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ROCKVILLE, MD – If approved for treatment-resistant depression, intranasal esketamine will be strictly regulated in the clinic, with federal monitoring requirements designed to prevent misuse, abuse, or diversion of the drug.
Managed under a Food and Drug Administration Risk Evaluation and Mitigation Strategy (REMS), such a program would establish a stringent post-administration protocol of observation and blood pressure monitoring and require every provider – whether a large health care center or a single clinician – to obtain federal certification to dispense the medication.
At a joint meeting of FDA’s Psychopharmacologic Drugs Advisory and Drug Safety and Risk Management Advisory committees, some members offered a more tempered view while still supporting the approval pathway of the N-methyl-D-aspartate receptor antagonist. By a vote of 14-2, with one abstention, they agreed Feb. 12 that the benefits outweigh the risks of esketamine for treatment-resistant depression.
“I think it has the potential to be a game changer in treatment-resistant depression,” said Walter Dunn, MD, PhD, of the University of California, Los Angeles. “We may someday talk about 2019 in the same way we now talk about the late ’80s, when the first [selective serotonin reuptake inhibitors] were approved.”
Janssen Pharmaceuticals, which is developing the drug, incorporated concerns about misuse from the beginning. Even the delivery device is designed to prevent such issues, a company spokesman said.
Each disposable intranasal delivery device contains 28 mg esketamine; it will come in prepackaged units of one, two, or three devices to deliver the prescribed doses of 28 mg, 56 mg, or 84 mg, respectively. The device does not require priming and, after use, contains only about 30 microliters of residual medication. Its interlocking design, with a glass vial inside the plastic outer assembly, would make it very difficult to pull apart, should anyone want to obtain the residue.
The proposed REMS – the key requirement for approval at this point – would include the following measures:
- Prescriber training on the risks of esketamine and importance of monitoring patients after their dose is administered and the need to register patients
- Administration of esketamine only in certain health care settings that ensure patient monitoring by a health care clinician for 2 hours after administration
- Pharmacies, clinicians, or health care settings that dispense the drug are specially certified to ensure that esketamine is not dispensed directly to patients and that patients are monitored
- Enrollment of patients who are treated with esketamine in a registry to better characterize the risks associated with esketamine administration and inform risk mitigation strategies
After administration, patients would be monitored for at least 2 hours for the common side effects, sedation and dissociation that typically clear within that time. Transient blood pressure fluctuations also can occur shortly after administration and would be monitored until stable. Patients should also be counseled not to drive the day of treatment, and to bring a companion along to drive them home.
Dr. Dunn, however, suggested that some facets of the proposed REMS might create unnecessary barriers for some patients and that stringent monitoring after every single dose – potentially for years – might not be necessary for everyone.
“The REM is certainly important to address the potential for diversion and misuse and adverse effects, but there needs to be a pathway to reduce monitoring requirements” on an individual basis. “If a patient is doing well for a year or so, in remission with no side effects, we should have a way to reduce the need for monitoring. If we make it too much of a burden to go in, get the medication, stay for a couple of hours for monitoring, it’s easy to skip a dose. And we know the number one predictor of relapse is medication nonadherence.”
The facility certification requirement also could curtail access to esketamine, said Steven B. Meisel, PharmD, of Minneapolis.
“How do we define a medically supervised center? Is it somewhere with a nurse onsite? A physician onsite? Does it have to have access to emergency services? This issue of access vs. control and safety is a very important one.”
He posed a clinical conundrum: A patient doing well on regular esketamine who wants to go on an extended trip. Under the proposed REMS, that patient would not be able to access his regular dose, which could only be handled, sorted, and administered by a certified health care clinician. “How are we going to deal with this? There will be great pressure to loosen this up in some manner. But if we allow a patient who’s been doing well on regular treatment with no relapse to have this at home, do we open the way for a teenager to take a bottle or two to a party? Those are real-world issues and must be considered when we establish a REM in a real world that demands access to needed therapy.”
Erring on the side of caution is the responsibility of policymakers, argued Kim Witczak, executive director of Woodymatters, a consumer-driven, nonprofit drug safety organization dedicated to FDA reform. Ms. Witczak was one of two dissenting voices on the vote.
