Lessons on using cannabinoids for pediatric epilepsy

DENVER – The Colorado experience with medical marijuana products for the treatment of pediatric epilepsy holds useful lessons for physicians in states where legal marijuana is a far more recent development, Amy R. Brooks-Kayal, MD, said at the annual meeting of the Teratology Society.

Medical marijuana has been legal in Colorado for nearly 20 years. But the drug’s potential role in treating intractable pediatric epilepsy started getting a lot more attention in 2013 when a CNN report by Sanjay Gupta, MD, chronicled a child’s remarkable turnaround in response to medical marijuana. The story triggered a migration to the state by what has been termed “marijuana refugees”: desperate families with children who had the most severe, complex, treatment-refractory seizure disorders, said Dr. Brooks-Kayal, professor of pediatrics and neurology and chief of pediatric neurology at the University of Colorado at Denver, Aurora.

Today, Dr. Brooks-Kayal and her colleagues at Children’s Hospital Colorado provide care for roughly 300 children on cannabinoids for refractory epilepsy. Back when the CNN story went viral, however, they were caught off guard by the patient influx. They weren’t familiar with medical marijuana, and they had to learn on the fly. They quickly discovered that there were, at that time, no reliable data on the safety, efficacy, pharmacokinetics, or drug interactions of medical marijuana products. And the products were not reliably standardized as to content, quality, or purity.

The situation, fortunately, has improved. There is now phase 3 randomized, double-blind, placebo-controlled clinical trial evidence of efficacy for an investigational proprietary cannabidiol oral solution known as Epidiolex for children and young adults with Dravet syndrome and drug-resistant seizures, as well as documentation of multiple adverse effects (N Engl J Med. 2017 May 25;376[21]:2011-20).

Dr. Brooks-Kayal, a past president of the American Epilepsy Society, said she believes this medication is potentially approvable by the Food and Drug Administration.

“In the world of new seizure medications, what is usually required by the FDA is a 50% reduction in seizures, which this agent gets close to reaching. But it does have a higher adverse event rate than many of our medications. However, this is a tough crowd. These are very, very difficult-to-treat children. So I think any addition to our armamentarium for these kids is going to be beneficial,” she said. “Unfortunately, though, it’s not going to be the panacea that I think some of our families are looking for.”

Based upon the Colorado experience, Dr. Brooks-Kayal offered the following suggestions for colleagues around the country as they begin fielding questions from families about medical marijuana for pediatric epilepsy:
 

• Provide families with the current data, discuss what’s known and still unknown, and encourage families to disclose the use of cannabinoids so the child can be monitored.
• Have the family keep a seizure diary. Get a baseline EEG and another at about 12 weeks. Do routine laboratory monitoring every 4 weeks, including liver function tests. “We think CBDs [cannabinoids] have the potential to worsen liver function,” she said.
• Stress the importance of leaving other seizure medications unchanged. “When this first started, the medical marijuana providers were recommending patients stop their other medications. The providers don’t do that anymore, fortunately,” Dr. Brooks-Kayal said. “Every week we were putting a child in a medically induced coma because they had status epilepticus, and it was the only way to stop their seizures. They started using marijuana products, they were sure it was going to be the cure, they stopped all their other medications, and they developed status epilepticus.”
• Establish policies with the hospital administration and pharmacy about how to handle marijuana products when a child is in the hospital. The Children’s Hospital Colorado pharmacy cannot store or dispense marijuana products because of federal regulations. And again, it’s unsafe to stop seizure medications abruptly, including marijuana products. Informed consent procedures need to be developed for when patients on cannabinoids are hospitalized.
• Encourage families to participate in one of the six Food and Drug Administration–approved double-blind, placebo-controlled trials of Epidiolex for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms sponsored by GW Pharmaceuticals.

Breaking down the evidence

Here’s what’s known and what is still unknown about the safety and efficacy of cannabinoids for the treatment of refractory pediatric epilepsy, according to Dr. Brooks-Kayal.

 

The knowns

Cannabinoids show activity against seizures in animal models. Moreover, initial clinical data suggest they may decrease seizures in some children with refractory epilepsy. This evidence includes a retrospective study from Children’s Hospital Colorado reliant upon parental reports of improvement (Epilepsy Behav. 2015 Apr;45:49-52), an Israeli retrospective study (Seizure. 2016 Feb;35:41-4), a positive open-label trial of an investigational oral oil-based solution of a pharmaceutical-grade cannabidiol known as Epidiolex (Lancet Neurol. 2016 Mar;15[3]:270-8), and evidence from a Food and Drug Administration–authorized phase 3, randomized clinical trial of Epidiolex (N Engl J Med. 2017 May 25;376[21]:2011-20).

