Animal & Veterinary

2010 Action Letter - NADA 113-645 Estrumate® (cloprostenol sodium) Injectable Solution

September 16, 2010

NADA 113-645 (L0014, L0116)

S. Lee Whaley, MS
Director, Regulatory Affairs
Intervet/Schering-Plough Animal Health
556 Morris Avenue
Summit, NJ 07901

RE: NADA 113-645 Estrumate® (cloprostenol sodium) Injectable Solution

Dear Mr. Whaley:

The Center for Veterinary Medicine (CVM) has reviewed your websites, http://www.estrumate.comdisclaimer icon; http://www.estrumate.com/product_information.htmldisclaimer icon; http://www.intervetusa.com//products/130_163306/productdetails_130_163568.aspxdisclaimer icon; and http://www.estrumate.com/treatment_studies.htmldisclaimer icon. We have also reviewed the promotional pieces BV-EST-38153 and SPAH-EST-104A, which were distributed at the Annual Conference of the American Society of Theriogenologists, held from August 31 – September 3, 2010, in Seattle, WA; SPAH-EST-48B and 7/09-37822 O&B Estrumate-sw-36930, which were distributed at the 42nd Annual Convention of the American Association of Bovine Practitioners, September 10-12, 2009, in Omaha, Nebraska; and SPAH-EST-125, which was submitted by Schering-Plough Animal Health under cover of form FDA 2301 dated August 5, 2008, and distributed at the Annual Conference of the American Society of Theriogenologists, August 25-29, 2009, in Albuquerque, NM.

Through these websites and other promotional materials, you are promoting Estrumate® for new intended uses that are not the subject of an approved new animal drug application (NADA). When promoted for these new unapproved uses, Estrumate® is unsafe within the meaning of section 512(a) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 360b(a)] and thus adulterated within the meaning of section 501(a)(5) of the Act [21 U.S.C. § 351(a)(5)]. Furthermore, you make superiority claims in comparison with a competitor’s product that are misleading because they suggest that Estrumate® is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The inclusion of these statements in your firm’s promotional pieces also misbrands your product under sections 502(a) and 502(n) of the Act [21 U.S.C. §§ 352(a), 352(n)] and FDA implementing regulations. Cf. 21 CFR § 202.1(e)(6)(i), (ii), (vii), and (x).

Background

Estrumate® Injectable Solution is a synthetic prostaglandin F2α analogue with luteolytic activity. The approved labeling contains the following indications for cattle:

  • For intramuscular use to induce luteolysis in beef and dairy cattle. The luteolytic action of Estrumate can be utilized to manipulate the estrous cycle to better fit certain management practices, to terminate pregnancies resulting from mismatings, and to treat certain conditions associated with prolonged luteal function.

In addition, the approved labeling includes the following recommended uses:

  • Unobserved or nondetected estrus
  • Pyometra or Chronic Endometritis
  • Mummified Fetus
  • Luteal Cysts
  • Pregnancies from Mismating
  • Controlled Breeding

Your product Estrumate® is a drug as that term is defined by section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(g)(1) because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to affect the structure or any function of the body of man or animals. Moreover, this product is also a new animal drug, as defined by section 201(v) of the Act, 21 U.S.C. § 321(v), because it is not generally recognized as safe and effective for its labeled uses.

Unapproved Claims

Your website http://www.estrumate.com/treatment_studies.htmldisclaimer icon includes the statement:

- For best results, use ESTRUMATE prostaglandin to treat Metritis and Endometritis, and for your Presynch protocol.

