Released by FDA:  8/17/04.  Posted by FDA:  8/24/04

Mr. Michael W. Bonney
President & CEO
Cubist Pharmaceuticals
65 Hayden Avenue
Lexington, MA 02421

Re:  NDA # 21-572
        Cubicin^TM (daptomycin for injection)
        MACMIS # 12433

Dear Mr. Bonney:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a professional journal advertisement (ad) for Cubicin^TM (daptomycin for injection), submitted by Cubist Pharmaceuticals (Cubist) under cover of Form FDA 2253.  The ad fails to reveal important risk information associated with the use of Cubicin and, therefore, misbrands the drug within the meaning of the Federal Food, Drug, and Cosmetic Act (the Act) and FDA implementing regulations. See 21 U.S.C. 321(n), 352(n); 21 C.F.R. 202.1(e)(3)(i).  Additionally, DDMAC has reviewed promotional statements for this drug that appear on a website (URL: http://www.cubicin.com) maintained by Cubist, and also submitted on Form FDA 2253. The website is misleading because it broadens the indication for Cubicin, fails to reveal important risk information associated with the use of Cubicin, and makes an unsubstantiated comparative claim.  Therefore, the website misbrands Cubicin. See 21 U.S.C. 321(n), 352(a), (n).  Your broadening of the indication for Cubicin and failure to reveal important risk information associated with the use of Cubicin poses serious public health and safety concerns because the inappropriate use of Cubicin can result in therapeutic failure, and increases in morbidity and mortality in infections for which Cubicin has not been proven safe and effective.

Background

The Indications and Usage section of the approved product labeling (PI) for Cubicin states:

"CUBICIN (daptomycin for injection) is indicated for the treatment of complicated skin and skin structure infections caused by susceptible strains of the following Gram-positive microorganisms (see also DOSAGE AND ADMINISTRATION): Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimillis and Enterococcus faecalis (vancomycin-susceptible strains only).  Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms (see CLINICAL STUDIES).

Daptomycin is not indicated for the treatment of pneumonia.

Cubicin is associated with several important contraindications, warnings, precautions, and adverse events.  For example, the Precautions section of the PI for Cubicin contains the following important risk information:

"Skeletal Muscle: In Phase 3 complicated skin and skin structure infection (cSSSI) trials, elevations in serum creatine phosphokinase (CPK) were reported as clinical adverse events in 15/534 (2.8%) daptomycin-treated patients, compared to 10/558 (1.8%) comparator-treated patients. Skeletal muscle effects associated with daptomycin were observed in animals (see ANIMAL PHARMACOLOGY).

Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness, particularly of the distal extremities.  CPK levels should be monitored weekly in patients who receive CUBICIN.  Patients who develop unexplained elevations in CPK while receiving daptomycin should be monitored more frequently. Among patients with abnormal CPK (>500 U/L) at baseline, 2/19% (10.5%) treated with CUBICIN and 4/24 (16.6%) treated with comparator developed further increases in CPK while on therapy. In this same population, no patients developed myopathy. Daptomycin-treated patients with baseline CPK >500 U/L (n=19) did not experience an increased incidence of CPK elevations or myopathy relative to those treated with comparator (n=24).

CUBICIN should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation >1000U/L (-5x ULN), or in patients without reported symptoms who have marked elevations in CPK (>10x UNL).  In addition, consideration should be given to temporarily suspending agents associated with rhabdomyolysis, such as HIVIG-CoA reductase inhibitors, in patients receiving CUBICIN."

Broadening of Indication

Your website implies that Cubicin is safe and effective, and FDA-approved, for the treatment of all infections caused by Staphylococcus aureus (including methicillin-resistant strains).

For example, the following claims appear on the first page of your website:

These claims are misleading because they imply that Cubicin is safe and effective, and FDAapproved, for all infections caused by MRSA and MSSA (e.g., endocarditis and pneumonia), when this has not been demonstrated by substantial evidence or substantial clinical experience.  The PI specifically states that Cubicin is indicated for "the treatment of complicated skin and skin structure infections [cSSSI] caused by susceptible strains of the following Gram-positive microorganisms:  Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimillis and Enterococcus faecalis (vancomycin-susceptible strains only) (emphasis added).  Also, the PI specifically states that "Daptomycin is not indicated for the treatment of pneumonia" (emphasis added). The Adverse Reactions section of the PI also describes an important reason for this limitation: "In Phase 3 studies of community-acquired pneumonia (CAP), the death rate and rates of serious cardiorespiratory adverse events were higher in daptomycin-treated patients than in comparator-treated patients.  These differences were due to lack of therapeutic effectiveness of daptomycin in the treatment of CAP in patients experiencing these adverse events" (emphasis added).

