NEW YORK, Jan. 15 -- The FDA has approved the selective serotonin and norepinephrine dual reuptake inhibitor milnacipran (Savella) for fibromyalgia, the drug makers announced.
The approval was made on the basis of two phase III trials of 2,084 patients with fibromyalgia (1,460 on active treatment and 624 on placebo). They showed that doses of 100 mg/day and 200 mg/day caused significant improvement in a composite of pain, patient global assessment, and physical function.
In a three-month trial, about a quarter of the patients on active treatment were classified as responders on the basis of the primary endpoint, but that was significantly higher than the 13.4% of placebo patients who responded. (See: ACR: Investigational Agent Shows Edge Over Placebo in Reducing Fibromyalgia Pain)
Forest Laboratories and Cypress Bioscience, which own the North American rights to milnacipran, expect the drug to be available by March. It is sold outside the U.S. as an antidepressant by Pierre Fabre Laboratories in France.
The exact mechanism by which milnacipran eases the symptoms of fibromyalgia is unknown, according to the drug makers.
The drug is not approved for use in children, and should not be used in patients taking monoamine oxidase inhibitors or in those with uncontrolled narrow-angle glaucoma, the drug makers said.
The drug's label includes a boxed warning for increased risk of suicidal ideation, thinking, and behavior in children, adolescents, and young adults who are taking antidepressants for major depressive disorder or other psychiatric disorders.
The most common adverse reactions in the pivotal trials were nausea, constipation, hot flush, hyperhidrosis, vomiting, palpitations, increased heart rate, dry mouth, and hypertension.
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Not approved for Children or Pregnancy
Savella is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) concomitantly or within 14 days of discontinuing treatment of an MAOI or in patients with uncontrolled narrow-angle glaucoma.
Development of a potentially life-threatening serotonin syndrome may occur with agents that inhibit serotonin reuptake, including Savella, particularly with concomitant use of serotonergic drugs (including triptans and tramadol) and with drugs which impair metabolism of serotonin (including MAOIs). The concomitant use of Savella with serotonin precursors is not recommended.
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Objective
To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM).
Methods
A 27-week, randomized, double-blind, multicenter study compared milnacipran 100 and 200 mg/day with placebo in the treatment of 888 patients with FM. Two composite responder definitions were used to
classify each patient's individual response to therapy. "FM responders" concurrently satisfied response criteria for improvements in pain (visual analog scale 24-h morning recall), patient global impression of change (PGIC), and physical functioning (SF-36 Physical Component Summary); while
"FM pain responders" concurrently satisfied response criteria for improvements in pain and PGIC.
Results
At the primary endpoint, after 3-month stable dose treatment, a significantly higher percentage of milnacipran-treated patients met criteria as FM responders versus placebo (milnacipran 200 mg/day, p=0.017; milnacipran 100 mg/day, p=0.028). A significantly higher percentage of patients treated with milnacipran 200 mg/day also met criteria as FM pain responders versus placebo (p = 0.032). Significant pain reductions were observed after Week 1 with both milnacipran doses. At 15 weeks, milnacipran 200 mg/day led to significant improvements over placebo in pain (real-time, daily and weekly recall; all measures, p<0.05), PGIC (p<0.001), fatigue (p=0.016), cognition (p=0.025), and multiple SF-36
domains. Milnacipran was safe and well tolerated by the majority of patients during 27 weeks of treatment; nausea and headache were the most common adverse events.
Conclusion
Milnacipran is safe and effective for the treatment of multiple symptoms of FM.
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Excerpts from the FDA's - NDA 22-256 Savella Addendum to Division Director Review and Summary Basis for Approval Recommendation January 13, 2009
Drs. Filie, Buenconsejo, Price and Kashoki undertook extensive and in depth analyses of the data from the two pivotal efficacy studies and have concluded that, in spite of their initial concerns, there is adequate evidence to support the indication of “For the management of FM.” The safety profile of this product is not dissimilar to others in its class, and an approved label would have to include a boxed warning for suicide and suicidality as part of the class labeling for antidepressant medications.
On October 7, 2008, we received a letter from the Government Accountability Project which stated that a whistleblower had reported that certain improprieties had occurred in regard to the data collected for one of the pivotal studies submitted in this application. While our initial review of this allegation did not appear to raise concerns regarding the integrity of the data from the study, it is necessary for FDA to complete a thorough investigation. The Division of Scientific Investigation is currently working to complete that investigation.
....the findings of embryofetal lethality and reduced pup weights and viability appear to be treatment related, and the labeling for Savella should clearly discourage the use of this drug during pregnancy and in breast feeding women. I also concur that, given the adverse effects noted in the reproductive toxicology studies, a juvenile animal study should be conducted prior to the initiation of pediatric clinical studies.
