Craig Collard
President and Chief Executive Officer
Cornerstone Therapeutics, Inc. 
1255 Crescent Green Drive, Suite 250
Cary, NC 27518

RE:  NDA # 21-222
       Spectracef® (cefditoren pivoxil) Tablets
       MACMIS ID # 16447

Dear Mr. Collard:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed two sales aids (CBS809A0107 [lung sales aid] and CBS813A0307 [skin sales aid]) for Spectracef® (cefditoren pivoxil) Tablets (Spectracef) submitted by Cornerstone Therapeutics, Inc.  (formerly known as Cornerstone BioPharma, Inc.) (Cornerstone) under cover of Form FDA 2253.  The sales aids are misleading because they broaden the indication for Spectracef, omit risks related to its use, make unsubstantiated superiority claims, overstate the efficacy of Spectracef, and make misleading dosing claims.  Thus, the sales aids misbrand the drug 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)(i), (ii); (e)(5); (e)(6)(i), (ii), (vii), (xviii), (xix) & (e)(7)(viii).  These violations are concerning from a public health perspective because they suggest that the product is both safer and more effective than has been demonstrated by substantial evidence or substantial clinical experience.

Background

According to the approved product labeling (PI) (emphasis original): SPECTRACEF® (cefditoren pivoxil) is indicated for the treatment of mild to moderate infections in adults and adolescents (12 years of age or older) which are caused by susceptible strains of the designated microorganisms in the conditions listed below.

Acute Bacterial Exacerbation of Chronic Bronchitis caused by Haemophilus influenzae (including β-lactamase-producing strains), Haemophilus parainfluenzae (including β-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), or Moraxella catarrhalis (including β-lactamase-producing strains).

Community-Acquired Pneumonia caused by Haemophilus influenzae (including βlactamase-producing strains), Haemophilus parainfluenzae (including β-lactamaseproducing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), or Moraxella catarrhalis (including β-lactamase-producing strains).

Pharyngitis/Tonsillitis caused by Streptococcus pyogenes.  NOTE: SPECTRACEF® is effective in the eradication of Streptococcus pyogenes from the oropharynx.  SPECTRACEF® has not been studied for the prevention of rheumatic fever following Streptococcus pyogenes pharyngitis/tonsillitis.  Only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever.

Uncomplicated Skin and Skin-Structure Infections caused by Staphylococcus aureus (including β-lactamase-producing strains) or Streptococcus pyogenes.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of SPECTRACEF® and other antibacterial drugs, SPECTRACEF® should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.  When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.  In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Additionally, the PI contains the following risk information, in pertinent part (emphasis original):

CONTRAINDICATIONS

SPECTRACEF® is contraindicated in patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency, because use of SPECTRACEF® causes renal excretion of carnitine….
SPECTRACEF® tablets contain sodium caseinate, a milk protein.  Patients with milk protein hypersensitivity (not lactose intolerance) should not be administered SPECTRACEF® .

WARNINGS

BEFORE THERAPY WITH SPECTRACEF® (CEFDITOREN PIVOXIL) IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFDITOREN PIVOXIL, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS.  IF CEFDITOREN PIVOXIL IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSSHYPERSENSITIVITY AMONG β-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY.  IF AN ALLERGIC REACTION TO CEFDITOREN PIVOXIL OCCURS, THE DRUG SHOULD BE DISCONTINUED.  SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefditoren pivoxil, and may range in severity from mild to life-threatening.  Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Furthermore, the PI contains a precaution against prolonged use of Spectracef due to the potential for carnitine deficiency, and reports potential drug interactions with antacids, H2receptor antagonists, and probenecid.  Additionally, use of Spectracef 200mg twice daily or 400mg twice daily is associated with the following treatment-related adverse events, respectively: diarrhea (11%, 15%), nausea (4%, 6%), headache (3%, 2%), abdominal pain (2%, 2%), vaginal moniliasis (3%, 6%), dyspepsia (1%, 2%), and vomiting (1%, 1%).

