Steve Thornton, Chief Executive Officer
Bioniche Pharma USA LLC
272 East Deerpath Road, Suite 304
Lake Forest, IL 60045

RE:  ANDA #40-541
       Sotradecol™ (sodium tetradecyl sulfate injection)
       MACMIS #17857

Dear Mr. Thornton:

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 two internet web pages for Sotradecol™ (sodium tetradecyl sulfate injection) (Sotradecol) located on the Bioniche Pharma (Bioniche) website (www.sotradecolusa.com or “Bioniche web page”) and the AngioDynamics, Inc.  (AngioDynamics) website (www.angiodynamics.com/pages/products/Sotradecol.asp or “AngioDynamics web page”).  AngioDynamics is the sole distributor of Sotradecol in the United States.  The web pages are false or misleading because they present efficacy claims for Sotradecol but fail to communicate any information about the risks associated with the product.  The web pages also broaden the approved indication for Sotradecol and overstate its efficacy.  Thus, the web pages misbrand Sotradecol in violation of the Federal Food, Drug, and Cosmetic Act (Act), 21

U.S.C. 352(a) & (n); 321(n).  Cf. 21 CFR 202.1(e)(3)(i); (e)(5), (e)(6)(i) & (xviii).  Furthermore, Bioniche failed to submit the web pages 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 extremely concerning from a public health perspective because they suggest that Sotradecol is safer and more effective than has been demonstrated by substantial evidence or substantial clinical experience. 

Moreover, we are very concerned by your continued violative promotion of this product.  Bioniche was cited for the same violations (omission of risk information and broadening of indication) in an April 4, 2006, Warning Letter from DDMAC.  We note that Bioniche’s April 18, 2006, response to the April 4, 2006, Warning Letter included a proposed promotional piece submitted for DDMAC comments.  On May 18, 2006, DDMAC responded that the proposed piece still failed to include risk information and broadened the indication of Sotradecol.  A follow-up letter from Bioniche, dated May 26, 2006, stated, “All comments in both [DDMAC] letters will be taken into consideration when preparing further promotional materials.” 

Background

According to the INDICATIONS AND USAGE section of the approved product labeling (PI):

Sotradecol® (sodium tetradecyl sulfate injection) is indicated in the treatment of small uncomplicated varicose veins of the lower extremities that show simple dilation with competent valves.  The benefit-to-risk ratio should be considered in selected patients who are great surgical risks. 

The CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections of the PI state in pertinent part (emphasis in original):

CONTRAINDICATIONS
Sotradecol (sodium tetradecyl sulfate injection) is contraindicated in previous hypersensitivity reactions to the drug; in acute superficial thrombophlebitis; valvular or deep vein incompetence; huge superficial veins with wide open communications to deeper veins; phlebitis migrans; acute cellulitis; allergic conditions; acute infections; varicosities caused by abdominal and pelvic tumors unless the tumor has been removed; bedridden patients; such uncontrolled systemic diseases as diabetes, toxic hyperthyroidism, tuberculosis, asthma, neoplasm, sepsis, blood dyscrasias and acute respiratory or skin diseases. 

WARNINGS
Sotradecol® (sodium tetradecyl sulfate injection), should only be administered by a healthcare professional experienced in venous anatomy and the diagnosis and treatment of conditions affecting the venous system and familiar with proper injection technique.  Severe adverse local effects, including tissue necrosis, may occur following extravasation; therefore, extreme care in intravenous needle placement and using the minimal effective volume at each injection site are important. 

Emergency resuscitation equipment should be immediately available.  Allergic reactions, including fatal anaphylaxis, have been reported.  As a precaution against anaphylactic shock, it is recommended that 0.5 mL of Sotradecol be injected into a varicosity, followed by observation of the patient for several hours before administration of a second or larger dose.  The possibility of an anaphylactic reaction should be kept in mind, and the physician should be prepared to treat it appropriately. 

Because of the danger of thrombosis extension into the deep venous system, thorough preinjection evaluation for valvular competency should be carried out and slow injections with a small amount (not over 2 mL) of the preparation should be injected into the varicosity.  Deep venous patency must be determined by noninvasive testing such as duplex ultrasound.  Venous sclerotherapy should not be undertaken if tests such as Trendelenberg and Perthes, and angiography show significant valvular or deep venous incompetence. 

The development of deep vein thrombosis and pulmonary embolism have been reported following sclerotherapy treatment of superficial varicosities.  Patients should have post-treatment follow-up of sufficient duration to assess for the development of deep vein thrombosis.  Embolism may occur as long as four weeks after injection of sodium tetradecyl sulfate.  Adequate post-treatment compression may decrease the incidence of deep vein thrombosis. 

PRECAUTIONS
GENERAL
Extreme caution must be exercised in the presence of underlying arterial disease such as marked peripheral arteriosclerosis or thromboangiitis obliterans (Buerger's Disease).. .  . . 

ADVERSE REACTIONS
Local reactions consisting of pain, urticaria or ulceration may occur at the site of injection.  A permanent discoloration may remain along the path of the sclerosed vein segment.  Sloughing and necrosis of tissue may occur following extravasation of the drug. .  . . 

Allergic reactions such as hives, asthma, hayfever and anaphylactic shock have been reported.  Mild systemic reactions that have been reported include headache, nausea and vomiting. .  . . 

