Frova Phase III Study Data Demonstrates That Short-Term Prevention Treatment Reduces Frequency and Severity of Menstrual Migraine

CHICAGO, IL, Jun 09, 2007 (MARKET WIRE via COMTEX News Network) -- Endo Pharmaceuticals Inc., a wholly owned subsidiary of Endo Pharmaceuticals Holdings Inc. (NASDAQ: ENDP), has presented results from a Phase III randomized, double-blind, placebo-controlled clinical trial evaluating Frova (frovatriptan succinate) 2.5 mg tablets as a six-day preventative treatment in women with difficult-to-treat menstrual migraine (MM). The data demonstrated that FROVA significantly reduced the frequency and severity of MM as well as the disabilities related to them. The results, which were presented here today at the annual meeting of the American Headache Society (AHS), were from the second of the two successful Phase III placebo-controlled clinical trials evaluating the efficacy and safety of FROVA in MM prophylaxis.
Women receiving FROVA started the six-day regimen two days prior to the onset of their anticipated headache. Starting treatment two days before the expected headache ensures that patients have adequate blood levels at the time they usually start to experience MM, and continuing treatment for six days ensures that they are covered during the whole period when they are likely to experience those headaches. Women in the study had responded poorly to previous acute triptan treatment for MM.

"In this study, appropriately timed short-term treatment with FROVA prevented or significantly reduced the pain of difficult-to-treat but often predictable migraines associated with the menstrual period," said the lead investigator in the trial, Jan Lewis Brandes, M.D., of the Nashville Neuroscience Group and assistant clinical professor of the Department of Neurology at Vanderbilt University School of Medicine. "This is exciting news for women and their physicians who need to realize that the debilitating pain of menstrual migraine is not inevitable and is not a normal part of their menstrual cycle."

"In patients with menstrual migraine and predictable menses, I am intrigued by the potential for a short-term prevention treatment to prevent or minimize MM symptoms without continuously exposing patients to a drug," said Stephen Silberstein, M.D., professor of neurology at the Jefferson Medical College of Thomas Jefferson University, director of the Jefferson Headache Center and lead investigator of the initial efficacy study of FROVA for the short-term prevention of menstrual migraine.

Study Results

In the trial, the MM status of study participants was confirmed during a placebo-controlled, single-blind, run-in phase. Women were randomized in the double-blind study to receive FROVA 2.5 mg once a day, FROVA 2.5 mg twice a day, or placebo (ratio 3:2:3).

FROVA once or twice daily significantly improved the number of headache-free perimenstrual periods (PMPs) compared to women who received placebo. FROVA also significantly reduced the incidence of severe migraines and therefore tended to improve the ratio of severe to mild headache compared to women who received placebo. Efficacy data were collected from 410 women in North America and Europe, 85 percent of whom participated in the study over three PMPs. Efficacy data were collected from 410 women in North America and Europe, 85 percent of whom participated in the study over three PMPs.

The study's primary endpoint was the number of completely headache-free PMPs. FROVA therapy significantly improved the number of headache-free PMPs per patient (0.92 [twice daily], p < 0.0001; 0.69 [once daily], p=0.009) versus 0.42 (placebo). The incidence of severe headache was significantly less with FROVA once daily (44 percent; p=0.007) and twice daily (40 percent; p=0.0003) compared with placebo (58 percent), lowering the ratio of severe to mild migraine from 11:1 with placebo to 4:1 [once daily] and 2:1 [twice daily] with FROVA.

Reductions in migraine symptoms were significant for nausea (twice daily only), photophobia, and phonophobia (p < 0.008; BID and QD vs. placebo), and patients experienced significantly less functional impairment during treatment with FROVA (p < 0.0001; QD and BID vs. placebo).

Both FROVA regimens were equally well tolerated with a low rate of adverse events. The most commonly reported adverse events were upper respiratory tract infection (37 patients), nausea (36 patients), and dizziness (31 patients). Most adverse events were rated mild or moderate in severity and did not increase in severity with increasing doses of FROVA; the percentage rated severe was 19 percent in the placebo group and 22 percent (once daily) and 14 percent (twice daily) in the FROVA groups.

Endo has submitted a supplemental New Drug Application (sNDA) for FROVA 2.5 mg tablets for the short-term (six days per month) prevention of MM to the U.S. Food and Drug Administration (FDA).

