AcelRx Pharmaceuticals, Inc.

The Office of Prescription Drug Promotion (OPDP) of the U.S. Food and Drug Administration (FDA) has reviewed an “SDS Banner Ad” (banner) (PM-US-DSV-0018) and a tabletop display (PM-US-DSV-0049) (display) for DSUVIA (sufentanil) sublingual tablet, CII (Dsuvia) submitted by AcelRx Pharmaceuticals, Inc. (AcelRx) under cover of Form FDA 2253. The promotional communications, the banner and display, make false or misleading claims and representations about the risks and efficacy of DSUVIA. Thus, the banner and display misbrand Dsuvia within the meaning of the Federal Food, Drug and Cosmetic Act (FD&C Act) and make its distribution violative. 21 U.S.C. 352(a), (n); 321(n); 331(a). See 21 CFR 202.1(e)(3)(ii); (e)(5); (e)(7)(viii). Oral opioids, such as Dsuvia, include risks for accidental ingestion, which may lead to fatal respiratory depression. To address such concerns associated with DSUVIA, the drug is subject to a Risk Evaluation and Mitigation Strategy (REMS) that restricts its use to certain healthcare settings, and the drug’s labeling includes strong limitations on its use and detailed administration instructions. These violations are especially concerning from a public health perspective given the importance of the administration instructions intended to protect from the serious and potentially life-threatening risks that may result from the accidental exposure to misplaced tablets of Dsuvia or overdosage with Dsuvia.

Below are the indication and summary of the most serious and most common risks associated with the use of Dsuvia.1 According to the FDA-approved product labeling (PI):

DSUVIA is indicated for use in adults in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments, for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of Use:

Not for home use or for use in children. Discontinue treatment with DSUVIA before patients leave the certified medically supervised healthcare setting.

Not for use for more than 72 hours. The use of DSUVIA beyond 72 hours has not been studied.

Only to be administered by a healthcare provider.

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve DSUVIA for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

- Have not been tolerated, or are not expected to be tolerated, - Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

The PI for Dsuvia contains boxed warnings regarding: accidental exposure and the Dsuvia Risk Evaluation and Mitigation Strategy (REMS) Program; life-threatening respiratory depression; addiction, abuse and misuse; Cytochrome P450 3A4 interactions; and risks from concomitant use with benzodiazepines or other CNS Depressants. Dsuvia is contraindicated in patients with significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected gastrointestinal obstruction, including paralytic ileus; and known hypersensitivity to sufentanil or components of Dsuvia. In addition, the PI for Dsuvia includes warnings and precautions regarding life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients; serotonin syndrome with concomitant use of serotonergic drugs; adrenal insufficiency; severe hypotension; risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness; risks of use in patients with gastrointestinal conditions; increased risk of seizures in patients with seizure disorders; bradycardia and neonatal opioid withdrawal syndrome. The most common adverse reactions reported with Dsuvia were nausea, headache, vomiting, dizziness, and hypotension.

Promotional materials misbrand a drug if they are false or misleading with respect to risk or benefits. The determination of whether promotional materials are misleading includes, among other things, not only representations made or suggested in promotional materials, but also failure 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 in the materials.

The banner includes the claim, “DSUVIA® comes in one strength for acute pain. . . TONGUE AND DONE.” (bolded emphasis original; reference omitted) in conjunction with an image of the single-dose applicator device. Similarly, the display prominently includes the claim “TONGUE AND DONE” (bolded emphasis original). These presentations are misleading because they imply that the administration of Dsuvia consists of a simple, one-step process, when this is not the case. In fact, there are numerous administration steps outlined in the PI, including a separate, distinct step to visually confirm tablet placement in the patient’s sublingual space of the mouth. For example, according to the DOSAGE AND ADMINISTRATION section of the PI, step 7 of the Administration Instructions specifically states (underlined emphasis added):

VISUALLY CONFIRM tablet placement in the sublingual space. See Figure 4. NOTE: If the tablet is NOT in the patient’s mouth, it is important to retrieve and dispose of the tablet according to institutional CII waste procedures.

The multiple steps involved in the administration of Dsuvia reflect the complexity of use of Dsuvia. Given the potency and the small size of the tablet, the risk of misplaced tablets is a serious safety concern to the patient and others. Risks include overdose and death due to accidental ingestion or exposure, improper dosing (i.e., over- or under-dosing and their associated risks), and the risk of diversion and its associated public health consequences. This is critical information for healthcare providers to know. Therefore, by oversimplifying the administration process, these presentations create a misleading impression about the safe administration of Dsuvia. These presentations are particularly concerning considering a REMS program was required for Dsuvia to ensure that the benefits of the drug outweigh the risk of respiratory depression that can result from accidental exposure.

