James H.  Medley, Ph.D. 
Vice President, Regulatory Affairs
Aton Pharma, a Division of Valeant Pharmaceuticals North America LLC
700 Route 202/206 North
Bridgewater, New Jersey 08807

RE:  NDA 010104
       Mephyton® (phytonadione) Vitamin K1 Tablets
       MACMIS #20321

Dear Dr.  Medley:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S.  Food and Drug Administration (FDA) has reviewed a booklet containing a slide presentation entitled, “Clinical Considerations in the Use of MEPHYTON” (MEP-10-1004)¹ (booklet) for Mephyton® (phytonadione) Vitamin K1 Tablets (Mephyton) submitted by Aton Pharma, a Division of Valeant Pharmaceuticals North America LLC (Aton), under cover of Form FDA­ 2253.  The booklet is misleading because it broadens the indication for Mephyton and makes unsubstantiated claims about the drug.  Thus, the booklet misbrands Mephyton in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a). Cf. 21 CFR 202.1(e)(6)(i), (ii); (e)(7)(i) & (iii). 

Background

Below is the indication and summary of the most serious and most common risks associated with the use of Mephyton.²

According to the FDA-approved product labeling (PI):

MEPHYTON is indicated in the following coagulation disorders which are due to faulty formation of factors II, VII, IX, and X when caused by vitamin K deficiency or interference with vitamin K activity. 

MEPHYTON tablets are indicated in:

• anticoagulant-induced prothrombin deficiency caused by coumarin or indanedione derivatives;
• hypoprothrombinemia secondary to antibacterial therapy;
• hypoprothrombinemia secondary to administration of salicylates;
• hypoprothrombinemia secondary to obstructive jaundice or biliary fistulas but only if bile salts are administered concurrently, since otherwise the oral vitamin K will not be absorbed. 

According to the WARNINGS section of the Mephyton PI, an immediate coagulant effect should not be expected after administration of Mephyton; the drug will not counteract the anticoagulant action of heparin; prothrombin time should be checked regularly as clinical conditions indicate; and the drug’s dosage should be kept as low as possible.  Additionally, when vitamin K1 is used to correct excessive anticoagulant-induced hypoprothrombinemia, with anticoagulant therapy still indicated, the patient remains exposed to the clotting risks existing prior to starting anticoagulant therapy.  The WARNINGS section of the PI also indicates that large, repeated doses of Vitamin K are not warranted in patients with liver disease if the response to initial use of vitamin K is unsatisfactory. 

The PRECAUTIONS section of the PI indicates that temporary resistance to prothrombindepressing anticoagulants may occur in patients using Mephyton, particularly when large doses are used.  In this case, it may be necessary to use larger doses of the prothrombindepressing anticoagulant, or use a different anticoagulant, such as heparin sodium, when reinstituting anticoagulant therapy. 

Furthermore, the PI contains ADVERSE REACTIONS associated with the use of Mephyton, such as severe hypersensitivity reactions, including anaphylactoid reactions and death, which have been reported following parenteral administration.  “Flushing sensations” and “peculiar” sensations of taste, as well as dizziness, rapid and weak pulse, profuse sweating, hypotension, dyspnea, and cyanosis have been observed, as has hyperbilirubinemia in newborns. 

Broadening of Indication

Promotional materials are misleading if they suggest that a drug is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience.  The booklet presents several slides that broaden the indication for Mephyton as noted below (this does not constitute a comprehensive list):

• “Pathogenesis of Vitamin K Deficiency” (Slide 6);
• “Vitamin K Deficiency: Inflammatory Bowel Disease” (Slide 9);
• “Vitamin K Deficiency: Cystic Fibrosis” (Slide 11);
• “Vitamin K Deficiency: Other Conditions” (Slide 12); and
• “Vitamin K Content in Food and Supplements” (Slide 19)

For example, slides 9 and 11 suggest that Mephyton is indicated for vitamin K deficiency in patients who have inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, celiac sprue, and post-traumatic short bowel syndrome) and cystic fibrosis, respectively.  Slide 6 suggests that Mephyton is approved to treat patients who have vitamin K deficiency due to the following: fat malabsorption, decreased production by gut bacteria, decreased dietary intake, drug antagonism, and liver dysfunction.  Slide 12 implies that Mephyton is approved to treat vitamin K deficiency in patients following bone marrow transplants and in adults in the intensive care unit.  Furthermore, slide 19 describes Mephyton as a “vitamin K therapy.” The totality of this presentation creates the overwhelming impression that that Mephyton is indicated for all patients with Vitamin K deficiency, including those who have Vitamin K deficiency due to the etiologies noted above, when this has not been demonstrated by substantial evidence or substantial clinical experience.  While we acknowledge that Vitamin K deficiency plays a role in developing coagulation disorders, Mephyton is not indicated for all patients with Vitamin K deficiency as implied by the presentation in the booklet.  The INDICATIONS AND USAGE section of the PI limits the use of Mephyton to coagulation disorders caused by vitamin K deficiency or interference with vitamin K activity secondary to specific conditions (see Background).  Therefore, such claims misleadingly broaden the indication for Mephyton.  We note that the indication is presented on slides 3 and 4 of the booklet; however, this does not mitigate the misleading impression. 

Unsubstantiated Claims

Slide 14 of the booklet, entitled, “Correction of Excess Warfarin Anticoagulation: Meta- Analysis,” presents the claim, “Oral and IV routes were similar in effectiveness at 24 hours” in conjunction with a graph showing the results of a meta-analysis of 21 separate clinical studies that compared the efficacy of different dosage forms of vitamin K (i.e., oral, intravenous, and subcutaneous) to treat excessive anticoagulation due to warfarin.  This presentation suggests that at 24 hours post-administration, Mephyton is as clinically effective as intravenously administered phytonadione and clinically superior to subcutaneously administered phytonadione, when this has not been demonstrated by substantial evidence or substantial clinical experience.  The presentation cites a retrospective review of multiple clinical studies³ that were performed in diverse patient populations, with different doses and dosage forms of phytonadione, and under varying clinical protocols.  Therefore, the cited reference does not constitute substantial evidence or substantial clinical experience to support the presentation noted above. 

Conclusion and Requested Action

For the reasons discussed above, the booklet misbrands Mephyton in violation of the Act, 21 U.S.C. 352(a).  Cf. 21 CFR 202.1(e)(6)(i), (ii); (e)(7)(i) & (iii). 

DDMAC requests that Aton immediately cease the dissemination of violative promotional materials for Mephyton such as those described above.  Please submit a written response to this letter on or before August 17, 2011, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Mephyton that contain violations such as those described above, and explaining your plan for discontinuing use of such violative 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, or facsimile at 301-847-8444.  In all future correspondence regarding this matter, please refer to MACMIS #20321 in addition to the NDA number.  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 Mephyton comply with each applicable requirement of the Act and FDA implementing regulations. 

Sincerely,

James S. Dvorsky, PharmD
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications

________________________________________________________________________

1 The description on Form FDA-2253 indicates that this booklet is “similar to MEP-9-1004.” The booklet cited in this letter includes the identifier, MEP-10-1004. 

2 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. 

3 Dezee KJ, Shimeall WT, Douglas KM, Shumway NM, O’Malley PG.  Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis.  Arch Intern Med.  2006;166(4):391-397.