FDA is not aware of substantial evidence or substantial clinical experience to support the efficacy of Cubicin in non-cSSSI infections. Blurring the distinction between cSSSI and non-cSSSI infections by statements that combine and generalize all Staphylococcus aureus infections, such as "Proven clinically successful against MRSA and MSSA," and suggesting that Cubicin is proven safe and effective, and approved by FDA, to treat all such infections is misleading and poses a significant public health risk because such practice could lead to therapeutic failure and death.

Failure to Reveal Important Risk Information

The ad and website fail to reveal material facts in light of representations made and with respect to consequences that may result from the use of the drug as recommended or suggested in the materials.  Specifically, the main part of the ad presents effectiveness claims for Cubicin, such as "New AGAINST STAPH" and "The only once-daily bactericidal antibiotic---with a distinct mechanism of action---proven effective against both MRSA and MSSA," but fails to provide any risk information.  For example, you fail to include information on the risk of increased CPK levels and the risk for development of muscle pain or weakness, which is described in the precautions section of the PI for Cubicin. This information is necessary to qualify the effectiveness claims appearing in the main part of the ad.  The main part of the ad includes a reference to the brief summary of prescribing information; however, this statement is not sufficient to provide the appropriate qualification or pertinent information for the claims made in the main part of the ad. See 21 CFR 202.1(e)(3)(i).

The website is similarly misleading because it fails to reveal important risk information necessary for context on pages containing information about the efficacy of Cubicin.  For example, you fail to include information on the risk of increased CPK levels and the risk for development of muscle pain or weakness, which is described in the Precautions section of the PI for Cubicin.

DDMAC had previously objected, in an untitled letter dated November 22, 2000, to your failure to disclose facts that are material in light of the representations made in promotion about CUBICIN.  Specifically, Cubist failed to disclose important risk information about Cubicin on your website.  We are concerned that you are continuing to promote Cubicin in a similarly violative manner.

Misleading Comparative Claim

Promotional materials are false or misleading if they suggest that a drug is superior to other products when such has not been demonstrated by substantial evidence or substantial clinical experience.  Your website includes the claim "Bactericidal antibiotics are generally regarded as superior to bacteriostatic agents for the treatment of most infections."  This claim implies that, because Cubicin is a bactericidal antibiotic, it is superior to other antibiotics intended for the same conditions when such has not been demonstrated by substantial evidence or substantial clinical experience. F urthermore, as noted in the Adverse Reactions section of the PI and previously described, Cubicin was determined to be inferior to comparator agents in the treatment of CAP.  FDA is not aware of substantial evidence or substantial clinical experience to support the superior efficacy of bactericidal antibiotics compared to bacteriostatic agents.  Furthermore, the statement in your website, "However, clinical data to support this position are lacking except in specific indications," does not adequately correct this misleading presentation.

Conclusion and Requested Action

Your ad and website fail to reveal material facts regarding important risk information associated with the use of Cubicin in accordance with 21 U.S.C. 321(n), 352(a), (n); 21 C.F.R. 202.1(e)(3)(i). F urthermore, your website suggests that Cubicin is useful in all infections caused by MRSA and MSSA when such has not been demonstrated by substantial evidence or substantial clinical experience and makes an unsubstantiated comparative claim in violation of 21 U.S.C. 201(n), 352(a), (n).

DDMAC requests that Cubist immediately cease the dissemination of violative promotional materials for Cubicin such as those described above.  Please submit a written response to this letter on or before August 31, 2004, stating whether you intend to comply with this request, listing all violative promotional materials for Cubicin such as those described above, and explaining your plan for discontinuing use of such materials. Because the violations described above are serious, we request that your submission include a plan of action to disseminate truthful, non-misleading, and complete information to the audience(s) that received the violative promotional materials.  Please direct your response to me at the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, BFD-42 Room 8B-45, 5600 Fishers Lane, Rockville MD 20857, facsimile at 301594-6771.  In all future correspondence regarding this matter, please refer to MACMIS ID # 12433 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 Cubicin 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., MBA
Director
Division of Drug Marketing,
   Advertising, and Communications