This statement suggests that Estrumate® is effective in treating metritis, as well as endometritis. The same claim is found in the promotional piece SPAH-EST-125, which is titled, Treating Metritis and Endometritis. The effectiveness of Estrumate® for treatment of metritis has not been evaluated by the FDA; metritis is a new and unapproved indication of the drug. Estrumate® is approved for the treatment of pyometra. Pyometra is also referred to as chronic endometritis, but it should not be confused with metritis. In metritis, deeper layers of the uterine wall are affected, including the smooth muscle, while pyometra is generally confined to the endometrium, the superficial layer. Metritis usually has acute onset and the affected animals are depressed, febrile, and inappetent, while pyometra has a chronic progression and the affected animals may not exhibit systemic signs of illness. Therefore, metritis in cows is not only different, but also more severe disease than pyometra.

Furthermore, the reference on www.estrumate.com/treatment_studies.htmldisclaimer icon and in the promotional piece SPAH-EST-125 to using Estrumate® “for your Presynch protocol” suggests using the drug in a specific estrus synchronization protocol. Similarly, “testimonials” found on the website also mention Estrumate® in a context of Ovsynch, a specific estrus-synchronization protocol. These protocols recommend using cloprostenol in addition to gonadorelin. Estrumate® has not been approved for use in combination with gonadorelin or any other drug. Promotion of Estrumate® for these uses constitutes promotion of Estrumate® for new intended uses that are unapproved.

Unsubstantiated Claims of Effectiveness

The Estrumate® web sites http://www.intervetusa.com//products/130_163306/productdetails_130_163568.aspxdisclaimer icon, http://www.estrumate.com/treatment_studies.htmldisclaimer icon, and http://www.estrumate.com/product_information.htmldisclaimer icon make various superiority claims in comparison with natural prostaglandin products that have not been demonstrated by substantial evidence or substantial clinical experience. For example, CVM is not aware of peer-reviewed, head-to-head studies demonstrating the superiority of one product over another with regard to the approved claims. The published body of evidence contains conflicting studies of Estrumate®, with some studies finding that one or the other product is superior and others finding no difference between the drugs. Thus, the evidence does not establish the superiority of Estrumate®. In addition, you cite studies that show differences between Estrumate® and other drugs, but those studies do not show that the differences result in greater clinical effectiveness. These studies do not provide substantial evidence of Estrumate®’s superiority and the references to them are misleading.

For instance, the website http://www.estrumate.com/treatment_studies.htmldisclaimer icon presents a table adapted from the publication by Hirsbrunner et al., 1998, which demonstrates that Estrumate® is more potent than natural prostaglandin in increasing intrauterine pressure and uterine motility during diestrus in experimental cows. Hence, the table in your advertising may suggest to a reader that Estrumate® is a superior product as compared to competitors’ products. However, the study was performed on healthy animals and the endpoints of that study were intrauterine pressure and uterine motility. These are only surrogate endpoints in relation to the approved indications, not necessarily having clinical significance with regard to the approved indications. As the authors of the cited study noted this in the last sentence of the Discussion section of the article: in order to evaluate the effects of diverse formulations of prostaglandins on intrauterine motility of cows with exudative endometritis or pyometra, further investigation using affected cows is indicated.

In addition, the web site http://www.estrumate.com/product_information.htmldisclaimer icon states the following, citing two 1997 EMEA reports, entitled “Cloporostenol and R-Cloporostenol” and “Dinoprost,” as support:

- Half-life for Estrumate prostaglandin is 3 hours versus a few minutes for Lutalyse
- Estrumate prostaglandin lasts much longer than Lutalyse

The Cloporostenol and R-Cloporostenol report states that the half-life of Estrumate® is 1 hour and 37 minutes in cows, and 3 hours and 10 minutes in swine.1 Because Estrumate® is approved for use in cattle only, the half-life values associated with swine are not relevant and serve to exaggerate the difference between Estrumate® vs. Lutalyse for treatment of cattle. Moreover, the website does not provide evidence that prolonged half-life is associated with greater effectiveness of prostaglandin. Therefore the website suggests superiority of Estrumate® based on the prolonged half-life, citing scientific evidence that does not support the claim that the prolonged half-life is associated with clinical effectiveness. Similar claims are posted on the website http://www.intervetusa.com//products/130_163306/productdetails_130_163568.aspxdisclaimer icon.