Finally, the Microbiology section of the PI states that “Cefditoren is inactive against methicillin-resistant Staphylococcus aureus.”

Broadening of Indication

Lung and Skin Sales Aids

The sales aids are misleading because they fail to reveal limitations to Spectracef’s indications in the main promotional spreads of the pieces, and therefore suggest that Spectracef is effective for a broader range of conditions than has been demonstrated by substantial evidence or substantial clinical experience.  Labeling for Spectracef is very clear in identifying the “designated microorganisms” to which the drug’s various approved indications (acute bacterial exacerbation of chronic bronchitis (ABECB), community-acquired pneumonia (CAP), uncomplicated skin and skin-structure infections (uSSSI), and pharyngitis/tonsillitis) apply.  However, the promotional pieces simply refer to “susceptible strains,” without indicating the specific organisms.  Specifically, the front promotional spreads on both sales aids claim that:

Spectracef is indicated for the treatment of mild to moderate infections in adults and adolescents 12 years of age or older which are caused by susceptible strains causing Community-Acquired Pneumonia, Acute Bacterial Exacerbation of Chronic Bronchitis, Pharyngitis/Tonsillitis, and Uncomplicated Skin and Skin-Structure Infections.

Similarly, the back cover of each sales aid contains a dosing chart that lists “Community-Acquired Pneumonia,” “Acute Bacterial Exacerbation of Chronic Bronchitis,” “Pharyngitis/Tonsillitis,” and “Uncomplicated Skin and Skin-Structure Infections.” The specific organisms for which the drug is indicated are omitted from each of these presentations of the drug’s indicated infections on the front and back covers.

We note that the back cover of the lung sales aid contains a claim that Spectracef is “a highly potent cephalosporin for the pathogens commonly associated with respiratory diseases,” followed by comparative graphs of Spectracef’s in vitro activity against clinical pneumoniae, H. influenzae, and M. catarrhalis.  This presentation suggests that the drug is effective against the pathogens listed in the graphs for acute bacterial exacerbation of chronic bronchitis (ABECB) or community-acquired pneumonia (CAP).  However, the presentation fails to disclose that these pathogens, along with Haemophilus parainfluenzae (including βlactamase producing strains), are the only organisms against which the drug has been shown to be effective for ABECB or CAP.  There are other bacteria that cause these infections for which Spectracef is not indicated.

The skin sales aid contains a similar presentation; it is headlined with a claim that Spectracef “is a highly potent cephalosporin for the pathogens commonly associated with uncomplicated skin and skin structure infections” followed by comparative graphs of Spectracef’s in vitro activity against clinical isolates of S. aureus and S. pyogenes.  This presentation similarly fails to reveal that these are the only organisms encompassed by the drug’s uSSSI indication.  Furthermore, both of these presentations, like the other presentations described above, lack any disclosure of the specific organisms for which the drug is indicated for either its non-respiratory indications (in the case of the lung sales aid) or its non-uSSSI indications (in the case of the skin sales aid).  Therefore, these presentations do not mitigate the misleading omission of the specific organisms for which the drug is indicated from the presentations of the drug’s indicated infections that appear on the sales aids’ front and back covers.

Moreover, the sales aids’ failure to reveal the specific organisms the drug is effective against causes both pieces to misleadingly suggest that Spectracef is effective against all betalactamase producing organisms that cause CAP when this is not the case.  Both the skin and the lung sales aids present the claims, “Stable β-lactamase profile” and “Spectracef is stable in the presence of β-lactamases, including penicillinases and some cephalosporinases” beneath the chart listing the infections for which Spectracef is indicated on the back cover.  Because this presentation fails to list the causative pathogens (including the β–lactamaseproducing pathogens) against which Spectracef is indicated for these infections, it suggests that Spectracef is stable in the presence of all β–lactamase-producing organisms that cause these infections, including CAP, when this is not the case.  Spectracef is stable in the presence of a variety of β–lactamases, but not all.  For example, it is not stable in the presence of various extended-spectrum β–lactamases, which may be produced by organisms that cause CAP but for which Spectracef is not approved.