The product is dose proportional after single and multiple dose administration. The elimination half-life is 6 to 8 hours. There is no food effect on the pharmacokinetics of the product, but food does appear to increase tolerability. Milnacipran is primarily excreted in the urine, with minimal metabolism by the CYP450 system. It is expected that other drugs that increase heart rate or blood pressure would be likely to result in a pharmacodynamic interaction with Savella.
Update, a 46 year old, female patient in an ongoing European Phase 3 FM study was reported to have committed suicide. It is possible that this death was related to treatment with Savella. The serious adverse events (SAEs) that were considered by the review team to be most likely related to treatment with Savella were primarily cardiac in nature. Indeed, cardiac disorders were the SAEs that occurred with the greatest frequency and they occurred with greater frequency in Savella-treated subjects compared to placebo-treated subjects. However, in general, they all occurred infrequently.
While relatively mild, more elevations in BP occurred in the Savella-treated subjects compared to the placebo-treated subjects. The mean increases in SBP were 3.1 mmHg in the 100mg/day arm and 3 mmHg in the 200-mg/day arm. The mean increases in DBP were 3.1 mmHg in the 100-mg/day arm and 2.6 mmHg in the 200-mg/day arm. The mean SBP change in the placebo-arm was -0.1 mmHg and the mean change in DBP in the placebo-arm was 0.4 mmHg. Shift data demonstrated that, for subjects with a SBP less than or equal to 120 mmHg at baseline, more Savella 100-mg and 200-mg treated subjects, 55% and 57%, respectively, than placebo-treated subjects, 47%, developed pre-hypertension, defined as a maximal SBP of greater than 120-140 mmHg. Shifts to higher SBP values were low without a clear difference across treatment groups. Patients who were pre-hypertensive at baseline again appeared to have a greater risk of worsened blood pressure when treated with Savella compared to placebo, and similar findings occurred in regard to DBP changes. Subjects who were normotensive at baseline also appeared to incur a greater risk of developing hypertension when treated with Savella compared to placebo, although the effect appears to be, oddly, inversely related to dose.
....the consult provided to DAARP from the Division of Cardiorenal Products, Dr. Stockbridge concludes: The effects of milnacipran on blood pressure and heart rate have not been well characterized, but they appear to be modest. However, if the effects were present throughout the interdosing interval and persist during chronic treatment, they can be expected to have an appreciable --perhaps 50% -- increase in risk of death, MI, and stroke, like any corresponding natural pressor effect. A 50% increase in mortal-morbid events may still be small if the baseline risk is small--young people, no hypertension, no diabetes, no hyperlipidemia. One should also not expect that monitoring will mitigate against the risk because clinicians are unlikely to detect effects of this magnitude.
..from page 99 of Dr. Filie’s review
In the patients with depression at baseline, the following psychiatric events were more frequent in the milnacipran-treated patients than in the placebo-treated patients: anxiety (6-7% vs. 4%) and insomnia (14% of MLN 200 mg/day patients vs. 11% of placebo patients).
In patients without depression at baseline, insomnia occurred with greater frequency in the milnacipran groups (12% of patients) compared to the placebo grout (10% of patients).
The CSS conclude the following regarding Savella’s potential to induce a withdrawal syndrome (from page 1 of first CSS consult):
…based on the presence of a withdrawal syndrome in non-fibromyalgia patients following milnacipran discontinuation (as cited in the proposed drug label), CSS concludes that milnacipran can induce physical dependence.
Overall, the results of the studies submitted in this application show that Savella is effective in treating the symptoms of FM in some patients, and that the safety profile of the product is similar to the class of NSRI antidepressants and supports a reasonable risk in the face of the product’s benefit in treating this debilitating disorder.
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Cypress Bioscience, Inc. Press release.
January 14, 2009 7:24 PM ETNew treatment option for the estimated 6 million Americans living with this chronic, debilitating condition
NEW YORK and SAN DIEGO, Jan. 14, 2009 /PRNewswire-FirstCall/ -- Forest Laboratories, Inc. FRX and Cypress Bioscience, Inc. CYPB today announced that Savella(TM) (milnacipran HCl), a selective serotonin and norepinephrine dual reuptake inhibitor, was approved by the U.S. Food and Drug Administration (FDA) for the management of fibromyalgia. Fibromyalgia is a chronic condition characterized by widespread pain and decreased physical function, afflicting as many as six million people in the United States. The safety and efficacy of Savella was established in two US pivotal phase III clinical trials involving over 2,000 patients with fibromyalgia. The studies showed that Savella doses of 100 mg/day and 200 mg/day demonstrated statistically significant and clinically meaningful concurrent improvements in pain, patient global assessment, and physical function. The companies expect Savella to be available in pharmacies by March 2009.
