FDA Sends Warning Letter to King Pharmaceuticals Over Embeda Videos

ROCKVILLE, Md., Oct. 21, 2009--The Food and Drug Administration today posted on its website a warning letter send to King Pharmaceuticals over two Embeda video news releases. The letter is below.

 King Pharmaceuticals Inc 10/8/09
  
 Department of Health and Human Services
Public Health Service
Food and Drug Administration
  Silver Spring, MD 20993


TRANSMITTED BY FACSIMILE


Brian A. Markison
Chairman, President and Chief Executive Officer
King Pharmaceuticals, Inc.
501 Fifth Street
Bristol, TN 37620


RE: NDA 22-321
EMBEDA™ (morphine sulfate and naltrexone hydrochloride) Extended Release Capsules for oral use - CII
MACMIS # 17810


WARNING LETTER


Dear Mr. Markison:
The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed two video news releases [EMBEDA™ Media Backgrounder (EMB6171) and EMBEDA™ Visual Media Technology (EMB6544)] for EMBEDA™ (morphine sulfate and naltrexone hydrochloride) Extended Release Capsules for oral use – CII (EMBEDA) submitted by King Pharmaceuticals Inc. (King) under cover of Form FDA 2253. These video news releases are false or misleading because they omit and minimize the risks associated with EMBEDA, fail to present the limitations to its approved indication, and present misleading claims. The video news releases therefore misbrand the drug in violation of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(5) & (e)(6)(i).

We are especially concerned from a public health perspective because the video news releases completely omit the potential risk of fatality as described in the extensive Boxed Warning and WARNINGS AND PRECAUTIONS sections of the approved product labeling (PI) for EMBEDA. The video news releases present limited information about the abuse potential of EMBEDA, yet make unsubstantiated claims regarding the reduction in abuse liability with EMBEDA. The omission of serious and potentially fatal risks associated with the use of EMBEDA, as well as the misleading presentation of the potential for abuse, is especially egregious and alarming in its potential impact on the public health.

DDMAC acknowledges that, following a teleconference between DDMAC and King on August 27, 2009, during which DDMAC outlined its serious concerns with the risk presentations in the pieces discussed above, King committed to comply with DDMAC’s request to immediately cease the dissemination of these materials and any materials with similar risk presentations for EMBEDA. We appreciate this commitment and the steps that King has taken thus far to address some of the issues outlined in this letter.

Background
EMBEDA is an extended-release oral formulation of morphine sulfate and naltrexone hydrochloride recently approved for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. EMBEDA was approved with a Risk Evaluation and Mitigation Strategy (REMS) due its potential for abuse, misuse, overdose and addiction. The INDICATIONS AND USAGE section of the PI for EMBEDA includes several important limitations to the drug’s indication as follows:

EMBEDA is NOT intended for use as a prn analgesic.
EMBEDA is not indicated for acute/postoperative pain or if the pain is mild or not expected to persist for an extended period of time.
EMBEDA is only indicated for postoperative use if the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesic as appropriate.

EMBEDA is associated with a number of serious risks, many of which are potentially fatal. The PI includes the following Boxed Warning concerning potentially fatal overdosing if EMBEDA capsules are chewed, crushed, or dissolved, or co-ingested with alcoholic beverages or prescription or non-prescription medications that contain alcohol, and describing other serious risks:

WARNING: EMBEDA™ capsules contain morphine, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid agonists. EMBEDA can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing EMBEDA in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

EMBEDA contains pellets of an extended-release oral formulation of morphine sulfate, an opioid receptor agonist, surrounding an inner core of naltrexone hydrochloride, an opioid receptor antagonist indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

EMBEDA is NOT intended for use as a prn analgesic.

EMBEDA 100 mg/4 mg IS FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. Ingestion of these capsules or the pellets within the capsules may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids.

Patients should not consume alcoholic beverages while on EMBEDA therapy. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on EMBEDA therapy. The co-ingestion of alcohol with EMBEDA may result in an increase of plasma levels and potentially fatal overdose of morphine. EMBEDA is to be swallowed whole or the contents of the capsules sprinkled on apple sauce. The pellets in the capsules are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of morphine.

Crushing, chewing, or dissolving EMBEDA will also result in the release of naltrexone which may precipitate withdrawal in opioid-tolerant individuals.