Furthermore, both the front and back promotional spreads of the lung and skin sales aids fail to reveal the material limitations to Spectracef’s pharyngitis/tonsillitis indication.  They also fail to reveal the important limitations on use and risk information that were added to the labeling of all antibiotics per the antibiotic labeling rule, 21 CFR 201.24.  The limitations on use and risk information relate to the reduction of resistance and maintenance of antibiotic efficacy by using Spectracef only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.

Lung Sales Aid

In addition to the issues described above, the lung sales aid is further misleading because it implies that Spectracef is effective for treating clinical infections caused by penicillin-intermediate and penicillin-resistant strains of Streptococcus pneumoniae when this has not been demonstrated by substantial evidence or substantial clinical experience.  The sales aid presents a graph that includes in vitro data for Spectracef based in part on the activity of the drug against penicillin-intermediate and penicillin-resistant isolates of Streptococcus pneumoniae.  The graph indicates that Spectracef has a lower MIC₉₀ than cefdinir or cefuroxime against these isolates.  The sales aid also includes the following claims (footnotes omitted):

•  “Spectracef® has 98.4% susceptibility against penicillin-intermediate, penicillin-resistant, and erythromycin-resistant isolates of S. pneumoniae compared to 41.244.5% with other cephalosporins (cefuroxime and cefdinir respectively).”

•  “Spectracef® showed a MIC₉₀ of 1 μg/mL for penicillin-susceptible, -intermediate, and –resistant S. pneumoniae isolates compared to 8 μg/mL for both cefdinir and cefuroxime.”

These claims misleadingly suggest Spectracef is appropriate for use against penicillin-intermediate and penicillin-resistant strains of S. pneumoniae.  However, Spectracef is indicated for use only against penicillin-susceptible strains of S. pneumoniae.  Thus, these claims inappropriately broaden the indication of the drug.

*    *    *

These sales aids thus persistently and misleadingly suggest that Spectracef is effective against a wider range of pathogens than has been demonstrated by substantial evidence.  In conjunction with the omission of the full indication and the other misleading claims and presentations described above, the tagline, “Spectrum. Activity. Efficacy.” contributes to the misleading impression that the spectrum (or range) of organisms covered by Spectracef is wide, that the drug is active in vitro against this wide spectrum, and that it is effective clinically for the treatment of infections caused by this wide range of organisms.

We note that both of these sales aids contain a distinct “Brief Summary”¹ consisting of excerpted information from the full prescribing information on their center pages, and that this spread includes a reprinting of the drug’s full indications from the PI.  However, including this information solely in this distinct part of the sales aid is not sufficient to provide appropriate qualification or pertinent information for claims made in the main promotional parts of the sales aids.  For the pieces to be non-misleading, they must contain the limitations to the indication in each part as necessary to qualify any safety or effectiveness claims made in that part.  Cf.  21 CFR 202.1(e)(3)(i).

Omission of Risk

Lung and Skin Sales Aids

The sales aids are misleading because they fail to reveal facts that are material in light of the representations made in the materials or with respect to the consequences that may result from the use of the drug as recommended or suggested in the materials.  The sales aids present prominent efficacy claims such as:

•  “Spectracef® Changes the Way You WIPE OUT BUGS”
•  “Stable β-lactamase profile”
•  “Spectrum. Activity. Efficacy”

Additionally, the sales aids include the following positive claims about the tolerability of the
drug:

•  “Impressive tolerability”
•  “≤3% discontinuation rate in clinical trials due to adverse events”
•  “Favorable safety profile”
•  “Spectracef does not inhibit the cytochrome P450 enzyme system”
•  “Low potential for drug/drug interactions”
•  “No dosage adjustments necessary for:
   •  Geriatric patients with normal (for their age) renal function
   •  Patients with mild or moderate hepatic impairment or mild renal impairment”

