Richard Strauss, R.Ph. 
President and Chief Executive Officer
Pedinol Pharmacal, Inc. 
30 Banfi Plaza North
Farmingdale, NY 11735

RE:  NDA #17-604
       Nalfon® (fenoprofen calcium capsules) 200 mg and 400 mg
       MACMIS #15906

Dear Mr. Strauss:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a professional direct mailer (NN0507TL) for NALFON® (fenoprofen calcium capsules) 200 mg and 400 mg (Nalfon) submitted by Pedinol Pharmacal, Inc. (Pedinol) under cover of Form FDA 2253.  This professional direct mailer is false or misleading because it (1) recommends or suggests a specific use for Nalfon that the drug has not been evaluated by the FDA for and thus creates a new “intended use” for the drug for which the product lacks adequate direction, (2) omits and minimizes serious risks associated with the use of Nalfon, and (3) presents unsubstantiated superiority claims for Nalfon.  The professional direct mailer therefore misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. 352(a) & (f)(1), 321(n), and FDA implementing regulations.  See 21 CFR 201.100(c)(1) & 201.128; cf.  21 CFR 202.1(e)(5), (6)(i) & (ii).  These violations are concerning from a public health perspective because they encourage the use of Nalfon in circumstances other than those for which the drug has been shown to be safe and effective and omits and minimizes the risks of the drug. 

Background

According to its FDA approved product labeling (PI), Nalfon is indicated for: relief of mild to moderate pain in adults; relief of the signs and symptoms of rheumatoid arthritis; and relief of the signs and symptoms of osteoarthritis.  The Indications and Usage section of the PI also advises prescribers to “Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon.  Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.”

The PI for Nalfon contains the following Boxed Warnings:

Nalfon is also associated with a number of other serious risks, as reflected in its PI.  For example, Nalfon should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs because severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.  Nalfon is also contraindicated in patients with a history of significantly impaired renal function.  Other serious warnings associated with Nalfon use include: hypertension; congestive heart failure and edema; renal effects; anaphylactoid reactions; potentially fatal skin reactions; and birth defects if used in late pregnancy.  Additionally, the PI for Nalfon contains information pertaining to serious drug interactions and common adverse reactions. 

Unapproved New Use

The professional direct mailer is false or misleading because it suggests a new “intended use” for Nalfon – namely, the treatment of pain associated with plantar fasciitis.  The entire focus of the professional direct mailer is on plantar fasciitis; the piece contains cards providing a detailed overview, diagnosis, treatment, case study, and patient information for plantar fasciitis.  The piece also promotes the use of Nalfon for this condition, listing it as a pharmacologic treatment for the pain associated with plantar fasciitis, presenting a case study where a plantar fasciitis patient is prescribed Nalfon, and including the drug’s name on each of the cards in the professional direct mailer.  The front cover of the professional direct mailer also prominently presents the drug’s name in conjunction with the claims “Free Your Sole” and “Foot Pain Doesn’t Wait … So Why Should Relief?” However, according to its FDA-approved PI, Nalfon is approved for relief of mild to moderate pain in adults and for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.  We recognize that plantar fasciitis is a condition that causes pain in the foot, but Nalfon’s indication for relief of mild to moderate pain is a general one; the drug is not approved and has not been evaluated by FDA for the treatment of pain associated with plantar fasciitis.  Rather, the mild to moderate pain indication was supported by studies in patients with episiotomy pain, pain due to post-partum uterine cramping, and post-operative pain.  The PI does not include any information regarding the safety and efficacy of Nalfon for the pain associated with plantar fasciitis.  Furthermore, we note that you submitted a Citizen’s Petition to FDA (received on May 1, 2008) requesting that FDA permit amendment of the Nalfon labeling to include an indication for the relief of the signs and symptoms of plantar fasciitis without the submission of clinical data, and that the petition was denied on July 30, 2009 (Docket No.  2008P0279/CP1).  In order to promote the drug for the pain associated with plantar fasciitis, one or more adequate and well-controlled clinical trials evaluating the drug in the treatment of plantar fasciitis would need to be conducted and the PI would need to be updated to reflect this information.  Therefore, the claims and presentations about treating plantar fasciitis with Nalfon misbrand the drug by creating a new “intended use” for which Nalfon’s PI lacks adequate directions. 

Omission and Minimization of Risk Information

Promotional materials are misleading if they fail to reveal material facts with respect to the consequences that may result from the use of the drug as recommended or suggested by the materials.  The professional direct mailer is misleading because it presents numerous effectiveness claims for Nalfon but omits and minimizes important risk information from the body of the piece, including crucial facts about serious, potentially fatal risks associated with Nalfon.  By omitting and minimizing the risks associated with the drug, the professional direct mailer misleadingly suggests that Nalfon is safer than has been demonstrated. 

