Drugs

Orexigen Therapeutics, Inc. (Contrave) Untitled Letter 5/18/2017

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Stacy Hennings
Sr. Director, Regulatory Affairs Advertising & Promotions
Orexigen Therapeutics, Inc.
3344 North Torrey Pines Ct., Ste. 200
La Jolla, CA 92037

RE: NDA 200063
CONTRAVE (naltrexone HCl and bupropion HCl) Extended-Release Tablets
MA 301

Dear Ms. Hennings:

The Office of Prescription Drug Promotion (OPDP) of the U.S. Food and Drug Administration (FDA) has reviewed a Direct-to-Consumer broadcast television advertisement (TV ad) entitled “BRAIN BOR WOMAN’S DAY: 60” (CON-0303) for CONTRAVE (naltrexone HCl and bupropion HCl) Extended-Release Tablets (Contrave) submitted by Orexigen Therapeutics, Inc. (Orexigen) under cover of Form FDA 2253. This TV ad makes false or misleading representations about the risks associated with Contrave. Thus, the TV ad misbrands Contrave within the meaning of the Federal Food, Drug and Cosmetic Act (FD&C Act), and makes its distribution violative. 21 U.S.C. 352(n); 331(a); 321(n). 21 CFR 202.1(e)(1); 202.1(e)(5). This violation is concerning from a public health perspective because it creates a misleading impression about the safety of Contrave.

Background

Below are the indication and summary of the most serious and most common risks associated with the use of Contrave.1 According to the FDA-approved product labeling (PI) (emphasis original):

CONTRAVE is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:

  • 30 kg/m2 or greater (obese) or
  • 27 kg/m2 or greater (overweight) in the presence of at least one weight-related
    comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or
    dyslipidemia).

Limitations of Use:

  • The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established.
  • The safety and effectiveness of CONTRAVE in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

This product is associated with a number of serious risks. The PI for the drug contains boxed warnings regarding suicidal thoughts and behaviors and neuropsychiatric reactions.  Contrave is contraindicated in uncontrolled hypertension, seizure disorder or a history of seizures; use of other bupropion-containing products; bulimia or anorexia nervosa, chronic opioid or opiate agonist or partial agonists use, or acute opiate withdrawal; patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs; concomitant administration of monoamine oxidase inhibitors; known allergy to bupropion, naltrexone or any other component of Contrave; and pregnancy. The PI also contains warnings and precautions regarding seizures, patients receiving opioid analgesics, increase in blood pressure and heart rate, allergic reactions, hepatotoxicity, activation of mania, angle-closure glaucoma, and the potential risk of hypoglycemia in patients with type 2 diabetes on antidiabetic therapy. In addition, the PI indicates that the most common adverse reactions associated with Contrave are nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea.

False or Misleading Risk Presentation

Promotional materials misbrand a drug if they are false or misleading with respect to risk. The determination of whether promotional materials are misleading includes, among other things, not only representations made or suggested in promotional materials, but also failure to reveal facts that are material in light of representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials. 

The TV ad is misleading because it includes efficacy claims for Contrave, but fails to include important risk information associated with the drug. For example, the TV ad includes the statement “Do not take with opioids,” but fails to include any of the other conditions for which Contrave is contraindicated. Additionally, the TV ad includes the statement, “CONTRAVE may increase suicidal thoughts or actions in some children, teens, and young adults within the first few months,” but fails to disclose any information about neuropsychiatric reactions also discussed in the BOXED WARNING section of the PI for Contrave. We note that the TV ad includes the statements, “CONTRAVE is not for everyone” and “Other side effects may occur.” However, this does not mitigate the omission of these important risks from the TV ad.  By omitting serious risks associated with Contrave, the TV ad misleadingly suggests that Contrave is safer than has been demonstrated.

The TV ad is also misleading because it communicates important risk information in the visual portion of the TV ad only, i.e., as SUPERs, and presents unrelated risk information in competing audio messages. For example, the TV ad discloses important risk information regarding the warning and precaution for the potential risk of hypoglycemia in patients with type 2 diabetes only as a SUPER, although, television advertisements shall include information relating to the major side effects and contraindications of the advertised drugs in the audio or audio and visual parts of the presentation. 21 CFR 202.1(e)(1). Additionally, the TV ad discloses important risk information about the contraindication for concomitant opioid use in the audio portion of the proposed TV ad simultaneously with a SUPER containing unrelated risk information about the most common adverse reactions. The overall effect of disclosing important risk information in SUPERs only, along with the simultaneous presentation of SUPERs and competing audio messages, undermines the communication of important risk information and thereby misleadingly minimizes the risks associated with the use of Contrave. The presentation in the video is especially problematic from a public health perspective given the serious and potentially life-threatening risks associated with the drug.

Conclusion and Requested Action

For the reasons discussed above, the TV ad misbrands Contrave within the meaning of the FD&C Act and makes its distribution violative. 21 U.S.C. 352(n); 331(a); 321(n). 21 CFR 202.1(e)(1); 202.1(e)(5).

OPDP requests that Orexigen immediately cease violating the FD&C Act, as discussed above. Please submit a written response to this letter on or before June 2, 2017, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Contrave that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials.

Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Prescription Drug Promotion, 5901-B Ammendale Road, Beltsville, Maryland 20705-1266.  A courtesy copy can be sent by facsimile to (301) 847-8444. To ensure timely delivery of your submissions, please use the full address above and include a prominent directional notation (e.g. a sticker) to indicate that the submission is intended for OPDP. Please refer to MA 301 in addition to the NDA number in all future correspondence relating to this particular matter. All correspondence should include a subject line that clearly identifies the submission as a Response to Untitled Letter. OPDP reminds you that only written communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Contrave comply with each applicable requirement of the FD&C Act and FDA implementing regulations.


Sincerely,

{See appended electronic signature}

Meena Ramachandra, PharmD
Regulatory Review Officer
Division of Advertising & Promotion Review 2
Office of Prescription Drug Promotion

{See appended electronic signature}

Melinda McLawhorn, PharmD, BCPS, RAC
Team Leader
Division of Advertising & Promotion Review 2
Office of Prescription Drug Promotion Division
Reference ID: 4100080
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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
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/s/
----------------------------------------------------
MEENA RAMACHANDRA
05/18/2017
MELINDA W MCLAWHORN
05/18/2017

_____________________________________________________

1 This information is for background purposes only and does not necessarily represent the risk information that should be included in the promotional piece cited in this letter.


Reference ID: 4100080
 

Page Last Updated: 05/23/2017
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