Mark Gaydos
Senior Director, US Regulatory Affairs Marketed Products
sanofi-aventis U.S. Inc.
PO Box 5925, 55 Corporate Drive
Bridgewater, NJ 08807

RE:  NDA 021731
        Eligard 45mg (leuprolide acetate for injectable suspension)
        MACMIS #18481

Dear Mr. Gaydos:

As part of its monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S.  Food and Drug Administration (FDA) has reviewed a Patient Profile Piece (patient profile) entitled, “6 Month Got Time Patient Profile Piece” (US.LEU.08.10.009) for Eligard 45mg (leuprolide acetate for injectable suspension) (Eligard) submitted by sanofi-aventis U.S. Inc.  (sanofi) under cover of Form FDA-2253.  The patient profile is false or misleading because it omits and minimizes important risks for Eligard, overstates the efficacy, makes misleading presentations, and makes unsubstantiated efficiency and convenience claims for Eligard.  Thus, the patient profile misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) and 321(n).  Cf. 21 CFR 202.1(e)(3)(i), (e)(5), (e)(6)(i) & (e)(7)(viii). 

Background

The INDICATIONS AND USAGE section of the FDA-approved product labeling (PI) for Eligard states:

ELIGARD® is indicated for the palliative treatment of advanced prostate cancer. 

Eligard is associated with several contraindications, warnings, precautions, and adverse reactions.  In particular, the CONTRAINDICATIONS section of the PI states (in pertinent part, footnote omitted):

ELIGARD® is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogs or any of the components of ELIGARD.  Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature. 

ELIGARD® is contraindicated in women and in pediatric patients and was not studied in women or children.  Moreover, leuprolide acetate can cause fetal harm when administered to a pregnant woman....  The possibility exists that spontaneous abortion may occur. 

The WARNINGS section of the PI states (in pertinent part):

…ELIGARD® 45mg causes a transient increase in serum concentration of testosterone during the first two weeks of treatment.  Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, or bladder outlet obstruction.  Isolated cases of ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or without fatal complications, have been observed in the palliative treatment of advanced prostate cancer using LH-RH agonists…. 

If spinal cord compression or ureteral obstruction develops, standard treatment of these complications should be instituted. 

The PRECAUTIONS section of the PI states (in pertinent part):

General: Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy…. 

Laboratory Tests: Response to ELIGARD® should be monitored by measuring serum concentrations of testosterone and prostate specific antigen periodically. 

The ADVERSE REACTIONS section of the PI states (in pertinent part, footnote omitted):

…ELIGARD®, like other LH-RH analogs, caused a transient increase in serum testosterone concentrations during the first one to two weeks of treatment.  Therefore, potential exacerbations of signs and symptoms of the disease during the first weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria.  If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms…. 

Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog.  It can be anticipated that long periods of medical castration in men will have effects on bone density. 

The most commonly reported injection site adverse events include transient burning/stinging (16%), pain (4.6%), and mild bruising (2.3%).  The most commonly reported systemic adverse events include hot flashes/sweats (57.7%), malaise and fatigue (11.7%), testicular atrophy (7.2%), myalgia (4.5%), weakness (3.6%), gynecomastia (3.6%), night sweats (2.7%), and pain in limb (2.7%). 

Omission/Minimization 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 patient profile is misleading because it omits material risk information relating to warnings and adverse reactions for Eligard, some of which are fatal.  Specifically, the promotional piece fails to reveal that cases of ureteral obstruction and/or spinal cord compression have been observed in the palliative treatment of advance prostate cancer using LH-RH agonists, and may contribute to paralysis with or without fatal complications.  It also fails to disclose a common injection site adverse event (i.e., bruising (2.3%)), as well as several common systemic adverse events (i.e., sweats (57.7%), malaise (11.7%), myalgia (4.5%), gynecomastia (3.6%), and weakness (3.6%)). 

Additionally, the patient profile claims “ELIGARD, like other LHRH agonists, causes a transient increase in serum testosterone during the first week of treatment” (emphasis added).  This claim misleadingly suggests that serum testosterone levels will decline after the first week of therapy, leading to a direct decrease in testosterone-related adverse events after this first week.  However, as stated in the Warnings section of the PI, the transient increase in serum testosterone levels following Eligard injections may last up to two weeks, rendering patients susceptible to related adverse events for several weeks following Eligard injection. 

