The FDA’s Office of Prescription Drug Promotion (OPDP) issued its third Untitled Letter of 2022 on June 2 to Althera Pharmaceuticals L.L.C. over a Doctor Info Letter for Roszet (rosuvastatin and ezetimibe) tablets.

The Untitled Letter alleged that the promotional communication "makes false or misleading claims and representations about the risks and the efficacy of Roszet,” which is used to lower cholesterol. “These violations are especially concerning from a public health perspective because the promotional communication creates a misleading impression regarding the safety and effectiveness of Roszet, which is a drug with multiple serious and potentially life-threatening risks.”

The letter noted that Roszet is contraindicated in patients with acute liver failure or decompensated cirrhosis and in patients with hypersensitivity to rosuvastatin, ezetimibe, or any excipients in Roszet. “The PI for Roszet includes warnings and precautions regarding myopathy and rhabdomyolysis, immune-mediated necrotizing myopathy, hepatic dysfunction, proteinuria and hematuria, and increases in HbA1c and fasting serum glucose levels. The most common adverse reactions reported with rosuvastatin were headache, nausea, myalgia, arthralgia, dizziness, asthenia, constipation, and abdominal pain; and with ezetimibe were upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. The most common adverse reactions reported with ezetimibe co-administered with a statin were nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea, back pain, influenza, pain in extremity, and fatigue,” the letter said.

OPDP contended the info letter contained false or misleading claims about Roszet’s efficacy in that “claims about the effect of Roszet, attributing specific levels of LDL-C reductions to the drug product at various dosages, are misleading.” Specifically, the letter noted that “the LDL-C reductions claimed in the promotional communication are not the findings of any study of Roszet. Rather, the analysis used to generate these percentages combines the results of two separate and unrelated studies from the CLINICAL STUDIES section of the Roszet PI.”

“The LDL-C reductions represented in the claims that are attributed to Roszet actually depict numbers that were retrospectively calculated by combining the results of these two unrelated studies, neither of which evaluated the specific combination of rosuvastatin and ezetimibe (i.e., Roszet). In fact, rosuvastatin was not actually one of the statins used in the study of ezetimibe added to ongoing statin therapy,” OPDP said.

The Untitled Letter noted that the LDL-C reductions claimed in the promotional communication for each dose of Roszet were calculated by taking the percent change from baseline LDL-C reduction observed in the rosuvastatin monotherapy study and then applying an additional 25 percent LDL-C reduction, which was observed in the separate ezetimibe added to ongoing statin therapy study. “FDA is not aware of a scientific basis for combining study results in this manner,” the Untitled Letter said.

OPDP also noted that the studies differed in patient population and type and dose of statin(s), as well as duration. “Such differences between studies limit the interpretability of any cross-study comparisons and any analysis combining the results of these studies. Thus, such an analysis does not support these claims that attribute specific levels of LDL-C reductions to each dose of Roszet. The clinical studies described in the Roszet PI and cited in the promotional communication support FDA’s finding of safety and efficacy of the drug with respect to its labeled indication, involving the reduction of LDL-C in certain patients, but not in achieving the specific levels of LDL-C reductions claimed. Thus, the promotional communication creates a misleading impression regarding the effect of Roszet,” OPDP concluded.

The FDA also alleged that two other studies cited in the Doctor Letter did not “support claims and presentations regarding the magnitude of treatment effect of Roszet on LDL-C” due to multiple limitations of design and analytic strategy.

The Untitled Letter also alleged that claims such as, “Roszet Delivers Powerful LDL-C Reductions” and “Patients Can Get Below 70 mg/dL with One Pill Daily,” were “misleading because they omit material information from the full indication about the relative effect of diet. According to the INDICATIONS AND USAGE section of the PI, one of Roszet’s indications is as an adjunct to diet to reduce LDL-C in patients with primary non-familial hyperlipidemia.”

While OPDP acknowledged that the full indication was included at the bottom of page one of the promotional communication, the agency found that “unlike the benefit claims in the promotional communication, which utilize significant white space and large colorful font, the full indication is included under an “Important Safety Information” header in paragraph format in a much smaller font size and with minimal white space at the bottom of the page. Therefore, this does not mitigate the misleading impression. By omitting this information from these claims, this presentation misleadingly suggests that Roszet alone, in the absence of diet, provides these benefits to patients with primary non-familial hyperlipidemia when this has not been demonstrated.”

The Untitled Letter also alleged the promotional communication was misleading because it failed to “present information relating to the contraindications and warnings and precautions for Roszet with a prominence and readability reasonably comparable with the presentation of information relating to the benefits of Roszet. Factors impacting prominence and readability include typography, layout, contrast, headlines, paragraphing, white space, and other techniques apt to achieve emphasis.”

OPDP noted the benefit claims were presented in conjunction with colorful graphics and large bolded headlines, with significant white space but the risk information regarding some of the contraindications was relegated to the bottom of the first page and the remaining contraindications and warnings and precautions were presented on a subsequent page.

In addition, the risk information was presented in small font and in paragraph format. “We note that some of the most common adverse reactions are presented in the body of the promotional communication in table format under the header ‘Safety and Tolerability.’ However, only presenting common adverse reactions associated with Roszet under this header and relegating the serious risks (i.e., contraindications and warnings and precautions) to the bottom of the page and subsequent page in small font and paragraph format creates a misleading impression regarding the risk profile of Roszet,” the Untitled Letter said.

“For example, event rates for myalgia are prominently presented under the header ‘Safety and Tolerability,’ however the warning and precaution for myopathy and rhabdomyolysis is relegated to the subsequent page in small font and paragraph format. The overall effect of disclosing risk information in this manner undermines the communication of risk information and thereby misleadingly minimizes the risks associated with the use of Roszet.”

Editor’s Note: All FDA Warning and Untitled Letters are available in Thompson Information Services’ FDA Enforcement Letter Database, which is available to subscribers of Thompson's FDA Compliance Expert.