FDA Warning Letter – NorthWestPharmacy.com

Public Health Service
Food and Drug Administration
Silver Spring, MD  20993-0002

TO: CustomerService@NorthWestPharmacy.com
FROM:United States Food and Drug Administration
Center for Drug Evaluation and Research
Office of Compliance
Office of Drug Security, Integrity and Recalls
Division of Supply Chain Integrity
RE:    Internet Marketing of an Unapproved and Misbranded Drug
DATE:     May 24, 2012

WARNING LETTER

The United States Food and Drug Administration (FDA) reviewed your website, www.NorthWestPharmacy.com, on January 4, 2012 and has determined that your website offers products for sale in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). More specifically, the website offers an unapproved and misbranded new drug for sale in violation of sections 502(f) and 505(a) of the FD&C Act [21 U.S.C. §§ 352(f) and 355(a)], which are prohibited acts under sections 301(a) and 301(d) of the FD&C Act [21 U.S.C. §§ 331(a) and 331(d)], respectively. We request that you immediately cease marketing violative drug products to United States consumers.

Unapproved New Drug

Alitretinoin, trade name, Toctino, is offered for sale on your website “to treat severe long-term eczema that affects the hands … for patients who have not found success using other corticosteroid treatments.” Based on this claim, Toctino appears to be a drug within the meaning of section 201(g) of the FD&C Act [21 U.S.C. §321(g)] because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and/or it is intended to affect the structure or function of the body. Moreover, Toctino appears to be a new drug within the meaning of section 201 (p) of the FD&C Act [21 U.S.C. §321(p)] because it is not generally recognized as safe and effective for its labeled use. Although Toctino is approved in Canada, no approved application pursuant to section 505 of the FD&C Act [21 U.S.C. §355] is in effect for this product. Accordingly, its introduction or delivery for introduction into interstate commerce violates section 505(a) of the FD&C Act [21 U.S.C. §355(a)] and is prohibited under section 301(d) of the FD&C Act [21 U.S.C. §331(d)].

Misbranded Drug

Alitretinoin is a retinoid that is potentially dangerous when orally administered due to its teratogenicity. Because of this potential toxicity, its Canadian labeling states that it should be prescribed only by physicians knowledgeable in the use of systemic retinoids and who understand the risks of teratogenicity in females of childbearing potential. In addition, these females are required to have pregnancy tests before, at regular intervals during, and after discontinuation of alitretinoin therapy to exclude pregnancy. Because Toctino is unapproved in the United States, these safety controls are bypassed when alitretinoin is purchased over the Internet by customers in the United States without consultation with and a valid prescription from a physician. This places American patients who use the drug at risk for adverse effects. Thus, Toctino offered for sale on your website is misbranded within the meaning of section 502(f)(1) of the FD&C Act [21 U.S.C. §321(f)(1)] in that the labeling for Toctino fails to bear adequate directions for use. The introduction or delivery for introduction into interstate commerce of a misbranded drug product is a prohibited act under section 301(a) of the FD&C Act [21 U.S.C. §331(a)].

FDA is taking action against your firm because of the inherent risk in buying unapproved and misbranded new drugs. Unapproved new drugs may not have the same assurance of safety, efficacy, and quality as drugs subject to FDA oversight, and such drugs have been found to be contaminated, counterfeit, contain varying amounts of active ingredients, or contain different ingredients altogether. FDA- regulated drugs offer protections that include rigorous scientific standards for new drug approval, labeling review for accuracy and completeness, and manufacturing procedures and testing performed under closely controlled conditions at FDA-registered and inspected facilities. In addition, pharmacies and wholesalers who sell or distribute prescription drugs in the U.S. are licensed by the states. Unapproved new drugs delivered to the American public may not be safe and effective.

This letter is not intended to identify all of the ways in which your activities might be in violation of law. It is your responsibility to ensure that all products marketed by your firm are in compliance with FD&C Act and its implementing regulations. You should take prompt action to correct the violations noted above. Failure to correct these violations promptly may result in FDA regulatory action, including but not limited to, seizure or injunction, without further notice.

Please notify this office in writing within 15 working days of receipt of this letter of any steps you have taken or will take to correct the noted violations and to prevent their recurrence. If the corrective action(s) cannot be completed within 15 working days, state the reason for the delay and the time within which the correction(s) will be completed. Your response should be sent to DrugSupplyChainintegrity@fda.hhs.gov. Please direct any inquiries concerning this letter to Leigh Verbois, Acting Deputy Director for the Division of Supply Chain Integrity at the above address.

