2010 Action Letter - NADA 141-297 ProZinc™ (protamine zinc recombinant human insulin)
November 3, 2010
NADA 141-297 (L0009, L0013, L0015)
Jody R. Farrell, Specialist
Pharmaceutical Regulatory Affairs
Boehringer Ingelheim Vetmedica, Inc.
1411 Oak Street
P.O. Box 338
Elwood, KS 66024
RE: NADA 141-297 ProZinc™ (protamine zinc recombinant human insulin)
Dear Ms. Farrell:
The Center for Veterinary Medicine (CVM) has reviewed the following advertisements for ProZinc™, submitted by Boehringer Ingelheim Vetmedica, Inc.:
- PRO1209001, submitted under cover of form FDA 2301, dated February 22, 2010, and filed as L0009;
- PRO0410001, submitted under cover of form FDA 2301, dated March 5, 2010, and filed as L0013;
- PRO1009006, PRO1009007, PRO1009001, PRO1009009, and PRO1009011, submitted under cover of form FDA 2301, dated November 20, 2009, and filed as L0015; and
- The web site www.ProZinc.us.
Many of these advertisements make false and misleading claims regarding the conditions under which Pro-Zinc™ is effective. Others omit information about risks, and therefore do not present a fair balance of information about effectiveness, side effects and, contraindications. The inclusion of these statements in your firm’s promotional pieces misbrands your product under section 502(n) of the Act [21 U.S.C. § 352(n)] and FDA implementing regulations 21 C.F.R. 202.1(e)(5), (e)(6), and (e)(7).
ProZinc™ is an injectable solution of recombinant human insulin. It has been approved for the reduction of hyperglycemia and hyperglycemia-associated clinical signs in cats with diabetes mellitus. The initial recommended ProZinc dose is 0.1 – 0.3 IU insulin/pound of body weight every 12 hours. The dose should be given concurrently with or right after a meal. The veterinarian should re-evaluate the cat at appropriate intervals and adjust the dose based on both clinical signs and glucose nadirs until adequate glycemic control has been attained. Further adjustments in the dosage may be necessary with changes in the cat’s diet, body weight, or concomitant medication, or if the cat develops concurrent infection, inflammation, neoplasia, or an additional endocrine or other medical disorder.
The advertisements PRO1209001 and PRO1009006 include the statement:
For consistent, round-the-clock control of feline diabetes.
The advertisement PRO1009007 includes the statement:
Delivers round-the-clock glycemic control in diabetic felines.
The advertisement PRO1009001 includes the statements:
Round-the-clock control of feline diabetes is here.
The first FDA-approved long-acting insulin specifically for cats.
The advertisements PRO0410001, PRO1009009, and PRO1009011 include the statements:
Introducing new ProZinc™ (protamine zinc recombinant human insulin), the first FDA-approved long-acting insulin specifically for cats.
Proven to deliver consistent round-the-clock glycemic control, new PROZINC…
The web site http://www.prozinc.us/, as accessed on August 19, 2010, contains the statements:
The only long-acting insulin that’s FDA-approved for use in cats.
It’s time for round-the-clock control of feline diabetes.
False and Misleading Promotional Claims:
The above claims in the ProZinc™ promotional material are misleading because they suggest that ProZinc is better, more effective, or useful in a broader range of conditions than has been demonstrated by substantial evidence or substantial clinical experience. 21 CFR 202.1(e)(6)(i).
Statements referencing round-the-clock control of feline diabetes, or any variation thereof, are misleading because they suggest that a once-a-day injection of ProZinc™ is sufficient to control diabetes in cats for 24 hours. In common usage, “round the clock” means duration of 24 hours.1 This claim conflicts with the approved ProZinc™ labeling, which recommends initial ProZinc™ dose of 0.1 - 0.3 IU insulin/pound of body weight (0.2 - 0.7 IU/kg) to be administered every 12 hours.