The incidence of short-term adverse events associated with cannabinoids is substantial. The rate seems to be higher with Epidiolex than with many other medical marijuana products, although the potency is greater, too. These include somnolence, fatigue, and convulsions.

In addition, gastrointestinal side effects are common with Epidiolex. “Some are probably due to the oil base; some [are] probably due to the cannabidiol itself,” said Dr. Brooks-Kayal.
 

The unknowns

What types of seizures does it work for? This is under study in a series of FDA-authorized phase 3 randomized trials.

What is the placebo-subtracted response rate to cannabidiol? In the randomized trial published in the New England Journal of Medicine, the median monthly frequency of seizures decreased from 12.4 to 5.9 with cannabidiol, compared with a reduction from 14.9 to 14.1 with placebo. This needs confirmation in additional trials.

What’s the optimal dose? The randomized trial tested just one dose – 20 mg/kg per day.

What are the drug interactions and their possible impact on cannabidiol efficacy? Outcomes appear to be better in patients on concomitant clobazam (Onfi), perhaps because of the significantly higher blood levels of clobazam’s major metabolite in children on cannabidiol.
 

Long-term effects

The jury is still out on the long-term adverse effects. “These medical marijuana products are being given by families to 2- and 3-month-olds. It will be years before we know about potential long-term cognitive and behavioral effects,” Dr. Brooks-Kayal said.

Dr. Brooks-Kayal reported having no financial conflicts of interest regarding her presentation.
 

bjancin@frontlinemedcom.com

DENVER – The Colorado experience with medical marijuana products for the treatment of pediatric epilepsy holds useful lessons for physicians in states where legal marijuana is a far more recent development, Amy R. Brooks-Kayal, MD, said at the annual meeting of the Teratology Society.

Medical marijuana has been legal in Colorado for nearly 20 years. But the drug’s potential role in treating intractable pediatric epilepsy started getting a lot more attention in 2013 when a CNN report by Sanjay Gupta, MD, chronicled a child’s remarkable turnaround in response to medical marijuana. The story triggered a migration to the state by what has been termed “marijuana refugees”: desperate families with children who had the most severe, complex, treatment-refractory seizure disorders, said Dr. Brooks-Kayal, professor of pediatrics and neurology and chief of pediatric neurology at the University of Colorado at Denver, Aurora.

Today, Dr. Brooks-Kayal and her colleagues at Children’s Hospital Colorado provide care for roughly 300 children on cannabinoids for refractory epilepsy. Back when the CNN story went viral, however, they were caught off guard by the patient influx. They weren’t familiar with medical marijuana, and they had to learn on the fly. They quickly discovered that there were, at that time, no reliable data on the safety, efficacy, pharmacokinetics, or drug interactions of medical marijuana products. And the products were not reliably standardized as to content, quality, or purity.

The situation, fortunately, has improved. There is now phase 3 randomized, double-blind, placebo-controlled clinical trial evidence of efficacy for an investigational proprietary cannabidiol oral solution known as Epidiolex for children and young adults with Dravet syndrome and drug-resistant seizures, as well as documentation of multiple adverse effects (N Engl J Med. 2017 May 25;376[21]:2011-20).

Dr. Brooks-Kayal, a past president of the American Epilepsy Society, said she believes this medication is potentially approvable by the Food and Drug Administration.

“In the world of new seizure medications, what is usually required by the FDA is a 50% reduction in seizures, which this agent gets close to reaching. But it does have a higher adverse event rate than many of our medications. However, this is a tough crowd. These are very, very difficult-to-treat children. So I think any addition to our armamentarium for these kids is going to be beneficial,” she said. “Unfortunately, though, it’s not going to be the panacea that I think some of our families are looking for.”

Based upon the Colorado experience, Dr. Brooks-Kayal offered the following suggestions for colleagues around the country as they begin fielding questions from families about medical marijuana for pediatric epilepsy:
 

• Provide families with the current data, discuss what’s known and still unknown, and encourage families to disclose the use of cannabinoids so the child can be monitored.
• Have the family keep a seizure diary. Get a baseline EEG and another at about 12 weeks. Do routine laboratory monitoring every 4 weeks, including liver function tests. “We think CBDs [cannabinoids] have the potential to worsen liver function,” she said.
• Stress the importance of leaving other seizure medications unchanged. “When this first started, the medical marijuana providers were recommending patients stop their other medications. The providers don’t do that anymore, fortunately,” Dr. Brooks-Kayal said. “Every week we were putting a child in a medically induced coma because they had status epilepticus, and it was the only way to stop their seizures. They started using marijuana products, they were sure it was going to be the cure, they stopped all their other medications, and they developed status epilepticus.”
• Establish policies with the hospital administration and pharmacy about how to handle marijuana products when a child is in the hospital. The Children’s Hospital Colorado pharmacy cannot store or dispense marijuana products because of federal regulations. And again, it’s unsafe to stop seizure medications abruptly, including marijuana products. Informed consent procedures need to be developed for when patients on cannabinoids are hospitalized.
• Encourage families to participate in one of the six Food and Drug Administration–approved double-blind, placebo-controlled trials of Epidiolex for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms sponsored by GW Pharmaceuticals.