Sincerely,

/s/

Thomas Christl, Office Director (Acting)
Office of Drug Security, Integrity and Recalls
Office of Compliance

FDA Warning Letter – Best Price Rx

TO:          Best Price Rx
#501-2906 West Broadway
Vancouver, BC, Canada V6K 208

FROM:     United States Food and Drug Administration
Center for Drug Evaluation and Research
Office of Compliance
Office of Drug Security, Integrity and Recalls
Division of Supply Chain Integrity

RE:           Internet Marketing of an Unapproved and Misbranded Drug

DATE:       May 24, 2012

WARNING LETTER

The United States Food and Drug Administration (FDA) reviewed your website, http://www.bestpricerx.com, on January 31, 2012 and has determined that your website offers products for sale in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). More specifically, the website offers an unapproved and misbranded new drug for sale in violation of sections 502(f) and 505(a) of the FD&C Act [21 U.S.C. §§ 352(f) and 355(a)], which are prohibited acts under sections 301(a) and 301(d) of the FD&C Act [21 U.S.C. §§ 331(a) and 331(d)], respectively. We request that you immediately cease marketing violative drug products to United States consumers.

Unapproved New Drug

Alitretinoin, trade name, Toctino, which you offer for sale on your website is a drug within the meaning of section 201(g) of the FD&C Act [21 U.S.C. §321(g)] because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and/or it is intended to affect the structure or function of the body. Moreover, Toctino appears to be a new drug within the meaning of section 201(p) of the FD&C Act [21 U.S.C. §321(p)] because it is not generally recognized as safe and effective for its labeled use. Although Toctino is approved in Canada, no approved application pursuant to section 505 of the FD&C Act [21 U.S.C. §355) is in effect for this product. Accordingly, its introduction or delivery for introduction into interstate commerce violates section 505(a) of the FD&C Act [21 U.S.C. §355(a)] and is prohibited under section 301(d) of the FD&C Act [21 U.S.C. §331(d)].

Misbranded Drug

Alitretinoin is a retinoid that is potentially dangerous when orally administered due to its teratogenicity. Because of this potential toxicity, its Canadian labeling states that it should be prescribed only by physicians knowledgeable in the use of systemic retinoids and who understand the risks of teratogenicity in females of childbearing potential. In addition, these females are required to have pregnancy tests before, at regular intervals during, and after discontinuation of alitretinoin therapy to exclude pregnancy. Because Toctino is unapproved in the United States, these safety controls are bypassed when alitretinoin is purchased over the Internet by customers in the United States without consultation with and a valid prescription from a physician. This places American patients who use the drug at risk for adverse effects. Thus, Toctino offered for sale on your website is misbranded within the meaning of section 502(f)(1) of the FD&C Act [21 U.S.C. §321(f)(1)] in that the labeling for Toctino fails to bear adequate directions for use. The introduction or delivery for introduction into interstate commerce of a misbranded drug product is a prohibited act under section 301(a) of the FD&C Act [21 U.S.C. §331(a)].

FDA is taking action against your firm because of the inherent risk in buying unapproved and misbranded new drugs. Unapproved new drugs may not have the same assurance of safety, efficacy, and quality as drugs subject to FDA oversight, and such drugs have been found to be contaminated, counterfeit, contain varying amounts of active ingredients, or contain different ingredients altogether. FDA-regulated drugs offer protections that include rigorous scientific standards for new drug approval, labeling review for accuracy and completeness, and manufacturing procedures and testing performed under closely controlled conditions at FDA-registered and inspected facilities. In addition, pharmacies and wholesalers who sell or distribute prescription drugs in the U.S. are licensed by the states. Unapproved new drugs delivered to the American public may not be safe and effective.

This letter is not intended to identify all of the ways in which your activities might be in violation of law. It is your responsibility to ensure that all products marketed by your firm are in compliance with FD&C Act and its implementing regulations. You should take prompt action to correct the violations noted above. Failure to correct these violations promptly may result in FDA regulatory action, including but not limited to, seizure or injunction, without further notice.

