Misplaced Pages

Revision as of 00:46, 5 January 2007

Duloxetine

Clinical data
License data	EU EMA: by INN US FDA: duloxetine
Pregnancy category	C (USA)
Routes of administration	Oral
ATC code	N06AX21 (WHO)
Legal status
Legal status	US: WARNING Prescription only (USA)
Pharmacokinetic data
Protein binding	>90%
Metabolism	Liver, two P450 isozymes, CYP2D6 and CYP1A2.
Elimination half-life	8-17 hours
Excretion	70% in urine, 20% in feces
Identifiers
IUPAC name (+)-(S)-N-methyl-3-(1-naphthyloxy)- 3-(thiophen-2-yl)-propan-1-amine
CAS Number	136434-34-9
PubChem CID	60835
DrugBank	APRD00060
CompTox Dashboard (EPA)	DTXSID6048385
ECHA InfoCard	100.116.825
Chemical and physical data
Formula	C18H19NOS
Molar mass	297.416 g/mol

Duloxetine hydrochloride (brand names: Cymbalta/Yentreve and in parts of Europe known as Xeristar or Ariclaim) is a drug that primarily targets major depressive disorders (MDD), pain related to diabetic peripheral neuropathy and in some countries stress urinary incontinence (SUI). Duloxetine has not not been FDA approved for SUI. Duloxetine has not been FDA-approved for fibromyalgia. It is manufactured and marketed by Eli Lilly and Company.

The effectiveness of Cymbalta in hospitalized patients with MDD has not been studied.

The effectiveness of Cymbalta in long-term use for major depressive disorder, that is, for more than 9 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use Cymbalta for extended periods should periodically evaluate the long-term usefulness of the drug for the individual patient.

Duloxetine is labeled an SNRI for serotonin norepinephrine reuptake inhibitor. Duloxetine is a systemic drug therapy that 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 NE- and 5-HT transporter sites. It is a less potent inhibitor of dopamine reuptake.

Dosing and administration

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.

The recommended oral dose for initiation of therapy in MDD is 40 mg/day (administered as 20 mg twice daily) to 60 mg/day (administered either as once daily or as 30 mg twice daily). The recommended dose for diabetic peripheral neuropathic pain is 60 mg once daily. Although doses up to 120 mg/day have been utilized, no clinical superiority has been demonstrated when compared to 60 mg/day and an increase of adverse events were noted at higher doses.

How it works

When serotonin and noradrenaline 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 noradrenaline released from nerve cells in the brain.

Duloxetine works by preventing serotonin and noradrenaline from being reabsorbed back into the nerve cells in the brain, specifically on the 5-HT receptor. This helps prolong the "mood lightening" effect of any released serotonin and noradrenaline. In this way, duloxetine is thought to help relieve depression.

Serotonin and norepinephrine in the brain and spinal cord are believed to both mediate core depression symptoms and 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.

It may take between two to four weeks for the benefits of this medicine to appear, so the manufacturer suggests it is very important that you keep taking it, even if it doesn't seem to make much difference at first. They go on to state that if the patient feels that the depression has gotten worse, has any of the listed side effects, or any distressing thoughts or feelings in these first few weeks, then they should talk to their prescribing doctor.

Duloxetine is also used to treat nerve pain in the feet, legs or hands that is due to nerve damage caused by poorly controlled diabetes. Duloxetine is thought to enhance the nerve signals within the central nervous sytem that 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.

Contraindications

• Hypersensitivity

Cymbalta 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 (MAOIs) is contraindicated.

• Uncontrolled Narrow-Angle Glaucoma

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

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

• Cymbalta and thioridazine should not be co-administered.
• Cymbalta should not be administered to patients with any hepatic insufficiency or patients with end-stage renal disease (requiring dialysis) or severe renal impairment (creatinine clearance <30 mL/min).
• Postmarketing, cases of severe elevations of liver enzymes or liver injury with a hepatocellular, cholestatic or mixed pattern have been reported.
• Because it is possible that Cymbalta and alcohol may interact to cause liver injury or that Cymbalta may aggravate pre-existing liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
• Orthostatic hypotension and syncope have been reported with therapeutic doses of Cymbalta. Consideration should be given to discontinuing Cymbalta in patients who experience symptomatic orthostatic hypotension and/or syncope.
• In MDD clinical trials, treatment with Cymbalta was associated with mean increases in blood pressure averaging 2 mm Hg systolic and 0.5 mm Hg diastolic vs placebo. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment.
• In the 12-week acute treatment phase of the diabetic peripheral neuropathic pain (DPNP) studies, HbA1c was stable in both Cymbalta and placebo-treated patients. In the extension phase of these studies (up to 52 weeks), an increase in HbA1c in both the Cymbalta and the routine care groups was noted, but the mean increase was 0.3% greater in the Cymbalta group.
• Safety and effectiveness not established in pediatric patients.
• As with many antidepressants, Cymbalta should be used cautiously in patients with a history of mania or with a history of a seizure disorder.
• As with other antidepressants, Cymbalta has been associated with cases of clinically signigificant hyponatremia that appeared to be reversible when Cymbalta was discontinued.
• On abrupt discontinuation, spontaneous reports of adverse events, some of which may be serious, have been reported during the marketing of other SSRIs and SNRIs. A gradual reduction in dose rather than abrupt cessation is recommended when possible.
• There are no adequate and well-controlled studies of Cymbalta in pregnant women. Cymbalta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Nursing while taking Cymbalta is not recommended.

