FDA Sends Letter to Aton Pharma Over Flash Card

ROCKVILLE, Md., April 7, 2010 - The FDA today posted on its website a letter sent to Aton Pharma over a flash card for Mephyton Vitamin K1. The letter is below.

 

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Food and Drug Administration Silver Spring, MD 20993

TRANSMITTED BY FACSIMILE
Kevin Halloran VP Regulatory Affairs & Quality Aton Pharma, Inc. 3150 Brunswick Pike, Suite 230 Lawrenceville, NJ 08648

RE: NDA #010104
MEPHYTON® (PHYTONADIONE) Vitamin K1 MACMIS #18433
Dear Mr. Halloran:
The Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has reviewed Aton Pharma, Inc.’s (Aton) flash card (MEP-091011) (flash card) for its drug product, MEPHYTON® (PHYTONADIONE) Vitamin K1 (Mephyton). This flash card was obtained at the American College of Gastroenterology annual meeting held on October 23-28, 2009, in San Diego, CA. The flash card is misleading because it omits information about the drug’s approved indication(s), broadens the indicated patient population for Mephyton, minimizes the risks associated with the drug, overstates its efficacy, and makes unsubstantiated claims. Thus, the flash card misbrands Mephyton in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(3)(ii); (e)(5)(i) & (iii); (e)(6)(i) & (e)(7)(i). Furthermore, Aton failed to submit a copy of the flash card accompanied by a completed transmittal Form FDA-2253 at the time of its initial dissemination, as required by 21 CFR 314.81(b)(3)(i).

Background
According to its FDA-approved product labeling (PI), Mephyton is indicated for the following:
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
Mephyton is associated with numerous risks. The PI contains Contraindications for patients who are hypersensitive to any component of the product. The PI also includes Warnings that an immediate coagulant effect should not be expected after administration of Mephyton, that the drug will not counteract the anticoagulant action of heparin, that prothrombin time should be checked regularly as clinical conditions indicate, and the drug’s dosage should be kept as low as possible. Furthermore, the PI includes Precautions that temporary resistance to prothrombin-depressing anticoagulants may result, particularly when large doses of Mephyton are used. In this case, it may be necessary to use somewhat larger doses of the prothrombin-depressing anticoagulant, or to use one which acts on a different principle, such as heparin sodium, when reinstituting anticoagulant therapy.
Furthermore, the PI contains Adverse Reactions associated with 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. Finally, the Clinical Pharmacology section of the Mephyton PI states, “MEPHYTON tablets generally exert their effect within 6 to 10 hours.”

Omission of Indication Information
Promotional materials are misleading if they fail to reveal facts that are material in light of the representations made by the materials. The flash card presents information about the “critical role of vitamin K in the body” and claims regarding Mephyton, “[t]he only oral prescription vitamin K,” but fails to communicate any of the drug’s approved indications (see Background section). The statement, “PLEASE SEE FULL PRESCRIBING INFORMATION ENCLOSED” (emphasis in original) does not mitigate the misleading omission of information about Mephyton’s approved indications.

Broadening of Indication/Unsubstantiated Claims
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 front side of the flash card contains the following claim:

“The goal of having sufficient VK [vitamin K] levels is to ensure that all VK-dependent proteins in the body are fully carboxylated”

1

The back side of the flash card contains the following claims (emphasis in original):
“Knowing when a patient has VK deficiency
1 Wilson DC, Rashid M, Durie PR, et al. Treatment of vitamin K deficiency in cystic fibrosis: effectiveness of a daily fat-soluble vitamin combination. J Pediatr. 2001;138:851-5.

Because of diagnostic advances, it’s now easier to track Kevin Halloran Page 3 Aton Pharma, Inc. NDA #010104/MACMIS #18433
• Undercarboxylated VK-dependent proteins are functional endpoints for VK deficiency”1
• “Previously, prothrombin time (PT) was widely used to assess VK status”2
• “However, PT is considered an insensitive marker – prothrombin must decrease to approximately 50% of normal levels before a change in PT status is noted”2
• “PT induced by VK absence for factor II (PIVKA-II) is now considered a highly sensitive and specific marker that is increasingly being used to assess VK status and determine the severity of subclinical VK deficiency”2,3
• “PIVKA-II values >3 ng/mL are indicative of VK deficiency”1