Please notify this office in writing within 15 working days of receipt of this letter of any steps you have taken or will take to correct the noted violations and to prevent their recurrence. If the corrective action(s) cannot be completed within 15 working days, state the reason for the delay and the time within which the correction(s) will be completed. Your response should be sent to DrugSupplyChainintegrity@fda.hhs.gov. Please direct any inquiries concerning this letter to Leigh Verbois, Acting Deputy Director for the Division of Supply Chain Integrity at the above address.

Sincerely,

/S/

Thomas Christl, Office Director (Acting)
Office of Drug Security, Integrity and Recalls
Office of Compliance

FDA Issue Warning – Natural Zing, LLC

FEI: 2000030242
WARNING LETTER
CMS # 115549
December 21, 2010
VIA OVERNIGHT MAIL
RETURN RECEIPT REQUESTED
Mr. Jeffery R. Rose, President
Natural Zing, LLC
1851 Florence Road
Mount Airy, MD 21771
Dear Mr. Rose:

The United States Food and Drug Administration (FDA) conducted an inspection of your facility located at 1851 Florence Road, Mount Airy, MD, from April 27-29, 2010, and determined that your firm is a distributor, labeler, and relabeler of foods and dietary supplements and distributes these products in interstate commerce. During the inspection, our investigators collected samples of a number of products bearing the Natural Zing label. FDA collected additional samples of your products in July 2010. FDA also reviewed your website at www.naturalzing.com in December 2010 and has determined that this site is labeling within the meaning of section 201(m) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 321(m)]. Based on our review of your product labels and website, we have determined that your Goji Berries, Mesquite Pod Meal, Milk Thistle Seed Powder, Rice Bran Solubles, Acai Powder, and Yacon Syrup products are in violation of the Act and regulations implementing the food labeling requirements of the Act, which are found in Title 21, Code of Federal Regulations, Part 101 (21 CFR 101). You may find the Act and FDA regulations through links in FDA’s home page at www.fda.gov.

Unapproved New Drugs
FDA reviewed your website www.naturalzing.com in December 2010 and has determined that your Milk Thistle Seed Powder, Rice Bran Solubles, Acai Powder and Yacon Syrup products are promoted for conditions that cause them to be drugs under section 201(g)(1)(B) of the Act [21 U.S.C. § 321(g)(1)(B)]. The therapeutic claims on your website establish that the products are drugs because they are intended for use in the cure, mitigation, treatment, or prevention of disease. The marketing of these products with these claims violates the Act.
Examples of some of the claims observed on your website include:
Milk Thistle Seed Powder (Raw, Organic) 8 oz webpage:
• “Virtually all parts of the plant have been used as both food and medicine at one time or another with no reports of toxicity.”
• “[A] remedy for snake bites. They [milk thistle seeds] are also used as a preventive-antidote to poisoning by death-cap mushroom.”

• “[M]ilk thistle is known for curing jaundice and other liver disorders.”

• “[M]ilk thistle also soothes and moistens the mucous membranes and skin, making it excellent for psoriasis.”
Tocotrienols (Rice Bran Solubles) 1 lb webpage:
• “Other studies indicate a possible role for tocotrienols in protecting against cancer (particularly breast and skin cancer).”
Acai Powder (Raw, Organic Fair-traded) 100 g webpage:
• “Experienced Benefits: Anti-Inflammatory; Antimutagenic; Anti-Bacterial . . .”
Yacon Syrup (Raw, Organic) 8 fl oz, webpage:

• ”[Y]acon . . . safeguards against colon cancer . . . .”

