FDA Approval for Savella

Forest Laboratories, Inc. and Cypress Bioscience, Inc. have announced that Savella^TM (milnacipran hydrochloride), a selective serotonin and norepinephrine dual reuptake inhibitor, has been approved by the U.S. Food and Drug Administration (FDA) for the management of Fibromyalgia Syndrome (Fibro).

This is the third drug to get FDA approval for Fibro, after Lyrica (Pregabalin) and Cymbalta (Duloxetine).

Forest Laboratories is a US-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. Cypress Bioscience, Inc. is a US-based pharmaceutical company that provides therapeutics and personalized medicine services, facilitating improved and individualized patient care. They aim to address 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 Fibro and rheumatoid arthritis. Forest Laboratories, Inc. and Cypress Bioscience, Inc. have been working together to develop Savella^TM (milnacipran hydrochloride) as a marketable medication in the US. The medication was originally developed by the Pierre Fabre group, France’s second biggest independent pharmaceutical laboratory.

The safety and efficacy of Savella^TM (milnacipran hydrochloride) was established in two US pivotal phase III clinical trials involving over 2,000 patients with Fibro. 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.

In both studies, a greater proportion of patients in the Savella^TM (milnacipran hydrochloride) 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^TM (milnacipran hydrochloride) that persisted throughout these studies.

The clinical development program demonstrated that Savella^TM (milnacipran hydrochloride) 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.

Savella^TM (milnacipran hydrochloride) has not previously been available in the US, but Forest and Cypress expect it to be available in American pharmacies by March 2009. Milnacipran, which is also marketed as Ixel, Dalcipran and Toledomin, is licensed for depression in a number of countries, including Austria, france, Israel and Japan. It is not licensed in the UK but has been used in research studies there.

Dr Daniel Clauw MD, Professor of Anesthesiology and Medicine (Rheumatology) at the University of Michigan and a member of FibroAction's Professional Advisory Board, has said that:

"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...The introduction of Savella is important because it is the first drug approved to treat the symptoms of fibromyalgia using a composite responder analysis.

Jay D. Kranzler, MD, PhD, Chairman and CEO of Cypress Bioscience explained that:

"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."

Most studies of medications for Fibro use pain scores as the only primary endpoint, although measures of functionality and the impact of the condition are sometimes used as secondary endpoints. The clinical development program for Savella^TM (milnacipran hydrochloride) 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).

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.”

Jean-Pierre Garnier, Chief Executive Officer of Pierre Fabre SA, added that:

"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”

Although the exact mechanism by which Savella^TM (milnacipran hydrochloride) improves the symptoms of Fibro is unknown, some researchers believe that abnormalities in certain brain neurotransmitters may be central to the condition. Savella^TM (milnacipran hydrochloride) blocks the reuptake of both norepinephrine and serotonin, and laboratory tests have suggested that it blocks the reuptake of norepinephrine most. This may be the mechanism by which Savella acts to improve the symptoms of fibromyalgia.

Important Safety Information from the press release

Savella^TM (milnacipran hydrochloride) is a selective serotonin and norepinephrine inhibitor (SNRI), similar to some drugs used 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^TM (milnacipran hydrochloride) 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^TM (milnacipran hydrochloride), 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^TM (milnacipran hydrochloride) 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^TM (milnacipran hydrochloride). Savella^TM (milnacipran hydrochloride) 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^TM (milnacipran hydrochloride), either dose reduction or discontinuation should be considered.

Savella^TM (milnacipran hydrochloride) should be prescribed with caution in patients with a history of a seizure disorder, mania or controlled narrow-angle glaucoma.

Savella^TM (milnacipran hydrochloride) has been associated with mild elevations of ALT and AST (liver function tests). Rarely, fulminant hepatitis has been reported in patients treated with milnacipran. Savella^TM (milnacipran hydrochloride) 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^TM (milnacipran hydrochloride) 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^TM (milnacipran hydrochloride). Discontinuation should be considered for patients with symptomatic hyponatremia.

SSRIs and SNRIs, including Savella^TM (milnacipran hydrochloride), may increase the risk of bleeding events. Patients should be cautioned regarding the risk of bleeding associated with concomitant use of Savella™ (milnacipran hydrochloride) 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.

According to the statement released, Savella^TM (milnacipran hydrochloride) is unlikely to be involved in clinically significant pharmacokinetic drug interactions. Pharmacodynamic interactions of Savella with other drugs can occur. Savella^TM (milnacipran hydrochloride) 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 (≥ 5% and twice that of placebo) were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension.