First OPDP Warning Letter of 2019 Focuses on Risk Information

J.W. Schomisch
August 27, 2019 at 12:51 PM EST
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The FDA Office of Prescription Drug Promotion (OPDP) issued its first Warning Letter of 2019. The Aug. 16 letter was sent to Metuchen Pharmaceuticals over a direct-to-consumer print ad and two web display banners that allegedly failed to include important risk information.

The ad and banners were for the Freehold, N.J., company’s Stendra (avanafil) tablets, for oral use, which contain a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction.

OPDP said Stendra is contraindicated with any form of organic nitrates, in patients with known hypersensitivity to any component of the tablet, and in patients who are using a guanylate cyclase stimulator. The PI for Stendra includes warnings and precautions regarding cardiovascular risks, concomitant use of CYP3A4 inhibitors, prolonged erection, effects on eye, sudden hearing loss, alpha-blockers and other antihypertensives, alcohol, combination with other PDE5 inhibitors or erectile dysfunction therapies, effects on bleeding, and counseling patients about sexually transmitted diseases. The most common adverse reactions reported with use of Stendra include headache, flushing, nasal congestion, nasopharyngitis, and back pain.

The Warning Letter said the print ad, slated to appear in CardioSmart magazine, included several efficacy claims for Stendra, as well as a statement communicating the warning and precaution regarding alcohol and most common side effects of Stendra. “However, the print ad fails to disclose any of the contraindications or other warnings and precautions associated with the product.”

The letter added the print ad included the claims – “Treat ED and Reduce Risk of Heart Failure with a PDE-5 Inhibitor,” and “Stendra (Avanafil) is . . . safe and effective for those with heart disease . . . .” “These claims are false or misleading because they suggest that Stendra is safe for all patients with heart disease, including all patients with heart failure. While there is evidence that PDE-5 inhibitors, including Stendra, may be safe and effective for men with some types of heart disease, the PI for Stendra contains a warning and precaution for cardiovascular risks associated with the drug. These risks include avoiding use of Stendra in men for whom sexual activity is inadvisable because of their underlying cardiovascular status, the particular sensitivity to the actions of Stendra of patients with left ventricular outflow obstruction or severely impaired autonomic control of blood pressure, and the potential for Stendra to augment the blood pressure-lowering effect of other anti-hypertensive medications, such as alpha-blockers, which may lead to hypotension,” the Warning Letter said.

The print ad also included the claim “Stendra is the next-generation, PDE-5 inhibitor that improves erectile function.” “This claim is misleading because it suggests that by being ‘the next-generation, PDE-5 inhibitor,’ Stendra is safer or more effective than its competitors. No references were cited in support of this claim and we are not aware of evidence to support the suggestion that Stendra is safer or more effective than its competitors,” the letter said.

OPDP requested that the company submit any  data it might have to support this claim to  to the FDA for review.

The Warning Letter added that the print ad “prominently presents efficacy claims in large, bolded font size and colorful text and graphics surrounded by a significant amount of white space. In contrast, the limited risk information is presented in much smaller font size, surrounded by little white space, and in single-spaced format at the bottom of the ad. As such, the print ad fails to present the risk information with a prominence and readability reasonably comparable to the presentation of information relating to the effectiveness of the drug, thus further minimizing the risks associated with Stendra.”

The Warning Letter added that the print ad headline stated: “Treat ED and Reduce Risk of Heart Failure with a PDE-5 Inhibitor.” “This claim provides evidence that Stendra is intended for a new use for which it lacks approval, and for which its labeling does not provide adequate directions for use. Stendra is not approved for reducing the risk of heart failure, and its labeling does not contain adequate directions for such use, thereby rendering the drug misbranded. This claim, which misleadingly suggests that Stendra is safe and effective for a use for which it is not approved and for which you have provided no evidence to support, is especially concerning from a public health perspective given that the PI contains a warning and precaution regarding cardiovascular risks, and specifically states that Stendra is not recommended for patients with New York Heart Association Class 2 or greater congestive heart failure,” the letter said. 

FDA Also Concerned With Banner Claims

The letter noted that one of the banners includes the claims – “Get Hard & Stay Hard” and “Indulge in life’s sweetest pleasures whenever you want,” but failed to communicate any risk information about the product. “These presentations create a misleading impression about the product’s safety, which is further exacerbated by the efficacy claim, ‘Get Hard & Stay Hard’ when there is a warning and precaution regarding prolonged erection, which can result in irreversible damage to the erectile tissue,” OPDP said.