At least six deaths have been reported with the use of Sotradecol.  Four cases of anaphylactic shock leading to death have been reported in patients who received Sotradecol.  One of these four patients reported a history of asthma, a contraindication to the administration of Sotradecol®. .  . . 

One death has been reported in a patient who received Sotradecol and who had been receiving an antiovulatory agent.  Another death (fatal pulmonary embolism) has been reported in a 36-year-old female treated with sodium tetradecyl acetate and who was not taking oral contraceptives. 

Omission of Risk Information

Promotional materials are misleading if they fail to reveal material facts 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 AngioDynamics and Bioniche web pages include efficacy claims such as, “Well-Known Molecule in the US Sclerotherapy Market” (emphasis in original) and “SOTRADECOL is a non-pyrogenic sclerosing agent for IV use only...,” respectively.  However, these web pages entirely omit risk information for Sotradecol, including the Contraindication, Warnings (including the information about allergic reactions, including fatal anaphylaxis), Precautions, and the most frequently reported adverse events from the PI.  Additionally, the promotional piece, MLC203 Rev E 03/08, provided in a PDF titled “Sotradecol™ Promotional Literature” on the AngioDynamics Sotradecol web page also provides claims for Sotradecol but fails to present any risk information in the body of the promotional piece. 

We note the statements on the AngioDynamics web page, “For further information on Sotradecol™, including its approved indication and possible side effects, please visit www.sotradecolusa.com,” and on the Bioniche web page, “For further information on Sotradecol, including its approved indication and possible side effects, please refer to the ‘Sotradecol™ Prescribing Information’ link above.”  However, these links are not sufficient to provide appropriate qualification or pertinent information for the claims made on these pages.  Additionally, we note that the PI is included on the second page of promotional piece MLC 203 Rev E, but this is not sufficient to provide appropriate qualification or pertinent information for the claims made in the main body of the piece.  Promotional materials must contain risk and effectiveness information in each part as necessary to qualify any safety or effectiveness claims made (21 CFR 202.1(e)(3)(i)). 

Broadening of Indication

The web pages are misleading, presenting an unbalanced picture of the benefits and uses of Sotradecol and suggesting that Sotradecol is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience.  Specifically, the AngioDynamics web page includes claims such as, “Well-Known Molecule in the US Sclerotherapy Market” (emphasis in original) and “Sotradecol™ is now available through AngioDynamics, Inc.  for use in both sclerotherapy clinics and hospitals,” and the Bioniche web page includes claims such as, “Sotradecol is a non-pyrogenic sclerosing agent for IV use only….”  These claims entirely avoid mention of the actual indication, which is for the treatment of a very limited subset of varicose veins, and misleadingly suggest that Sotradecol is appropriate for use in all sclerotherapy patients and procedures.  In fact, Sotradecol is indicated “in the treatment of small uncomplicated varicose veins of the lower extremities that show simple dilation with competent valves.  The benefitto-risk ratio should be considered in selected patients who are great surgical risks.”  The Contraindications and Precautions sections of the PI also list numerous conditions in which Sotradecol is either inappropriate or should be used with extreme caution (see Background section).  The web pages fail to present these material limitations, thereby broadening the indication of Sotradecol. 

Overstatement of Efficacy

The promotional piece, MLC203 Rev E 03/08, provided in a PDF titled “Sotradecol™ Promotional Literature” on the AngioDynamics Sotradecol web page presents a graphic of a woman squatting down at the beach.  The majority of her body is covered with a long-sleeved, over-sized sweater, except for her legs, which are bare and show clear, varicose-free skin without blemishes or visual imperfections.  This graphic overstates the efficacy of Sotradecol by suggesting that patients should expect to achieve varicose-free legs akin to those portrayed in the graphic.  This promotional piece fails to provide any information regarding the range of results patients may achieve depending on variables including, but not limited to, varicose vein severity, disease progression, depth of skin tone, technical skills of the practitioner, clinical time point assessment, and number of treatments.  Further, some patients may experience “permanent discoloration along the path of the sclerosed vein segment” as detailed in the Adverse Reactions section of the PI.  Therefore, this presentation is misleading. 

Failure to Submit Under Form FDA-2253

FDA regulations require companies to submit specimens of 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 and Biologics for Human Use) and is required to include a copy of the product’s current professional labeling.  A copy of the web pages and the promotional piece, MLC203 Rev E, were not submitted 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). 

Conclusion and Requested Action

For the reasons discussed above, these web pages misbrand Sotradecol in violation of the Act, 21 U.S.C. 352(a) & (n); 321(n).  Cf. 21 CFR 202.1(e)(3)(i); (e)(5), (e)(6)(i) & (xviii).  In addition, you failed to submit the web pages 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 Bioniche immediately cease the dissemination of violative promotional materials for Sotradecol such as those described above.  Please submit a written response to this letter on or before September 28, 2009, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) in use for Sotradecol 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.  Additionally, since we have cited you for the same violations in the recent past, we request a response in writing indicating what policies and procedures your firm and its marketing partner, AngioDynamics, intend to adopt to ensure your prescription drug promotional activities comply with the Act and its implementing regulations, and an explanation of why/how you expect these policies and procedures to succeed.  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 #17857 in addition to the ANDA 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 Sotradecol 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, RPh, MBA
Director Division of Drug Marketing,
Advertising, and Communications

CC:  William Appling, Sr. Vice President, Research & Development
        AngioDynamics
        603 Queensbury Avenue
        Queensbury, NY 12804