FDA advisory panelists reject Buvaya for acute pain

 

HYATTSVILLE, MD. – Two Food and Drug Administration advisory panels voted May 22 to reject buprenorphine sublingual spray for the treatment of moderate to severe postoperative pain.

At a joint meeting, advisers of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 1 not to recommend the spray for approval. The proposed trade name for the spray is Buvaya.

The rejection of Buvaya by the committees is consistent with the views of FDA reviewers who expressed concerns with particularly high rates of nausea, vomiting, and dizziness. Sublingual buprenorphine also had significant delays to time of meaningful pain reduction, compared with similar opioids like oxymorphone and oxycodone. In fact, more than half of the patients treated with lower doses of Buvaya never experienced any level of pain relief. The FDA reviewers’ views were echoed by several advisory committee members.

“I think that if this were a standard schedule II opioid with the efficacy profile of this drug, we probably would not be here,”stated Steven Meisel, PharmD, system director of medication safety at Fairview Health Services, Minneapolis. “We would not be here, because the efficacy [is] so weak compared to what is already out there. It just does not work for acute postoperative pain.”

According to INSYS Therapeutics, developer of the buprenorphine sublingual spray, opioid painkillers remain one of the best treatment options in managing moderate to severe pain despite the risk of addiction. The sublingual spray formulation also has a lower abuse potential, according to the company. This was corroborated in a briefing document of currently marketed buprenorphine products by the FDA.

Buprenorphine, an opioid partial agonist-antagonist, is a long-acting Schedule III opioid. The sublingual spray was developed as part of the Buprenorphine Sublingual Spray clinical development program, consisting of 10 studies including 7 phase 1 studies, a phase 2 open label study, and two phase 3 efficacy studies. The company’s application was based on the results of those two efficacy studies. Both phase 3 studies had similar designs, randomizing patients to receive varying doses of the sublingual spray. They also shared the primary endpoint of assessing postoperative pain using the Numeric Rating Scale (NRS) Summed Pain and Intensity Difference 48 hours (SPID-48) after surgery. The similarities continued with secondary endpoints, with both phase 3 studies looking at NRS-SPID scores at 4, 8, and 24 hours after surgery, NRS pain intensity difference (NRS PID) and score at each time point, and total pain relief (TOTPAR) at 4, 8, 24, and 48 hours after surgery. The only difference between the studies were the doses of sublingual buprenorphine administered to patients.

One of the phase 3 trials was discontinued when several patients because of sedation events at higher doses, but that trial still was used to guide the dose selection for the pivotal phase 3 study. In that study, 40 patients postoperative bunionectomy patients were randomized to receive placebo, 0.5 mg, or 1.0 mg of sublingual buprenorphine (SBS) three times daily (t.i.d.) or 1.0 mg of SBS twice a day (b.i.d.). The study demonstrated that all doses were superior to placebo in reducing pain based on reductions in NRS SPID-48 scores. In fact, the mean NRS SPID-48 scores were 260%, 216%, and 236% higher for the 0.5-mg t.i.d., 1.0-mg b.i.d., and 1.0-mg t.i.d. doses, respectively, compared with placebo, indicating a decrease in pain. The study also found that sublingual buprenorphine doses of greater than 0.5 mg were not more effective in treating postoperative pain.

 

The pivotal phase 3 efficacy study randomized 322 patients after bunionectomy into one of four treatment groups: placebo, 0.5 mg t.i.d., 0.25 mg t.i.d., or 0.125 mg t.i.d. Sublingual buprenorphine was much more effective in reducing pain and SPID-48 scores, compared with placebo. Patients taking placebo had SPID-48 scores of 93.40, compared with 135.84, 125.75, and 182.81 for the 0.125-mg, 0.25-mg, and 0.5-mg SBS groups, respectively.

The most common adverse events were nausea, vomiting, and hypoxia. Specifically, in the pivotal study, nausea was reported at all three doses of 0.125 mg, 0.25 mg, and 0.50 mg in 43.9%, 58.8%, and 83.3% of patients.

Anne-Michelle Ruha, MD, of the University of Arizona, Phoenix, cited the risk of hypoxia as her biggest concern. “There’s so many factors that we can’t predict, like undiagnosed sleep apnea,” she said. “We just don’t know when the respiratory depression worsens, so I’m uncomfortable with the high rate of hypoxia.”

Although not directly related to this application, INSYS had been the subject of an investigation by the federal government in regard to an illegal marketing scheme that provided incentives for doctors to prescribe Subsys, a powerful and highly addictive synthetic opioid. Documents recently have been unsealed in federal court that prompted the federal government to investigate INSYS. The company has addressed the previous allegations of wrongdoing and states that INSYS has become a “... new and better company in many important respects across the organization,” according to a statement.The FDA usually follows the recommendations of its advisory panels, but they are not binding.