However, the serious risks associated with use of the drug are omitted from the main promotional spreads of the pieces.  These risks include contraindications related to significant carnitine deficiency and milk protein hypersensitivity, warnings related to cross-hypersensitivity among β-lactams, serious acute hypersensitivity reactions, and pseudomembranous colitis, precautions related to use of Spectracef for long-term antibiotic therapy, and common adverse events associated with use of Spectracef.  The main promotional spreads of each sales aid fail to present any of the risks associated with the drug.  Instead, these risks are presented in the “Brief Summary” appearing inside each sales aid that consists of excerpted information from the full prescribing information.  However, including this information solely in this distinct part of the sales aid is not sufficient to provide appropriate qualification or pertinent information for claims made in the main promotional parts of the sales aids.  For the pieces to be non-misleading, they must contain risk information in each part as necessary to qualify effectiveness claims made in that part. Cf. 21 CFR 202.1(e)(3)(i).

Additionally, the claim, “Low potential for drug/drug interactions” is misleading because it minimizes the risk of drug interactions with Spectracef therapy.  The sales aids accurately state that Spectracef does not inhibit the cytochrome P450 system.  However, there are other drug interactions that are important to Spectracef therapy.  For example, the PI reports that antacids and H2-receptor antagonists should not be given with Spectracef due to their potential to reduce Spectracef levels in the plasma.  Therefore, in the absence of context regarding other potential drug interactions, this claim is misleading.

Unsubstantiated Superiority Claims

Lung and Skin Sales Aids

The sales aids are misleading because they use in vitro data to suggest that Spectracef is clinically superior to other antibiotics for respiratory infections and uSSSI when this has not been demonstrated by substantial evidence or substantial clinical experience.  The front cover of each sales aid contains a prominent header that claims, “Spectracef® Changes the Way You WIPE OUT BUGS.” The back covers of the sales aids present graphs comparing the MIC₉₀ of Spectracef versus other antibiotics against pathogens commonly associated with respiratory diseases or uSSSI.  The MIC₉₀ represents the minimum concentration of antibiotic necessary to inhibit 90% of a particular pathogen in vitro.  Each graph shows Spectracef with the lowest MIC₉₀ against each pathogen.  The totality of these presentations imply that Spectracef is the most effective agent for treating respiratory and skin infections, respectively.  However, none of the references cited in support of these presentations present a head-tohead clinical comparison of Spectracef to the other antibiotics.^2,3,4,5,6,7 The references present comparisons of in vitro data only.  In vitro data do not necessarily predict clinical efficacy.  Additionally, several of the studies cited in support of the in vitro data^2,6,7 only tested clinical isolates obtained in Japan and Europe; these data are not sufficient to predict and compare in vitro activity of antibiotic agents against isolates likely to be encountered in U.S.  environments.  We are not aware of substantial evidence or substantial clinical experience to support the implication created by these sales aids that Spectracef is superior to the other listed drugs in the treatment of respiratory or uncomplicated skin and skin-structure infections.

Lung Sales Aid

Similarly, the lung sales aid contains multiple claims regarding the superior potency of Spectracef over other antibiotics used to treat respiratory infections.  These claims include the following (footnotes omitted):

•  “Spectracef® (MIC₉₀ 0.06 mg/L) is the most active against H. Influenzae when compared to other cephalosporins such as cefdinir (MIC₉₀ 1 mg/L) and cefuroxime (MIC₉₀ 4 mg/L).”
•  “Spectracef® was the most potent oral cephalosporin tested; it demonstrated greater than 60-fold more potent activity than cefuroxime, cefprozil, and ampicillin against H. Influenzae.”
•  “Spectracef® showed a MIC₉₀ of 0.5 μg/mL for M. catarrhalis when compared to other cephalosporins which range from 2-4 μg/mL (cefuroxime and cefprozil respectively)."
•  “Spectracef® was the most potent oral cephalosporin tested; it demonstrated 4-fold or greater activity against M. catarrhalis when compared to cefuroxime, cefprozil, and ampicillin.”

For the reasons discussed above, these claims are misleading because they use in vitro data to suggest that Spectracef is clinically superior to other antibiotics for respiratory infections when this has not been demonstrated by substantial evidence or substantial clinical experience.

