King Pharmaceutical.

Bristol, TN, March 24 (DDMAC)

The Division of Drug Marketing, Advertising, and Communications (DDMAC) warned that Avinza (morphine sulfate extended-release capsules) is misbranded because its 22-page File Card is false or misleading and fails "to communicate and minimizes risks associated with its use, fails to present the limitations to its approved indication, and presents unsubstantiated efficacy claims," FDA wrote in its warning letter.

"We are especially concerned from a public health perspective because the File Card fails to present any information from the extensive Boxed Warning and Warnings sections of the approved product labeling (PI) for Avinza or any information about the abuse potential of Avinza, a controlled substance under Schedule II of the Controlled Substances Act," FDA wrote, omissions that "are exacerbated by the fact that the File Card minimizes the little risk information that is presented."

Further, FDA stated that the File Card implied that the drug may be used for a much broader range of patients and conditions than indicated. The File Card also makes several unsubstantiated efficacy claims about the outcomes of treatment with Avinza, FDA stated.

"The combination of such broad and unsubstantiated efficacy claims about the benefits of Avinza and the omission of the serious, potentially fatal risks associated with its use, as well as its potential for abuse, is especially egregious and alarming in its potential impact on the public health," the agency wrote.

The Indications and Usage section of the FDA-approved product labeling for Avinza states that the capsules "are a modified-release formulation of morphine sulfate intended for once daily administration indicated for the relief of moderate to severe pain requiring continuous, around-the-clock opioid therapy for an extended period of time." The label states that Avinza is not intended for use as a prn analgesic nor in the postoperative setting.

The label also warns that Avinza is associated with a number of serious risks, many of which are potentially fatal. The PI includes a Boxed Warning concerning potentially fatal overdosing if Avinza capsules are chewed, crushed, or dissolved, or combined with alcoholic beverages or medications containing alcohol.

The PI states that Avinza is contraindicated in patients with respiratory depression in the absence of resuscitative equipment and in patients with acute or severe bronchial asthma. The label also includes warnings related to the maximum daily dose of Avinza; the potentially fatal abuse potential of opioids; interactions with alcohol and drugs of abuse; impaired respiration; head injury and increased intracranial pressure; hypotensive effect; and gastrointestinal obstruction. The PI outlines several serious drug interactions for Avinza, including central nervous system (CNS) depressants, muscle relaxants, mixed agonists/antagonist opioid analgesics, monoamine oxidase inhibitors and cimetidine.

The File Card is misleading, FDA stated, because it presents numerous efficacy claims for Avinza, but the risk information lists only the most common adverse events associated with the use of opioids and minimal information about the drug's physical dependence.

Inclusion of the statement, "Please see full Prescribing Information enclosed," in fine print on the bottom of the last page of the 22-page File Card does not mitigate this misleading omission of risk information, FDA wrote.

The File Card fails to disclose the limitations to the drug's indication, the agency observed. Specifically, the material presents broad claims that Avinza is indicated "For Chronic Moderate-to-Severe Pain" (front cover) and "Continuous 24-Hour Pain Relief" (front cover) without revealing that Avinza is only for the relief of moderate-tosevere pain requiring continuous, around-the-clock therapy for an extended period of time.

The material makes misleading claims, implying that an outcome of treatment with Avinza is the ability to resume an active lifestyle. "FDA is not aware of any evidence to support these claims. In fact, no references were cited to support them. Furthermore, the accuracy of this implication is called into question by the modest reduction in pain intensity Avinza has been shown to provide," the agency wrote. Avinza reduced pain intensity by an average of 18.5% versus 4% pain reduction in patients taking placebo.

Additionally, in conjunction with a graph entitled, "Improvement in Physical Function Score From baseline (mm)," the File Card presents claims of improved overall function, long lasting improvements in physical function and sustained improvement over months. These claims are misleading, FDA wrote, suggesting that patients who are treated with the drug experience an improvement in their overall function, social function and ability to perform daily activities "when this has not been demonstrated by substantial evidence or substantial clinical experience." Similarly, claims that that Avinza improves sleep quality are misleading, according to FDA.

DDMAC requested that King Pharmaceuticals "immediately cease the dissemination of violative promotional materials for Avinza such as those described above" and submit a written response on or before April 7 stating "whether you intend to comply with this request, listing all violative promotional materials for Avinza such as those described above, and explaining your plan for discontinuing use of such materials."

Because the violations described are serious, FDA requested further that the 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." F-B; Lab