[email protected]

 

HYATTSVILLE, MD. – Two Food and Drug Administration advisory panels voted May 22 to reject buprenorphine sublingual spray for the treatment of moderate to severe postoperative pain.

At a joint meeting, advisers of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 1 not to recommend the spray for approval. The proposed trade name for the spray is Buvaya.

The rejection of Buvaya by the committees is consistent with the views of FDA reviewers who expressed concerns with particularly high rates of nausea, vomiting, and dizziness. Sublingual buprenorphine also had significant delays to time of meaningful pain reduction, compared with similar opioids like oxymorphone and oxycodone. In fact, more than half of the patients treated with lower doses of Buvaya never experienced any level of pain relief. The FDA reviewers’ views were echoed by several advisory committee members.

“I think that if this were a standard schedule II opioid with the efficacy profile of this drug, we probably would not be here,”stated Steven Meisel, PharmD, system director of medication safety at Fairview Health Services, Minneapolis. “We would not be here, because the efficacy [is] so weak compared to what is already out there. It just does not work for acute postoperative pain.”

According to INSYS Therapeutics, developer of the buprenorphine sublingual spray, opioid painkillers remain one of the best treatment options in managing moderate to severe pain despite the risk of addiction. The sublingual spray formulation also has a lower abuse potential, according to the company. This was corroborated in a briefing document of currently marketed buprenorphine products by the FDA.

Buprenorphine, an opioid partial agonist-antagonist, is a long-acting Schedule III opioid. The sublingual spray was developed as part of the Buprenorphine Sublingual Spray clinical development program, consisting of 10 studies including 7 phase 1 studies, a phase 2 open label study, and two phase 3 efficacy studies. The company’s application was based on the results of those two efficacy studies. Both phase 3 studies had similar designs, randomizing patients to receive varying doses of the sublingual spray. They also shared the primary endpoint of assessing postoperative pain using the Numeric Rating Scale (NRS) Summed Pain and Intensity Difference 48 hours (SPID-48) after surgery. The similarities continued with secondary endpoints, with both phase 3 studies looking at NRS-SPID scores at 4, 8, and 24 hours after surgery, NRS pain intensity difference (NRS PID) and score at each time point, and total pain relief (TOTPAR) at 4, 8, 24, and 48 hours after surgery. The only difference between the studies were the doses of sublingual buprenorphine administered to patients.

One of the phase 3 trials was discontinued when several patients because of sedation events at higher doses, but that trial still was used to guide the dose selection for the pivotal phase 3 study. In that study, 40 patients postoperative bunionectomy patients were randomized to receive placebo, 0.5 mg, or 1.0 mg of sublingual buprenorphine (SBS) three times daily (t.i.d.) or 1.0 mg of SBS twice a day (b.i.d.). The study demonstrated that all doses were superior to placebo in reducing pain based on reductions in NRS SPID-48 scores. In fact, the mean NRS SPID-48 scores were 260%, 216%, and 236% higher for the 0.5-mg t.i.d., 1.0-mg b.i.d., and 1.0-mg t.i.d. doses, respectively, compared with placebo, indicating a decrease in pain. The study also found that sublingual buprenorphine doses of greater than 0.5 mg were not more effective in treating postoperative pain.

 

The pivotal phase 3 efficacy study randomized 322 patients after bunionectomy into one of four treatment groups: placebo, 0.5 mg t.i.d., 0.25 mg t.i.d., or 0.125 mg t.i.d. Sublingual buprenorphine was much more effective in reducing pain and SPID-48 scores, compared with placebo. Patients taking placebo had SPID-48 scores of 93.40, compared with 135.84, 125.75, and 182.81 for the 0.125-mg, 0.25-mg, and 0.5-mg SBS groups, respectively.

The most common adverse events were nausea, vomiting, and hypoxia. Specifically, in the pivotal study, nausea was reported at all three doses of 0.125 mg, 0.25 mg, and 0.50 mg in 43.9%, 58.8%, and 83.3% of patients.

Anne-Michelle Ruha, MD, of the University of Arizona, Phoenix, cited the risk of hypoxia as her biggest concern. “There’s so many factors that we can’t predict, like undiagnosed sleep apnea,” she said. “We just don’t know when the respiratory depression worsens, so I’m uncomfortable with the high rate of hypoxia.”

Although not directly related to this application, INSYS had been the subject of an investigation by the federal government in regard to an illegal marketing scheme that provided incentives for doctors to prescribe Subsys, a powerful and highly addictive synthetic opioid. Documents recently have been unsealed in federal court that prompted the federal government to investigate INSYS. The company has addressed the previous allegations of wrongdoing and states that INSYS has become a “... new and better company in many important respects across the organization,” according to a statement.The FDA usually follows the recommendations of its advisory panels, but they are not binding.