Skin Sales Aid

The skin sales aid is further misleading because it implies that Spectracef is clinically superior to cefuroxime and cefadroxil in the treatment of uSSSI when this has not been demonstrated by substantial evidence or substantial clinical experience.  The interior promotional spread that appears on the third page of the sales aid contains the following claims⁸:

Spectracef versus cefuroxime
In a randomized, double-blind, multicenter, parallel-group study, 857 patients aged ≥12
years comparing Spectracef 200 mg BID and cefuroxime 250 mg BID for 10 days:

•  Spectracef had a clinical cure rate at the test-of-cure visit of 88% for cellulitis, 91% for wound infection, and 91% for simple abscess compared to 87%, 88%, and 90% for cefuroxime.

Spectracef versus cefadroxil
In a randomized, double-blind, multicenter, parallel-group study, 828 patients aged ≥12
years comparing Spectracef 200 mg BID and cefadroxil 500 mg BID for 10 days:

•  Spectracef had a clinical cure rate at the test-of-cure visit of 94% for wound infection and 85% for simple abscess compared to 90% and 85% for cefadroxil.
•  Spectracef had an overall skin pathogen eradication rate at the test-of-cure visit of 87% compared to 77% with cefadroxil.

These claims misleadingly present clinical cure and pathogen eradication rates that show Spectracef as superior in most cases to comparator antibiotics for selected skin infections.  These analyses are flawed and misleading.  The cure rates and skin pathogen eradication rate presented in the sales aid are not supported by substantial evidence because the data were generated using criteria for clinical cure for both the Spectracef and comparator treatment groups that are inconsistent with the FDA-defined criteria for clinical cure for these trials.  The percentages of patients reported as experiencing “clinical cure” in the sales aid include patients who continued to have multiple (i.e., more than two) remaining symptoms following antibiotic treatment.  However, the approval of Spectracef for uSSSI was based on clinical cure defined as patients having two or less remaining symptoms after treatment.  The primary endpoint of these clinical trials was the overall clinical cure rate across multiple skin infections, not for selected skin infections.  The FDA analysis of the data from the trials demonstrated that the efficacy of Spectracef is similar to cefuroxime and cefadroxil, not superior.  In the clinical trial comparing cefuroxime to Spectracef, the overall cure rate was actually higher for cefuroxime (84%) than for Spectracef (80%).  In the clinical trial comparing cefadroxil to Spectracef, the overall clinical cure rate was 79% for both cefadroxil and Spectracef.  With regard to skin pathogen eradication in the clinical trial comparing Spectracef to cefadroxil, the pathogen eradication rates for the two target pathogens in uSSSI, S.  aureus and S.  pyogenes, were higher for cefadroxil than for Spectracef: 77% and 100%, respectively, for cefadroxil, and 74% and 73%, respectively, for Spectracef.⁹  Pathogen eradication rates for Spectracef versus cefuroxime, which were also higher for cefuroxime than Spectracef, were omitted from the sales aid.  Both clinical trials demonstrated similar efficacy of Spectracef compared to cefuroxime and cefadroxil, not superiority of Spectracef.

In summary, the FDA is unaware of any data demonstrating superior efficacy of Spectracef to any comparator for the treatment of respiratory infections or uSSSI.  In the absence of adequate and well-controlled head-to-head clinical studies of Spectracef versus other antibiotics demonstrating the superior efficacy of Spectracef, claims and presentations suggesting the clinical superiority of Spectracef over other antibiotics are misleading.

Overstatement of Efficacy

Lung and Skin Sales Aids

The sales aids are misleading because they include presentations that overstate the efficacy of Spectracef.  Specifically, the front covers of the sales aids present graphics of either diseased lungs or legs being wiped completely clean of disease and organisms by a prescription for Spectracef.  These images appear underneath a claim stating, “Spectracef® Changes the Way You WIPE OUT BUGS.” These presentations suggest that the drug will “wipe out,” i.e., completely eradicate, lung and skin pathogens and symptoms of infection in patients.  In fact, not all patients in the clinical trials were cured by Spectracef, and even among patients who were assessed as clinical cures, the drug did not necessarily eliminate all symptoms of infection.  The pictures thus suggest that Spectracef is more effective than has been demonstrated by substantial evidence or substantial clinical experience.

