IVAX To Begin Selling Tramadol

IVAX currently has 35 ANDAs and one tentative approval pending at the FDA. The company is continuing its aggressive filing schedule for new ANDA submissions.

IVAX Corporation, headquartered in Miami, Florida, discovers, develops, manufactures, and markets branded and brand equivalent (generic) pharmaceuticals and veterinary products in the U.S. and internationally.

Copies of this and other news releases may be obtained free of charge from IVAX' web site athttp://www.ivax.com. Shareholders and prospective investors can register to automatically receive the company's press releases via email at www.ivax.com/ComNewsv2.htm.> The "FDA" refers to the United States Food and Drug Administration.

Refractory osteoarthritis pain may respond to opioid treatment: tramadol, buprenorphine

BERLIN -- Consider a trial of opioids for patients with moderate-to-severe chronic osteoarthritis pain that doesn't respond to prescription nonsteroidal anti-inflammatory drugs, Dr. Nathaniel Katz advised at the 2003 World Congress on Osteoarthritis.

Opioids appear effective for a minority of patients whose pain is not relieved by conventional pain-management regimens, and for this subset opioids can be an effective, safe, and long-term option, said Dr. Katz, an anesthesiologist at Harvard Medical School, Boston.

In addition, addiction can occur with opioid use, but seems limited to a minority of patients. The best initial opioid options are probably the nonpure [micro]-agonists such as tramadol and possibly buprenorphine. Both may have reduced addiction potential compared with other opioids, but this has not been proved. If patients don't respond to tramadol, then try a pure [micro]-agonist, he suggested in an interview. Two posters presented at the congress reported a favorable clinical experience with new, once-daily formulations of tramadol that have yet to be approved in the United States.

More than 3 million American adults have uncontrolled, chronic, moderate-to-severe pain that's attributed to arthritis, according to the results of a 2001 survey of U.S. households. About 60% of those people have pain despite the use of prescription NSAIDs. These are the patients who are candidates for opioid therapy, Dr. Katz said.

NDA for Ralivia FlashDose

Business Editors/Health/Medical Writers

TORONTO--(BUSINESS WIRE)--March 11, 2004

Biovail Corporation (NYSE:BVF) (TSX:BVF) announced today that it has submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) for Ralivia(TM) FlashDose(R), an orally disintegrating tablet version of the analgesic medication tramadol hydrochloride, intended for the treatment of moderate to moderately severe pain. Biovail recently announced the filing of Ralivia(TM) ER a once daily, extended release form of tramadol.

Tramadol is currently sold in the United States under the brand name Ultram(R) with approximately 11 million prescriptions dispensed during for the twelve months ended December 31, 2003 including generics. Total sales for tramadol immediate release products were $150 million for the same period. The combined market for narcotic and non-narcotic analgesics generated sales of $13.9 billion in the United States for this same time period.

Eugene Melnyk, Chairman of the Board and Chief Executive Officer commented, "The filing of Ralivia FlashDose is very significant, complementing our filing of Ralivia ER and marking our development of a franchise of pain medications. We continue development of a FlashDose(R) form of a tramadol/acetaminophen combination product. The submission of this important product is a further establishment of Biovail's FlashDose technology and its application to making medicines more acceptable and convenient for patients." Biovail is evaluating options for commercialization of the pain franchise and is currently in discussions with multiple potential partners regarding out-licensing Ralivia ER alone or in conjunction with Biovail's orally disintegrating pain products.

The application for Ralivia FlashDose was submitted under the provisions of Section 505(b)(2) of the Food, Drug and Cosmetic Act. The goal of Biovail's biopharmaceutics program was to develop a formulation that would deliver an equivalent amount of drug to the systemic circulation as the listed drug Ultram(R), but in a dosage form that offers a choice of administration with or without water, thereby providing a benefit to patients of comparable efficacy and safety with a greatly simplified dosing regimen and potentially higher compliance.

Biovail NDA For Ralivia ER — Tramadol Extended Release Tablets — Accepted for Review

Business Editors

TORONTO--(BUSINESS WIRE)--Feb. 26, 2004

Biovail Corporation (NYSE:BVF) (TSX:BVF):

-- Conducting out-licensing discussions with multiple partners

-- Flashtab immediate-release tramadol NDA submission expected H1

2004

-- Acquires rights to tramadol/acetaminophen formulation from

Ethypharm

-- Biovail/Ethypharm Shareholders Agreement modified

-- Biovail reacquires North American rights to Diltiazem CR from

Ethypharm

Biovail Corporation (NYSE:BVF) (TSX:BVF) announced today that it has received confirmation, with an effective date of February 29, 2004, for the filing of its December 31, 2003 submission for a New Drug Application (NDA) to the Food and Drug Administration (FDA) for Ralivia ER(TM) (tramadol hydrochloride) Extended Release tablets. Ralivia ER(TM) is a once-daily oral controlled-release medication intended for the treatment of moderate to moderately severe pain.

