Pediatric labeling for OxyContin: Pros & Cons

In the throes of an opioid epidemic, the US Food and Drug Administration (FDA) decided in August 2015 to expand the indications for OxyContin, an extended-release form of the narcotic oxycodone, to children aged 11 years and older.

The decision sparked outrage in those who fear the move might fuel increasing opioid addiction among young Americans. Those for the change say it will give prescribers more information about how best to use the drug in children and could lead to better prescribing patterns.

Both sides agree, however, that responsible prescribing and patient compliance are at the heart of using the drug optimally in children who need it most.

Related: The opioid pediatric epidemic

The FDA’s intention, according to Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, is to provide safety and dosing information to physicians caring for a very small group of seriously ill and vulnerable children.

“[I]t is limited to opioid-tolerant pediatric patients 11 and up who are already taking and tolerating a minimum daily dose of at least 20 mg oxycodone orally or its equivalent and are in pain severe enough to require daily, around-the-clock, long-term opioid treatment, and for which alternative treatment options are inadequate,” Woodcock wrote in an e-mail to Contemporary Pediatrics.

The safety of OxyContin in pediatric patients has been evaluated in an open-label clinical trial of 155 opioid-tolerant pediatric patients aged 6 to 16 years with moderate to severe chronic pain. Use is limited to children aged 11 years and older because there were only 15 patients aged younger than 11 years studied. The mean duration of therapy was 20.7 days (range 1 to 43 days). The mean daily dose was 33.30 mg, with a range of 20 mg to 140 mg daily. In an extension study, 23 of the 155 patients were treated beyond 4 weeks; 13 of those were treated for 28 weeks, according to Woodcock.

Pro labeling change

Kathleen A Neville, MD, MS, MBA, a pediatric oncologist and chief of the section of clinical pharmacology and toxicology at Arkansas Children’s Hospital, Little Rock, and chairwoman of the Committee on Drugs at the American Academy of Pediatrics, says she thinks this is a move in the direction of better prescribing practices. The FDA has postmarketing requirements of OxyContin’s manufacturer Purdue Pharma (Stanford, Connecticut), that will help to track prescriptions to children and arm providers with important prescribing information.

“I actually think [the results of the clinical trial] may lead to less prescribing,“ Neville says. “Before there was a lack of knowledge and people would prescribe what they think and use it off label. But now there are clear guidelines about who the appropriate patient population is. And the company is required to do surveillance.”

The New York Times reported in October last year that the FDA is requiring Purdue Pharma to conduct postapproval studies, including 1 study with adverse event annual reporting and a comprehensive analysis of respiratory depression, overdoses, and more. Purdue is also required to report nationally representative data on the volume of OxyContin prescriptions for children aged younger than 17 years, and the clinician types prescribing OxyContin and for what conditions.¹

Any information that can be gathered and used to better prescribe opioids in children is an improvement, according to Neville. There’s no labeling information for children for morphine or methadone, and there’s scant information on other narcotics. “When prescribing any narcotic, there’s less information on children than adults,” she says. “That’s why I view this as an accomplishment.”

Sharon Levy, MD, MPH, director, Adolescent Substance Abuse Program, Boston Children’s Hospital, and associate professor of pediatrics at Harvard Medical School, Boston, Massachusetts, says she understands the concern that the new labeling could lead to more prescribing in the age group, but thinks it’s unlikely to happen in an environment in which physicians are getting more and more education about the risks of opioid use.

“Like adults, children can have extremely painful experiences-for example injuries and surgical procedures–and it is very important that they have access to appropriate pain medications,” Levy wrote in an e-mail to Contemporary Pediatrics. Having a formal indication allows these medications to be included in formal guidelines, which helps physicians make treatment decisions, she notes.

NEXT: Is this a bad move?

Is this is a bad move?

