Apotex' U.S. subsidiary Torpharm will run an advertisement in the August issue of the Journal of the American Medical Association referencing its safety education program for the first generic version of ticlopidine (Roche's Ticlid). Torpharm's ticlopidine cleared FDA July 1 with a therapeutically equivalent "AB" rating.

In addition to the journal ad, Torpharm plans to reach health care professionals through direct mailing efforts, the publication of a journal article and on-line continuing educational information.

Torpharm parent Apotex posted a continuing education program on its website July 1, featuring a paper on "Stroke Prevention: Antiplatelet Therapy" by Metta Lou Henderson, PhD, which was developed exclusively for Torpharm.

The CME paper discusses various stroke therapies and specifically refers to the hematological side effects of ticlopidine and the necessity to monitor patients every two weeks.

To gain marketing approval, Torpharm committed to implementing a post-approval educational program based on a standard template developed by FDA for generic ticlopidine products.

FDA's template for the educational program requires generic ticlopidine marketers to mount an "adequate educational campaign" targeting physicians who prescribe ticlopidine and nurse practitioners, physician assistants, and dispensing pharmacists "who are in a position...to educate patients and/or monitor compliance."

The substantive elements of the campaign include "a clear statement that ticlopidine is approved for use only in patients who are intolerant or allergic to aspirin therapy or who have failed aspirin therapy," a discussion of the risks of ticlopidine therapy such as neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura and aplastic anemia, and how monitoring can prevent them.

Companies must also provide information delineating a schedule for blood and clinical monitoring in the first three months of treatment and a statement reinforcing the need to report observed serious and fatal adverse events to FDA's MedWatch program.

In November, Roche petitioned FDA to require all generic ticlopidine manufacturers to implement a postmarketing safety program identical to Roche's efforts (¹ Also see "Ticlopidine Generics Postmarketing Safety Program Being Considered By FDA" - Pink Sheet, 17 May, 1999.).

Roche labeling currently has a section on "Important Information About Ticlid" which addresses the risk of TTP and severe neutropenia. The section also outlines blood monitoring procedures and informs patients that a "doctor will arrange for you to have your blood tested before you start taking Ticlid and then every two weeks for the first three months you are on Ticlid."

Torpharm is not required to provide blood monitoring to ticlopidine patients free of charge, as Roche has done as part of its safety program for Ticlid. There is no comparable section in generic ticlopidine labeling to Roche's "Important Information About Ticlid" section.

In a June 15 response to Roche's November citizen's petition, FDA stated "the agency believes that a sound education program can enhance the safety of a product such as ticlopidine [and]...therefore intends to strongly encourage all sponsors, including Roche, to maintain well-designed educational programs and to submit these programs to the agency for pre-market review."

FDA maintained in its response to Roche, however, that monitoring commitments are no longer necessary and generic applicants will not be required to implement monitoring programs. The agency added that Roche will be relieved of the commitment as well.

Since Ticlid has been on the market for seven years, FDA said it "expects physicians to provide [complete blood monitoring] as part of their routine medical practice pursuant to physician labeling."

"The CBC free service that was a component of Roche's commitment, at the time of approval...is no longer needed to help collect data on the incidence of neutropenia and we have no evidence that the modest cost of a CBC test is an impediment to appropriate monitoring," FDA said.

In a Jan. 14 letter to FDA, Roche reiterated its position "regarding the necessity of requiring a postmarketing safety program in connection with the sale and marketing of all forms of ticlopidine."

Roche added in its follow-up letter that despite FDA's efforts to inform all ANDA applicants in October that Roche had agreed to collaborate on the development of postmarketing safety programs, only one out of nine ANDA applicants, Purepac, had contacted Roche. Purepac placed an initial call, Roche said, but did not follow up.

Ticlopidine ANDAs from Purepac, Genpharm, and Teva have been tentatively approved by FDA. Those ANDAs were issued tentative approvals before FDA decided to require a postmarketing educational program.

Torpharm's ANDA and those of Invamed and Mylan were designated "approvable" in April and May, the first such designation for a generic product, while FDA was deciding what kind of postmarketing educational and monitoring program the agency would require. Granutec and Andrx have ANDAs pending for ticlopidine at FDA.

The tentatively approved ticlopidines may not be approved until Torpharm's 180-day marketing exclusivity expires under FDA's first-to-file ANDA guidelines.

Roche's Ticlid patent does not expire until 2003, however, no patent infringement suit was filed against Torpharm. In fact, in May 1998, Roche wrote to FDA in support of Torpharm's exclusivity rights.

A suit filed by Teva arguing that Roche's decision not to sue started the time clock on Torpharm's exclusivity period and the 180 days have elapsed was dismissed by D.C. federal court in January. Teva is appealing the decision.

In a Jan. 6 letter to FDA, Teva also maintained that Roche's safety program for Ticlid is promotional rather than educational (² Also see "Roche Ticlid Safety Program Is Promotional, Not Educational, Teva Asserts" - Pink Sheet, 25 January, 1999.).

Torpharm Ticlopidine Ad To Run In August JAMA; Educational Materials Cited

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