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AMAG Pharmaceuticals, Inc. 10/18/10

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 

Silver Spring, MD 20993 


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). 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