Ultram Generic Approval For Acute Pain Would Avoid Protected Label – Teva

Teva is seeking approval for a generic version of Johnson & Johnson's Ultram (tramadol) only for acute pain in order to circumvent the brand's patent-protected titration schedule.

"By only seeking approval of the non-exclusive, non-titration dosed use of tramadol in treating patients with acute pain, Teva's product is, by definition, equally safe as Ultram for that use," Teva's April 30 citizen petition maintains.

Approving the generic without a chronic pain indication and its attendant titration dosing would be analogous to FDA's standard practice of approving generics that omit an indication to which a brand name firm has exclusivity, Teva argued.

"Teva's tramadol is safe for use under the conditions prescribed, recommended or suggested in its proposed labeling," the petition states.

Teva acknowledged that Ultram labeling does not specify a distinct use for "acute" pain. Ultram is indicated for "the management of moderate to moderately severe pain in adults," labeling states.

"The Dosage & Administration section uses the grammatically inelegant phrase 'for the subset of patients for whom rapid onset analgesic effect is required...for pain relief,' and does not explicitly use the word 'acute,'" Teva's petition notes.

The "rapid onset" dosing paragraph in Ultram labeling also states that non-titrated dosing should be used in patients "for whom the benefits outweigh the risk of discontinuation." The first part of the dosage section describes the protected titration regimen "for patients with moderate to severe chronic pain."

"In medical terms," Teva argued, "'acute' is the antonym of 'chronic' and is defined in terms of speed of onset of the condition." In Ultram labeling, "reference to pain that requires 'rapid onset of analgesic effect' is clearly shorthand to acute pain."

J&J "appears to have intentionally sought to avoid the use of the word 'acute' in the Ultram labeling in order to protect its marketing strategy for Ultracet ," Teva declared. Ultracet (tramadol/acetaminophen) is indicated for "short-term (five days or less) management of acute pain," labeling states.

Generics for Ultram have been blocked by the titration labeling, which J&J argues is a safety improvement for the product. The titration labeling has exclusivity until June 2003, and J&J has listed a patent on the regimen which would run until 2020.

Apotex has argued that the titration relabeling was not made for safety reasons and therefore its generic version could omit the language and be approved based on the previous, discontinued labeling (¹ (Also see "J&J Ultram Titration Relabeling Should Not Block Generics, Apotex Argues" - Pink Sheet, 19 Nov, 2001.), p. 14).

Teva's petition maintains that FDA "must recognize" that its approach "is completely different than the 'discontinued labeling' approach advocated by other applicants, which would require a determination by FDA that the discontinued 50 mg titration schedule was not withdrawn for safety reasons."

"Teva is submitting this petition at the request of the Office of Chief Counsel in order to give the agency a final administrative opportunity to fulfill its statutory obligation to approve Teva's ANDA."

The petition requests a written reply in 10 business days "either granting immediate final approval, notifying Teva of changes that will allow immediate approval, or explaining in full the agency's reasons for refusing to grant approval." Teva submitted an ANDA amendment with the acute pain labeling Feb. 5.

Apotex recently submitted an opinion by Emory University School of Law professor David Bederman, PhD, which argues that "FDA has the statutory authority - if not the express obligation - to grant ANDAs with variant labeling." FDA is understood to be concerned about its authority to use discontinued labeling for generics (² , p. 24).

Apotex also submitted an analysis by Emory University School of Medicine anesthesiologist Michael Byas-Smith, MD, which notes that the label does not specifically cite a lower incidence of side effects as a result of using the titration schedule.

While the titration regimen lowered the discontinuation rate "in patients with chronic pain who were previously unable to tolerate it due to nausea and/or vomiting," it is unlikely that the same results would have been seen in the general population, Byas-Smith added.