About Menstrual Migraine

Menstrual migraine, distinct from other types of migraines, is largely an under-recognized condition. Of the approximately 21 million women in the U.S. who experience migraines, up to 60 percent suffer from MM and its debilitating effects. More than half of these women, however, may not be correctly diagnosed, and therefore may not be receiving adequate treatment. MM has been reported to be more severe and last longer than other migraines, and women who suffer from MM may experience significant restrictions in their daily activities. For many women with MM, currently available treatment options may not adequately reduce the debilitating symptoms, such as pain, nausea and vomiting, nor the migraine's duration. For more information about MM, visit www.menstrualmigraine.org.

Important Information about FROVA

FROVA is indicated for the acute treatment of migraine attacks with or without aura in adults. FROVA is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. The safety and effectiveness of FROVA have not been established for cluster headache, which is present in an older, predominantly male population.

FROVA should only be used when a clear diagnosis of migraine has been established.

As with other drugs in this class, FROVA should not be given to patients with ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, or documented silent ischemia), or to patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal's variant angina or other significant underlying cardiovascular disease.

FROVA should not be given to patients with cerebrovascular syndromes including (but not limited to) strokes of any type, as well as transient ischemic attacks.

FROVA should not be given to patients with peripheral vascular disease including (but not limited to) ischemic bowel disease.

FROVA should not be given to patients with uncontrolled hypertension.

It is strongly recommended that FROVA not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease.

It is strongly recommended that patients who are intermittent long-term users of 5-HT1 agonists, including FROVA, and who have or acquire risk factors predictive of CAD, undergo periodic cardiovascular evaluation as they continue to use FROVA.

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including FROVA treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with FROVA and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

The most common side effects associated with the use of FROVA are dizziness, fatigue, paresthesia, flushing, headache, dry mouth, hot or cold sensation, skeletal pain, chest pain, and dyspepsia.

About Endo

A wholly owned subsidiary of Endo Pharmaceuticals Holdings Inc., Endo Pharmaceuticals is a fully integrated specialty pharmaceutical company with market leadership in pain management products. The company researches, develops, produces and markets a broad product offering of branded and generic pharmaceuticals, meeting the needs of healthcare professionals and consumers alike. More information, including this and past press releases of Endo Pharmaceuticals Holdings Inc. is available online at www.endo.com.

Forward-Looking Statements This press release contains forward-looking statements, within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, as amended, that are based on management's beliefs and assumptions, current expectations, estimates and projections. Statements that are not historical facts, including statements which are preceded by, followed by, or that include, the words "believes," "anticipates," "plans," "expects" or similar expressions and statements are forward-looking statements. Endo's estimated or anticipated future results, product performance or other non-historical facts are forward-looking and reflect Endo's current perspective on existing trends and information. Many of the factors that will determine the Company's future results are beyond the ability of the Company to control or predict. These statements are subject to risks and uncertainties and, therefore, actual results may differ materially from those expressed or implied by these forward-looking statements. The reader

should not rely on any forward-looking statement. The Company undertakes no obligation to update any forward-looking statements whether as a result of new information, future events or otherwise. Several important factors, in addition to the specific factors discussed in connection with these forward-looking statements individually, could affect the future results of Endo and could cause those results to differ materially from those expressed in the forward-looking statements contained in this press release. Important factors that may affect future results include, but are not limited to: market acceptance of the Company's products and the impact of competitive products and pricing; dependence on sole source suppliers; the success of the Company's product development activities and the timeliness with which regulatory authorizations and product launches may be achieved; successful compliance with extensive, costly, complex and evolving governmental regulations and restrictions; the availability on commercially reasonable terms of raw materials and other third party manufactured products; exposure to product liability and other lawsuits and contingencies; dependence on third party suppliers, distributors and collaboration partners; the ability to timely and cost effectively integrate acquisitions; uncertainty associated with pre-clinical studies and clinical trials and regulatory approval; uncertainty of market acceptance of new products; the difficulty of predicting FDA approvals; risks with respect to technology and product development; the effect of competing products and prices; uncertainties regarding intellectual property protection; uncertainties as to the outcome of litigation; changes in operating results; impact of competitive products and pricing; product development; changes in laws and regulations; customer demand; possible future litigation; availability of future financing and reimbursement policies of government and private health insurers and others; and other risks and uncertainties detailed in Endo's filings with the Securities and Exchange Commission, including its Registration Statement on Form 10-K filed with the SEC on March 1, 2007. Readers should evaluate any statement in light of these important factors.

 

Posted: June 2007

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