“This has so much potential for so many people who just want a quick fix [for their mood disorders], and the marketing side will see this,” she predicted. “I would want to be very cautious. Once it gets out there into the real world, there will be a lot of people trying to get it. We don’t want to have ‘Esketamines “R” Us’ clinics popping up everywhere.”
The FDA usually follows its panels’ recommendations, which are not binding.
“The REMS program that was proposed by the company and seemingly endorsed by the FDA provides adequate protection,” Sanjay J. Mathew, MD, said in an interview. “I think that was one of the reasons it sailed through the panels.”
An important aspect of intranasal ketamine is that, as an N-methyl-D-aspartate receptor antagonist, it is “an entirely new class” for treating depression, said Dr. Mathew. “This is the first approval that does not work on serotonin or norepinephrine or dopamine. This is a big, big development. We can’t overstate that.”
Also, the nasal spray had to beat a placebo and a newly administered antidepressant. “There was a relatively high bar for showing convincing efficacy,” he said. “So if approved, this drug would be prescribed with an oral antidepressant. Intranasal esketamine represents 20 years’ worth of effort. Today was an important day for psychiatry,” he said. “It was an important day for patients with depression.”
Dr. Mathew is the Marjorie Bintliff Johnson and Raleigh White Johnson Jr. Vice Chair for Research and professor in the Menninger department of psychiatry & behavioral sciences at the Baylor College of Medicine in Houston. He has served as a consultant for and has had research funded by Janssen.
“The REMS program that was proposed by the company and seemingly endorsed by the FDA provides adequate protection,” Sanjay J. Mathew, MD, said in an interview. “I think that was one of the reasons it sailed through the panels.”
An important aspect of intranasal ketamine is that, as an N-methyl-D-aspartate receptor antagonist, it is “an entirely new class” for treating depression, said Dr. Mathew. “This is the first approval that does not work on serotonin or norepinephrine or dopamine. This is a big, big development. We can’t overstate that.”
Also, the nasal spray had to beat a placebo and a newly administered antidepressant. “There was a relatively high bar for showing convincing efficacy,” he said. “So if approved, this drug would be prescribed with an oral antidepressant. Intranasal esketamine represents 20 years’ worth of effort. Today was an important day for psychiatry,” he said. “It was an important day for patients with depression.”
Dr. Mathew is the Marjorie Bintliff Johnson and Raleigh White Johnson Jr. Vice Chair for Research and professor in the Menninger department of psychiatry & behavioral sciences at the Baylor College of Medicine in Houston. He has served as a consultant for and has had research funded by Janssen.
“The REMS program that was proposed by the company and seemingly endorsed by the FDA provides adequate protection,” Sanjay J. Mathew, MD, said in an interview. “I think that was one of the reasons it sailed through the panels.”
An important aspect of intranasal ketamine is that, as an N-methyl-D-aspartate receptor antagonist, it is “an entirely new class” for treating depression, said Dr. Mathew. “This is the first approval that does not work on serotonin or norepinephrine or dopamine. This is a big, big development. We can’t overstate that.”
Also, the nasal spray had to beat a placebo and a newly administered antidepressant. “There was a relatively high bar for showing convincing efficacy,” he said. “So if approved, this drug would be prescribed with an oral antidepressant. Intranasal esketamine represents 20 years’ worth of effort. Today was an important day for psychiatry,” he said. “It was an important day for patients with depression.”
Dr. Mathew is the Marjorie Bintliff Johnson and Raleigh White Johnson Jr. Vice Chair for Research and professor in the Menninger department of psychiatry & behavioral sciences at the Baylor College of Medicine in Houston. He has served as a consultant for and has had research funded by Janssen.
ROCKVILLE, MD – If approved for treatment-resistant depression, intranasal esketamine will be strictly regulated in the clinic, with federal monitoring requirements designed to prevent misuse, abuse, or diversion of the drug.
Managed under a Food and Drug Administration Risk Evaluation and Mitigation Strategy (REMS), such a program would establish a stringent post-administration protocol of observation and blood pressure monitoring and require every provider – whether a large health care center or a single clinician – to obtain federal certification to dispense the medication.
