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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 (code name LY248686, brand names Cymbalta, Yentreve, and in parts of Europe, Xeristar or Ariclaim) is a drug which is used in major depressive disorder (MDD), generalized anxiety disorder (GAD), pain related to painful diabetic neuropathy and in some countries for stress urinary incontinence (SUI). It is manufactured and marketed by Eli Lilly and Company.

Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI): it is a potent dual reuptake inhibitor of serotonin and norepinephrine, possessing comparable affinities in binding to norepinephrine transporter and serotonin transporter sites. It is a less potent inhibitor of dopamine reuptake.

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.

History

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."

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 and the dose was increased to as high as 120mg in subsequent clinical trials done by Eli Lilly.

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.

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. PharmaBio, the investment arm of Quintiles, invested $100 million to help develop Cymbalta.

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.

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% of royalties from net sales of Cymbalta for depression and other neuroscience indications for eight years.

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. Duloxetine as Yentreve and Ariclaim was approved for use of stress urinary incontinence (SUI) in the EU on August 13, 2004. Eli Lilly rescinded their request for FDA approval for SUI use in the United States. 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. 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.

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. 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% 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. On November 1, 2007, Health Canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain. Duloxetine is now available in Canadian pharmacies since January 2008.

The large number of side effects occurring during duloxetine treatment and the 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.

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.

Indications

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

Major depressive disorder

A study by Bymaster and colleagues found that duloxetine inhibited binding to the human norepinephrine (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. Thus, duloxetine more potently blocks serotonin and norepinephrine transporters in vitro and in vivo than venlafaxine, 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.

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

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

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:

• Dry mouth
• Headache
• Insomnia
• Sleepiness or somnolence
• Dizziness or 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.

Pharmacokinetics

When serotonin and norepinephrine are released from nerve cells (neurons) in the brain they are reabsorbed into the nerve cells through reuptake. 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 NE and D2 receptors respectively.

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).

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.

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

• Serotonin-norepinephrine reuptake inhibitors
• Eli Lilly and Company
• Thiophenes