Skin Sales Aid

The skin sales aid is also misleading in suggesting that Spectracef is more effective for the treatment of uncomplicated skin and skin-structure infections than has been demonstrated by substantial evidence or substantial clinical experience.  The sales aid includes the following claims regarding Spectracef efficacy in the treatment of individual skin infections:

“In a randomized, double-blind, multicenter, parallel-group study, 857 patients aged ≥12
years comparing Spectracef 200 mg BID and cefuroxime 250 mg BID for 10 days:

•  Spectracef had a clinical cure rate at the test-of-cure visit of 88% for cellulitis, 91% for wound infection, and 91% for simple abscess .  .  .  .”

“In a randomized, double-blind, multicenter, parallel-group study, 828 patients aged ≥12
years comparing Spectracef 200 mg BID and cefadroxil 500 mg BID for 10 days:
o Spectracef had a clinical cure rate at the test-of-cure visit of 94% for wound infection and 85% for simple abscess .  .  .  .

•  Spectracef had an overall skin pathogen eradication rate at the test-of-cure visit of 87% .  .  .  .”

However, these claims are not supported by substantial evidence.  As described above, the cure rates and skin pathogen eradication rate presented in the sales aid were generated using criteria for clinical cure that are inconsistent with the FDA-defined criteria for clinical cure for these trials.  The percentages of patients reported as experiencing “clinical cure” in the sales aid include patients who continued to have multiple (i.e., more than two) remaining symptoms following antibiotic treatment.  However, the approval of Spectracef for uSSSI was based on clinical cure defined as patients having two or less remaining symptoms after treatment.  The FDA analysis of the data from these clinical trials demonstrates that the overall cure rates for Spectracef were 80% (in the trial comparing Spectracef to cefuroxime) and 79% (in the trial comparing Spectracef to cefadroxil).  In the trial comparing Spectracef to cefadroxil, the Spectracef eradication rates for the two most important skin infection pathogens, S.  aureus and S.  pyogenes, were only 74% and 73%, respectively.  These rates are lower than those given in the sales aid.

The skin sales aid is also misleading because it presents in vitro susceptibility data for
S. aureus on the back cover but fails to reveal that the study cited in support of the data was performed using only methicillin-susceptible isolates.  The presentation thus suggests that the susceptibility data presented is representative of Spectracef’s activity against all S.  aureus, including methicillin-resistant S. aureus, when this is not the case.  In fact, as indicated in the Clinical Pharmacology section of the PI, “Cefditoren is inactive against methicillin-resistant Staphylococcus aureus.”

Misleading Dosing

Lung and Skin Sales Aids

The sales aids are misleading because they suggest that drug dosages properly recommended for use in the treatment of certain disease conditions are safe and effective for the treatment of other disease conditions when this is not the case.  The lung sales aid is misleading because it suggests that a Spectracef regimen of 400 mg twice daily (bid) for 10 days is safe and effective for all infections for which Spectracef is indicated when this has not been demonstrated by substantial evidence or substantial clinical experience.  The front cover of the sales aid includes a graphic depicting completely and severely diseased lungs being wiped clean of organisms and disease by a prescription pad presenting the aforementioned dosing regimen for Spectracef.  Beneath the graphic, Spectracef’s four approved indications are partially presented.  However, Spectracef is only indicated for use at this dose and duration for the treatment of ABECB.  CAP is treated with 400 mg bid for 14 days, not 10 days as shown.  In addition, the approved dosing regimen for pharyngitis/tonsillitis and for uSSSI is 200 mg bid for 10 days, not 400 mg as shown.

