The U.S. Food and Drug Administration (FDA) has approved Cymbalta(R) (duloxetine hydrochloride) for the management of fibromyalgia, a chronic widespread pain disorder( Note:- Fibromyalgia is a complex disease with a variety of symptoms in addition to a defining symptom - chronic widespread pain. These include fatigue, non-restorative sleep, morning stiffness, irritable bowel and bladder, restless legs, cognitive dysfunction often referred to as "fibro fog", depression, and anxiety. This drug is only to manage pain.) , Eli Lilly and Company (NYSE: LLY) announced. Cymbalta is the first serotonin-norepinephrine reuptake inhibitor with proven efficacy for reducing pain in patients with fibromyalgia. The fibromyalgia indication represents the second FDA-approved use for Cymbalta for a pain disorder, demonstrating the medication's analgesic effect.
"The approval of Cymbalta is important because it provides physicians and patients with a new treatment option shown to help reduce pain and improve functioning in this difficult-to-treat disorder," said Madelaine Wohlreich, M.D., medical advisor and research physician at Lilly.
(Note:- The Committee for Medicinal Products for Human Use (CHMP) has submitted a negative recommendation on Cymbalta (common name: Duloxetine hydrochlorideis) today (24.10.2008) to the EMEA, the European regulatory agency for medicines. Cymbalta is the first medication for the treatment of Fibromyalgia that has been filed in Europe by Eli Lilly for the treatment of Fibromyalgia. The medicine was approved by the US Food and Drug Administration for Fibromyalgia since June 2008... more info )
The cause of fibromyalgia remains unknown; however, scientists believe it may be related to some combination of changes in brain and spinal cord chemistry,(i) genetics(ii) and stress(iii). Some researchers believe fibromyalgia is a disorder of increased sensitivity to pain. Although the way Cymbalta works in people is not fully known, medical experts believe it increases the activity of two naturally occurring substances called serotonin and norepinephrine. ( more info) These substances aid communication in many areas of the brain and spinal cord that affect emotion. Research also suggests that these substances are part of the body's natural pain-suppressing system.
"The FDA approval of Cymbalta for the management of fibromyalgia is another important step in the efforts to ensure that people with fibromyalgia will have the availability of effective medications to help reduce the chronic, widespread pain of this life-altering disorder," said Lynne Matallana, president of the National Fibromyalgia Association and a fibromyalgia patient.
Fibromyalgia is estimated to affect 2 percent of the U.S. population - approximately 5 million people - the majority of those diagnosed being women.(iv),(v) The disorder is characterized by chronic widespread pain and tenderness. Some patients may have additional symptoms.(i) Although there is no known cure for fibromyalgia, some physicians recommend a comprehensive care plan that can include education, medication, and lifestyle changes to help manage the symptoms of the disorder.(i)
"In fibromyalgia, there is no one-size-fits-all approach to managing the disorder," said Dan Clauw, M.D., professor of medicine in the University of Michigan's Division of Rheumatology and director of the Chronic Pain and Fatigue Research Center at the University of Michigan.
The approval marks the fourth disorder that the FDA has approved for Cymbalta. In addition to fibromyalgia, Cymbalta is approved for the management of diabetic peripheral neuropathic pain (DPNP) and the treatment of major depressive disorder and generalized anxiety disorder, all in adults age 18 years and older.Additional important changes have been made to the Cymbalta prescribing information, including updates to the Warnings and Precautions section. Full prescribing information can be found at http://www.cymbalta.com.
Data HighlightsLilly established the efficacy of Cymbalta in two pivotal three-month clinical trials involving 874 patients with fibromyalgia. In both studies, Cymbalta reduced pain at study endpoint compared with placebo as measured by the Brief Pain Inventory (BPI) 24-hour average pain scale.(vi),(vii) The BPI is a scale that measures the severity of pain.
Significant improvement in pain for Cymbalta vs. placebo was observed in the first week of each study. Fifty-one percent and 55 percent of patients on Cymbalta had a 30 percent improvement on the BPI at endpoint (clinically meaningful relief is considered at least 30 percent pain reduction(viii)).
In addition, 65 percent and 66 percent of patients taking Cymbalta 60 mg daily reported feeling better at endpoint as measured by the Patient Global Impression of Improvement (PGI-I). The PGI-I is a patient-rated scale that evaluates how much improvement has occurred since beginning treatment.
Cymbalta 60 mg was superior to placebo on the Fibromyalgia Impact Questionnaire (FIQ) Total Score. The FIQ is a scale that is used to assess and evaluate the impact of fibromyalgia on aspects of health and functioning believed to be most affected by the disorder.
