Released by FDA: 11/20/01.  Posted by FDA:  11/28/01

Ms. June Bray
Director, Regulatory Affairs 
Berlex Laboratories, Inc. 
340 Changebridge 
Road PO Box 1000
Montville, NJ 07045-1000

RE:    NDA 19-596
         Magnevist (gadopentetate dimeglumine) Injection 
         MACMIS # 10 157

Dear Ms. Bray:

This letter objects to Berlex Laboratories, Inc.'s (Berlex) dissemination of violative promotional materials for Magnevist.   Specifically, as part of its routine monitoring program, the Division of Drug Marketing, Advertising, and Communications (DDMAC), has identified a brochure (00-MAG-053) submitted under cover of Form FDA 2253 that is false or misleading under the Federal Food, Drug, and Cosmetic Act and its implementing regulations.  Our specific objections follow:

Promotion of Unapproved New Uses---Breast and Musculoskeletal Imaging

Promotional materials are false or misleading if they contain suggestions or representations not approved or permitted in the approved package insert (PI), that a drug is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence.  Your brochure is violative because it states that Magnevist is useful for breast imaging and musculoskeletal imaging when such has not been demonstrated by substantial evidence.

For example, in a table on page 2, you present a heading "Broad Indications" and compare the indications of Magnevist to Prohance (gadoteridol injection),  Omniscan (gadodiamide injection), and Optimark (gadoversetamide injection).  In the table, you show that Magnevist and Omniscan are indicated for abdominal, pelvis, thorax, retroperitoneal, and pediatric imaging.  You also show that only Magnevist is indicated for musculoskeletal, and breast imaging (emphasis added).  However, Magnevist is not approved for use to image the breast or musculoskeletal areas of the body.  Also on page 4, you state that Magnevist is indicated "for adult whole body imaging."  Your addition of the term "whole" to your approved indication for imaging the "body" also implies that the drug is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence. Thus, your brochure is misleading because it promotes unapproved new uses for Magnevist.

We are especially concerned with Berlex's promotion of these unapproved new uses for Magnevist considering the fact that the Agency and Berlex have discussed Magnevist's approved indications.  We have previously advised you that your database for imaging breast (8 patients) and musculoskeletal tissue (22 patients), described in the clinical trials section of your labeling, is inadequate to support the safety and efficacy of Magnevist for these uses.

We are also concerned because your violative promotion of Magnevist for unapproved new uses continues despite our previous written objections.  Specifically, in our letter to you dated April 15, 1999, we objected to your promotional brochure that presented two case studies regarding imaging the carotid arteries, an unapproved new use.  You claimed in that brochure that Magnevist in magnetic resonance arteriography could: 1) identify stenosis and its severity in the carotid arteries, 2) assess other arteries including the proximal common carotid artery, and 3) confirm ultrasound, which may obviate the need for angiography.  These claims also are not supported by substantial evidence.

In that same letter, we objected to your dissemination of a poster including an unlabeled MRI image of angiography, presumably of the aorta and iliac arteries.

We stated that you have no basis to promote Magnevist for magnetic resonance arteriography (MRA), and specifically we were not aware of evidence to support the efficacy of Magnevist for MRA.  You assured us that you would cease using the violative materials.

Unapproved Dosing Regimen

Your brochure is misleading because it suggests that Magnevist has a flexible dosing regimen and is approved for single dose injections of 0.3 mmol/kg.   As you know, Magnevist only has a recommended dosing and administration regimen of 0.1 mmol/kg body weight administered at a rate not to exceed 10 mL per 15 seconds.¹   However, you claim in a table on page 3 of the brochure that Magnevist has "High Dose Safety" at 0.3 nunol/kg single dose injection, i.e., 3 times the recommended dose.   This misleading claim takes a statement out of context from the clinical trials section of the PI and implies that Magnevist is efficacious for single dose injections of 0.3 mmol/kg_.

We are particularly concerned about this promotional claim because there may be a hazard using Magnevist at dosages and rates inconsistent with its approved labeling. Magnevist has not been shown to be safe at higher rates of injection.  It is known that Magnevist is associated with vascular related adverse events.  In fact, your PI has warnings regarding patients with predisposition to the development of thrombotic syndromes, and includes a precaution that cases of phlebitis and thromboplhlebitis have been reported in association with Magnevist that have resulted in amputation of the dosed limb.

Misleading Safety Presentation

Promotional materials are false or misleading if they contain suggestions or representations not approved or permitted in the approved product labeling (PI), that a drug is safer, has fewer, or less incidence of, or less serious side effects than has been demonstrated by substantial evidence.  On page 2 you claim that Magnevist has proven safety based on a well-documented global profile.  You further claim its injection safety record provided a positive clinical experience in more than 20 million patients.  You present the drug's most frequently reported adverse experiences from clinical trials, but fail to provide important information from the PI regarding its injection safety record. Specifically, there have been cases associated with the use of Magnevist where patients have had severe cases of phlebitis and thrombophlebitis resulting in surgical intervention, including compartment release or amputation of the dosed limb.

Lack of Fair Balance

Promotional materials are misleading if they fail to present information relating to side effects and contraindications with a prominence and readability reasonably comparable with the presentation of information relating to the effectiveness of the drug.  On page 5 of the brochure, you present the abbreviated indications for Magnevist (gadopentetate dimeglumine) Injection, as well as for your drug products Ultravist (iopromide) Injection, Feridex IN. (ferumoxides injectable solution), Quadramet (Samarium Sm-153 Lexidronarn Injection), Neotect (Kit for the preparation of Technetium Tc-99m Depreotide Injection), and Acutect (Kit for the preparation of Technetium Tc-99m Apcitide Injection).  Although you present risk information at the bottom of the page regarding each of these drug products, the information is presented in a manner that is not reasonably comparable to your presentation relating to the effectiveness of the drug thereby minimizing its importance.

Further, we note that you misrepresented the indication for Neotect by claiming that it is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence.  The drug is indicated for identifying somatostatin receptor-bearing pulmonary masses in patients presenting with pulmonary lesions on CT or x-ray who have shown malignancy or who are highly suspect for malignancy.  However, you claim that the drug is used in patients with pulmonary lesions on CT and/or X-ray who have either known or suspected malignancy. The drug is approved for use in a much different population.

Requested Actions

In order to address these objections, we request that you immediately cease the dissemination of this violative brochure and all similar promotional materials that contain the same or similar messages.

You should respond in writing to us regarding this issue by December 5, 2001.  Your response should include Berlex's intent to comply with the above request, the date that it ceased disseminating these and any other violative promotional materials with the same or similar messages, and a list of the discontinued materials.

If you have any questions, please contact me by facsimile at (301) 594-6771, or by written communication at the Division of Drug Marketing, Advertising, and Corornunications, IIFD-42; Room 17B-20; 5600 Fishers Lane; Rockville, MD 20857. DDMAC reminds Berlex that only written communications are considered official.

In all fixture correspondence regarding this matter, please refer to MACMIS # 10157 and NDA 19-596.

Sincerely,

Warren Rumble 
Regulatory Review Officer 
Division of Drug Marketing, 
Advertising, and Communications

____________________________

¹ The maximum approved volume is 26 mL.