Your products are not generally recognized as safe and effective for the above referenced uses and, therefore, the products are “new drugs” under section 201(p) of the Act [21 U.S.C. § 321(p)]. New drugs may not be legally marketed in the U.S. without prior approval from FDA as described in section 505(a) of the Act [21 U.S.C. § 355(a)]. FDA approves a new drug on the basis of scientific data submitted by a drug sponsor to demonstrate that the drug is safe and effective.
Unauthorized Nutrient Content Claims
Under section 403(r)(1)(A) of the Act [21 U.S.C. § 343(r)(1)(A)], a claim that characterizes the level of a nutrient which is of the type required to be in the labeling of the food must be made in accordance with a regulation promulgated by the Secretary (and, by delegation, FDA) authorizing the use of such a claim. The use of a term not defined by regulation in food labeling to characterize the level of a nutrient misbrands a product under section 403(r)(1)(A) of the Act.
Nutrient content claims that use the defined terms “rich in,” “excellent source,” or “high,” (“superb source” is an unauthorized synonym for “excellent source”) may be used in the labeling of a food only if the food contains 20 percent or more of the daily value (DV) of that nutrient per reference amount customarily consumed (RACC) [21 CFR 101.54(b)(1)].  Such claims may not be made about a nutrient for which there is no established DV. The labels of your Authentic Tibetan Goji Berries and Wildcrafted Mesquite Pod Meal products bear the following claims that must meet the requirements set forth in 21 CFR 101.54(b)(1):
Authentic Tibetan Goji Berries:
• “[Superb source of vitamin A . . . .”
• “[R]ich source of . . . germanium.”
• “[R]ich source of . . . selenium . . . .”
Wildcrafted Mesquite Pod Meal:
• “[R]ich in calcium . . . iron . . . .”
• “[R]ich in . . . lysine.”
• “[R]ich in . . . magnesium, potassium . . . zinc . . . .”
However, these claims are unauthorized nutrient content claims because they do not meet all of the requirements of 21 CFR 101.54(b)(1). Specifically, according to the product label, your Authentic Tibetan Goji Berries product does not contain 20 percent or more of the DV of Vitamin A, and your Wildcrafted Mesquite Pod Meal product does not contain 20 percent or more of the DV of calcium or iron. Further, a DV has not been established for germanium or lysine, so “rich” cannot be used to make a claim about these nutrients. Finally, your Authentic Tibetan Goji Berries product label does not provide information about the amount of selenium in the product, and your Wildcrafted Mesquite Pod Meal product label does not provide information about the amount of magnesium, potassium, or zinc in the product, which makes it impossible to determine whether these products contain a sufficient amount of the DV of these nutrients to make “rich” claims about the nutrients. Because the above nutrient content claims do not meet the requirements set forth in 21 CFR 101.54(b)(1), your Authentic Tibetan Goji Berries and Wildcrafted Mesquite Pod Meal products are misbranded under section 403(r)(1)(A) of the Act.
Your Authentic Tibetan Goji Berries product is further misbranded within the meaning of section 403(r)(1)(A) of the Act because the product label bears a “more” nutrient content claim that is not authorized by regulation. The label of your Authentic Tibetan Goji Berries product bears the following claim: “[M]ore beta carotene than carrots.” FDA has defined the nutrient content claim “more” and its authorized synonyms in 21 CFR 101.54(e).  “More” nutrient content claims may be used on the label or in the labeling of foods to describe the level of nutrients, provided that (1) the food contains at least 10 percent more of the DV for the nutrient per RACC than an appropriate reference food; (2) where the claim is based on nutrients that are added to the food, that the fortification is in accordance with the policy on fortification of foods in 21 CFR 104.20; and (3) the claim bears the required information for relative claims as described in 21 CFR 101.13(j)(2) and 101.54(e)(1)(iii). Beta carotene is a form of Vitamin A. The nutrition facts panel for this product declares the amount of vitamin A as 2% of the DV. Carrots contain approximately 280% of the DV per RACC. Because the label of this product does not indicate that the product contains at least 10 percent more of the DV of Vitamin A per RACC than the reference food, carrots, this claim does not meet the requirements for a “more” claim and misbrands the product.
Other Food Labeling Violations
Your Milk Thistle Seed Powder and Wildcrafted Mesquite Pod Meal products are misbranded under section 403(q)(1) of the Act [21 U.S.C. § 343(q)(1)] because their labels fail to declare the nutrition facts information in accordance with 21 CFR 101.9. Specifically, your Milk Thistle Seed Powder product label fails to declare any nutrition facts information as required by 21 CFR 101.9, and your Wildcrafted Mesquite Pod Meal product label fails to declare trans fat on the nutrition facts information panel as required by 21 CFR 101.9(c)(2)(ii).
Your Milk Thistle Seed Powder product is further misbranded under section 403(e)(1) of the Act [21 U.S.C. § 343(e)(1)] in that the label does not properly declare the statement of your place of business as required by 21 CFR 101.5(d).
The above violations are not meant to be an all-inclusive list of deficiencies in your products and their labeling. It is your responsibility to ensure that all products marked by your firm comply with the Act and its implementing regulations. You should take prompt action to correct these violations. Failure to promptly correct these violations may result in regulatory action, including seizure and/or injunction, without further notice.
Please respond in writing within fifteen (15) working days from your receipt of this letter. Your response should outline the specific things you are doing to correct these violations. You should include in your response documentation such as copies of the new labels for the products that your firm manufactures and distributes, or other useful information that would assist us in evaluating your corrections.  If you cannot complete all corrections before you respond, you should explain the reason for your delay and state when you will correct any remaining violations.
Please send your reply to the U.S. Food and Drug Administration, Attention: Anne Aberdeen, Compliance Officer, 6000 Metro Drive, Suite 101, Baltimore, MD 21215. If you have questions regarding any issues in this letter, please contact Ms. Aberdeen at (410) 779-5134.
Sincerely,
/S/
Evelyn Bonnin
District Director
Baltimore District

