FDA panel not convinced by opiate combination safety

SILVER SPRING, MD. – An immediate-release combination of morphine and oxycodone in an oral capsule formulation should not be approved, a Food and Drug Administration advisory panel has recommended.

At a meeting on April 22, the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted 14-0 that the morphine-oxycodone combination should not be approved for the management of moderate to severe pain, because there is no evidence that the combined product is safer than morphine and oxycodone when used individually at comparable doses. The manufacturer, QRxPharma, had proposed that different dose combinations of the two opioids be approved for the management of moderate to severe acute pain in outpatient and inpatient settings. If approved, this would be the first combination product that contains two opioids, and it would be marketed as Moxduo.

Since the company first filed for approval in 2011, the FDA has rejected approval twice for reasons that included the failure of the company to provided adequate evidence that there is a patient population that could benefit from treatment with Moxduo. Additionally, although the combination was shown to be as effective in alleviating postoperative pain as equally potent doses of morphine and oxycodone given separately, more evidence for a benefit over existing therapeutic options is needed for products combining drugs that are available separately, based on regulations for combination drug products.

In response to the FDA’s earlier decision, QRxPharma had conducted a post hoc analysis of a respiratory safety study in an attempt to show the combination had a safety advantage in terms of respiratory depression over equivalent doses of the separate components. In another vote, the panel unanimously agreed that the company had not provided evidence that Moxduo was safer than the individual components.

The study evaluated oxygen desaturation rates among adults after a bunionectomy who were divided into three treatment groups. Study participants received either Moxduo (12 mg of morphine/8 mg of oxycodone) every 6 hours (127 patients); 24 mg of morphine every 6 hours (124 patients); or 6 mg of oxycodone every 6 hours (24 patients).

The highest proportion of patients who dropped below 95% oxygen saturation was in the Moxduo group. The proportion of those who had more serious levels of oxygen desaturation (at or below 80%, at or below 75%, at or below 70%) was lower among those on Moxduo, compared with those on either morphine or oxycodone, however.

Dr. Pamela Horn, an FDA medical officer, said that the FDA review concluded that the analyses favoring Moxduo could be a chance finding. She noted that the clinical relevance of these findings was not clear, since the depth of desaturation was not correlated with clinically notable events or clinical interventions. In addition, Moxduo was not associated with a benefit regarding common opioid-related adverse events, including nausea and vomiting. The FDA also noted that the study was small and that it was unclear how many patients receiving Moxduo were started on oxygen therapy, which could have skewed the results.

Panelist Dr. Gregory W. Terman, professor in the department of anesthesiology and pain medicine at the University of Washington, Seattle, said the study did not evaluate what he considered clinically relevant patients, noting that opiates are not typically administered on a schedule postoperatively, as was the case in the study. Respiratory depression associated with opiate treatment is a huge problem, and it would be useful to have an opiate that could reliably reduce the risk of respiratory depression, he said, noting that it is important to continue to look for solutions to this problem.

The panel agreed that more appropriately designed studies would be helpful in determining whether the combination provided any clinically relevant advantages. One panelist stressed the importance of making all oral opiate products crush-resistant to deter injection and snorting.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts. Occasionally, a panelist is given a waiver but not at this meeting. A decision on approval is expected by May 25.

[email protected]

SILVER SPRING, MD. – An immediate-release combination of morphine and oxycodone in an oral capsule formulation should not be approved, a Food and Drug Administration advisory panel has recommended.

At a meeting on April 22, the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted 14-0 that the morphine-oxycodone combination should not be approved for the management of moderate to severe pain, because there is no evidence that the combined product is safer than morphine and oxycodone when used individually at comparable doses. The manufacturer, QRxPharma, had proposed that different dose combinations of the two opioids be approved for the management of moderate to severe acute pain in outpatient and inpatient settings. If approved, this would be the first combination product that contains two opioids, and it would be marketed as Moxduo.

Since the company first filed for approval in 2011, the FDA has rejected approval twice for reasons that included the failure of the company to provided adequate evidence that there is a patient population that could benefit from treatment with Moxduo. Additionally, although the combination was shown to be as effective in alleviating postoperative pain as equally potent doses of morphine and oxycodone given separately, more evidence for a benefit over existing therapeutic options is needed for products combining drugs that are available separately, based on regulations for combination drug products.

In response to the FDA’s earlier decision, QRxPharma had conducted a post hoc analysis of a respiratory safety study in an attempt to show the combination had a safety advantage in terms of respiratory depression over equivalent doses of the separate components. In another vote, the panel unanimously agreed that the company had not provided evidence that Moxduo was safer than the individual components.

The study evaluated oxygen desaturation rates among adults after a bunionectomy who were divided into three treatment groups. Study participants received either Moxduo (12 mg of morphine/8 mg of oxycodone) every 6 hours (127 patients); 24 mg of morphine every 6 hours (124 patients); or 6 mg of oxycodone every 6 hours (24 patients).