Furthermore, promotional materials are misleading if they fail to present risks associated with a drug with a prominence and readability reasonably comparable with the presentation of information relating to the effectiveness of the drug.  The patient profile, including its four pullout profile tabs, prominently presents efficacy claims with large bolded characters, prominent headers, and colorful graphics throughout the first 11 pages of the piece, but fails to convey any risks specific to Eligard in these 11 pages.  In contrast to the large and colorful effectiveness presentations contained in these first 11 pages, a limited risk disclosure is presented on the bottom of the back page in small font type in single-spaced paragraph format.  As such, the piece fails to present risk information with a prominence and readability reasonably comparable with the presentation of information relating to the effectiveness of the drug. 

We note the statement, “Please see Important Safety Information on the back cover and accompanying Full Prescribing Information in back pocket,” appears on the bottom of the second page and the back of the patient profile pages.  However, this statement does not mitigate the misleading omission and minimization of risk information. 

Overstatement of Efficacy

Promotional materials are misleading if they contain representations or suggestions that a drug is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience.  The patient profile includes the following claims concerning several patient types receiving Eligard therapy (emphasis added):

•  “PATIENT TYPE: LIMITED MOBILITY” (describes an 80-year-old mechanic who needs a wheelchair):
   --  “He is considering moving into an assisted living facility to have access to more care”
   --  “Convenience for patients. . . 
•  Fewer injections helps minimizes trips to his doctors office, keeping him at home and more comfortable
•  Subcutaneous delivery of medication is optimal for wheelchair-bound individuals and preserves patient dignity
•  Patient’s comfort is maintained by allowing him to remain seated during administration, with the abdomen being an ideal injection site”

•  “PATIENT TYPE: SEASONAL TRAVELER” (describes a 65-year-old retired financial advisor):
   -- “Wants his retirement to be interrupted less frequently”

These claims suggest that treatment with Eligard will be comfortable for patients, preserve patient dignity, allow patients to remain at home (rather than moving to an assisted living facility), and interrupt a patient’s retirement less frequently.  There are no references cited in support of these claims, and we are unaware of substantial evidence or substantial clinical experience to support the above-claimed effects of Eligard treatment.  While Eligard can result in a decrease in the frequency of injections for patients (from injections every three- or four-months to injections every six-months for this patient population), such a decrease does not necessarily correlate with the above implications.  The patient population Eligard is approved to treat has advanced disease and is likely to require monitoring and other aspects of disease management; it is not known whether a reduction in the frequency of injections alone would generate a significant improvement to a patient’s comfort, dignity, living arrangements and/or interruptions during retirement.  Furthermore, simply because a patient is able to remain seated during the administration of the drug does not necessarily guarantee comfort with the overall administration process or side effects of Eligard therapy, including those related to the injection (e.g., transient burning/stinging, pain, and bruising).  In the absence of substantial evidence or substantial clinical experience to support these claims, the above presentations misleadingly overstate the efficacy of Eligard. 

Misleading Presentations

The “SEASONAL TRAVELER” patient profile includes the following claims (emphasis added):

•  “Doesn’t want the hassle of seeing two doctors in different cities or traveling for a checkup and an LHRH agonist injection”
•  “Convenience for patients. . . 
  --  There is no longer a need for a doctor in each city”

These claims are misleading because they suggest that the inconvenience of visiting doctors in different cities would be eliminated simply because of Eligard’s dosing schedule.  A decrease in the frequency of injections from three- or four-months to injections every six-months for this patient population does not eliminate the need for a doctor in each city of residence.  It is misleading and inappropriate to suggest that this particular patient population, who are suffering from advanced disease and are likely to exhibit multiple health issues, would no longer need a healthcare provider in each city of residence if they use Eligard. 

In addition, the piece claims, “Fewer injections means fewer reminders that he has cancer; he knows he’s covered without getting confronted with frequent treatments.” We are not aware of support for this claim.  Patients being treated with Eligard have advanced disease and are monitored for early and long-term pharmacological effects such as hot flashes, impotence, decreased libido, gynecomastia and testicular atrophy.  Some of these adverse events are frequent, common (e.g., hot flashes/sweats [57.7%]), and/or severe.  Such adverse events serve as a reminder of the underlying ailment, as do any necessary monitoring or treatment for such adverse events or disease complications.  Thus, the implication that fewer injections will lessen a patient’s awareness of his cancer is not substantiated. 