At a joint meeting of FDA’s Psychopharmacologic Drugs Advisory and Drug Safety and Risk Management Advisory committees, some members offered a more tempered view while still supporting the approval pathway of the N-methyl-D-aspartate receptor antagonist. By a vote of 14-2, with one abstention, they agreed Feb. 12 that the benefits outweigh the risks of esketamine for treatment-resistant depression.
“I think it has the potential to be a game changer in treatment-resistant depression,” said Walter Dunn, MD, PhD, of the University of California, Los Angeles. “We may someday talk about 2019 in the same way we now talk about the late ’80s, when the first [selective serotonin reuptake inhibitors] were approved.”
Janssen Pharmaceuticals, which is developing the drug, incorporated concerns about misuse from the beginning. Even the delivery device is designed to prevent such issues, a company spokesman said.
Each disposable intranasal delivery device contains 28 mg esketamine; it will come in prepackaged units of one, two, or three devices to deliver the prescribed doses of 28 mg, 56 mg, or 84 mg, respectively. The device does not require priming and, after use, contains only about 30 microliters of residual medication. Its interlocking design, with a glass vial inside the plastic outer assembly, would make it very difficult to pull apart, should anyone want to obtain the residue.
The proposed REMS – the key requirement for approval at this point – would include the following measures:
- Prescriber training on the risks of esketamine and importance of monitoring patients after their dose is administered and the need to register patients
- Administration of esketamine only in certain health care settings that ensure patient monitoring by a health care clinician for 2 hours after administration
- Pharmacies, clinicians, or health care settings that dispense the drug are specially certified to ensure that esketamine is not dispensed directly to patients and that patients are monitored
- Enrollment of patients who are treated with esketamine in a registry to better characterize the risks associated with esketamine administration and inform risk mitigation strategies
After administration, patients would be monitored for at least 2 hours for the common side effects, sedation and dissociation that typically clear within that time. Transient blood pressure fluctuations also can occur shortly after administration and would be monitored until stable. Patients should also be counseled not to drive the day of treatment, and to bring a companion along to drive them home.
Dr. Dunn, however, suggested that some facets of the proposed REMS might create unnecessary barriers for some patients and that stringent monitoring after every single dose – potentially for years – might not be necessary for everyone.
“The REM is certainly important to address the potential for diversion and misuse and adverse effects, but there needs to be a pathway to reduce monitoring requirements” on an individual basis. “If a patient is doing well for a year or so, in remission with no side effects, we should have a way to reduce the need for monitoring. If we make it too much of a burden to go in, get the medication, stay for a couple of hours for monitoring, it’s easy to skip a dose. And we know the number one predictor of relapse is medication nonadherence.”
The facility certification requirement also could curtail access to esketamine, said Steven B. Meisel, PharmD, of Minneapolis.
“How do we define a medically supervised center? Is it somewhere with a nurse onsite? A physician onsite? Does it have to have access to emergency services? This issue of access vs. control and safety is a very important one.”
He posed a clinical conundrum: A patient doing well on regular esketamine who wants to go on an extended trip. Under the proposed REMS, that patient would not be able to access his regular dose, which could only be handled, sorted, and administered by a certified health care clinician. “How are we going to deal with this? There will be great pressure to loosen this up in some manner. But if we allow a patient who’s been doing well on regular treatment with no relapse to have this at home, do we open the way for a teenager to take a bottle or two to a party? Those are real-world issues and must be considered when we establish a REM in a real world that demands access to needed therapy.”
Erring on the side of caution is the responsibility of policymakers, argued Kim Witczak, executive director of Woodymatters, a consumer-driven, nonprofit drug safety organization dedicated to FDA reform. Ms. Witczak was one of two dissenting voices on the vote.
“This has so much potential for so many people who just want a quick fix [for their mood disorders], and the marketing side will see this,” she predicted. “I would want to be very cautious. Once it gets out there into the real world, there will be a lot of people trying to get it. We don’t want to have ‘Esketamines “R” Us’ clinics popping up everywhere.”
The FDA usually follows its panels’ recommendations, which are not binding.
ROCKVILLE, MD – If approved for treatment-resistant depression, intranasal esketamine will be strictly regulated in the clinic, with federal monitoring requirements designed to prevent misuse, abuse, or diversion of the drug.
