Amy D. Rock, Ph.D. 
Senior Director, Regulatory & Scientific Affairs
Cumberland Pharmaceuticals Inc. 
2525 West End Avenue, Suite 950
Nashville, TN 37203

RE:  NDA 021539
       ACETADOTE® (acetylcysteine) Injection
       MACMIS #18719

Dear Dr. Rock:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S.  Food and Drug Administration (FDA) has reviewed a professional Sales Aid (PSA1100709) (sales aid) for ACETADOTE® (acetylcysteine) Injection (Acetadote) submitted by Cumberland Pharmaceuticals Inc.  (Cumberland) under cover of Form FDA 2253.  This piece omits and minimizes risk information associated with the drug, contains unsubstantiated superiority claims, overstates the efficacy of Acetadote, and omits material facts about Acetadote.  Thus, this piece misbrands Acetadote 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)(5)(i) & (iii); (e)(6)(i), (ii) & (iv); and (e)(7)(i). 

Background

The INDICATIONS AND USAGE section of Acetadote’s FDA-approved product labeling (PI) states the following (in pertinent part):

Acetadote, administered intravenously within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen, is indicated to prevent or lessen hepatic injury . . . .
. . . 

Acetadote should be administered within 8 hours from acetaminophen ingestion for maximal protection against hepatic injury for patients whose serum acetaminophen levels fall above the “possible” toxicity line on the Rumack-Matthew nomogram . . . . [emphasis added
. . . 

NOTE: The critical ingestion-treatment interval for maximal protection against severe hepatic injury is between 0 – 8 hours.  Efficacy diminishes progressively after 8 hours and treatment initiation between 15 and 24 hours post-ingestion of acetaminophen yields limited efficacy. 

Acetadote is also associated with serious risks, as reflected in its PI.  For example, Acetadote is contraindicated in patients with previous anaphylactoid reactions to acetylcysteine. 

Furthermore, the WARNINGS AND PRECAUTIONS section of the PI states the following (in pertinent part):

Serious anaphylactoid reactions, including death in a patient with asthma, have been reported in patients administered acetylcysteine intravenously. . . . If a reaction to acetylcysteine involves more than simply flushing and erythema of the skin, it should be treated as an anaphylactoid reaction.  This usually entails administering antihistaminic drugs and in severe cases may require administration of epinephrine.  In addition, the acetylcysteine infusion may be interrupted until treatment of the anaphylactoid symptoms has been initiated and then carefully restarted.  If the anaphylactoid reaction returns upon reinitiation of treatment or increases in severity, intravenous acetylcysteine should be discontinued and alternative patient management should be considered. 

Acetadote should be used with caution in patients with asthma, or where there is a history of bronchospasm. 

The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction. . . . If volume is not adjusted fluid overload can occur, potentially resulting in hyponatremia, seizure and death. 

The ADVERSE REACTIONS section of the PI states the following (in pertinent part):

In the literature the most frequently reported adverse reactions attributed to I.V.  acetylcysteine administration were rash, urticaria and pruritus.  The frequency of adverse reactions has been reported to be between 0.2% and 20.8%, and they most commonly occur during the initial loading dose of acetylcysteine. 

Omission/Minimization of Risk Information

Promotional materials are misleading if they fail to reveal facts that are material in light of 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 sales aid is misleading because it minimizes and omits risks associated with Acetadote.  For example, the sales aid includes the following claims:

•  “‘Intravenous administration, therefore, has advantages when compared with oral NAC administration during the initial dosing period due to the absence of emesis and rapid treatment.’ – Rocky Mountain Poison and Drug Center” (page six; reference omitted)

•  “No nausea or vomiting due to taste and smell” (multiple pages)

These claims are misleading because they minimize the risks of nausea and vomiting associated with Acetadote.  Specifically, these claims imply that treatment with Acetadote results in the “absence of emesis” and that adverse reactions of nausea and vomiting occur exclusively due to the taste and smell of orally administered acetylcysteine, and therefore would not be expected to occur with intravenously administered Acetadote.  However, according to the PI, in the 15-minute loading dose regimen, the following incidences of moderate nausea and vomiting occurred: 6% (n=6) and 10% (n=11), respectively.  In the 60minute loading dose regimen, the following incidences of moderate nausea and vomiting occurred: 1% (n=1) and 6% (n=4), respectively.  Therefore, these presentations are misleading. 