The second banner included the claims: “The ED Pill For Your Lifestyle,” “Stendra prescriptions can be taken with or without food and alcohol,” “The Fast-Acting ED Prescription,” and “Stendra can be effective in as little as 15 minutes, with or without food.”

OPDP noted that although the banner included the statement – “Common side effects include: headache, flushing, and nasal congestion” – it  failed “to include any of the contraindications or warnings and precautions of the drug, creating a misleading impression about the safety of Stendra. This misleading impression is further exacerbated by claiming that ‘Stendra prescriptions can be taken with or without food and alcohol,’ while failing to disclose that there is a specific risk related to drinking too much alcohol when taking Stendra which can increase patients’ chances of headache, dizziness, increased heart rate, or lowered blood pressure.”

The letter acknowledged that the Clinical Studies section of the PI stated that food and alcohol intake was not restricted during the studies. “However, this does not mitigate the omission of material information regarding the risk of alcohol use with Stendra as described in the Warnings and Precautions and Patient Counseling Information sections of the PI and in the Patient Information,” OPDP said.

“By omitting risks associated with Stendra, the banners and print ad fail to provide material information about the consequences that may result from the use of the drug and create a misleading impression about the drug’s safety,” the Warning Letter said. “These misleading presentations are especially problematic from a public health perspective due to the multiple serious risks associated with the drug.”

OPDP acknowledged that the banners and print ad include the statements – “Ask your doctor for more information” and “Learn more at BIT.LY/STENDRA.” “However, these statements do not mitigate the misleading impressions regarding Stendra’s safety created by the omission of risk information from the banners and print ad.”

The Warning Letter added the banner claim – “Indulge in life’s sweetest pleasures whenever you want” – “is misleading because it suggests that Stendra can safely be dosed to provide efficacy at any timepoint (i.e., ‘whenever you want’), when this is not the case,” as the PI states “the maximum recommended dosing frequency is once per day.

In addition, “the duration of Stendra’s effect is inconclusive. The development program for Stendra evaluated the efficacy of the drug between 15 minutes and two hours of dosing. Data points beyond two hours of dosing were too few to support meaningful efficacy conclusions. Therefore, given that the PI recommends a maximum dosing frequency of once a day and that efficacy beyond two hours after administration is inconclusive, the claim that Stendra is effective ‘whenever’ a patient wants is misleading.”

The agency requested that if the company had data to support this claim, it should submit it to the FDA for review.

The Warning Letter also said the banner representations of “Get Hard & Stay Hard” and “Indulge in life’s sweetest pleasures whenever you want”  were misleading because they failed to communicate material information regarding the indication for Stendra. “Specifically, they omit the following material information from the Indications and Usage section of the PI: Stendra is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction. By omitting this information, the banners create a misleading impression about the indication for Stendra. Specifically, they create the misleading impression that Stendra has been demonstrated to be safe and effective as an aid to achieve and maintain an erection for people other than those with the medical condition of erectile dysfunction (ED). The omission of the indication is particularly concerning from a public health perspective due to the serious health risks associated with Stendra,” the Warning Letter said.

OPDP requested the company “immediately cease misbranding Stendra and/or cease introducing the misbranded drug into interstate commerce.” The agency also requested the company submit a written response to FDA by Aug. 30 stating whether it intends to comply with the request and including a listing of all promotional materials (with the 2253 submission date) for Stendra that contain representations such as those described in the Warning Letter and an explanation of the company’s plan for discontinuing the use of such materials, or, in the alternative, for ceasing distribution of Stendra.

In addition, because the violations were serious, OPDP requested a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in the letter to the audience(s) that received the violative promotional materials.

“In order to clearly identify the violative promotional piece(s) and/or activity and focus on the corrective message(s), OPDP recommends that corrective piece(s) include a description of the violative promotional piece(s) and/or activity, include a summary of the violative message(s), provide information to correct each of the violative message(s), and be free of promotional claims and presentations,” the Warning Letter said. “To the extent possible, corrective messaging should be distributed using the same media, and generally for the same duration of time and with the same frequency that the violative promotional material was disseminated. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration,” the letter said.

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.

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