The application for Ralivia ER(TM) was submitted under the provisions of Section 505(b)(2) of the Food, Drug and Cosmetic Act. Clinical and safety data has been obtained from four original adequate and well-controlled trials on over 3000 patients receiving doses of up to 400mg of Ralivia ER(TM) once-daily. The submission also included 12 definitive and 5 supportive pharmacokinetic studies which demonstrated that once-daily dosing of Ralivia ER(TM) delivers the same amount of drug as Ultram given three times (TID) or four times (QID) per day, with somewhat smaller peak-to-trough fluctuations.

Ralivia ER(TM) uses Biovail's Smartcoat Technology, which is similar to that used in the development of Biovail's Wellbutrin XL formulation. Biovail believes that there is considerable opportunity for a product line offering that includes Ralivia ER(TM) intended for chronic use and oral disintegrating tablet presentations of tramadol and tramadol/acetaminophen for the treatment of acute pain. Though a final decision has not been made regarding the commercialization of Biovail's pain franchise, Biovail is currently in discussions with multiple potential partners regarding outlicensing Ralivia ER(TM) alone or in conjunction with Biovail's orally disintegrating pain products. Biovail will develop a timeline for presenting this extensive clinical data set after determining whether Biovail will launch Ralivia ER(TM) through its own sales force in the United States or outlicense it to a partner.

Biovail also confirms today that it has completed all relevant studies for its Flashtab version of immediate-release tramadol HCl. Biovail expects to submit an NDA to the FDA in the first half of 2004 for this product. The North American rights to this product were acquired from Ethypharm SA (Ethypharm) in September 2003. An immediate release form of tramadol HCl -- dosed up to 6 times daily was introduced in 1995 and is currently marketed in the United States under the brand name Ultram with sales of approximately $150 million and approximately 11 million prescriptions dispensed during 2003 including generics. The combined market for narcotic and non-narcotic analgesics generated sales of $13.9 billion in the United States for this same time period.

Furthermore, Biovail today announced that it has acquired North American rights to Ethypharm SA's (Ethypharm) Flashtab combination tramadol and acetaminophen (Flashtab tramadol/acetaminophen) product, which complements Biovail's September 2003 purchase from Ethypharm of Flashtab tramadol. A current combination tramadol and acetaminophen product is sold under the Ultracet brand for the treatment of short-term management of acute pain by a division of J&J and had sales of $262 million in the United States in 2003. Flashtab tramadol/acetaminophen may offer the convenience of an Orally Disintegrating Tablet (ODT or Flashtab or Flash Dose) for an acute pain use. This dosage presentation may be particularly advantageous for a drug that is taken multiple times per day (up to 8 tablets per day) and is further evidence of Biovail's commitment to providing innovative treatment options for pain management.

As part of the licensing agreement for Flashtab tramadol/acetaminophen, Biovail has modified its Shareholder Agreement with Ethypharm with respect to having protection on the value of its 15% equity investment in Ethypharm from an indefinite period of time to 18 months. Biovail and Ethypharm have agreed to terminate the September 2003 Diltiazem CR License Agreement and the Supply Agreement as well as terminating Biovail's obligation to provide convertible debenture financing to Ethypharm. As a result of these initiatives, the elimination of Biovail's financing commitment to Ethypharm removes a contingent obligation, simplifies reporting and provides enhanced transparency. Biovail will finalize the accounting for the transaction with Ethypharm and announce the accounting treatment as part of its 2003 earnings release scheduled for March 3, 2004.

Additional information

Tramadol

Tramadol is one of a number of analgesics, which are among the most effective medications for the treatment of chronic pain. Tramadol's minimal propensity to induce adverse effects is an advantage over morphine-like agents. Relative to morphine, tramadol causes less dependence and less respiratory depression. Ralivia ER(TM) has been developed to offer continued pain control over 24 hours as compared to the immediate-release formulations, which must be taken multiple times per day.

Subject to FDA approval, Ralivia ER(TM) will be available in 100mg, 200mg and 300mg extended release tablets. Ralivia ER(TM) should offer patients the convenience of a once-daily form of tramadol, as opposed to its current dosing regimen of up to 4 to 6 times per day.

Tramadol/acetaminophen (Ultracet)

What is the addiction risk associated with tramadol?

Evidence of tramadol abuse in the US comes primarily from federally operated programs collecting adverse drug event (ADE) data. The MedWatch program of the Food and Drug Administration (FDA) provides a central depository for receiving and compiling postmarketiug voluntary case reports. While passive reporting systems can significantly underestimate serious ADE numbers, these reports are often the first evidence of an ADE after a new drug's release into the market. (1) MedWatch has received 766 case reports of abuse associated with tramadol, as well as 482 cases of withdrawal associated with tramadol from the drug's initial US marketing in 1995 through September 2004. (2,3)

The Drug Abuse Warning Network (DAWN) is a federally operated, national surveillance system that monitors trends in drug-related emergency department visits. Over the period from 1995 to 2002, DAWN reported drug-related emergency department visits mentioning tramadol in more than 12,000 cases. Tramadol case numbers significantly increased 165% during this time. For perspective, during the same period, DAWN found nalbuphine (Nubain, also not CSA scheduled) in 118 cases, propoxyphene drug combinations (CSA Class IV) in more than 45,000 cases, codeine drug combinations (CSA Classes III & V) in about 50,000 cases, and hydrocodone drug combinations (CSA Class III) in around 128,000 cases.