Evidence from a new study to support the safety and pharmacokinetics of Butrans (buprenorphine; Purdue Pharma) transdermal pain patch in children falls short, according to some members of a joint US Food and Drug Administration (FDA) advisory committee.
The committee met to discuss the study and determine whether, on the basis of the new findings, any changes should be made to the drug's label.
For the most part, committee members the study was too small and too short and included inappropriate participants, such as those with migraine.
Committee members also questioned some of the new safety data.
"The sample size was too small from the outset, and the population under study is not the population likely to use this medicine in future," said Randall Flick, MD, director, Mayo Clinic Children's Center, and associate professor of Anesthesiology & Pediatrics, Mayo Clinic, Rochester. "In fact, many patients in the study were, in my view, inappropriate for this medication."
Butrans, a partial mu-opioid receptor agonist, was approved in 2010 for the management of pain severe enough to require daily, round-the-clock, long-term opioid treatment, and for which alternative treatment options are inadequate. The indication was updated in 2016 according to the extended-release/long-acting opioid analgesic class labeling change.
During the meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and Safety and Risk Management Advisory Committee, representatives from Purdue Pharma revealed the results of their new study in patients aged 7 to 16 years.
The study was conducted in response to a postmarketing requirement under the Pediatric Research Equity Act (PREA). According to the FDA, the purpose of pediatric assessments under PREA is to obtain data that will support the safe and effective use of agents in pediatric patients who already use or could benefit from their use.
Most opioid — and nonopioid — analgesic products don't have pediatric efficacy, safety, or dosing information because they haven't been studied in children, Sharon Hertz, MD, director, Division of Anesthesia, Analgesia and Addition Products, Office of Drug Evaluation, and Office of New Drugs, FDA, told the meeting attendees. It's critically important, she said, to provide clinicians with age-appropriate information about the efficacy, safety, and pharmacokinetics of the products they use.
Recruitment a Major Challenge
Stacy Baldridge, MSN, RN, pediatric lead, Purdue Pharma, discussed the challenges of carrying out a trial of analgesics in children. Recruitment is difficult because few sites are qualified and few young patients require opioids for more than 2 weeks.
After screening thousands of children, the study included 41 "nononcologic" patients from 11 centers with persistent pain who required continuous opioid analgesics for at least 2 weeks. The study was completed before the FDA revised recommendations for the study of opioids in pediatric patients.
As of 2016, a database of 125 patients in the 12- to 17-year age range and 50 in the 7- to 11-year age range, is required, Robert A. Levin, MD, medical officer, Division of Anesthesia, Analgesia and Addiction Products, FDA, told the meeting attendees.
Most study participants (n = 35) were aged 12 to 16 years. The most common causes of pain were: back pain (n = 8), migraine (n = 6), sickle cell anemia (n = 5), and abdominal pain (n = 8) from such conditions as Crohn's disease or a gunshot wound.
Patients with postoperative pain had to be at least 48 hours postsurgery.
Participants aged 7 to 11 years could not be taking more than 40 mg of morphine or equivalent per day, and those aged 12 to 16 years could not be taking more than 80 mg/day. Other opioids that patients were taking had to be tapered.
Younger patients started on a Butrans dose of 2.5 µg/h and older ones, 5 µg/h. The design of the open-label study included flexible dosing throughout.
Children received treatment for up to 24 weeks. About 83% of the younger children and all of the older ones were exposed to the drug for at least a week, and 50% of the younger and 97% of the older group had at least 2 weeks of exposure. None of the younger kids and 37% of the older ones were exposed to the drug for 24 weeks or more.
The final data set included 38 patients and a total of 151 plasma concentrations.
For children aged 12 to 16 years who weighed at least 50 kg, the pharmacokinetics data suggested that no dose modification is needed from adult dosing, said Baldridge. For those in this age category who weighed less, the pharmacokinetics data suggested that half the adult dose should be used.
As for safety, adverse events occurred in all six patients aged 7 to 11 years and in 74% of the older kids, and most of these were mild or moderate. The most common adverse events included nausea, application site irritation, somnolence, headache, and vomiting.
Eight patients had a serious adverse event. These were mostly attributed to the patients' underlying medical condition.
Two patients who had a QT reading on electrocardiography that exceeded the protocol parameter discontinued the study. Another patient with hypersomnolence also withdrew from the study.
About 98% of the study group received some supplemental pain medication, for the most part an opioid.
The study showed no clinically significant changes in blood pressure or pulse or treatment-emergent respiratory depression. Most patients stayed within the normal range for hematologic and blood chemistry values during the study.
Baldridge concluded that there were no new safety issues specific to pediatric patients and that the reported adverse events for 12- to 16-year-olds were consistent with known safety profile of Butrans seen in adult studies and in the postmarketing experience. There were insufficient data to permit conclusions in the younger age group, she said.
Purdue officials noted that the number of pediatric patients who would quality for this treatment is extremely small and the duration of treatment in clinical practice tends to be less than 3 weeks.
They pointed out that in 2015, of almost 2 million children aged 7 to 16 years who were dispensed opioid analgesics, only 0.3% were dispensed an extended-release opioid.
Given the small sample size and the open-label design of the study, Purdue representatives stressed that the company is not requesting a pediatric indication — only that the pediatric study data be included in the prescribing information.
During discussions, committee members raised several concerns. In addition to the small sample size, some noted that included patients may not represent those who would receive the treatment in the "real" world, such as patients with cancer.
Study "Woefully Inadequate"
Some members believe the study should have been adequately powered to address some endpoints of concern, such as hypersomnolence and prolonged QT.
For others, it was difficult to interpret the pharmacokinetics data because of shifting doses. At least one member voiced concern about the impact of opioids on the developing adolescent brain.
Peter L. Havens, MD, director, Pediatric HIV Program, Children's Hospital of Wisconsin, and professor of pediatrics, Medical College of Wisconsin, Milwaukee, stressed the importance of weight-based dosing. With a transdermal system, he said, skin depth, and whether a patient is obese or at ideal body weight, might influence the drug exposure.
It also wasn't clear to some members whether the given doses of Butrans were truly effective, as so much additional analgesic was required.
One member called the study "woefully inadequate."
The committee held mixed views on whether information from the study should be added to labeling. There was a concern that doing so would wrongly suggest that robust safety and efficacy data now exist in the pediatric population.
"There is a risk here that this is misinformation or information that is so incomplete as to mislead the prescriber and suggest that this study implies in some way that this medicine has been adequately studied in children when it clearly has not," said Dr Flick. "It's not something that should be added to the label."
However, some members, including Ronald S. Litman, DO, professor of anesthesiology and pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, thought the new information might be valuable to providers.
"Any data that we can get on pediatric patients should be given to practitioners," and the new data "should somehow be listed," said Dr Litman. He stressed that this drug will not be used often in kids and would be mostly prescribed by specialists in pediatric pain, hematology, or oncology.
Some committee members felt that if information from the study is included in labeling, there should be clarifiers about the restrictions on the population included in the trial, about the need to monitor for hypersomnolence and prolonged QT, and about the frequent need for supplemental analgesics.
Medscape Medical News © 2017
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