The highest proportion of patients who dropped below 95% oxygen saturation was in the Moxduo group. The proportion of those who had more serious levels of oxygen desaturation (at or below 80%, at or below 75%, at or below 70%) was lower among those on Moxduo, compared with those on either morphine or oxycodone, however.

Dr. Pamela Horn, an FDA medical officer, said that the FDA review concluded that the analyses favoring Moxduo could be a chance finding. She noted that the clinical relevance of these findings was not clear, since the depth of desaturation was not correlated with clinically notable events or clinical interventions. In addition, Moxduo was not associated with a benefit regarding common opioid-related adverse events, including nausea and vomiting. The FDA also noted that the study was small and that it was unclear how many patients receiving Moxduo were started on oxygen therapy, which could have skewed the results.

Panelist Dr. Gregory W. Terman, professor in the department of anesthesiology and pain medicine at the University of Washington, Seattle, said the study did not evaluate what he considered clinically relevant patients, noting that opiates are not typically administered on a schedule postoperatively, as was the case in the study. Respiratory depression associated with opiate treatment is a huge problem, and it would be useful to have an opiate that could reliably reduce the risk of respiratory depression, he said, noting that it is important to continue to look for solutions to this problem.

The panel agreed that more appropriately designed studies would be helpful in determining whether the combination provided any clinically relevant advantages. One panelist stressed the importance of making all oral opiate products crush-resistant to deter injection and snorting.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts. Occasionally, a panelist is given a waiver but not at this meeting. A decision on approval is expected by May 25.

[email protected]

SILVER SPRING, MD. – An immediate-release combination of morphine and oxycodone in an oral capsule formulation should not be approved, a Food and Drug Administration advisory panel has recommended.

At a meeting on April 22, the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted 14-0 that the morphine-oxycodone combination should not be approved for the management of moderate to severe pain, because there is no evidence that the combined product is safer than morphine and oxycodone when used individually at comparable doses. The manufacturer, QRxPharma, had proposed that different dose combinations of the two opioids be approved for the management of moderate to severe acute pain in outpatient and inpatient settings. If approved, this would be the first combination product that contains two opioids, and it would be marketed as Moxduo.

Since the company first filed for approval in 2011, the FDA has rejected approval twice for reasons that included the failure of the company to provided adequate evidence that there is a patient population that could benefit from treatment with Moxduo. Additionally, although the combination was shown to be as effective in alleviating postoperative pain as equally potent doses of morphine and oxycodone given separately, more evidence for a benefit over existing therapeutic options is needed for products combining drugs that are available separately, based on regulations for combination drug products.

In response to the FDA’s earlier decision, QRxPharma had conducted a post hoc analysis of a respiratory safety study in an attempt to show the combination had a safety advantage in terms of respiratory depression over equivalent doses of the separate components. In another vote, the panel unanimously agreed that the company had not provided evidence that Moxduo was safer than the individual components.

The study evaluated oxygen desaturation rates among adults after a bunionectomy who were divided into three treatment groups. Study participants received either Moxduo (12 mg of morphine/8 mg of oxycodone) every 6 hours (127 patients); 24 mg of morphine every 6 hours (124 patients); or 6 mg of oxycodone every 6 hours (24 patients).

The highest proportion of patients who dropped below 95% oxygen saturation was in the Moxduo group. The proportion of those who had more serious levels of oxygen desaturation (at or below 80%, at or below 75%, at or below 70%) was lower among those on Moxduo, compared with those on either morphine or oxycodone, however.

Dr. Pamela Horn, an FDA medical officer, said that the FDA review concluded that the analyses favoring Moxduo could be a chance finding. She noted that the clinical relevance of these findings was not clear, since the depth of desaturation was not correlated with clinically notable events or clinical interventions. In addition, Moxduo was not associated with a benefit regarding common opioid-related adverse events, including nausea and vomiting. The FDA also noted that the study was small and that it was unclear how many patients receiving Moxduo were started on oxygen therapy, which could have skewed the results.

Panelist Dr. Gregory W. Terman, professor in the department of anesthesiology and pain medicine at the University of Washington, Seattle, said the study did not evaluate what he considered clinically relevant patients, noting that opiates are not typically administered on a schedule postoperatively, as was the case in the study. Respiratory depression associated with opiate treatment is a huge problem, and it would be useful to have an opiate that could reliably reduce the risk of respiratory depression, he said, noting that it is important to continue to look for solutions to this problem.

The panel agreed that more appropriately designed studies would be helpful in determining whether the combination provided any clinically relevant advantages. One panelist stressed the importance of making all oral opiate products crush-resistant to deter injection and snorting.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts. Occasionally, a panelist is given a waiver but not at this meeting. A decision on approval is expected by May 25.

[email protected]