The PI states that EMBEDA is contraindicated in patients with known hypersensitivity to morphine, morphine salts, naltrexone, or in any situation where opioids are contraindicated. EMBEDA is also contraindicated in patients with significant respiratory depression or severe bronchial asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment, as well as in any patient who has or is suspected of having paralytic ileus. The PI includes WARNINGS AND PRECAUTIONS related to crushing, chewing, or dissolving the capsule due to the potential for fatal morphine overdose, particularly in opioid-naïve patients, and to the risk of precipitating withdrawal symptoms in opioid-tolerant patients. The PI contains additional WARNINGS AND PRECAUTIONS regarding the potential for abuse, which can lead to overdose and death, the potential for fatal drug interactions with alcohol and other drugs of abuse, impaired respiration, use in patients with head injuries and/or increased intracranial pressure, hypotensive effects, interactions with other CNS depressants, gastrointestinal effects, use in patients scheduled for cordotomy, use in patients with biliary tract disease, including acute pancreatitis, tolerance and dependence, and use in special risk groups (e.g., elderly or debilitated patients, patients with severe renal or hepatic insufficiency, patients with Addison’s disease, myxedema, hypothyroidism, prostatic hypertrophy or urethral stricture, or patients with CNS depression, toxic psychosis, acute alcoholism, and delirium tremens). The PI also includes WARNINGS AND PRECAUTIONS related to driving and operating machinery, anaphylaxis, accidentally precipitated withdrawal, and laboratory tests.

The ADVERSE REACTIONS section of the PI indicates that EMBEDA may be associated with serious adverse reactions in clinical use including respiratory depression, respiratory arrest, apnea, circulatory depression, cardiac arrest, hypotension, and/or shock. The most common adverse events seen on initiation with EMBEDA include drowsiness, dizziness, constipation, and nausea.

The PI outlines several serious drug interactions for EMBEDA, including interactions with CNS depressants, muscle relaxants, mixed agonist/antagonist opioid analgesic, monoamine oxidase inhibitors, cimetidine, diurectics, antichorlinergics and P-Glycoprotein inhibitors.

The Pharmacodynamics section of the PI states that the clinical significance of the degree of reduction in drug liking and euphoria reported in clinical trials has not been established and there is no evidence that the naltrexone in EMBEDA reduces the abuse liability of EMBEDA.

Omission and Minimization of Risk
Promotional materials are misleading if they fail to reveal facts that are material 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. Both video news releases are misleading because they make efficacy claims regarding EMBEDA but omit and minimize serious and potentially fatal risks associated with EMBEDA. For example, the video news releases include claims related to EMBEDA such as:

• “EMBEDA™ is the first opioid approved by the FDA with pharmacological properties developed in response to the need for opioid analgesics that could reduce drug liking and euphoria when tampered with by crushing or chewing.” (Media Backgrounder)

• “Using an innovative and patented technology, EMBEDA™ contains pellets of an extended-release (ER) formulation of morphine sulfate surrounding an inner core of naltrexone hydrochloride.” (Visual Media Technology)

• “If crushed or chewed, the naltrexone within EMBEDA™ is released and absorbed with the morphine. Naltrexone reverses the subjective and analgesic effects of morphine….” (Media Backgrounder, Visual Media Technology)

Each piece contains an Important Safety Information section that discloses some of the risks associated with the drug. However, both pieces entirely fail to disclose the potential for fatal risks associated with EMBEDA. For example, while the Important Safety information section in each piece indicates that EMBEDA should not be crushed, chewed, or dissolved, it completely omits the information in the BOXED WARNING and WARNING AND PRECAUTIONS sections of the EMBEDA PI that crushing, chewing, or dissolving the capsules results in a rapid release and absorption of a potentially fatal dose of morphine. Similarly, while these Important Safety Information sections indicate that “Patients should not consume alcoholic beverages or use prescription or nonprescription medications containing alcohol while on EMBEDA™ therapy,” they fail to reveal that co-ingestion of alcohol with EMBEDA may result in a potentially fatal overdose of morphine. The pieces also entirely fail to disclose the fact that the use of EMBEDA by opioid-naïve patients can cause fatal respiratory depression. Furthermore, while, as stated above, the pieces indicate that the EMBEDA capsules should not be crushed, chewed or dissolved, and go on to indicate that such tampering will result in the release of naltrexone, they fail to reveal the risk of precipitation of withdrawal in opioid-tolerant individuals associated with this naltrexone release.