The professional direct mailer does not provide any specific risk information for Nalfon.  The only risk information within the professional direct mailer is located on the “TREATMENT” card.  This card includes the following statements:

•  “NSAIDs are generally safe and well-tolerated when used as directed in appropriately selected patients.”
•  “The individual patient’s risk of GI bleeding, cardiovascular or cerebrovascular complications should be taken into account when choosing an appropriate NSAID.”
•  “Long-term or high-dose therapy with non-COX-2 selective NSAIDs are associated with increased risk of GI bleeding.”
•  “The scientific evidence to date indicates that NSAIDs with COX-2 selectivity are associated with increased risk of cardiovascular or cerebrovascular complications.”
•  “If a physician has decided to use an NSAID for a patient with known cardiovascular disease or risk factors for ischemic heart disease, the American Heart Association recommends using non-COX-2 selective NSAIDs before NSAIDs with some COX-2 activity or COX-2 selective NSAIDs.”

These statements also minimize the risks associated with NSAIDs such as Nalfon by failing to convey the serious and potentially fatal nature of the cardiovascular and gastrointestinal risks contained in Nalfon’s Boxed Warnings.  Moreover, these claims are inconsistent with the Warnings section of Nalfon’s PI, which states in direct and unequivocal language, “Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.  All NSAIDs, both COX-2 selective and nonselective, may give a similar risk” (emphasis added). 

Moreover, we note that the last two bullets are misleading because they imply that non-COX2 selective NSAIDs, such as Nalfon, are safer than those with COX-2 selectivity, when this has not been demonstrated by substantial evidence and directly contradicts the PI.  Finally, framing the presentation of this risk information in the non-specific terms of the class of NSAIDs, when the mailer refers to Nalfon by name when presenting efficacy information, serves to further minimize the risks associated with Nalfon. 

Unsubstantiated Superiority Claims

The professional direct mailer is false or misleading because it suggests that Nalfon is superior to other drug therapies in the treatment of plantar fasciitis when this has not been demonstrated by substantial evidence or substantial clinical experience.  The card titled “TREATMENT” states: “An agent offering a more rapid onset of action and shorter duration (half-life) may be preferred for managing pain associated with more minor musculoskeletal injuries” (footnote omitted).  This statement is followed by a table comparing the dosing information as well as some selective pharmacokinetic properties of Nalfon, Naprosyn, and Celebrex.  The table depicts Nalfon as having a more rapid onset of action and shorter half-life compared to Naprosyn and Celebrex.  The totality of this presentation misleadingly suggests that Nalfon confers a therapeutic benefit greater than Naprosyn and Celebrex because of its pharmacokinetic properties, when this has not been demonstrated by substantial evidence or substantial clinical experience.  The reference cited¹ is a chapter of a text book which does not contain any mention or reference to studies specifically comparing Nalfon to other agents (i.e., Naprosyn, Celebrex) for the treatment of plantar fasciitis.  Therefore, this reference does not provide substantial evidence to support the implication that Nalfon is a superior treatment option to Naprosyn and Celebrex for the treatment of plantar fasciitis.  Moreover, it is hard to understand why having to take a drug more often, as is the case with Nalfon because of its short half life, represents an advantage.  In fact, when used for a chronic pain condition, it appears to be a disadvantage.  In addition, any advantage of a shorter time of onset, even if this were shown (which it has not been), is no advantage after the first dose. 

Conclusion and Requested Action

For the reasons discussed above, the professional direct mailer misbrands Nalfon in violation of the Act (21 U.S.C. 352(a) & (f)(1); 321(n)), and FDA implementing regulations.  See 21 CFR 201.100(c)(1) & 201.128; cf.  21 CFR 202.1(e)(5), (6)(i) & (ii). 

DDMAC requests that Pedinol immediately cease the dissemination of violative promotional materials for Nalfon such as those described above.  Please submit a written response to this letter on or before September 3, 2009, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) in use for Nalfon as of the date of this letter, identifying which of these materials 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 comprehensive 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, or facsimile at 301-847-8444.  In all future correspondence regarding this matter, please refer to MACMIS #15906 in addition to the NDA number.  We remind you that only written communications are considered official.  If you choose to revise your promotional materials, DDMAC is willing to assist you with your revised materials by commenting on your revisions before you use them in promotion. 

The violations discussed in this letter do not necessarily constitute an exhaustive list.  It is your responsibility to ensure that your promotional materials for Nalfon 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,

Thomas W. Abrams, R.Ph., M.B.A.
Director
Division of Drug Marketing,
Advertising, and Communications

______________________________________________________________

1  Burke A, Smythe E, Fitzgerald GA.  Analgesic-antipyretic agents; pharmacotherapy of gout.  In: Brunton L, Lazo J, Parker K, eds.  Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed.  New York: McGraw-Hill 2006.  Accessed online April 21, 2009.