In four pooled studies, the most commonly observed adverse events in Cymbalta-treated patients with fibromyalgia (greater than or equal to 5 percent and at least twice placebo) were nausea (29 percent), dry mouth (18 percent), constipation (15 percent), decreased appetite (11 percent), sleepiness (11 percent), increased sweating (7 percent) and agitation (6 percent). In the placebo-controlled clinical trials, the overall discontinuation rates due to adverse events for Cymbalta vs. placebo were 20 percent and 12 percent, respectively.(ix)
(Note:- Investigators found that duloxetine-treated women improved significantly more than placebo-treated women on both the primary and secondary end points, while male subjects treated with duloxetine did not have significantly better responses than the placebo-treated men on either primary or secondary efficacy measures.
"I was surprised by the lack of effect in men. I think the power was not great enough to show an effect in men. We need to study a larger group of men before coming to any firm conclusion about duloxetine in the treatment of men with fibromyalgia," Arnold2,6 says.)
Serotonin and norepinephrine in the brain and spinal cord are believed to both mediate core mood symptoms and help regulate the perception of pain. Based on preclinical studies, Cymbalta is a balanced and potent reuptake inhibitor of serotonin and norepinephrine that is believed to potentiate the activity of these chemicals in the central nervous system (brain and spinal cord). While the mechanism of action of Cymbalta is not fully known, scientists believe its effects on depression and anxiety symptoms, as well as its effect on pain perception, may be due to increasing the activity of serotonin and norepinephrine in the central nervous system.
Cymbalta is approved in the United States for the acute and maintenance treatment of major depressive disorder, the acute treatment of generalized anxiety disorder, and the management of fibromyalgia and diabetic peripheral neuropathic pain in adults age 18 years and older. Cymbalta is not approved for use in pediatric patients.
Important Safety InformationCymbalta is approved to treat major depressive disorder and generalized anxiety disorder, and to manage diabetic peripheral neuropathic pain and fibromyalgia. Antidepressants can increase suicidal thoughts and behaviors in children, adolescents, and young adults. Patients should call their doctor right away if they experience new or worsening depression symptoms, unusual changes in behavior, or thoughts of suicide. Be especially observant within the first few months of treatment or after a change in dose. Cymbalta is approved only for adults 18 and over.
Cymbalta is not for everyone. Patients should not take Cymbalta if they have recently taken a type of antidepressant called a monoamine oxidase inhibitor (MAOI), are taking Mellaril(R) (thioridazine), or have uncontrolled glaucoma. Patients should speak with their doctor about any medical conditions they may have including kidney problems, glaucoma, or diabetes. Patients should talk to their doctor if they have itching, right upper belly pain, dark urine, yellow skin or eyes, or unexplained flu-like symptoms, which may be signs of liver problems. Severe liver problems, sometimes fatal, have been reported. They should also talk to their doctor about alcohol consumption. Patients should tell their doctor about all their medicines, including those for migraine, to avoid a potentially life-threatening condition. Taking Cymbalta with NSAID pain relievers, aspirin, or blood thinners may increase bleeding risk. Patients should consult with their doctor before stopping Cymbalta or changing the dose and if they are pregnant or nursing.
Patients taking Cymbalta may experience dizziness or fainting upon standing. The most common side effects of Cymbalta include nausea, dry mouth, sleepiness, and constipation. This is not a complete list of side effects.
If patients have any questions, they should talk to their doctor before taking Cymbalta.
For full Prescribing Information, including Boxed Warning and medication guide, visit http://www.cymbalta.com.
This press release contains forward-looking statements about the potential of Cymbalta for the management of fibromyalgia, and reflects Lilly's current beliefs. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. There is no guarantee that the product will continue to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.
ReferencesThe Committee for Medicinal Products for Human Use (CHMP) received data on the use of duloxetine in the treatment of fibromyalgia in 1,411 patients in four placebo-controlled studies and 350 patients in one open-label safety study, a total of 1,761 patients in five clinical trials.(1,2,3,4,5)
The CHMP refused this change (marketing authorisation so that Duloxetine could be officially indicated as a treatment for Fibromyalgia Syndrome), citing as reasons that they were concerned that the effectiveness of Cymbalta/Xeristar (Duloxetine) in treating Fibro had not been shown sufficiently, and that at that point in time, they were of the opinion that the benefits of Cymbalta/Xeristar (Duloxetine) in the treatment of Fibro did not outweigh its risks. The CHMP stated that their concern about the lack of effectiveness of the drug was because the “modest effects” could be due to the medicine’s effect of improving the patients’ mood.
Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.