"Fibromyalgia is a complicated chronic pain condition, so it is important that physicians and patients have access to treatments that have been shown to help manage the symptoms that define the experience of fibromyalgia," said Dr. Daniel Clauw, Professor of Anesthesiology and Medicine (Rheumatology) at the University of Michigan. "The introduction of Savella is important because it is the first drug approved to treat the symptoms of fibromyalgia using a composite responder analysis.".
"Savella is the product of a unique clinical development program, one that considered a patient to be a responder to therapy only if they demonstrated concurrent clinically significant changes in multiple aspects of their fibromyalgia, including pain, patient global assessment and physical function. Savella is the only product approved for the management of fibromyalgia that used this complete responder analysis as its primary endpoint," said Jay D. Kranzler, MD, PhD, Chairman and CEO of Cypress Bioscience.
Howard Solomon, Chairman and Chief Executive Officer of Forest said, "We and our partner Cypress Bioscience are very pleased to receive marketing approval for Savella, following a first-cycle review, from the FDA. Fibromyalgia is a chronic and often debilitating condition with a significant need for new therapies. Savella is a valuable new treatment for patients afflicted with fibromyalgia. Its effectiveness was evaluated based upon the multiple symptoms included in the responder analysis."
"This approval is crucial for Pierre Fabre Laboratories as milnacipran is one of the flagship products of our portfolio and represents another product of Pierre Fabre research registered in the United States," said Jean-Pierre Garnier, Chief Executive Officer of Pierre Fabre SA.
Although the exact mechanism by which Savella improves the symptoms of fibromyalgia is unknown, some researchers believe that abnormalities in certain brain neurotransmitters may be central to fibromyalgia. Savella blocks the reuptake of both norepinephrine and serotonin, with greater selectivity for the inhibition of norepinephrine reuptake in vitro. This may be the mechanism by which Savella acts to improve the symptoms of fibromyalgia.
Data HighlightsThe clinical development program for Savella was unique in its use of a composite responder analysis as the primary endpoint. This endpoint required individual patients to demonstrate concurrent improvement to multiple validated measures, including pain (visual analog scale), patient global assessment (patient global impression of change), and physical function (Short Form-36 Physical Component Summary).
The efficacy of Savella was established in two US pivotal Phase III clinical trials involving 2,084 treated patients (1,460 Savella; 624 placebo), which showed that Savella demonstrated clinically significant improvements compared to placebo in treating fibromyalgia. The first study was 6 months in duration and the second study was 3 months in duration.
In both studies, a greater proportion of patients in the Savella treatment arms (100 mg/day and 200 mg/day) as compared with placebo treatment, at 3 months, experienced at least a 30% reduction in pain from baseline and also rated themselves as "very much improved" or "much improved" based on the patient global assessment. In addition, a greater proportion of patients treated with Savella as compared with placebo treatment met the criteria for a treatment response as measured by concurrent improvements in pain, physical function, and patient global assessment. In both studies, some patients who rated themselves as globally "much" or "very much" improved experienced a decrease in pain as early as week 1 of treatment with a stable dose of Savella that persisted throughout these studies.
The clinical development program demonstrated that Savella was safe and generally well tolerated. The most frequently occurring adverse reaction was nausea. Other common adverse reactions reported in these clinical trials were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth and hypertension. The majority of adverse reactions reported were mild to moderate in nature.
About SavellaSavella is a dual-reuptake inhibitor that preferentially blocks the reuptake of norepinephrine with higher potency than serotonin (in-vitro), two neurotransmitters thought to a play a central role in the symptoms of fibromyalgia. Savella will be marketed by Forest and its licensor, Cypress Bioscience. Pierre Fabre, who originally developed and sells milnacipran outside the U.S., licensed the rights for North America to Cypress Bioscience.
About FibromyalgiaFibromyalgia is a chronic and debilitating condition characterized by widespread pain and decreased physical functioning. According to the American College of Rheumatology fibromyalgia is estimated to affect over 6 million Americans. It is most often diagnosed in the primary care setting and is the second most commonly diagnosed condition in rheumatology clinics in the United States after osteoarthritis. Despite the high prevalence and severity of this condition, there are limited treatment options specifically approved for fibromyalgia in the United States.
Important Safety InformationSavella is a selective serotonin and norepinephrine inhibitor (SNRI), similar to some drugsused for the treatment of depression and other psychiatric disorders.Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on Savella should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Savella is not approved for use in the treatment of major depressive disorder. Savella is not approved for use in pediatric patients.