The statements characterizing ProZinc™ as “long-acting” insulin are also misleading, particularly in light of the claim that ProZinc™ provides "round the clock control" and in the absence of a number quantifying the onset and duration of the effect. The term “long-acting” provides little direction to a veterinarian or a pet owner and could lead to confusion with the term “long-acting”, as used in human medicine. Long-acting insulin products for use in humans are characterized by the onset of action at 4-6 hours, peak activity at 16-18 hours, and duration of action of 20-36 hours.2 After subcutaneous administration in cats, ProZinc™ peaks at 4-12 hours, time to blood glucose nadir is 1-12 hours, and the duration of action is 8-24 hours.3 Therefore, the use of the term “long-acting” may confuse the cat owners with regard to the duration of action of ProZinc. Additionally, it is false to claim that ProZinc™ is the only long-acting insulin approved for use in cats when another insulin product, approved for use in cats, Intervet/Schering-Plough’s Vetsulin (New Animal Drug Application 141-236), has the same twice-a-day dosing recommendation as ProZinc™ and both products are effective when administered every 12 hours. It is also inaccurate to claim that ProZinc™ is the first long-acting insulin approved for use in cats. ProZinc™ was approved on October 28, 2009, while Vetsulin, with the same twice-a-day dosing, was approved on April 01, 2004, for use in cats as well as dogs.
Lack of Fair Balance:
Advertisements for prescription drugs must contain a true statement of information in brief summary relating to side effects, contraindications, and effectiveness. 21 CFR 202.1(e)(1). An advertisement does not satisfy this requirement if it fails to present a fair balance between information relating to side effects and contraindications and information relating to effectiveness of the drug…." 21 CFR 202.1(e)(5). The advertisements PRO1209001, PRO0110002, and PRO0110004 provided information relating to effectiveness while omitting User Safety Warnings, information relating to side effects and contraindications.
The approved drug labeling lists Warnings: User Safety: For use in cats only. Keep out of the reach of children. Avoid contact with eyes. In case of contact, immediately flush eyes with running water for ate least 15 minutes. Accidental injection may cause hypoglycemia. In case of accidental injection, seek medical attention immediately. Exposure to product may induce a local or systemic allergic reaction in sensitized individuals.
The labeling further states Contraindications: ProZinc insulin is contraindicated in cats sensitive to protamine zinc recombinant human insulin or any other ingredients in the ProZinc product. ProZinc insulin is contraindicated during episodes of hypoglycemia.
The Cat Owner Information sheet states that serious side effects can occur with or without warning. Please contact your veterinarian immediately if you think your cat has a medical problem or side effect from ProZinc therapy. The most common insulin-related side effect is low blood glucose (hypoglycemia). Signs of hypoglycemia may occur suddenly and can include: weakness, depression, lethargy, sluggishness, staggering gait, behavioral changes, muscle twitching, seizures, coma, and death.
In presenting a fair balance between information about effectiveness and information about risk, the ads should list the User Safety Warnings, as stated on the approved drug labeling, as well as animal safety concerns, such as the risk of hypoglycemia and how to mitigate this risk.
Conclusion and Requested Actions:
The false and misleading claims and lack of fair balance in advertisements for ProZinc™ cause the drug to be misbranded within the meaning of section 502(n) of the Act and the implementing regulations at 21 C.F.R. § 202.1(e).
CVM requests that Boehringer Ingelheim Vetmedica, Inc. immediately cease the dissemination of the violative advertisements for ProZinc™ described above. Future promotional labeling and advertisements, including those on internet sites, should accurately represent the facts regarding the approved indications for use of ProZinc™ in cats and should not make misleading claims or lack fair balance. 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-210, 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 ProZinc™, as well as other Boehringer Ingelheim Vetmedica Inc. 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 141-297.
/s/ Lynn O. Post, D.V.M., PhD, DABVT
Director, Division of Surveillance
Center for Veterinary Medicine
J. Martin Carroll,
President and CEO
Boehringer Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Road
P.O. Box 368
Ridgefield, CT 06877-0368
1See, e.g., the following dictionary definitions of “round the clock”: “continuously for 24 hours: day and night without cessation,” Merriam Webster Online, http://www.merriam-webster.com/dictionary/round%20the%20clock; “throughout the day and night; without interruption,” Webster's New World College Dictionary, http://www.yourdictionary.com/round-the-clock; and “lasting or continuing throughout the entire 24 hours of the day; continuous,” The American Heritage® Dictionary of the English Language, http://www.yourdictionary.com/round-the-clock., all accessed on July 22, 2010.
2Brunton, L, Blumenthal, D, Buxton, I, Parker, K eds. 11th ed., Goodman & Gilman's Manual of Pharmacology and Therapeutics. New York: McGraw Hill; 2007.
3R.W. Nelson, K. Henley, C. Cole, and the PZIR Clinical Study GroupField Safety and Efficacy of Protamine Zinc Recombinant Human Insulin for Treatment of Diabetes Mellitus in Cats. J Vet Int Med 2009, 23; 787-793