The skin sales aid is similarly misleading; the front cover includes a graphic depicting diseased legs being wiped clear of organisms and the resultant infection by a prescription for Spectracef 200 mg bid for 10 days.  Beneath the graphic, Spectracef’s four approved indications are partially presented.  The graphic, combined with the partial presentation of Spectracef’s four approved indications at the bottom of the page, suggests that a regimen of 200 mg bid for 10 days is safe and effective for all of the approved indications for Spectracef, including the respiratory infections, when this is not the case.

While the approved dosing regimens for all the infections are presented on the back cover of each sales aid, the location of this information is not sufficient to mitigate the misleading impression created by the graphic and indication claims on the front covers.

Conclusion and Requested Action

The sales aids are broadly misleading because they broaden the indication of Spectracef, omit risks related to its use, make unsubstantiated superiority claims, overstate the efficacy of Spectracef, and make misleading dosing claims.  Accordingly, the sales aids misbrand Spectracef in violation of the Act, 21 U.S.C.  352(a) & 321(n).  Cf. 21 CFR 202.1(e)(3)(i), (ii); (e)(5); (e)(6)(i), (ii), (vii), (xviii), (xix) & (e)(7)(viii).

DDMAC requests that Cornerstone immediately cease the dissemination of violative promotional materials for Spectracef such as those described above.  Please submit a written response to this letter on or before May 18, 2009, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) in use for Spectracef 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 #16447 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 Spectracef 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  Although the brief summary states, "For full prescribing information, see package insert", we note that the sales aids do not appear to have been disseminated with the full FDA-approved product labeling (PI) for Spectracef, in violation of 21 CFR 201.100(d).

²  Inoue M, Kohno S, Yamaguchi K, et al.  PROTEKT 1999-2000: a multicentre study of the antimicrobial susceptibility of respiratory tract pathogens in Japan.  International Journal of Infectious Diseases.  2005;9:27-36.

³  Hoban D, Felmingham D.  The PROTEKT Surveillance Study: Antimicrobial susceptibility of Haemophilus influenzae and Moraxella catarrhalis from community-acquired respiratory tract infections.  Journal of Antimicrobial Chemotherapy.  2002;50 S2:49-59. 

⁴  Sahm DF, Karlowsky, JA, Selman LJ, et al.  Comparative activities of cefditoren and other antimicrobials against recent clinical isolates of H. Influenzae and M. catarrhalis collected throughout the United States.  Presented at: The 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).  Toronto, Ontario, Canada; September 17-20, 2000.  Poster #369. 

⁵  Jacobs MR, Bajaksouzian S, Windau A, et al.  Comparative susceptibility of cefditoren against otitis media isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.  Presented at: The 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).  Toronto, Ontario, Canada; September 17-20, 2000.  Poster #372. 

⁶  Granizo JJ, Fernadez-Roblas R, Coronel P, et al.  In vitro susceptibility of 590 isolates of S.  pyogenes against cefditoren and 10 other antimicrobials.  A multicenter international study in southern Europe (ARISE Project).  Presented at: The 12th European Congress of Clinical Microbiology and Infectious Disease.  Milan, Italy; April 21-24, 2002.  Poster #1368. 

⁷  Fernandez-Roblas R, Granizo JJ, Coronel P, et al.  In vitro susceptibility of 709 isolates of methicillin-susceptible S.  aureus (MSSA) against cefditoren and 10 other antimicrobials.  A multicenter international study in southern Europe (ARISE Project).  Presented at: The 12th European Congress of Clinical Microbiology and Infectious Disease.  Milan, Italy; April 21-24, 2002.  Poster #1366.

⁸  Bucko AD, Hunt BJ, Kidd, SL, et al.  Randomized, double-blind, multicenter comparison of oral cefditoren 200 or 400 mg BID with either cefuroxime 250 mg BID or cefadroxil 500 mg BID for the treatment of uncomplicated skin and skin-structure infections.  Clinical Therapeutics.  2002;24(7):1134-1147.

⁹  The number of S.  pyogenes isolates was small across all arms of the study; thus, no conclusions can be made regarding the comparisons of the drugs.