Side effects

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here, it does not mean that all people using this medicine will experience that or any side effect.

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

In a trial for mild major depressive diorder (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
• Increased sweating
• Decreased appetite and weight loss
• Rapid weight gain
• 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 possibly indefinitely even after the drug has been completely withdrawn. This disorder is known as Post SSRI Sexual Dysfunction.

Antidepressants may cause the amount of sodium in the blood to drop - a condition called hyponatraemia. This can cause symptoms such as drowsiness, confusion, muscle twitching or convulsions. Elderly people may be particularly susceptible to this effect. There may also be an increased risk in people with liver cirrhosis and those who are dehydrated or taking diuretic medicines. You should consult your doctor if you develop any of these symptoms while taking this medicine so that your blood sodium level can be checked if necessary.

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

Serious Adverse Effects

Since duloxetine is a newer drug (FDA-approval 2004), not many peer-reviewed articles have been published on its adverse effects and effect of long term use is still unknown.

• 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.

• The French journal Prescrire International stated the 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."

• The Los Angeles County Department of Coroner released a report of the first postmortem studies of duloxetine, which found cases of multiple drug reactions involving duloxetine which was the ultimate cause of death.

• A case of hyponatremia induced by duloxetine was reported by doctors at Weil Medical College in New York.

• 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 conjuction 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.

Discontinuing Duloxetine

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt. Although these events are generally self-limiting, some have been reported to be severe. This withdrawal phenomenon is known as the SSRI discontinuation syndrome.

The manufacturer of Cymbalta, Eli Lilly, warns that one should not suddenly stop taking this medicine, as this may cause withdrawal symptoms such as dizziness, pins and needles sensations, nausea, difficulty sleeping, intense dreams, headache, tremor, agitation or anxiety. Withdrawal symptoms are temporary and are not the same as addiction.

Discontinuation symptoms systematically evaluated in patients taking duloxetine following abrupt discontinuation in MDD placebo-controlled clinical trials of up to 9-weeks duration, the following symptoms occurred 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.

Subsequently, Eli Lilly recommendeds that, "whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment." Tapering process may be moot for some patients, and they will still have discontinuation/withdrawal symptoms.

Many patients on the drug longer than the Lilly test trials on discontinuation (which only studied patients after 9 weeks of exposure to Cymbalta), report anecdotal evidence of major withdrawals from Cymbalta lasting from weeks to many months.

Efficacy of Duloxetine (Cymbalta) versus Venlafaxine (Effexor)

In a study by Bymaster and colleagues it was found that duloxetine inhibited binding to the human NE and 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.

The depletion of rat brain 5-HT by p-chloramphetamine and depletion of rat hypothalamic NE by 6-hydroxydopamine was blocked by duloxetine with ED(50) values of 2.3 and 12 mg/kg, respectively. Venlafaxine had ED(50) values of 5.9 and 94 mg/kg for blocking p-chloramphetamine- and 6-hydroxydopamine-induced monoamine depletion, respectively.

Thus, duloxetine more potently blocks 5-HT and NE transporters in vitro and in vivo than venlafaxine.

Controversy

In the 1980s, Eli Lilly waged a successful campaign to get fluoxetine, brand name Prozac, through the FDA even though not a single study submitted to the agency showed the drug to be effective for depression when taken alone. Once approved, Eli Lilly marketed the drug as a revolutionary substance that selectively targeted the brain chemical serotonin: “This medicine works by bringing the level of serotonin in your brain back to normal.” Unlike the cheap generics on the market, the Prozac class of drugs does not affect norepinephrine, which was said to cause all the side effects of the older tricyclic antidepressants. Thus began a marketing campaign that made Prozac and the other SSRI antidepressants billions of dollars in profits.

In August 2000, the U.S. Court of Appeals ruled that a generic drug company could begin making a Prozac substitute nearly three years earlier than planned. The ruling, which shortened Lilly's patent protection on Prozac from December 2003 to Feb. 2 of 2001 (later extended to Aug. 2, 2001), was a financial blow because Lilly was deriving one quarter of its sales from Prozac. After fighting for six years to maintain its patent on Prozac, Eli Lilly & Company reached the end of the legal road when the Supreme Court refused to consider reinstating its rights to the drug.

