Pharmacology
FDA Approves Tramadol ODT for the Treatment of Moderately Severe Pain in Adults
By Biovail Corporation
May 6, 2005, 21:48

Biovail Corporation (NYSE:BVF)(TSX:BVF) today announced that it has received an Approval Letter from the United States Food & Drug Administration (FDA) for Tramadol ODT (tramadol hydrochloride), an orally disintegrating tablet version of the analgesic medication tramadol hydrochloride in 50mg dosage format, intended for the treatment of moderate to moderately severe pain in adults.

In March, Biovail filed a Complete Response to address routine matters raised in the Approvable Letter received from the FDA in early January. More specifically, these matters involved the resolution of labeling issues only, including, but not limited to, resolution of final packaging, content and format for the product's blister card and carton.

Significant Milestone

The approval of Tramadol ODT is the first milestone in Biovail's development of a franchise of pain medications. The Company received an Approvable Letter for its New Drug Application for a once-daily extended-release formulation of tramadol HCl in October 2004.

"Patients may benefit from the convenience of Tramadol in an orally disintegrating dosage format - particularly those who have difficulty swallowing tablets, or those who may not, or do not, always have access to water," said Biovail Chief Executive Officer Dr. Douglas Squires. "The approval of Tramadol ODT is a further establishment of Biovail's patented oral disintegrating tablet technologies, such as FlashDose and Flashtab, and their application to making medicines more acceptable and convenient for patients."

A 2004 study of the American population concluded that nearly 40% of adults have experienced problems with swallowing tablets - and a significant proportion of those fail to comply properly with their prescribed and ongoing dosage. Conditions such as post-procedural pain with swelling, associated with swallowing impairment, that require acute analgesic treatment, will benefit from the immediate orally dissolving tablet form.

Market Opportunity

Biovail believes a considerable market opportunity exists for Tramadol ODT in the United States analgesia market, where sales for the 12 months ended March 30, 2005 were $14.3 billion. Over the same period, tramadol-based products generated revenues of $463.3 million and 19.4 million prescriptions.

To maximize the opportunity presented by Tramadol ODT in the United States, Biovail intends to engage a strategic partner to commercialize the product. At this time, Biovail is in late-stage discussions with potential strategic partners. Under the terms of an agreement with a marketing partner, and subject to regulatory approvals, Biovail anticipates it will manufacture and supply all the partner company's trade and sample supply requirements. At this time, FDA is willing to allow Biovail to choose a trademark when an agreement is reached with a partner, and a final trademark is mutually agreed. Therefore, a trademark is not being announced at this time.

How Tramadol ODT Works

Biovail's Tramadol ODT (tramadol hydrochloride orally disintegrating tablets) is a central acting analgesic in an orally disintegrating formulation using a Flashtab tablet formulation base. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to u-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall profile of tramadol. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two or three hours.

Clinical Highlights

According to labeling derived from its reference listed drug, Ultram, tramadol has been given in single oral doses of 50mg, 75mg and 100mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars). In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50mg and 75mg. A dose of 100mg tramadol tended to provide analgesia superior to codeine sulfate 60mg, but it was not as effective as the combination of aspirin 650mg with codeine phosphate 60mg.

Tramadol has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250mg of tramadol in divided doses were generally comparable to five doses of acetaminophen 300mg with codeine phosphate 30mg daily, five doses of aspirin 325mg with codeine phosphate 30mg daily, or two to three doses of acetaminophen 500mg with oxycodone hydrochloride 5mg daily.

In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily tramadol dose of 200mg (50mg q.i.d.), attained in 50mg increments every three days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only four days or no titration.

Safety Information

Tramadol ODT should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Tramadol ODT is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol ODT may worsen central nervous system and respiratory depression in these patients.

Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking:

-- Selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics),

-- Tricyclic antidepressants, and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or

-- Opioid drugs.

Administration of tramadol may enhance the seizure risk in patients taking:

-- MAO inhibitors,

-- Neuroleptics, or

-- Other drugs that reduce the seizure threshold.

Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure.

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Tramadol ODT.

About Tramadol

Tramadol is a centrally acting synthetic opioid analgesic, effective in the treatment of 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.

Tramadol is currently available under the brand name Ultram(R) (a product of Ortho-McNeil, a division of Johnson and Johnson), and in several generic formulations. Branded and generic formulations of tramadol are indicated for the management of moderate to moderately severe pain, and may be dosed four to six times per day, not to exceed 400mg.

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