CanadaDrugs.com FDA Express Safety Concerns

Department of Health and Human Services

Public Health Service
Food and Drug Administration
Rockville MD 20857

March 31, 2004

Via Fax: (603) 271-7630

The Honorable Craig Benson
The Governor of New Hampshire
Office of the Governor
107 North Main Street
Room 208
Concord, New Hampshire 03301

Dear Governor Benson:

It has come to our attention that you may endorse the purchase by citizens of New Hampshire of unapproved, illegal drugs from a foreign pharmacy, specifically CanadaDrugs.com of Winnipeg, Manitoba. We are writing to express our concern over this possibility. We strongly believe that the endorsement by a public official such as yourself would undermine one of our nation’s key consumer protection statutes and place your constituents at unnecessary risk of harm from unregulated pharmaceuticals.

As you may know, sixty-five years ago Congress enacted the Food, Drug, and Cosmetic Act to create a strong drug regulatory system requiring that drugs be carefully tested before marketing, produced under exacting standards overseen by the Food and Drug Administration, and dispensed by state-licensed pharmacies and pharmacists. That regulatory system has enabled our citizens to have the safest, most advanced drug supply in the world, and every day in this country millions of patients are successfully treated by safe and effective medications. Drugs made or distributed in other countries, including Canada, are not necessarily subject to our strict regulatory standards, and we have no way to assure that drugs imported from such places are safe and effective. FDA has, therefore, been vigilant in protecting unknowing patients from those who would lure our citizens to buy unproven, unregulated drugs from foreign countries.

The drugs that your citizens will purchase from the Canadian pharmacies to which you refer them will clearly be illegal in virtually all instances. However, our concerns are far greater than that. Indeed, the report to your Health and Human Services Director arising from a visit to a Canadian pharmacy that was found to be “acceptable” is telling. For example,

  • The “inspection” of CanadaDrugs.com was apparently carried out by a Department of Corrections employee and by an employee of a chain drugs store in New Hampshire, not by trained, experienced inspectors from your Board of Pharmacy.
  • The inspectors’ report noted their apparent satisfaction that CanadaDrugs.com was accredited by the Internet and Mail order Pharmacy Accreditation Commission, a voluntary “accrediting” body with no legal standing and no Federal or State regulatory or enforcement authority. Nor would FDA or the National Association of Boards of Pharmacy endorse such a program.
  • The visit determined that CanadaDrugs.com has no malpractice insurance. But then, perhaps they need none, as their “terms of service” require the patient to sign a statement that “CanadaDrugs.com will not be liable for damages arising from personal injury or death” from the use of drugs sold by that business. Since New Hampshire citizens sent to Canadadrugs.com will apparently have no recourse from the dispensing pharmacy if injured by such drugs, who will accept responsibility for any injuries arising from use of the unapproved, illegal drugs marketed by CanadaDrugs.com?
  • The drugs that your citizens will purchase from any foreign pharmacies that you designate have not been manufactured, shipped or held within the oversight of the FDA, and Canadian drug regulators have said repeatedly that they will not assure that drugs exported from Canada meet American safety requirements. So you would be sending your citizens to buy drugs whose assurance of safety might come only from the commercial operators that profit from those sales, since CanadaDrugs.com disclaims any safety assurance.
  • Despite the fact that New Hampshire law does not permit a pharmacy in New Hampshire from accepting a prescription faxed by a patient, you are apparently considering recommending that such faxes be accepted by Canadian pharmacies selling drugs to your citizens.
  • Although generic versions of brand name drugs are usually less expensive in the United States, your “program” would apparently encourage the sale of Canadian generic drugs to your citizens. And your “inspectors” report notes that many of the Canadian generics are not approved for sale in the United States, and thus cannot be FDA-approved, U.S.-manufactured drugs. This is further acknowledgement of the intention to encourage the sale of illegal, unapproved drugs that will cost your citizens more than they would pay at a legitimate, New Hampshire-licensed pharmacy.