When the patent expired on Prozac, in 2001, and annual sales for Eli Lilly went down from billions to millions, Eli Lilly went to work to bring out a new antidepressant, Cymbalta. Despite providing no peer reviewed data (all trials were done by researchers on the Lilly payroll), Cymbalta was approved by the FDA for major depressive disorder (MDD) in August 2004. The drug scored a second FDA approval a month later when it also became the first FDA-approved treatment for pain caused by diabetic peripheral neuropathy. With its approval came a new and highly innovative marketing message: Cymbalta is better than Prozac because it has a dual action in the brain. It not only targets serotonin, it also impacts another important neurochemical, norepinephrine. This flatly contradicts the ‘serotonin/good, norepinephrine/bad’ story that launched the SSRI revolution that Lilly started with fluoxetine.

Duloxetine as Yentreve and Ariclaim was approved for use of 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 to jointly develop and commercialize duloxetine hydrochloride.

Although the FDA approved Cymbalta for MDD and diabetic neuropathy, and Yentreve was approved for use of Stress Urinary Incontinence (SUI) in the European Union, Eli Lilly rescinded their request for FDA approval for SUI use in the United States. As of June, 2005, in trials of Cymbalta for the treatment of SUI in women who were mostly middle-aged, eleven suicide attempts and three cases of suicidal ideation were reported. 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 its packet insert, Eli Lilly claims "that no suicides were committed" during trials of Cymbalta. The trials including 19 year old Traci Johnson and four other patients who committed suicide during Lilly trials for duloxetine were cleared by the FDA, stating that underlying depression - not the drug - 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. Consequently, many critics claim that the FDA approval of duloxetine for MDD and diabetic neuropathy is irresponsible, and is a case illustration of the agency's failure to prevent harmful drugs from being marketed in the name of big profits.

At the time of its release in 2004, duloxetine was by far the most promising medicine in Eli Lilly's pipeline. Like venlafaxine, brand name Effexor, a SNRI that affects both serotonin and norepinephrine sold by Wyeth that had $2 billion in sales annually since 2003, analysts say that Cymbalta may outperform even Effexor. Sales for Cymbalta could reach $2.6 billion to $3.1 billion in 2009, according to Merrill Lynch.

With Cymbalta's patents set to expire on June 11, 2008, Lilly states it is working on at least two new antidepressants to bring to market to ensure its place in the SSRI antidepressant market. Eli Lilly originally patented duloxetine on June 11, 1991 and has asked the U.S. Patent and Trademark Office for an extension on the exclusivity of the chemical compound beyond 2008 (to June 11, 2013) with an official patent extension application on January 5th, 2006.

As of Feb. 28, 2005, more than 1 million Cymbalta prescriptions have been dispensed since FDA approval in August 2004. For the year 2006, Cymbalta outperformed all branded antidepressants in the U.S. in terms of market growth as measured by both new prescriptions and total prescriptions. "Globally, the Cymbalta launch has been one of the most successful in both Lilly's history and that of the entire antidepressant market." Worldwide sales for Cymbalta grew at 91 percent in the third quarter compared with the same period last year. Eli Lilly is estimated to generate over $1 billion in annual sales in only its second full year with the drug on the market.

Recent News

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. Every year four million Americans age 18 to 54 are diagnosed with generalized anxiety disorder, the majority of them women.

References

1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
2. Essential Science Indicators
3. Cymbalta® package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.
4. 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)
5. The Independent 19 June 2005
6. "Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects.". Prescrire International. (2006 Oct;15(85):168-72)
7. 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)
8. Safdieh JE, Rudominer R. "A case of hyponatremia induced by duloxetine". J Clin Psychopharmacol. 2006 Dec;26(6):675-6.
9. Deuschle M, Mase E, Zink M. "Dyskinesia during treatment with duloxetine". Pharmacopsychiatry. 2006 Nov;39(6):237-8.
10. J Clin Psychopharmacol. 2006 Dec;26(6):681-683, Anesth Analg. 2006 Dec;103(6):1466-8.
11. 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.
12. 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.
13. 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
14. FORTUNE Magazine June 28, 2004
15. FDA Historical Information on Duloxetine
16. 2006E-0004: Patent Extension Application for CYMBALTA (duloxetine hydrochloride), U.S. Patent No. 5,023,269
17. Cymblata Healthcare Professional Website
18. CNNMoney.com December 07, 2006

Related Publications

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

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
• Cymbalta List of Side Effects - rxlist.com
• Cymbalta User Ratings - askapatient.com

• Lilly
• Serotonin-norepinephrine reuptake inhibitors