'Little Merit' in Sublingual Buprenorphine for Pain, Says FDA Panel

Alicia Ault

May 23, 2018

A joint US Food and Drug Administration (FDA) advisory committee has voted overwhelmingly against approving a sublingual form of buprenorphine for the treatment of moderate-to-severe acute pain.

The joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18-1 against the approval of Buvaya (Insys Therapeutics), a spray form of buprenorphine — an opioid that is primarily used for medication-assisted treatment.

The FDA usually follows its panels' advice.

The panelists commended the company for what they said was an innovative formulation that, at least on the surface, seemed to provide a lower abuse potential than other opioids, as well as some other potential advantages. But they said that the efficacy data were not impressive, and a higher incidence of hypoxia, nausea, and vomiting than seen with other opioids was concerning.

Significant Concerns

Insys has said the drug, which is a Schedule III and not a Schedule II opioid, would fill an unmet clinical need because it has less risk for misuse, addiction, overdose, and death.

However, Robert Levin, MD, a clinical reviewer with the FDA's Division of Anesthesia, Analgesia, and Addiction Products, said that patients taking Buvaya in clinical trials had double the rate of nausea and four times the rate of vomiting when compared with standard opioid therapy. The rates of dizziness and hypoxia were also higher than with other commonly used opioids, he added.

"If this were a standard Schedule II opioid with the efficacy profile of this drug, we probably wouldn't be here today because the efficacy profile is so weak," said committee member Steven B. Meisel, PharmD, director of medication safety at Fairview Health Services, Minneapolis, Minnesota.

Committee member Ronald S. Litman, DO, ML, noted that just because it was a Schedule III did not mean it presented any less danger. Ketamine is a Schedule III product used for pain, "but I don't think any of us would send a patient home with a ketamine spray," said Litman, professor of anesthesiology and pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

The panel said it was also worried about a lengthy delay in onset of pain relief, at a median of 92 minutes for the 0.5-mg dose the company was seeking to market. That delay could translate into a safety problem, noted panel member Randall Flick, MD, MPH, professor of anesthesiology and pediatrics, Mayo Clinic, Rochester, Minnesota.

"The time to onset will inevitably prompt the user to switch to some other opioid or nonopioid, or dose earlier with the sponsor's drug," added Flick.

"Somebody's going to reach for another opioid," agreed panel member Kevin L. Zacharoff, MD, faculty and clinical instructor, pain and medical ethics, State University of New York Stony Brook School of Medicine, New York.

Zacharoff and other panelists noted that Insys had not provided any data on the potential consequences when an opioid was added to the product.

The committee also doubted the feasibility of the manufacturer's recommendation that the first two doses be given in a medically supervised setting where patients could be monitored for 12 hours. That was aimed at mitigating the risk for the potentially dangerous hypoxia and other side effects, which often appeared within the first 8 hours of initiating therapy.

Weak Efficacy

Insys conducted two randomized, double-blind, placebo-controlled phase 3 studies and one additional pivotal phase 2 study to determine whether prophylactic antiemetics might reduce Buvaya-associated nausea and vomiting postoperatively. One of the placebo-controlled studies had to be stopped early because of a marked increase in somnolence and decreased efficacy at doses higher than the proposed dosing of 0.5 mg every 8 hours.

In the other placebo-controlled trial, the 0.5-mg dose was statistically significantly better at relieving pain intensity on a scale that measured efficacy at different intervals over a 48-hour period. But the median time to meaningful pain relief was 92 minutes and ranged from 79 to 120 minutes, putting it well behind reported times of 53 to 77 minutes for various doses of immediate-release oxycodone. In addition, 83% of patients had nausea, 72% experienced vomiting, and more than half experienced dizziness.

In an open-label study that compared 0.5 mg of the drug to morphine sulfate 4 mg intravenously twice daily followed by 10 mg of immediate-release oxycodone orally twice daily, no efficacy data were collected. Instead, investigators attempted to see whether ondansetron and dexamethasone given perioperatively would reduce postoperative nausea and vomiting in patients undergoing bunionectomy, breast augmentation, or abdominoplasty.

The antiemetics barely touched the nausea or vomiting, which was experienced by 78% and 52% of the patients taking Buvaya, respectively. In addition, 28% of the surgical patients taking the novel product were reported as having hypoxia and required oxygen, compared to just 6% of those taking the standard opioid regimen.

"I voted no because of the hypoxia," said Litman.

The committee's "no" vote is another setback for Insys, which has been under fire for what has been alleged to be overaggressive marketing of its fentanyl spray product, Subsys. A handful of states have sued Insys, resulting in millions of dollars in settlements paid out by the company.

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