Managed under a Food and Drug Administration Risk Evaluation and Mitigation Strategy (REMS), such a program would establish a stringent post-administration protocol of observation and blood pressure monitoring and require every provider – whether a large health care center or a single clinician – to obtain federal certification to dispense the medication.
At a joint meeting of FDA’s Psychopharmacologic Drugs Advisory and Drug Safety and Risk Management Advisory committees, some members offered a more tempered view while still supporting the approval pathway of the N-methyl-D-aspartate receptor antagonist. By a vote of 14-2, with one abstention, they agreed Feb. 12 that the benefits outweigh the risks of esketamine for treatment-resistant depression.
“I think it has the potential to be a game changer in treatment-resistant depression,” said Walter Dunn, MD, PhD, of the University of California, Los Angeles. “We may someday talk about 2019 in the same way we now talk about the late ’80s, when the first [selective serotonin reuptake inhibitors] were approved.”
Janssen Pharmaceuticals, which is developing the drug, incorporated concerns about misuse from the beginning. Even the delivery device is designed to prevent such issues, a company spokesman said.
Each disposable intranasal delivery device contains 28 mg esketamine; it will come in prepackaged units of one, two, or three devices to deliver the prescribed doses of 28 mg, 56 mg, or 84 mg, respectively. The device does not require priming and, after use, contains only about 30 microliters of residual medication. Its interlocking design, with a glass vial inside the plastic outer assembly, would make it very difficult to pull apart, should anyone want to obtain the residue.
The proposed REMS – the key requirement for approval at this point – would include the following measures:
- Prescriber training on the risks of esketamine and importance of monitoring patients after their dose is administered and the need to register patients
- Administration of esketamine only in certain health care settings that ensure patient monitoring by a health care clinician for 2 hours after administration
- Pharmacies, clinicians, or health care settings that dispense the drug are specially certified to ensure that esketamine is not dispensed directly to patients and that patients are monitored
- Enrollment of patients who are treated with esketamine in a registry to better characterize the risks associated with esketamine administration and inform risk mitigation strategies
After administration, patients would be monitored for at least 2 hours for the common side effects, sedation and dissociation that typically clear within that time. Transient blood pressure fluctuations also can occur shortly after administration and would be monitored until stable. Patients should also be counseled not to drive the day of treatment, and to bring a companion along to drive them home.
Dr. Dunn, however, suggested that some facets of the proposed REMS might create unnecessary barriers for some patients and that stringent monitoring after every single dose – potentially for years – might not be necessary for everyone.
“The REM is certainly important to address the potential for diversion and misuse and adverse effects, but there needs to be a pathway to reduce monitoring requirements” on an individual basis. “If a patient is doing well for a year or so, in remission with no side effects, we should have a way to reduce the need for monitoring. If we make it too much of a burden to go in, get the medication, stay for a couple of hours for monitoring, it’s easy to skip a dose. And we know the number one predictor of relapse is medication nonadherence.”
The facility certification requirement also could curtail access to esketamine, said Steven B. Meisel, PharmD, of Minneapolis.
“How do we define a medically supervised center? Is it somewhere with a nurse onsite? A physician onsite? Does it have to have access to emergency services? This issue of access vs. control and safety is a very important one.”
He posed a clinical conundrum: A patient doing well on regular esketamine who wants to go on an extended trip. Under the proposed REMS, that patient would not be able to access his regular dose, which could only be handled, sorted, and administered by a certified health care clinician. “How are we going to deal with this? There will be great pressure to loosen this up in some manner. But if we allow a patient who’s been doing well on regular treatment with no relapse to have this at home, do we open the way for a teenager to take a bottle or two to a party? Those are real-world issues and must be considered when we establish a REM in a real world that demands access to needed therapy.”
Erring on the side of caution is the responsibility of policymakers, argued Kim Witczak, executive director of Woodymatters, a consumer-driven, nonprofit drug safety organization dedicated to FDA reform. Ms. Witczak was one of two dissenting voices on the vote.
“This has so much potential for so many people who just want a quick fix [for their mood disorders], and the marketing side will see this,” she predicted. “I would want to be very cautious. Once it gets out there into the real world, there will be a lot of people trying to get it. We don’t want to have ‘Esketamines “R” Us’ clinics popping up everywhere.”
The FDA usually follows its panels’ recommendations, which are not binding.