The FDA made a terrible mistake, according to Andrew Kolodny, MD, senior scientist at the Heller School for Social Policy and Management at Brandeis University, Waltham, Massachusetts; executive director for Physicians for Responsible Opioid Prescribing (PROP); and chief medical officer for Phoenix House, a national nonprofit addiction agency. “I think it was an awful decision on several levels. I don’t even know where to begin,” he says.

In 2013, PROP filed a petition with the FDA to narrow the indication on opioid labels for the then-adult indication because of the concern that OxyContin was being promoted for chronic noncancer pain, a condition for which opioids haven’t been proven safe and effective, according to Kolodny.²

“When that label change effort was made, FDA agreed that evidence was lacking to support opioids as safe and effective for long-term use and actually, at that point, required manufacturers to start doing long-term studies and studies to demonstrate whether or not opioids are safe and effective for chronic noncancer pain,” Kolodny says. “Those studies never came in. So even though FDA agrees that opioids may not be safe and effective for adults with chronic pain, it allowed a new label indication for use in children with chronic pain.”

More: Is the OxyContin label change as bad as we think?

Studies supporting long-term use of OxyContin for chronic pain are still lacking and increasing evidence suggests that risks of chronic use may outweigh benefits, Kolodny says. The director of the Centers for Disease Control and Prevention (CDC), Thomas R Frieden, MD, MPH, recently wrote in a New England Journal of Medicine editorial that whereas "the benefits of opioids for chronic pain remain uncertain, the risks of addiction and overdose are clear."³

Kolodny says another concern is that although Purdue Pharma has indicated it will not promote OxyContin for use in children and, hopefully, the company will keep its word, we shouldn’t be at the mercy of a drug company trying to do the right thing. Purdue Pharma was punished with some $600 million in fines in 2007 for misleading OxyContin marketing practices. (See “Oxy’s checkered marketing history”)

Drug studies are needed in children, says Kolodny, and he thinks it’s worthwhile for the FDA to try to incentivize drug companies to research use of medications for children. However, he also believes that studying opioids in children with chronic pain raises ethical concerns. He criticized the FDA for failing to consider the increased risk of addiction in its decision to approve marketing of OxyContin for children.

“Before the brain is fully mature, we have reason to believe that addiction can set in more easily and become more lifelong and difficult to treat. We know this from studies on tobacco, that the younger somebody starts smoking the more likely [he/she is] to become a lifelong smoker and the more difficult it is to treat [his/her] nicotine addiction,” Kolodny says. “That [higher addiction risk potential] was not considered or taken into account [in this decision].”

Finally, Kolodny says it’s a big concern that the FDA didn’t heed its own policy on when to bring decisions before an advisory committee. The FDA, he explains, has 3 criteria to help it decide when to bring a decision to outside experts, and if any 1 of the 3 criteria is met, the FDA should consult outside experts. The criteria include if a decision is of significant public interest, if it would be potentially controversial, and if the FDA would benefit from consulting experts in certain disciplines. In Kolodny’s view, all 3 criteria were met and the FDA shouldn’t have approved the label extension without consulting an advisory committee.

“The argument FDA made is that by doing this we learn more about proper dosing in children, so that we can give better dosing guidance. That never happened. There is no difference in dosing on the pediatric label from the adult label. There’s no upper dose limit. There’s no limit other than to say it shouldn’t be given to opioid-naive children,” Kolodny says. “If you look at the studies that were done for the new indication, there are children who had nonfatal overdoses on OxyContin.⁴ You would think the label would have more conservative, more cautious dosing.”

The bottom line is that Kolodny thinks the labeling change will increase the likelihood that more young people will become addicted.

