Released by FDA: 7/20/00.  Posted by FDA:  8/2/00

James L. Gaskill, R.Ph.
Associate Director, Regulatory Affairs 
DuPont Pharmaceuticals Company 
Chestnut Run Plaza, MR 2416 
974 Centre Road 
Wilmington, DE 19805

RE:   NDA #20-484 
         Innohep (tinzaparin sodium injection) 
         MACMIS ID #9154

Dear Mr. Gaskill:

This letter concerns the dissemination of promotional labeling and advertising by DuPont Pharmaceuticals Company (“DuPont”) for Innohep (tinzaparin sodium injection).  The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a Press Release for Innohep disseminated on July 18, 2000, as part of its monitoring program, and has concluded that DuPont is disseminating materials that lack fair balance and contain misleading promotional claims in violation of the Federal Food, Drug, and Cosmetic Act and implementing regulations.  A description of our objections follows.

Lack of Fair Balance

The Press Release minimizes the serious risks associated with Innohep therapy by failing to include important risk information contained in the approved product labeling for lnnohep.  Specifically, the boxed and bolded warnings that: “Spinal or epidural hematoma can occur with the associated use of low molecular weight heparins or heparinoids and spinal/epidural anesthesia or spinal puncture which can result in long- term or permanent paralysis.  The risk of these events is higher with the use of post- operative indwelling epidural catheters or with the concomitant use of additional drugs affecting hemostasis such as NSAIDs,” is omitted.  The bolded warning, "Innohep should not be used in patients with a history of heparin-induced thrombocytopenia,” is also omitted, as are the contraindications in “patients with known hypersensitivities to heparin, sulfites, benzyl alcohol, or pork products.”  The Press Release statement that “like other anticoagulants, Innohep should be used with caution in conditions with increased risk of hemorrhage,” is not sufficient to provide the necessary risk information.

Also, the adverse event information that does appear in the Press Release is incomplete and does not fairly balance the promotional claims for Innohep.  Specifically, the most common adverse events of injection site hematomas (16%), and abnormal elevations of AST (8.8%) and ALT (13%) are not included in the press release, nor is the incidence of urinary tract infection (3.7%) or pulmonary embolism/chest pain (2.3%).

Expanded Indication

The statement that “Innohep offers the advantage of being the only once-a-day heparin product for all patients with DVT,” is false or misleading because it suggests that Innohep is indicated for use in all DVT patients, that it is approved for monotherapy, and that it is the only low molecular weight heparin that is administered once-a-day. However,

• the safety and efficacy of Innohep has not been studied in DVT outpatient populations.

• Innohep is not approved as monotherapy for the treatment of DVT patients.  Its only approved used is in conjunction with the administration of warfarin sodium.  The clinical trial that supported the approval of Innohep in DVT patients studied only patients on concomitant warfarin therapy.

• Innohep is not the only low molecular weight heparin (LMWH) that is approved for administration as a once-a-day treatment for DVT patients.

Misrepresentation of Clinical Data

The Press Release is misleading because it misrepresents the significance of clinical data from the double-blind clinical trial used for the basis of approval.  The Press Release states that the total thromboembolic events (DVTs and/or PEs) were 2.8% in the Innohep treatment arm, as compared to 6.8% in the heparin treatment arm, with a thromboembolic event rate difference of 4.0%.  However, the Press Release fails, to also state that the 90-day cumulative thromboembolic (TE) rate [recurrent DVT or PE] with Innohep was not significantly different than the rate with unfractionated heparin.

Requested Action

In order to address these objections, DDMAC requests that DuPont:

1. Immediately ceases further use of these and other materials and practices with the same or similar messages.

2. Provide DDMAC, in writing, with DuPont’s intent to comply with the above.  This response should include a list of all violative promotional materials and DuPont’s methods for discontinuing their use.

DuPont’s response should be received no later than July 31, 2000.  If you have any questions, you should direct them to the undersigned in writing or by facsimile at (301) 594-6759 or at the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, HFD-42, Rm. 17B-20, 5600 Fishers Lane, Rockville, MD 20857.  DDMAC reminds DuPont that only written communications are considered official.  In all future correspondence regarding this particular matter, please refer to MACMIS ID #9154 in addition to the NDA number.

Sincerely,

Patricia Kuker Staub, R.Ph, J.D. 
Regulatory Review Officer 
Division of Drug Marketing, 
    Advertising and Communications