Savella is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) concomitantly or within 14 days of discontinuing treatment of an MAOI or in patients with uncontrolled narrow-angle glaucoma.
Development of a potentially life-threatening serotonin syndrome may occur with agents that inhibit serotonin reuptake, including Savella, particularly with concomitant use of serotonergic drugs (including triptans and tramadol) and with drugs which impair metabolism of serotonin (including MAOIs). The concomitant use of Savella with serotonin precursors is not recommended.
Blood pressure and heart rate should be monitored prior to initiating treatment with Savella and periodically throughout treatment. SNRIs, including Savella, have been associated with reports of increases in blood pressure and heart rate. Pre-existing hypertension, tachyarrhythmias and other cardiac diseases should be treated before starting therapy with Savella. Savella should be used with caution in patients with significant hypertension or cardiac disease. For patients who experience a sustained increase in blood pressure or heart rate while receiving Savella, either dose reduction or discontinuation should be considered.
Savella should be prescribed with caution in patients with a history of a seizure disorder, mania or controlled narrow-angle glaucoma.
Savella has been associated with mild elevations of ALT and AST. Rarely, fulminant hepatitis has been reported in patients treated with milnacipran. Savella should be discontinued in patients who develop jaundice or other evidence of liver dysfunction and should not be resumed unless another cause can be established.
Savella should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
As with other SNRIs and SSRIs withdrawal symptoms have been observed following discontinuation of milnacipran. A gradual dose reduction is recommended.
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Savella. Discontinuation should be considered for patients with symptomatic hyponatremia.
SSRIs and SNRIs, including Savella, may increase the risk of bleeding events. Patients should be cautioned regarding the risk of bleeding associated with concomitant use of Savella and NSAIDs, aspirin, warfarin or other drugs that affect coagulation.
Male patients with a history of obstructive uropathies may experience higher rates of genitourinary adverse events.
Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions. Pharmacodynamic interactions of Savella with other drugs can occur.
Savella contains FD&C Yellow No. 5, which may cause allergic-type reactions in susceptible persons.
In clinical trials, the most frequently occurring adverse reaction was nausea. The most commonly occurring adverse reactions (greater than or equal to 5% and twice that of placebo) were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension.
About Forest LaboratoriesForest Laboratories FRX is a U.S.-based pharmaceutical company with a long track record of building partnerships and developing and marketing products that make a positive difference in people's lives. In addition to its well-established franchises in therapeutic areas of the central nervous and cardiovascular systems, Forest's current pipeline includes product candidates in all stages of development and across a wide range of therapeutic areas. The company is headquartered in New York, NY. To learn more about Forest Laboratories, visit www.FRX.com.
Except for the historical information contained herein, this release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements involve a number of risks and uncertainties, including the difficulty of predicting FDA approvals, the acceptance and demand for new pharmaceutical products, the impact of competitive products and pricing, the timely development and launch of new products, and the risk factors listed from time to time in Forest Laboratories' Annual Report on Form 10-K, Quarterly Report on Form 10-Q, and any subsequent SEC filings.
About Cypress BioscienceCypress Bioscience, Inc. provides therapeutics and personalized medicine services, facilitating improved and individualized patient care. Cypress addresses the evolving needs of specialist physicians and their patients by identifying unmet medical needs in the areas of pain, rheumatology, and physical medicine and rehabilitation, including challenging disorders such as fibromyalgia and rheumatoid arthritis. This approach to improving patient care creates a unique partnership with physicians.
For more information about Cypress, please visit the Company's website at www.cypressbio.com.This press release, as well as Cypress' SEC filings and website at www.cypressbio.com, contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 including statements about the potential of Savella to treat fibromyalgia syndrome and its availability in pharmacies by March 2009. Actual results could vary materially from those described as a result of a number of factors, including those set forth in Cypress' Annual Report on Form 10-K, the most recent Quarterly Report on Form 10-Q and any subsequent SEC filings and including, but not limited to, that Savella may not achieve market acceptance.
About Pierre FabreThe Pierre Fabre group, France's second biggest independent pharmaceutical laboratory, achieved a turnover of 1.7 billion euros in 2007. It employs nearly 10,000 people including 1,400 in the research sector. Its business sectors are ethical products, healthcare products and dermocosmetics with the brands Avene, Ducray, A Derma, Galenic, Klorane and Rene Furterer. The Pierre Fabre group dedicates 25% of its annual turnover to R&D in five main therapeutic directions: oncology (PFM's priority R&D sector with 50% of the over all R&D budget), the Central Nervous System, cardiology, internal medicine /urology and dermatology.
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