Breaking down the evidence

Here’s what’s known and what is still unknown about the safety and efficacy of cannabinoids for the treatment of refractory pediatric epilepsy, according to Dr. Brooks-Kayal.

 

The knowns

Cannabinoids show activity against seizures in animal models. Moreover, initial clinical data suggest they may decrease seizures in some children with refractory epilepsy. This evidence includes a retrospective study from Children’s Hospital Colorado reliant upon parental reports of improvement (Epilepsy Behav. 2015 Apr;45:49-52), an Israeli retrospective study (Seizure. 2016 Feb;35:41-4), a positive open-label trial of an investigational oral oil-based solution of a pharmaceutical-grade cannabidiol known as Epidiolex (Lancet Neurol. 2016 Mar;15[3]:270-8), and evidence from a Food and Drug Administration–authorized phase 3, randomized clinical trial of Epidiolex (N Engl J Med. 2017 May 25;376[21]:2011-20).

The incidence of short-term adverse events associated with cannabinoids is substantial. The rate seems to be higher with Epidiolex than with many other medical marijuana products, although the potency is greater, too. These include somnolence, fatigue, and convulsions.

In addition, gastrointestinal side effects are common with Epidiolex. “Some are probably due to the oil base; some [are] probably due to the cannabidiol itself,” said Dr. Brooks-Kayal.
 

The unknowns

What types of seizures does it work for? This is under study in a series of FDA-authorized phase 3 randomized trials.

What is the placebo-subtracted response rate to cannabidiol? In the randomized trial published in the New England Journal of Medicine, the median monthly frequency of seizures decreased from 12.4 to 5.9 with cannabidiol, compared with a reduction from 14.9 to 14.1 with placebo. This needs confirmation in additional trials.

What’s the optimal dose? The randomized trial tested just one dose – 20 mg/kg per day.

What are the drug interactions and their possible impact on cannabidiol efficacy? Outcomes appear to be better in patients on concomitant clobazam (Onfi), perhaps because of the significantly higher blood levels of clobazam’s major metabolite in children on cannabidiol.
 

Long-term effects

The jury is still out on the long-term adverse effects. “These medical marijuana products are being given by families to 2- and 3-month-olds. It will be years before we know about potential long-term cognitive and behavioral effects,” Dr. Brooks-Kayal said.

Dr. Brooks-Kayal reported having no financial conflicts of interest regarding her presentation.
 

bjancin@frontlinemedcom.com

DENVER – The Colorado experience with medical marijuana products for the treatment of pediatric epilepsy holds useful lessons for physicians in states where legal marijuana is a far more recent development, Amy R. Brooks-Kayal, MD, said at the annual meeting of the Teratology Society.

Medical marijuana has been legal in Colorado for nearly 20 years. But the drug’s potential role in treating intractable pediatric epilepsy started getting a lot more attention in 2013 when a CNN report by Sanjay Gupta, MD, chronicled a child’s remarkable turnaround in response to medical marijuana. The story triggered a migration to the state by what has been termed “marijuana refugees”: desperate families with children who had the most severe, complex, treatment-refractory seizure disorders, said Dr. Brooks-Kayal, professor of pediatrics and neurology and chief of pediatric neurology at the University of Colorado at Denver, Aurora.

Today, Dr. Brooks-Kayal and her colleagues at Children’s Hospital Colorado provide care for roughly 300 children on cannabinoids for refractory epilepsy. Back when the CNN story went viral, however, they were caught off guard by the patient influx. They weren’t familiar with medical marijuana, and they had to learn on the fly. They quickly discovered that there were, at that time, no reliable data on the safety, efficacy, pharmacokinetics, or drug interactions of medical marijuana products. And the products were not reliably standardized as to content, quality, or purity.

The situation, fortunately, has improved. There is now phase 3 randomized, double-blind, placebo-controlled clinical trial evidence of efficacy for an investigational proprietary cannabidiol oral solution known as Epidiolex for children and young adults with Dravet syndrome and drug-resistant seizures, as well as documentation of multiple adverse effects (N Engl J Med. 2017 May 25;376[21]:2011-20).