NEXT: Addiction and children

There are certainly important reasons to prescribe opioids for end-of-life care and for acute pain, Kolodny says. “In those cases where an opioid is prescribed for an injury or for postoperative pain, [patients] should be exposed to the opioid at the lowest possible dose, for the shortest possible duration,” he says. “But this is an extended-release opioid, so you’re not giving it to the child when [his/her] pain becomes severe, and then stopping it as soon as the child is able to tolerate the pain. You’re putting [these children] on a dose that gives them round-the-clock opioid effects, and, if you do that, within just a few days, you’ve made the child physiologically dependent on the drug. And if you have the child on the drug for 30 days, there are neurologic changes that are visible on imaging studies. So, if you have a kid that just had surgery and you want to give [him/her] an opioid, you might have in the past given [hydrocodone] for a few days. But now, with OxyContin being one of the only opioids with a pediatric indication, I'm afraid some docs may prescribe it in place of a lower-dose immediate-release opioid. And that’s a really bad idea if the goal is to expose [the child] to as little opioid as possible.”

G Caleb Alexander, MD, MS, a practicing internist and codirector of the Center for Drug Safety and Effectiveness at Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, says there are concerning inconsistencies with the FDA’s move to add pediatric indications to OxyContin’s labeling, and he thinks it could result in more prescribing of the drug to children. Before the label extension, pediatricians were free to prescribe OxyContin off label, in accordance with best practices, so the FDA approval was not required to permit such use, according to Alexander.

More: Treatment of opioid use disorder

“The concern that has been raised by some is: Are we really at a point where we need more noninnovative opioids being approved? And I think many would argue no,” he says.

The suggestion that this move will encourage more research on OxyContin in children is also suspect, according to Alexander. The regulatory approval doesn’t necessarily encourage research, he says, but the FDA does incentivize manufacturers to study products on children by, in some cases, offering extra patent protection for those products.

“If Purdue is getting additional patent exclusivity for this label extension, all the more reason to have concern because essentially it means Purdue will be reaping greater revenues and OxyContin will not face patent competition for a longer amount of time,” Alexander says.

According to a 2012 report on CBS News, Purdue would receive a 6-month patent extension upon the completion of its study on children, which the company said it would add to the patents expiring in 2025 for newer formulations of the drug.⁵

Addiction and children

Levy says that, as an addiction specialist, the problem she sees most commonly is that kids use opioids because they’re available. “[I]t is the ‘reservoir’ of pain medications sitting in people’s medicine cabinets that seems to drive the epidemic,” she says. “We need to reduce the reservoir by prescribing more prudently and educating our patients about how to get rid of extra medication and the risks of leaving unused medications around. Pediatricians play a role in that-especially the education piece-but the large majority of the reservoir comes from prescriptions that were given to adult patients, and limiting prescribing to children is not likely to make much of a difference.”

Screening can play a part in preventing addiction that results from OxyContin prescribing, Levy notes. “From where I sit, opioid addiction is the end of a long road that nearly always starts with marijuana, alcohol, and/or tobacco use,” she says. “Of course not all kids who use marijuana or other drugs will go on to develop an opioid use disorder, but nearly all kids that develop an opioid use disorder start with some other substance. So, we need to screen routinely and deliver advice that not using is best for health.”

This screening is especially important before prescribing opioids because there is data suggesting that use of other substances, particularly marijuana, may “prime” the brain to be more vulnerable to opioid use disorders, Levy explains.⁶ “We want to take extra precaution with kids who have started using,” she says.

In addition, Levy points out that there have been studies showing that early exposure to opioids, even when used appropriately, increases the risk of later opioid use disorder.⁷ “So clearly we want to be careful with these medications and use them only when they are truly indicated, and when we do use them, we need to monitor to insure we are giving an appropriate dose and for an appropriate length of time,” she says.

NEXT: Best Rx practices

Kolodny, who sees adolescent patients who are opioid addicted, says young people are becoming opioid addicted in 3 ways. One route is through nonmedical use, or recreational use, and he agrees that the drugs most often come from somebody’s medicine chest.

Another route for young people to become addicted is through medical treatment, via iatrogenic addiction. “It’s hard for a person to be put on long-term opioids and not get addicted. I think if you could find some of the children who participated in these clinical trials, there’s a good likelihood that some of the children who participated are now addicted,” he notes.

