REMS Safety Program for Esketamine in Treatment-Resistant Depression

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The purpose and impact of the REMS program established to support the integration of intranasal esketamine into clinics that manage treatment-resistant depression.

Steven Levine, MD: Let us move on to discussing the practical considerations of delivering esketamine to patients and integrating this into patient care. Let us start with Angelos. Can you speak to the idea that intranasal esketamine has a risk evaluation and mitigation strategy [REMS]?

Angelos Halaris, MD, PhD, APA, ACNP, CINP: Absolutely. As I mentioned a while ago, we have to make sure there are no conditions, such as aneurysmal disease, uncontrolled hypertension, substance abuse, or any other blood disease—not necessarily aneurysmal disease but hardening of the arteries, which could theoretically cause a rise in the blood pressure acutely with the possibility of having a bleed in the brain or elsewhere. That is the main thing. Other than that, it is a safe drug to use.

It has to be done on-site in the office, whether it is a private practice office, a clinic, or a hospital. It has to be done under 2-hour observation, longer if necessary in the opinion of the treating physician. The patient is not allowed to drive—certainly not after termination of the treatment. He or she must have somebody to take them home. We want to make sure there is somebody to pick the patient up. We stipulate that the escort shows up to pick up the patient, so we know that they are not going to drive themselves. Not that they want to fool us, but we never know. In fact, 1 patient today told me, “Doctor, I don’t have anybody to bring me next week. I’m OK to drive.” I said, “Absolutely not. Let us skip it if you do not have a driver. I don’t like it, but that’s the best thing to do.”

Addiction is a major issue. Benzodiazepines are allowed, but we need to exercise professional judgment. How much are they taking, and how long is the patient addicted? Is the patient asking for ever-increasing doses? Are there other drugs of abuse, including—I hate to say this—marijuana? I make a point that if they smoke marijuana, there is the potential, backed by research data, that THC [tetrahydrocannabinol]—especially if the content is high—could interfere with the metabolism of psychiatric drugs in general, including esketamine, thereby reducing the efficacy. I make a point of asking if they are ready to discontinue use. I make it clear that I have to rely on their commitment to refraining. That is not so much the case with nicotine, although I prefer that they don’t smoke, or at least reduce the frequency and number of cigarettes per day. That may or may not happen.

There’s nothing else that’s critical. The issue of a dissociative reaction is a possibility. There are occurrences of a true psychotic episode. In that case, we have to again exercise judgment. Either we keep the patient under observation longer, or we administer proper medication to help them return to increase their reality testing, so to speak. Of course, do not drive. Initially, the requirements were to not drive for 24 hours. Later on, the FDA relaxed that, and the company, Janssen Pharmaceuticals, modified the precautionary note to saying you may drive or operate machinery the following day after you’ve had a “restful night’s sleep.” I asked them to please define for us what a restful night’s sleep is. I didn’t get an answer. Nobody wanted to define a restful night’s sleep. I tell my patients, “For now, until further notice, I don’t want you to drive for 24 hours.”

Lisa Harding, MD: You asked the question, “Why a REMS?” It is good for many reasons. I wish that a REMS existed for racemic ketamine. Patients and doctors enter contracts, whether verbally, or sometimes those of us who treat substance abuse have very arbitrary written contracts. This is a contract between you and your patient. This is a class 3 controlled substance. Ketamine is such a fantastic treatment. To protect it and it and not go the way of the opioid crisis, if we want to think of all the nefarious things that can happen, this is a great mitigating body that has been put in place to help us judiciously prescribe this.

For me, most patients have said, “Wow, this is really high tech.” They get a lot of confidence in knowing that the FDA is really overseeing this, that it is not some back-alley operation. Then they, too, understand their responsibility of the things that they are attesting to when they get enrolled in the REMS. We also have that ability where we do not see other prescribers, but if somebody tries to enroll the same patient at another site to try to get this medication, we can see that. If you think of it as an extension of a prescription monitoring program, it is a fantastic body that has been put in place to monitor how we are prescribing this drug.

Patricia Ares-Romero, MD, FASAM: I agree, Lisa. When I talked to my providers in the hospital at the beginning, everybody was concerned about prescribing and treating patients. I said, “This REMS is really put in place to protect us as well.” A patient cannot receive esketamine in another center if they are registered with you, so it really does protect us. The other thing is that they cannot understand why the patient cannot just get it at a pharmacy. Well, they cannot. We must receive it. It really does protect the patient, protect us, and—to Lisa’s point—protect the medication.

Steven Levine, MD: It certainly sounds like all 3 of you really value the formalization of a REMS to ensure patient safety.

Lisa Harding, MD: Absolutely.

Angelos Halaris, MD, PhD, APA, ACNP, CINP: Absolutely.

Steven Levine, MD: Angelos, to answer your question, “What is a restful night’s sleep?” I do not know how to define a restful night’s sleep, but I know it when I have had 1.

Transcript Edited for Clarity

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