Furthermore, the sales aid omits material information about risks associated with Acetadote.  Although page seven of the sales aid contains an “Important Safety Information” presentation, it fails to disclose important information regarding serious anaphylactoid reactions, including the symptoms that should be treated as anaphylactoid reactions and the steps that should be taken in response to such reactions.  Furthermore, it fails to disclose the most frequently reported adverse events associated with Acetadote.  As a result, the sales aid misleadingly suggests that Acetadote is safer than has been demonstrated by substantial evidence or substantial clinical experience. 

Unsubstantiated Superiority Claims

Promotional materials are misleading if they contain a drug comparison that represents or suggests that a drug is safer or more effective than another drug, when this has not been demonstrated by substantial evidence or substantial clinical experience.  The sales aid includes claims and presentations such as the following:

•  “Make ACETADOTE your first-line choice”

o  “The average transition time from oral NAC to I.V.  NAC (eg, due to excessive emesis) is 4.5 hours ^[1].  Any time lost in the critical 10-hour post-ingestion maximal protection window can increase the risk of liver damage.[1]” (page five; reference renumbered)

•  Graphic of an I.V.  bag and a liver, both inside an hourglass, along with the claims, “Short, 21-hour I.V.  infusion vs 72-hour oral administration” and “3-dose I.V.  treatment vs.  18-dose oral regimen” (front cover)

•  “‘Intravenous administration, therefore, has advantages when compared with oral NAC administration during the initial dosing period due to the absence of emesis and rapid treatment.’ – Rocky Mountain Poison and Drug Center” (page six; reference omitted)

The totality of these claims and presentations comparing Acetadote to oral N-acetylcysteine (NAC) therapy is misleading because it implies superiority over oral NAC.  Specifically, the totality of these claims and presentations implies that Acetadote is more efficacious than oral NAC and that Acetadote prevents time loss and completely prevents emesis.  None of these implications are supported by substantial evidence. 

The Culley, et al. reference cited to provide support for the transition time claim does not constitute substantial evidence to support this claim for several reasons.  First, it is a review article of an open label study of 25 patients treated with IV NAC (most initially administered oral NAC; change in route of administration based on Investigator’s judgment) and a historical control group of 29 patients treated with oral NAC only; such a design is strongly subject to the introduction of bias.  Furthermore, the cited “4.5 hours” transition time is not an accurate summary measure of time to transition patients from oral to IV NAC; rather, this information from the studies just looked at a summary measure of delay in administration rather than prospectively attempting to determine transition time.  In addition, although the transition time claim suggests transition can be “due to excessive emesis,” such a claim is not supported by the Culley, et al.  reference, as the percentages of patients that had delays in therapy due to excessive emesis are not provided in the reference.  Finally, the open label study in the cited reference was conducted 14-24 years ago while the historical control study discussed was conducted 14-21 years ago; therefore, these data may not accurately represent current practice patterns.  Therefore, this reference does not constitute substantial evidence or substantial clinical experience to support the presentation.  In general, claims of superiority should be supported by two adequate and well-controlled head-to-head clinical trials. 

Additionally, while we acknowledge that the claims regarding the length of treatment and number of doses for Acetadote are accurate, when presented in conjunction with the other claims in the sales aid regarding oral NAC, these statements contribute to the misleading impression that Acetadote is superior to oral NAC.  The quote from the Rocky Mountain Poison and Drug Center also contributes to the misleading impression that Acetadote is superior to oral NAC in that it prevents time loss and completely prevents emesis.  As detailed above, this claim is not accurate, as moderate nausea and vomiting were reported in the clinical trials supporting Acetadote’s approval.  We are not aware of any adequate and well-controlled head-to-head clinical trials to support the implication of superiority of Acetadote over oral NAC conveyed by the sales aid.  Therefore, these presentations are misleading. 