In addition, the banner includes the following claims (emphasis original, references omitted):

• “Minimum redosing interval 1 hour” • “Average redosing interval 3 hours*… *Shown over a 12-hour period in the pivotal trial.”

These claims create a misleading impression about the use of Dsuvia because the banner omits the following material information from the DOSING AND ADMINISTRATION section of the PI: “Do not exceed 12 tablets in 24 hours.” By omitting this material information about the maximum daily dosage, the banner creates a misleading impression about the safe use of Dsuvia. These omissions are concerning from a public health perspective due to the serious risks associated with overdose with Dsuvia, including respiratory depression and death, that should be considered when prescribing the product.

Furthermore, the banner includes the claim, “DSUVIA® comes in one strength for acute pain. . .” (reference omitted). Thus, the banner makes representations about the indication and use of the drug but fails to adequately convey material information regarding Dsuvia’s limitations of use, thereby creating a misleading impression about the drug.

OPDP acknowledges that the banner states “DSUVIA is for use only in a certified medically supervised healthcare setting” and that the full indication including limitations of use are included farther down on the banner under the header “IMPORTANT SAFETY INFORMATION” (ISI), (bolded emphasis added). However, unlike the benefit claims in the banner, which utilized a color background and large font, the full indication with the limitations of use are intermingled with risk information in a paragraph format in a much smaller font size and a plain white background, and are accessible only if viewers “scroll” down the banner. Therefore, this does not mitigate the misleading impression.

Finally, the banner and display fail to present information relating to the Boxed Warning, Contraindications, Warnings and Precautions, and Adverse Reactions for Dsuvia with a prominence and readability reasonably comparable with the presentation of information relating to the benefits of Dsuvia. Factors impacting prominence and readability include typography, layout, contrast, headlines, paragraphing, white space, and other techniques apt to achieve emphasis. Specifically, benefit claims for Dsuvia are presented in conjunction with colorful graphics and large bolded headlines, with significant white space. However, the risk information is relegated farther down in paragraph format with less prominence.

By failing to adequately present the risks and benefits associated with Dsuvia, the banner and display create a misleading impression about the safe and effective use of the drug.

For the reasons discussed above, the banner and display misbrand Dsuvia within the meaning of the FD&C Act and makes its distribution violative. 21 U.S.C. 352(a), (n); 321(n); 331(a). See 21 CFR 202.1(e)(3)(ii); (e)(5); (e)(7)(viii).

This letter notifies you of our concerns and provides you with an opportunity to address them. OPDP requests that AcelRx cease any violations of the FD&C Act. Please submit a written response to this letter within 15 days from the date of receipt, addressing the concerns described in this letter, listing all other promotional communications (with the 2253 submission date) for Dsuvia that contain representations like those described above, and explaining any plan for discontinuing use of such communications, or for ceasing distribution of Dsuvia.

Failure to adequately address this matter may lead to regulatory action. If you believe that your products are not in violation of the FD&C Act, please include in your submission to us your reasoning and any supporting information for our consideration, within 15 days from the date of receipt of this letter.

Additionally, we request that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective communication(s) about the concern(s) discussed in this letter. The corrective communication(s) should be disseminated to the audience(s) that received the promotional communication(s) identified in the opening paragraph of this letter. OPDP recommends that corrective communication(s) include a description of the promotional communication(s) identified in this letter, which misbrand Dsuvia; include a summary of the concern(s) described in this letter; and provide information to correct each of these concern(s). Corrective communication(s) should be free of promotional claims and presentations. To the extent possible, corrective communication(s) should be distributed using the same media, and generally for the same duration of time and with the same frequency as the promotional communication(s) identified in the opening paragraph of this letter.

The concerns discussed in this letter do not necessarily constitute an exhaustive list of potential violations. It is your responsibility to ensure compliance with each applicable requirement of the FD&C Act and FDA implementing regulations.

Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Prescription Drug Promotion, 5901-B Ammendale Road, Beltsville, Maryland 20705-1266. A courtesy copy can be sent by facsimile to (301) 847-8444. To ensure timely delivery of your submissions, please use the full address above and include a prominent directional notation (e.g. a sticker) to indicate that the submission is intended for OPDP. Please refer to MA 18 and 23 in addition to the NDA number in all future correspondence relating to this particular matter. All correspondence should include a subject line that clearly identifies the submission as a Response to Warning Letter.