There are many other ways that the state could pursue providing affordable, but safe, medications to your citizens, and we would welcome the opportunity to explain our thinking on that. We and others in the Federal government are ready to work with you to implement these approaches for the people of New Hampshire. These approaches include: promoting access to FDA-approved generic drugs, which are proven safe and effective, account for the majority of prescriptions filled in the U.S., and generally cost less than the generic drugs sold in Canada; disease management programs to help educate patients and practitioners about low cost ways to meet medical needs; and implementation of the new Medicare Drug Discount Program, which will become effective in June and will enable seniors who lack medical coverage to obtain medicines at reduced prices. Please contact me if you would like to discuss these further and we will be pleased to arrange a meeting.

Meanwhile, you should also know that we are working diligently to respond to our mandate from Congress to assess whether and how foreign drugs could be imported while providing assurances of their safety and effectiveness. Surgeon General Richard Carmona is chairing a Task Force on Importation, which was created by the Secretary of Health and Human Services (HHS), to advise and assist HHS in determining how drug importation might be conducted safely and its potential impact, positive and negative, on the health of American patients, medical costs and the development of new medicines. The task force intends to consider the public health questions posed by Congress in a way that is fair, public, and evidence-based. Indeed, the Surgeon General has begun a series of meetings with the various stakeholders in this important area, and we hope that you will provide your advice to the task force as it conducts its work.

We would be happy to discuss our concerns further with you at your convenience.

Sincerely,
William K. Hubbard
Associate Commissioner for Policy
and Planning

AMAG Pharmaceuticals, Inc -GastroMARK

TRANSMITTED BY FACSIMILE
Brian J.G. Pereira, MD
President and Chief Executive Officer
AMAG Pharmaceuticals, Inc.
100 Hayden Avenue
Lexington, MA 02421
RE: NDA 020410, 022180
GastroMARK® (ferumoxsil, oral suspension)
Feraheme™ (ferumoxytol) Injection For Intravenous (IV) use
MACMIS #18355
WARNING LETTER
Dear Dr. Pereira:
As part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has reviewed AMAG Pharmaceuticals, Inc.’s (AMAG) webpages for its drug products, GastroMARK® (ferumoxsil, oral suspension) (GastroMARK)1 and Feraheme™ (ferumoxytol) Injection For Intravenous (IV) use (Feraheme).2 Both the GastroMARK and Feraheme webpages omit risks associated with the drug products; in addition, the GastroMARK webpage omits important information about the approved indication for GastroMARK, and both webpages misleadingly suggest unapproved new uses for the drugs. Thus, the webpages misbrand the drugs in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a),(f)(1) & (n); 321(n), and FDA’s implementing regulations. See 21 CFR 201.100(c)(1); 201.128; 202.1(e)(3)(i);(e)(5) & (e)(6)(i).

Furthermore, AMAG failed to submit a copy of the GastroMARK and Feraheme webpages to FDA under cover of Form FDA-2253 at the time of their initial publication, as required by 21 CFR 314.81(b)(3)(i).
These violations are concerning from a public health perspective because they suggest that GastroMARK is useful in a broader range of patients and conditions than has been demonstrated by substantial evidence or substantial clinical experience, and that GastroMARK and Feraheme are safer than has been demonstrated by substantial evidence or substantial clinical experience.