Furthermore, your websites http://www.intervetusa.com//products/130_163306/productdetails_130_163568.aspxdisclaimer icon and www.estrumate.com/product_information.htmldisclaimer icon also state that:

- ESTRUMATE prostaglandin is a more potent luteolytic agent than Lutalyse

To support this claim, the websites cite a 2003 study by Martineau2 that demonstrated a trend in which cows treated with cloprostenol had higher conception rates and pregnancy rates when compared with cows treated with dinoprost. However, this study was designed to compare different routes of administration and not to compare the effectiveness of the drug, as clearly stated in the title. This study did not find any statistical difference in effectiveness between the two drugs.

Moreover, the promotional pieces BV-EST-38153, SPAH-EST-104A, SPAH-EST-125, SPAH-EST-48B, and 7/09-37822 O&B Estrumate-sw-36930 include unsubstantiated claims of effectiveness similar to those on your websites. For example, SPAH-EST-104A includes following:

- Half-Life for ESTRUMATE Prostaglandin is 3 Hours Versus a Few Minutes for Lutalyse
- Estrumate Prostaglandin Lasts Much Longer Than Lutalyse
- Estrumate Prostaglandin is a More Potent Luteolytic Agency than Lutalyse

Your use of these unsubstantiated superiority claims in your promotional materials misbrands Estrumate® within the meaning of sections 502(a) and 502(n) of the Act and the implementing regulations at 21 CFR 202.1(e)(6)(i), (ii), (vii) and (x).

Conclusion and Requested Actions

As described above, the unapproved claims on your websites and in your other promotional materials cause Estrumate® to be unsafe within the meaning of section 512(a) of the Act, 21 U.S.C. 360b(a), and adulterated within the meaning of section 501(a)(5) of the Act, 21 U.S.C. § 351(a)(5). In addition, the unsubstantiated claims on your websites and in your other promotional pieces which suggest that Estrumate® is more effective than other prostaglandin products are misleading and therefore cause your drug to be misbranded within the meaning of sections 502(n) and 502(a) of the Act, 21 U.S.C. 352(n) and 352(a).

CVM requests that Intervet/Schering-Plough Animal Health immediately cease the dissemination of violative materials for Estrumate® such as those described above. Future promotional labeling and advertisements, including those on internet sites and in convention materials, should accurately represent the facts regarding the approved indications for use of Estrumate® in cattle and should not suggest that the product is more effective than has been demonstrated by substantial evidence or substantial clinical experience. Please submit a written response within thirty (30) days of receipt of this letter describing your intent to comply with this request. Please direct your response to me at the Food and Drug Administration, Division of Surveillance, HFV-216, 7519 Standish Place, Rockville, MD 20855. We remind you that only written communications are official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to see that the promotional materials for Estrumate®, as well as other Intervet/Schering-Plough Animal Health products, comply with the requirements of the Act and FDA implementing regulations.

If you have any questions, please contact me at the address above, or call me at (240) 276-9061. All future written correspondence regarding this matter should reference our file number NADA 113-645.

Sincerely yours,

/s/ Lynn O. Post, D.V.M., PhD, DABVT
Director, Division of Surveillance
Center for Veterinary Medicine

cc:
Fred Hassan
Chairman of the Board and Chief Executive Officer
Schering-Plough Corporation
2000 Galloping Hill Road
Kenilworth, N.J. 07033-0530

1EMEA, The European Agency for the Evaluation of Medicinal Products. "Cloprostenol and R-Cloprostenol." Summary Report, April 1997. "Dinoprost." Summary Report, June 1997.
2Martineau, R. "Dinoprost Versus Cloprostenol: Does Route of Injection Modulate Their Efficacy in Dairy Cattle?" The Bovine Practitioner, pp. 10-19, February 2003.

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