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Duloxetine

Clinical data
License data	EU EMA: by INN US FDA: duloxetine
Routes of administration	Oral
ATC code	N06AX21 (WHO)
Legal status
Legal status	US: WARNINGRx-only
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
IUPAC name (+)-(S)-N-Methyl-3-(naphthalen-1-yloxy)- 3-(thiophen-2-yl)propan-1-amine
CAS Number	116539-59-4 136434-34-9 (hydrochloride)
PubChem CID	60835
DrugBank	APRD00060
CompTox Dashboard (EPA)	DTXSID6048385
ECHA InfoCard	100.116.825
Chemical and physical data
Formula	C18H19NOS
Molar mass	297.41456 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES CNCC(C1=CC=CS1)OC2=CC=CC3=CC=CC=C32

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 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 critical reviews concluding that duloxetine "should not be used" for stress urinary incontinence and "currently has no place in the treatment of depression or diabetic neuropathy" as well.

History

Duloxetine was created by Lilly researchers. David Robertson, David Wong, a co-discoverer of fluoxetine (Prozac), and Joseph Krushinski are listed as inventors on the patent application filed in 1986 and granted in 1990. The first publication on the discovery of the racemic form of duloxetine known as LY227942, was made in 1988. 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.

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

In 2001 Lilly filed a New Drug Application (NDA) for duloxetine for depression 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 readings of 140/90 vs. 9% of placebo patients."

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

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.

Indications

The main uses of duloxetine are in major depressive disorder, general anxiety disorder, stress urinary incontinence and painful peripheral neuropathy. In addition, it is being studied for various other indications.

Major depressive disorder

Duloxetine is efficacious for the treatment of major depression. In three out of six well-designed properly controlled pre-marketing trials duloxetine performed better than placebo; other three trials were inconclusive. 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. 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.

Stress urinary incontinence

Stress urinary incontinence is involuntary loss of urine when the bladder comes under strain, e.g. from coughing, sneezing or other movements that increase the intraabdominal pressure. Duloxetine was first reported to improve outcomes in SUI in 1998. Systematic reviews with meta-analysis, conducted in 2005 (Cochrane) and 2008 (University of Minnesota), each found ten controlled trials. Both systematic reviews concluded that duloxetine did not lead to cure of stress urinary incontinence in the vast majority of people, but that episodes of incontinence were reduced by about 50%. This was associated with an improvement in quality of life measurements. Mild side-effects were common, and about a fifth had to discontinue the medication because of poor tolerance.

Painful peripheral neuropathy

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% 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. At 60mg per day 89.5% of patients had some marked treatment adverse effects in one trial, and 87% in the other trial. 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.

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. 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, 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.

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.

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.

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.

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. 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.

Contraindications

The following contraindications are listed by the manufacturer:

• Hypersensitivity - duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
• Monoamine oxidase inhibitors - concomitant use in patients taking monoamine oxidase inhibitors is contraindicated.
• Uncontrolled narrow-angle glaucoma - in clinical trials, Cymbalta use was associated with an increased risk of mydriasis (dilation of the iris); 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

This article is in list format but may read better as prose. You can help by converting this article, if appropriate. Editing help is available. (May 2008)

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

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:

Other side-effects include:

• Orthostatic hypotension
• Fatigue
• Vivid nightmares
• Increased sweating
• Decreased appetite and weight loss
• Blurred vision
• Paresthesia
• 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
• 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. 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.

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 the ultimate cause of death. Five cases were declared multiple drug intoxication, and two were declared suicide.
• 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.
• A case of dyskinesia during treatment with duloxetine was reported in Germany.
• Two episodes of serotonin syndrome have been documented in the use of duloxetine in conjunction with other medications.
• 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.
• An attack of acute porphyria in a patient with known variegate porphyria who had been commenced on duloxetine.

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.

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." This tapering process may be ineffective for some patients.

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.

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.

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% or 20% 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. 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." 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. 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. 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.

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.

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. The New York Times article mentioned a withdrawal syndrome as a possible reason for this suicide.

Pharmacology

A study by Bymaster and colleagues found that duloxetine inhibited binding to the human norepinephrine (NE) and serotonin (5-HT) transporters.

See also

• Serotonin-norepinephrine reuptake inhibitor (SNRI)
• Neuropsychopharmacology
• Neuropharmacology
• Pharmacology
• Psychoactive drug

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External links

• Manufacturer website
• Duloxetine - medlineplus.org
• Eli Lilly Cymbalta Prescribing Guide
• FDA Alert for Healthcare Professionals - Cymbalta Serotonin Syndrome
• FDA Patient Information Sheet on Cymbalta

• Articles needing cleanup from May 2008
• Articles with sections that need to be turned into prose from May 2008
• Serotonin-norepinephrine reuptake inhibitors
• Eli Lilly and Company
• Thiophenes