Background
GastroMARK
According to its FDA-approved product labeling (PI), GastroMARK is indicated as follows:
GastroMARK is indicated in adult patients for oral use with magnetic resonance imaging to enhance the delineation of the bowel to distinguish it from organs and tissues that are adjacent to the upper regions of the gastrointestinal tract.
GastroMARK’s usefulness in the lower gastrointestinal tract and retroperitoneal region is limited (by transit time and dilution).
GastroMARK is not recommended for iron supplementation.
GastroMARK is contraindicated in patients with known or suspected intestinal perforation or obstruction, and in patients with known allergy to its active or inactive ingredients.
The PI for GastroMARK includes the following Warnings:
The ingestion of GastroMARK may cause abdominal pain, diarrhea, nausea and vomiting. In 78/256 (30%) of patients and normal volunteers, gastrointestinal adverse events occurred within the first 2 hours after ingestion of GastroMARK. In 30 (12%), gastrointestinal events had their onset within 30 minutes. In 63/256 (24%), diarrhea occurred within 24 hours.
Vomiting can be associated with aspiration. Precautions should be taken to avoid aspiration.
The effects of GastroMARK on human peritoneal tissues are not known. In animal studies, intraperitoneal injection of GastroMARK was associated with a foreign body reaction that persisted for at least 30 days.
Additionally, the PI contains numerous Precautions, including the possibility of increased severity of nausea, vomiting, diarrhea, and abdominal cramping in patients who have these symptoms prior to GastroMARK administration; “This could confound the ability to distinguish adverse effects of GastroMARK from the signs and symptoms of obstruction or perforation, and from the pre-existing conditions.” In addition, studies have not been conducted in patients who have a current or recent history of hiatal hernia, esophageal reflux, nausea, vomiting, or abdominal pain; or to describe the effects of drugs that increase or decrease gastrointestinal transit time on the GastroMARK image quality or gastrointestinal adverse events. GastroMARK should be given with caution to patients who cannot tolerate large fluid shifts, who are on specific fluid intake requirements, and who have disorders associated with iron overload (e.g., hemosiderosis, chronic hemolytic anemia with frequent blood transfusions, or chronic iron replacement). Furthermore, the safety of GastroMARK in patients with inflammatory bowel disease has not been well studied.
Feraheme
According to its PI, “Feraheme™ (ferumoxytol) Injection is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD).”
Feraheme is contraindicated in patients with evidence of iron overload, known hypersensitivity to Feraheme or any of its components, and anemia not caused by iron deficiency.
Feraheme is associated with other serious risks. The PI includes Warnings and Precautions regarding the following (emphasis in original):
. . . HYPERSENSITIVITY REACTIONS
Feraheme may cause serious hypersensitivity reactions, including anaphylaxis and/or anaphylactoid reactions. In clinical studies, serious hypersensitivity reactions were reported in 0.2% (3/1,726) of subjects receiving Feraheme. Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1,726) of these subjects. Observe patients for signs and symptoms of hypersensitivity for at least 30 minutes following Feraheme injection and only administer the drug when personnel and therapies are readily available for the treatment of hypersensitivity reactions. . . .
. . . HYPOTENSION
Hypotension may follow Feraheme administration. In clinical studies, hypotension was reported in 1.9% (33/1,726) of subjects, including three patients with serious hypotensive reactions. Monitor patients for signs and symptoms of hypotension following Feraheme administration. . . .
. . . IRON OVERLOAD
Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Regularly monitor the hematologic response during parenteral iron therapy. . .

In the 24 hours following administration of Feraheme, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in the Feraheme complex.
. . . MAGNETIC RESONANCE (MR) IMAGING
Administration of Feraheme may transiently affect the diagnostic ability of MR imaging
. . . . Alteration of MR imaging studies may persist for up to 3 months following the last Feraheme dose. . . .
Feraheme will not interfere with X-ray, computed tomography (CT), positron emission tomography (PET), single photon emission tomography (SPECT), ultrasound or nuclear medicine imaging.