2 Mager DR, McGee PL, Furuya KN, Roberts EA. Prevalence of vitamin K deficiency in children with mild to moderate chronic liver disease. J Pediatr Gastroenterol Nutr. 2006;42;71-76. 3 Rashid M, Durie P, Andrew M, et al. Prevalence of vitamin K deficiency in cystic fibrosis. Am J Clin Nutr. 1999;70:378-82.
The totality of these claims misleadingly suggests that Mephyton is indicated to treat vitamin K deficiency caused by under-gammacarboxylation, and that the measurement of PIVKA-II to measure the level of non-gammacarboxylated proteins has clinical utility in the diagnosis of vitamin K deficiency/the identification of patients who should be treated with Mephyton, when such has not been demonstrated by substantial evidence or substantial clinical experience.
While vitamin K has a role in the gammacarboxylation of coagulation factors, FDA is unaware of any evidence that varying degrees of under-gammacarboxylation, as measured by PIVKAII, are associated with clinical disease. Mephyton is only approved to treat anticoagulant-induced prothrombin deficiency or hypoprothrombinemia secondary to certain specific conditions (see Background section). The implication that Mephyton therapy is appropriate for any patient with a “VK deficiency” as indicated by “PIVKA-II values >3 ng/mL” misleadingly suggests that the drug is useful in a broader range of patients or conditions than has been demonstrated by substantial evidence or substantial clinical experience, including patients who may have no clinical disease. The misleading nature of these claims is exacerbated by the flash card’s complete omission of the drug’s approved indication(s).
Furthermore, the Wilson, et al., Mager, et al., and Rashid et al. references cited to support the above claims do not constitute substantial evidence or substantial clinical experience. Among other deficiencies, the studies included in these references do not show that the administration of Mephyton induces a clinical benefit in patients with a recognizable and generally accepted disease process.
In addition, FDA is unaware of any substantial evidence that suggests that the measure of prothrombin time will be replaced by PIVKA-II in the management of anticoagulant therapy or in the assessment of the need for vitamin K therapy to achieve optimal coagulation function. Kevin Halloran Page 4 Aton Pharma, Inc. NDA #010104/MACMIS #18433
Minimization of Risk Information
The back side of the flash card contains the claim, “There is no known toxicity associated with large doses of VK.”4 This claim misleadingly implies that large doses of Mephyton are not associated with any toxicity, when this is not the case. There are numerous risks associated with the drug, including several warnings, precautions, and adverse reactions, even when Mephyton is used at therapeutic doses. For example, the Warnings section of the PI states, “Dosage should be kept as low as possible, and prothrombin time should be checked regularly as clinical conditions indicate.” In addition, the Adverse Reactions section of the PI states that hyperbilirubinemia has been observed in newborns following Mephyton therapy and occurs primarily with higher-than-recommended doses. Furthermore, the Suttie, et al. reference cited to support this claim does not constitute substantial evidence or substantial clinical experience. Among other deficiencies, the studies included in this reference were performed in animals, not humans.

Overstatement of Efficacy/Unsubstantiated Claims
Promotional materials are misleading if they represent or suggest that a drug is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The back side of the flash card contains the following claims:
• “Absorption of VK1* has been shown to be approximately 6 times greater when ingested in the pure form of a tablet than when ingested in the form of food”5
• “Peak serum concentrations of VK have been seen 2 to 3 hours after consumption of the tablet, compared with a delayed response to food”5
• “*Vitamin K1 is the form of VK contained in Mephyton® tablets.”

4 Suttie JW. Vitamin K. In: Ziegler EC, Filer LJ, eds. Present Knowledge in Nutrition, 7th ed. ISLI Press, Washington, DC;1996:137-43. 5 Garber AK, Binkley NC, Krueger DC, Suttie JW. Comparison of phylloquinone bioavailability from food sources or a supplement in human subjects. J Nutr. 1999;129:1201-03.
These claims misleadingly imply that the rapidity and degree of absorption, as well as the exposure of vitamin K, is clinically superior with Mephyton tablets compared to food containing vitamin K, when such has not been demonstrated by substantial evidence or substantial clinical experience. The Garber, et al. reference cited to support these claims does not provide evidence that these pharmacokinetic differences in vitamin K administration were clinically meaningful. In addition, the claim, “Peak serum concentrations of VK have been seen 2 to 3 hours after consumption of the tablet . . .” (emphasis added), is not supported by the Mephyton PI, and overstates the demonstrated efficacy of the drug. The Clinical Pharmacology section of the Mephyton PI states, “MEPHYTON tablets generally exert their effect within 6 to 10 hours” (emphasis added), not 2 to 3 hours as claimed above.

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 Kevin Halloran Page 5 Aton Pharma, Inc. NDA #010104/MACMIS #18433
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. Aton did not submit a copy of the flash card referred to in this letter to DDMAC under cover of Form FDA-2253 at the time of its initial dissemination, as required by 21 CFR 314.81(b)(3)(i). Specifically, the piece was disseminated as early as October 2009 at the American College of Gastroenterology annual meeting, but was not submitted on Form FDA-2253 until February 22, 2010.

Conclusion and Requested Action
For the reasons discusses above, the flash card misbrands Mephyton in violation of the Act 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(3)(ii); (e)(5)(i) & (iii); (e)(6)(i) & (e)(7)(i). Furthermore, Aton failed to submit a copy of the flash card accompanied by a completed transmittal Form FDA-2253 at the time of its initial dissemination, as required by 21 CFR 314.81(b)(3)(i).
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 April 20, 2010, 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, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS #18433 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,
{See appended electronic signature page}
Michelle Safarik, MSPAS, PA-C Regulatory Review Officer Division of Drug Marketing, Advertising, and Communications -------------------- -------------------- -------------------- ------------------------------------------ --------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------- ---------------------------------------------------- Application Submission
Submitter Name Product Name
Type/Number Type/Number
NDA-10104 ORIG-1 ATON PHARMA Mephyton (Phytonadione) INC Tablets, 150mcg

This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
/s/
MICHELLE L SAFARIK 04/06/2010
 

Posted: April 2010


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