In addition, other serious adverse reactions associated with EMBEDA have been omitted from the promotional materials such as respiratory arrest, apnea, circulatory depression, cardiac arrest, hypotension, and/or shock.

The overall presentation of risk information within these promotional materials grossly minimizes the serious potential risks associated with EMBEDA. We are particularly concerned that these significant risk omissions, taken in conjunction with the presentations quoted above from the pieces regarding EMBEDA’s innovative technology and pharmacological properties, misleadingly suggests that EMBEDA is not associated with the fatal risks of opioid analgesics due to the naltrexone component of the formulation when this is not the case. Your minimization of the serious risk profile of your drug raises severe public health concerns.

Broadening of Indication
The video news releases omit important limitations to EMBEDA’s indication. Specifically, they fail to disclose that EMBEDA is not intended for acute/postoperative pain or if the pain is mild or not expected to persist for an extended period of time. EMBEDA is only for postoperative pain when the patient is already receiving chronic opioid therapy or if the pain is expected to be moderate to severe and persist for an extended period of time. By failing to disclose these limitations, the video press releases misleadingly imply that EMBEDA is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. This is especially concerning given that neither of these pieces reveals the potentially fatal risks associated with the use of EMBEDA in opioid-naïve patients.

Misleading Claims
As noted above, the video news releases present claims such as:

• “EMBEDA™ is the first opioid approved by the FDA with pharmacological properties developed in response to the need for opioid analgesics that could reduce drug liking and euphoria when tampered with by crushing or chewing.”
(Media Backgrounder) (emphasis added)

• “Naltrexone reverses the subjective and analgesic effects of morphine” (Media Backgrounder)

• “Naltrexone reverses the subjective and analgesic effects of morphine by competitively binding at mu-opioid receptors.” (Visual Media Technology)

This first claim implies that EMBEDA’s pharmacological properties have been shown to have a clinically significant effect in reducing drug liking and euphoria when the drug is tampered with. The second and third claims imply that the naltrexone in EMBEDA will reverse the subjective and analgesic effects of morphine, thus reducing the likelihood of a morphine overdose if the drug is crushed, chewed, or dissolved. However, EMBEDA’s formulation has not been shown to confer abuse resistance and reduced abuse liability. The PI for EMBEDA states that the clinical significance of the degree of reduction in drug liking and euphoria has not yet been established, and that there is no evidence that the naltrexone in EMBEDA reduces the abuse liability of EMBEDA. We acknowledge that the promotional materials present the statement, “The clinical significance of this effect has not been established, and there is no evidence that the naltrexone in EMBEDA™ reduces the abuse liability of EMBEDA™”; however, this does not mitigate the misleading implication created by these presentations in the pieces that EMBEDA’s properties result in abuse resistance and decreased abuse liability.

Moreover, we remind you that during a teleconference between DDMAC and King on March 19, 2009, similar concerns were communicated to King about claims and presentations that imply abuse resistance and decreased liability with EMBEDA, which are not supported by substantial evidence.

Conclusion and Requested Action
For the reasons discussed above, the video news releases misbrand EMBEDA in violation of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(5) & (e)(6)(i).

DDMAC requests that you submit a written response to this letter on or before October 23, 2009, with a complete listing of the promotional materials that you have discontinued for EMBEDA as a result of the August 27, 2009, teleconference and this letter. 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 17810 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 EMBEDA 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,
{See appended electronic signature page}
Thomas Abrams, RPh, MBA
Director
Division of Drug Marketing,
Advertising, and Communications
 
Application       Submission           Submitter Name      Product Name
Type/Number    Type/Number
NDA-22321       ORIG-1               ALPHARMA              EMBEDA
                                              PHARMACEUTICA
                                              LS LLC KING
                                             PHARMACEUTICA
                                             LS
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This is a representation of an electronic record that was signed electronically
and this page is the manifestation of the electronic signature.
----------------------------------------------------------
/s/
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THOMAS W ABRAMS
10/08/09

Posted: October 2009


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