The third route, which may be more common, is a little of both-a young person who gets exposed to an opioid medically, for wisdom teeth, sports injury, or some kind of surgical procedure. If that patient likes the effect of the opioid and no longer fears, Kolodny says that’s the perfect storm for later recreational use and subsequent addiction.

Best Rx practices

Of concern is that many physicians report they’re not confident about how to safely prescribe opioids.⁸

The truth is that OxyContin is a rare consideration for the community pediatrician, according to Neville. “This is not for a toothache or a sprained ankle or common ailments. This is for kids with sickle cell disease or cancer-most likely patients who are otherwise going to be seeing a specialist,” she says. Pediatricians need to know how opioid analgesics should be considered in pediatric patients when other drugs fail to sufficiently manage patients’ pain.

Warnings and precautions for pediatric patients taking OxyContin are the same as for adults. Every physician prescribing OxyContin to children and adolescents should use the lowest dose for the shortest amount of time, Neville advises. Also, don’t dispense a lot of pills; rather, dispense a reasonable amount that won’t end up as extra pills in the medicine cabinet, she says.

Next: Chest wall rigidity in fentanyl abuse

Careful prescribing includes careful monitoring as patients wean off the drug, cautions Neville. “For the general pediatrician, it’s like any drug; you should be educated on drugs you are prescribing. So, if you’re prescribing this drug, you should know the appropriate patient population and if a patient should be closely followed,” Neville says. “This is not an appropriate drug for short-term resolving of acute pain. Never has been.”

REFERENCES

1. Saint Lewis C. FDA approval of OxyContin use for children continues to draw scrutiny. New York Times. October 8, 2015. http://www.nytimes.com/2015/10/09/health/fda-approval-of-oxycontin-for-children-continues-to-draw-scrutiny.html. Accessed August 22, 2016.

2. Purdue Pharma LP. Response to citizen petition filed by Physicians for Responsible Opioid Prescribing. Available at: http://www.supportprop.org/wp-content/uploads/2014/12/Purdue_Pharma_LP_Comment_PPLP_Response_to_PROP_CP_1_30_13.pdf. Published January 30, 2013. Accessed August 22, 2016.

3. Frieden TR, Houry D. Reducing the risks of relief-the CDC opioid-prescribing guideline. N Engl J Med. 2016;374(16):1501-154.

4. ClinicalTrials.gov. Pharmacokinetics and safety of ORF tablets in pediatric patients. NCT01160614. Available at: https://clinicaltrials.gov/ct2/show/results/NCT01160614?term=PEDIATRIC+OXYCODONE&rank=4&sect=X40156#othr. Verified October 11, 2012. Accessed August 22, 2016.

5. Castillo M. Purdue Pharma LP conducting children’s trial of OxyContin. CBS News website. Available at: http://www.cbsnews.com/news/purdue-pharma-lp-conducting-childrens-trial-of-oxycontin/. Published July 6, 2012. Accessed August 22, 2016.

6. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014;370(23):2219–2227.

7. Miech R, Johnston L, O’Malley PM, Keyes KM, Heard K. Prescription opioids in adolescence and future opioid misuse. Pediatrics. 2015;136(5):e1169-e1177.

8. Volkow ND, McLellan AT. Opioid abuse in chronic pain-misconceptions and mitigation strategies. N Engl J Med. 2016;374(13):1253-1263.

Ms Hilton is a medical writer who has covered health and medicine for 25 years. She resides in Boca Raton, Florida. She has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article. 

Disclosures: Dr Kathleen Neville sits on the US Food and Drug Administration’s Pediatric Committee for Oncology Drugs and the Clinical Pharmacology Committee. Drs G. Caleb Alexander, Andrew Kolodny, and Sharon Levy report no conflicts of interest.