Unsubstantiated Efficiency and Convenience Claims

The patient profile includes multiple efficiency claims for healthcare providers regarding the use of Eligard in their practice.  Examples of such claims include:

•  “ELIGARD 45 mg: Time To Do More”
•  “Efficiency for you and your practice”
•  “Reduced frequency of LHRH injections means your practice benefits¹”
•  Chart displaying the following benefits to physicians, nurses, or office managers:
   --  “More time for new patients”
   --  “More time with current patients”
   --  “Reduced paperwork, with only 1 reimbursement submission every 6 months”
   --  “Extra flexibility for follow-up visits” -“Simplified inventory management”
•  “Efficiency for you
   --  Two injections a year allows more time for you to see new patients or perform in-office procedures”

These claims misleadingly suggest that treatment with Eligard will improve the efficiency of daily office practice activities for healthcare providers by minimizing time spent on LHRH-associated activities.  The claims suggest that the shift in time requirements will provide physicians, nurses, or office managers more time with current patients, more time for new patients and extra flexibility for follow-up visits. 

Similarly, the patient profile includes multiple convenience claims regarding the use of Eligard for patients.  For example:

•  “Convenience for patients
   --  A 6-month LHRH agonist treatment option instead of a 3- or 4-month option means having the same coverage over the year while spending less time in his doctor’s office.”
•  “Convenience for patients
   --  A less demanding injection schedule makes it easy to keep LHRH appointments in between business trips.”

These patient convenience claims misleadingly suggest that the six-month dosing of Eligard will make it “easy” for patients to keep their medical appointments and spend “less time” at medical appointments. 

We are not aware of any evidence to support the above claims and presentations.  One of the summary claims cites to Eligard’s PI; however, the PI does not provide evidence to support any of the above suggestions.  Treatment of patients with advanced prostate cancer requires regular monitoring, including the measurement of serum testosterone concentrations and prostate specific antigen.  Eligard causes a transient increase in serum testosterone concentrations during the first one to two weeks of therapy.  Accordingly, patients may experience a worsening of symptoms or onset of new symptoms during the first few weeks of therapy.  Some of these symptoms may be severe, such as bone pain, spinal cord compression, or allergic reaction, and may require interaction with healthcare providers.  In particular, patients with metastatic vertebral lesions and/or urinary obstruction must be closely monitored during initial therapy.  Aggravation of these conditions may lead to paralysis, worsening of urinary symptoms or death.  Patients may require additional interaction with healthcare providers to address such events as well as other consequences of treatment with Eligard, such as hot flashes, impotence, decreased libido, gynecomastia, and testicular atrophy.  It can also be anticipated that long periods of medical castration in men will affect bone density, and healthcare providers should adequately monitor patients for potential sequelae. 

Thus, the suggestions that a reduction in the frequency of injections alone has a significant positive impact on time expenditures for healthcare providers and convenience for patients are unsubstantiated and misleading.  Similarly, the suggestion that the use of Eligard will increase efficiency in a healthcare practitioner’s practice, resulting in more time for new and current patients and enhanced schedule flexibility, is unsubstantiated and misleading.  We are not aware of any evidence to support the implications that the use of Eligard will improve efficiency for healthcare providers and convenience for patients.  If you have evidence to support these claims, please submit it to FDA for review. 

In addition, the suggestion that Eligard’s dosing regimen makes it “easy” for patients to keep their LHRH appointments in the absence of any evidence is misleading because there are a multitude of other factors that impact patients’ ability to keep their appointments. 

Conclusion and Requested Action

For the reason discussed above, the patient profile misbrands Eligard in violation of the Act, 21 U.S.C. 352(a) & 321(n).  Cf. 21 CFR 202.1(e)(3)(i), (e)(5), (e)(6)(i) & (e)(7)(viii). 

DDMAC requests that sanofi immediately cease the dissemination of violative promotional materials for Eligard such as those described above.  Please submit a written response to this letter on or before May 4, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Eligard 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 # 18481 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 Eligard comply with each applicable requirement of the Act and FDA implementing regulations. 

Sincerely,

Keith Olin, Pharm.D.
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications

___________________________________________________________

¹  Eligard® (leuprolide acetate for injectable suspension) 7.5 mg, 22.5 mg, 30 mg, 45 mg prescribing information.  Fort Collins, Colo: QLT USA, Inc.;2008.