Page five of the sales aid includes the following pharmacoeconomic claims (emphasis original):

•  “Reduced treatment time for reduced treatment costs”
•  “ACETADOTE I.V.  treatment can result in reduced treatment costs for hospitals”
•  “The approved Acetadote treatment regimen is 21 hours vs the 72-hour oral regimen.”
•  Chart titled, “Pharmacoeconomic Modeling Results^[2]” (reference renumbered; footnote omitted) that displays the costs of oral n-acetylcysteine (oral NAC) compared to intravenous n-acetylcysteine (IV NAC) in base case, best case, and worst case scenarios at <10 hours post-ingestion and 10-24 hours post-ingestion in intensive care units and wards. 

The cited reference, Marchetti, et al., is not adequately designed to support this presentation.  Specifically, the Marchetti, et al.  pharmacoeconomic model assumes equivalent effectiveness between the two treatment alternatives, when there is no data in the reference to support this assumption.  Absent substantial evidence of equivalent effectiveness, the validity of the treatment cost comparisons cannot be established.  We are not aware of substantial evidence assessing the comparative efficacy of IV versus oral acetylcysteine therapy.  Thus, the implication conveyed by the above presentation (i.e., that Acetadote and oral NAC are comparable in terms of efficacy, and Acetadote offers the added benefit of a reduction in treatment costs compared to oral NAC due to reduced treatment time) is misleading. 

Overstatement of Efficacy

The sales aid includes claims such as, “For maximal protection against hepatic injury – administer ACETADOTE within 8-10 hours post-ingestion” on multiple pages.  This claim is misleading because it indicates that maximum efficacy (“maximal protection”) can be reached when Acetadote is administered between 8 and 10 hours post-ingestion when such has not been demonstrated by substantial evidence or substantial clinical experience.  Rather, the PI states the following (in pertinent part, emphasis added):

The critical ingestion-treatment interval for maximal protection against severe hepatic injury is between 0 – 8 hours.  Efficacy diminishes progressively after 8 hours and treatment initiation between 15 and 24 hours post-ingestion of acetaminophen yields limited efficacy. 

The suggestion that maximal protection can be achieved by administering Acetadote up to 10 hours post-ingestion is therefore misleading.  We are concerned from a public health perspective by your misrepresentation of the optimal dosing timeframe for your drug. 

Omission of Material Facts

Page three of the sales aid includes the Rumack-Matthew Nomogram, followed by a chart listing Plasma or Serum APAP Concentrations, Risk of Hepatotoxicity, and Action (administer or discontinue Acetadote).  The totality of this presentation is misleading because it fails to reveal material information from the Indications and Usage section of Acetadote’s PI.  Specifically, the PI clearly states that the Rumack-Matthew Nomogram does not apply to patients with Repeated Supratherapeutic Ingestion (RSI), a fact which is not disclosed in the sales aid. 

Conclusion and Requested Action

For the reasons discussed above, the sales aid misbrands Acetadote in violation of the Act, 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(5)(i) & (iii); (e)(6)(i), (ii) & (iv); and (e)(7)(i). 

DDMAC requests that Cumberland immediately cease the dissemination of violative promotional materials for Acetadote such as those described above.  Please submit a written response to this letter on or before June 28, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Acetadote 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 #18719 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 Acetadote comply with each applicable requirement of the Act and FDA implementing regulations. 

Sincerely,

Kathleen Klemm, Pharm.D.
Regulatory Review Officer
Division of Drug Marketing, Advertising, and Communications

______________________________________________________________

1  Culley CM, Krenzelok EP.  A clinical and pharmacoeconomic justification for intravenous acetylcysteine: a US perspective.  Toxicol Rev.  2005;24(2):131-143. 

2  Data on file, Cumberland Pharmaceuticals Inc.: Marchetti A. and Rossiter R. Expected Costs to Manage Acute Acetaminophen Poisoning With Oral (PO) or Intravenous (IV) N-acetylcysteine (NAC): Hospital-Perspective Economic Analysis.