において、安全性評価対象例735例中、副作用（臨床検査値異常変動を含む）は663例（90.2％）に認められた。
主なものは、悪心269例（36.6％）、傾眠228例（31.0％）、口渇168例（22.9％）、頭痛154例（21.0％）、便秘102例（13.9％）、下痢87例（11.8％）、めまい80例（10.9％）、トリグリセリド上昇56例（7.6％）、腹部痛52例（7.0％）、ALT（GPT）上昇51例（6.9％）、不眠50例（6.8％）、倦怠感45例（6.1％）、AST（GOT）上昇38例（5.2％）、食欲減退38例（5.2％）であった。（承認時）

重大な副作用

1. セロトニン症候群（頻度不明※1）

不安、焦燥、興奮、錯乱、発汗、下痢、発熱、高血圧、固縮、頻脈、ミオクローヌス、自律神経不安定等があらわれることがある。セロトニン作用薬との併用時に発現する可能性が高くなるため、特に注意すること。異常が認められた場合には投与を中止し、体冷却、水分補給等の全身管理と共に適切な処置を行うこと。

2. 抗利尿ホルモン不適合分泌症候群（SIADH）（頻度不明※1）

低ナトリウム血症、低浸透圧血症、尿中ナトリウム排泄量の増加、高張尿、痙攣、意識障害等を伴う抗利尿ホルモン不適合分泌症候群（SIADH）があらわれることがあるので、異常が認められた場合には投与を中止し、水分摂取の制限等適切な処置を行うこと。

3. 痙攣（0.27％）、幻覚（頻度不明※1）

痙攣、幻覚があらわれることがあるので、異常が認められた場合には投与を中止し、適切な処置を行うこと。

4. 肝機能障害、肝炎、黄疸（頻度不明※1）

AST（GOT）、ALT（GPT）、γ-GTP、総ビリルビン等の上昇を伴う肝機能障害、肝炎、黄疸があらわれることがあるので、適宜肝機能検査を行うとともに、患者の症状を十分に観察し、異常が認められた場合には、減量、休薬又は中止するなど適切な処置を行うこと。

5. 皮膚粘膜眼症候群（Stevens-Johnson症候群）（頻度不明※1）

皮膚粘膜眼症候群（Stevens-Johnson症候群）があらわれることがあるので、観察を十分に行い、異常が認められた場合には投与を中止し、適切な処置を行うこと。

6. アナフィラキシー反応（頻度不明※1）

呼吸困難、痙攣、血管浮腫、蕁麻疹等を伴うアナフィラキシー反応があらわれることがあるので、観察を十分に行い、異常が認められた場合には投与を中止し、適切な処置を行うこと。

7. 高血圧クリーゼ（頻度不明※1）

高血圧クリーゼがあらわれることがあるので、高血圧又は心疾患のある患者においては血圧の推移等に十分注意しながら投与すること。異常が認められた場合には投与を中止し、適切な処置を行うこと。

8. 尿閉（頻度不明※1）

尿閉があらわれることがあるので、症状があらわれた場合には投与を中止し、導尿を実施するなど適切な処置を行うこと。

添付文書

http://www.info.pmda.go.jp/go/pack/1179052M1022_2_03/

[AHFS2015-1] "Duloxetine". Monograph. The American Society of Health-System Pharmacists. Retrieved 2015-02-26.

[2] National Institute for Health and Clinical Excellence. Clinical guideline 40: Urinary incontinence. London, 2006.

[3] National Institute for Health and Clinical Excellence. Clinical guideline 96: Neuropathic pain - pharmacological management. London, 2010.

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[5] Hershman DL, Lacchetti C, Dworkin RH et al. (June 2014). "Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline". J. Clin. Oncol. 32 (18): 1941–67. doi:10.1200/JCO.2013.54.0914. PMID 24733808.

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[58] "Summary Basis of Decision (SBD): Cymbalta". Health Canada. 2008-05-05.

[Yentreve-59] Steyer R (2006-02-15). "Lilly Won't Pursue Yentreve for U.S.". TheStreet.com. Retrieved 2008-05-18.

[60] Lenzer J (2005). "FDA warns that antidepressants may increase suicidality in adults". BMJ 331 (7508): 70. doi:10.1136/bmj.331.7508.70-b. PMC 558648. PMID 16002878. edit

[61] "FDA approves antidepressant Cymbalta (duloxetine HCl) for treatment of generalized anxiety disorder". News-Medical.Net. Retrieved 25 December 2013. |first1= missing |last1= in Authors list (help)

[62] Staton, Tracy (July 9, 2012). "Lilly could net $1.5B-plus from Cymbalta extension". FiercePharma. Retrieved 25 December 2013.

[Palmer-63] Palmer, Eric (April 11, 2013). "Eli Lilly to lay off hundreds in sales as Cymbalta nears edge of patent cliff". FiercePharma. Retrieved 25 December 2013.

[Anson-64] Anson, Pat (December 12, 2013). "Generic Cheaper Versions of Cymbalta Approved". National Pain Report. Retrieved January 2, 2014.

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