The most common adverse reactions reported in ≥2% of Feraheme-treated patients with CKD were nausea (3.1%), dizziness (2.6%), hypotension (2.5%), and peripheral edema (2.0%). Diarrhea (4.0%), constipation (2.1%), and hypertension (1.0%) have also been reported. In clinical trials, adverse reactions leading to treatment discontinuation in ≥2 Feraheme-treated patients included hypotension, infusion site swelling, increased serum ferritin level, chest pain, diarrhea, dizziness, ecchymosis, pruritus, chronic renal failure, and urticaria.
Omission of Risk/Indication Information
Promotional materials are misleading if they fail to reveal facts that are material in light of the 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 webpages present numerous efficacy claims for GastroMARK and Feraheme, but fail to communicate any of the risks associated with the drugs (see Background section above). By omitting the most serious and frequently occurring risks associated with these drugs, the webpages misleadingly suggest that GastroMARK and Feraheme are safer than has been demonstrated and therefore place the public at risk. For example, the GastroMARK webpage omits the drug’s contraindication in patients with known or suspected intestinal perforation or obstruction. We note that there are links to “Download the GastroMARK® Package Insert” at the bottom of the GastroMARK webpage and to “Download the Feraheme Package Insert” buried in the second sentence of the Feraheme webpage. However, these links do not mitigate the complete omission of risk information from the GastroMARK and Feraheme webpages.
Furthermore, the GastroMARK webpage fails to present the complete indication for GastroMARK, including material limitations to the indication. The webpage includes the following claims:
GastroMARK® (ferumoxsil) is AMAG Pharmaceuticals’ oral gastrointestinal (GI) imaging agent for delineation of the bowel. . . . By more clearly identifying the intestinal loops, GastroMARK® enhances the ability to distinguish the bowel from adjacent tissues and organs in the upper gastrointestinal tract.
This presentation fails to include that GastroMARK is indicated only in adult patients, and that its usefulness in the lower gastrointestinal tract and retroperitoneal region is limited by transit time and dilution. The webpage also fails to reveal that GastroMARK is not recommended for iron supplementation.
Promotion of Unapproved Uses
The Feraheme webpage includes the following claims:
• “Feraheme is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease.”
• “Feraheme is being developed to treat iron deficiency anemia associated with other conditions and disease states including women with abnormal uterine bleeding, and patients with cancer and gastrointestinal diseases.”
• “Feraheme is also being developed as a diagnostic agent for vascular-enhanced magnetic resonance imaging to assess peripheral arterial disease. . . .”
The presentation of both approved and unapproved product information for Feraheme together in this manner is misleading because it implies that Feraheme is effective for unapproved uses. However, Feraheme is not approved to treat iron deficiency anemia in women with abnormal uterine bleeding, or in patients with cancer and gastrointestinal diseases. In addition, Feraheme is not approved as a diagnostic agent for vascular-enhanced magnetic resonance imaging for the detection of clinically significant arterial stenosis or occlusion in subjects with peripheral arterial disease.
Similarly, the GastroMARK webpage first presents the product’s U.S. indication (minus limitations), along with efficacy claims for the drug, but states near the bottom of the page that, “In Europe Gastromark® is approved for rectal administration to delineate the lower intestinal system” (emphasis added). This statement, presented within a webpage that appears to be targeted to a U.S. audience, is concerning, as it suggests to U.S. healthcare professionals that GastroMARK is effective for delineating the lower intestinal system and for rectal administration, when in fact, the drug is not approved for this use or method of administration in the U.S.; the U.S. PI for GastroMARK specifically states that “GastroMARK is indicated. . . for oral use. . . .” and that “GastroMARK’s usefulness in the lower gastrointestinal tract and retroperitoneal region is limited (by transit time and dilution).”
The above statements thus misbrand Feraheme and GastroMARK.
Failure to Submit on Form FDA-2253
FDA regulations require companies to submit any labeling or advertising devised for promotion of the drug product at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product. Each submission is required to be accompanied by a completed transmittal Form FDA-2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product’s current professional labeling. Copies of the GastroMARK and Feraheme webpages were not submitted to DDMAC under cover of Form FDA-2253 at the time of initial publication as required by 21 CFR 314.81(b)(3)(i).
Conclusion and Requested Action
For the reasons discussed above, the webpages misbrand GastroMARK and Feraheme in violation of the Act, 21 U.S.C. 352(a),(f)(1) & (n); 321(n), and FDA’s implementing regulations. See 21 CFR 201.100(c)(1); 201.128; 202.1(e)(3)(i);(e)(5) & (e)(6)(i). Furthermore, you failed to submit the webpages to FDA under cover of Form FDA-2253 at the time of their initial publication, as required by 21 CFR 314.81(b)(3)(i).
DDMAC requests that AMAG immediately cease the dissemination of violative promotional materials for GastroMARK and Feraheme, such as those described above. Please submit a written response to this letter on or before November 1, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for GastroMARK and Feraheme that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violations described above are serious, we request, further, that your submission include a plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials. Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS #18355 in addition to the NDA numbers. We remind 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 GastroMARK and Feraheme comply with each applicable requirement of the Act and FDA implementing regulations.
Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.
Sincerely,
{See appended electronic signature page}
Thomas W. Abrams, R.Ph., M.B.A.
Director
Division of Drug Marketing,
Advertising, and Communications
CC: Russell D. Reed
Global Labeling Director
Mallinckrodt Inc.
675 McDonnell Boulevard
Hazelwood, MO 63042

1 GastroMARK webpage, at http://www.amagpharma.com/products/gastromark.php (last accessed October 18, 2010).
2 Feraheme webpage, at http://www.amagpharma.com/products/feraheme.php (last accessed October 18, 2010).
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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/
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THOMAS W ABRAMS
10/18/2010