Dr. Brooks-Kayal, a past president of the American Epilepsy Society, said she believes this medication is potentially approvable by the Food and Drug Administration.

“In the world of new seizure medications, what is usually required by the FDA is a 50% reduction in seizures, which this agent gets close to reaching. But it does have a higher adverse event rate than many of our medications. However, this is a tough crowd. These are very, very difficult-to-treat children. So I think any addition to our armamentarium for these kids is going to be beneficial,” she said. “Unfortunately, though, it’s not going to be the panacea that I think some of our families are looking for.”

Based upon the Colorado experience, Dr. Brooks-Kayal offered the following suggestions for colleagues around the country as they begin fielding questions from families about medical marijuana for pediatric epilepsy:
 

• Provide families with the current data, discuss what’s known and still unknown, and encourage families to disclose the use of cannabinoids so the child can be monitored.
• Have the family keep a seizure diary. Get a baseline EEG and another at about 12 weeks. Do routine laboratory monitoring every 4 weeks, including liver function tests. “We think CBDs [cannabinoids] have the potential to worsen liver function,” she said.
• Stress the importance of leaving other seizure medications unchanged. “When this first started, the medical marijuana providers were recommending patients stop their other medications. The providers don’t do that anymore, fortunately,” Dr. Brooks-Kayal said. “Every week we were putting a child in a medically induced coma because they had status epilepticus, and it was the only way to stop their seizures. They started using marijuana products, they were sure it was going to be the cure, they stopped all their other medications, and they developed status epilepticus.”
• Establish policies with the hospital administration and pharmacy about how to handle marijuana products when a child is in the hospital. The Children’s Hospital Colorado pharmacy cannot store or dispense marijuana products because of federal regulations. And again, it’s unsafe to stop seizure medications abruptly, including marijuana products. Informed consent procedures need to be developed for when patients on cannabinoids are hospitalized.
• Encourage families to participate in one of the six Food and Drug Administration–approved double-blind, placebo-controlled trials of Epidiolex for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms sponsored by GW Pharmaceuticals.

Breaking down the evidence

Here’s what’s known and what is still unknown about the safety and efficacy of cannabinoids for the treatment of refractory pediatric epilepsy, according to Dr. Brooks-Kayal.

 

The knowns

Cannabinoids show activity against seizures in animal models. Moreover, initial clinical data suggest they may decrease seizures in some children with refractory epilepsy. This evidence includes a retrospective study from Children’s Hospital Colorado reliant upon parental reports of improvement (Epilepsy Behav. 2015 Apr;45:49-52), an Israeli retrospective study (Seizure. 2016 Feb;35:41-4), a positive open-label trial of an investigational oral oil-based solution of a pharmaceutical-grade cannabidiol known as Epidiolex (Lancet Neurol. 2016 Mar;15[3]:270-8), and evidence from a Food and Drug Administration–authorized phase 3, randomized clinical trial of Epidiolex (N Engl J Med. 2017 May 25;376[21]:2011-20).

The incidence of short-term adverse events associated with cannabinoids is substantial. The rate seems to be higher with Epidiolex than with many other medical marijuana products, although the potency is greater, too. These include somnolence, fatigue, and convulsions.

In addition, gastrointestinal side effects are common with Epidiolex. “Some are probably due to the oil base; some [are] probably due to the cannabidiol itself,” said Dr. Brooks-Kayal.
 

The unknowns

What types of seizures does it work for? This is under study in a series of FDA-authorized phase 3 randomized trials.

What is the placebo-subtracted response rate to cannabidiol? In the randomized trial published in the New England Journal of Medicine, the median monthly frequency of seizures decreased from 12.4 to 5.9 with cannabidiol, compared with a reduction from 14.9 to 14.1 with placebo. This needs confirmation in additional trials.

What’s the optimal dose? The randomized trial tested just one dose – 20 mg/kg per day.

What are the drug interactions and their possible impact on cannabidiol efficacy? Outcomes appear to be better in patients on concomitant clobazam (Onfi), perhaps because of the significantly higher blood levels of clobazam’s major metabolite in children on cannabidiol.
 

Long-term effects

The jury is still out on the long-term adverse effects. “These medical marijuana products are being given by families to 2- and 3-month-olds. It will be years before we know about potential long-term cognitive and behavioral effects,” Dr. Brooks-Kayal said.

Dr. Brooks-Kayal reported having no financial conflicts of interest regarding her presentation.
 

bjancin@frontlinemedcom.com