[email protected]

 

HYATTSVILLE, MD. – Two Food and Drug Administration advisory panels voted May 22 to reject buprenorphine sublingual spray for the treatment of moderate to severe postoperative pain.

At a joint meeting, advisers of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 1 not to recommend the spray for approval. The proposed trade name for the spray is Buvaya.

The rejection of Buvaya by the committees is consistent with the views of FDA reviewers who expressed concerns with particularly high rates of nausea, vomiting, and dizziness. Sublingual buprenorphine also had significant delays to time of meaningful pain reduction, compared with similar opioids like oxymorphone and oxycodone. In fact, more than half of the patients treated with lower doses of Buvaya never experienced any level of pain relief. The FDA reviewers’ views were echoed by several advisory committee members.

“I think that if this were a standard schedule II opioid with the efficacy profile of this drug, we probably would not be here,”stated Steven Meisel, PharmD, system director of medication safety at Fairview Health Services, Minneapolis. “We would not be here, because the efficacy [is] so weak compared to what is already out there. It just does not work for acute postoperative pain.”

According to INSYS Therapeutics, developer of the buprenorphine sublingual spray, opioid painkillers remain one of the best treatment options in managing moderate to severe pain despite the risk of addiction. The sublingual spray formulation also has a lower abuse potential, according to the company. This was corroborated in a briefing document of currently marketed buprenorphine products by the FDA.

Buprenorphine, an opioid partial agonist-antagonist, is a long-acting Schedule III opioid. The sublingual spray was developed as part of the Buprenorphine Sublingual Spray clinical development program, consisting of 10 studies including 7 phase 1 studies, a phase 2 open label study, and two phase 3 efficacy studies. The company’s application was based on the results of those two efficacy studies. Both phase 3 studies had similar designs, randomizing patients to receive varying doses of the sublingual spray. They also shared the primary endpoint of assessing postoperative pain using the Numeric Rating Scale (NRS) Summed Pain and Intensity Difference 48 hours (SPID-48) after surgery. The similarities continued with secondary endpoints, with both phase 3 studies looking at NRS-SPID scores at 4, 8, and 24 hours after surgery, NRS pain intensity difference (NRS PID) and score at each time point, and total pain relief (TOTPAR) at 4, 8, 24, and 48 hours after surgery. The only difference between the studies were the doses of sublingual buprenorphine administered to patients.

One of the phase 3 trials was discontinued when several patients because of sedation events at higher doses, but that trial still was used to guide the dose selection for the pivotal phase 3 study. In that study, 40 patients postoperative bunionectomy patients were randomized to receive placebo, 0.5 mg, or 1.0 mg of sublingual buprenorphine (SBS) three times daily (t.i.d.) or 1.0 mg of SBS twice a day (b.i.d.). The study demonstrated that all doses were superior to placebo in reducing pain based on reductions in NRS SPID-48 scores. In fact, the mean NRS SPID-48 scores were 260%, 216%, and 236% higher for the 0.5-mg t.i.d., 1.0-mg b.i.d., and 1.0-mg t.i.d. doses, respectively, compared with placebo, indicating a decrease in pain. The study also found that sublingual buprenorphine doses of greater than 0.5 mg were not more effective in treating postoperative pain.

 

The pivotal phase 3 efficacy study randomized 322 patients after bunionectomy into one of four treatment groups: placebo, 0.5 mg t.i.d., 0.25 mg t.i.d., or 0.125 mg t.i.d. Sublingual buprenorphine was much more effective in reducing pain and SPID-48 scores, compared with placebo. Patients taking placebo had SPID-48 scores of 93.40, compared with 135.84, 125.75, and 182.81 for the 0.125-mg, 0.25-mg, and 0.5-mg SBS groups, respectively.

The most common adverse events were nausea, vomiting, and hypoxia. Specifically, in the pivotal study, nausea was reported at all three doses of 0.125 mg, 0.25 mg, and 0.50 mg in 43.9%, 58.8%, and 83.3% of patients.

Anne-Michelle Ruha, MD, of the University of Arizona, Phoenix, cited the risk of hypoxia as her biggest concern. “There’s so many factors that we can’t predict, like undiagnosed sleep apnea,” she said. “We just don’t know when the respiratory depression worsens, so I’m uncomfortable with the high rate of hypoxia.”

Although not directly related to this application, INSYS had been the subject of an investigation by the federal government in regard to an illegal marketing scheme that provided incentives for doctors to prescribe Subsys, a powerful and highly addictive synthetic opioid. Documents recently have been unsealed in federal court that prompted the federal government to investigate INSYS. The company has addressed the previous allegations of wrongdoing and states that INSYS has become a “... new and better company in many important respects across the organization,” according to a statement.The FDA usually follows the recommendations of its advisory panels, but they are not binding.

[email protected]