In 2012, researchers from Emory University published a paper on their finding of a substance that increases the effectiveness of GABA in people with central disorders of hypersomnolence, particularly idiopathic hypersomnia. In that paper, they discussed their findings in seven patients who were treated with flumazenil. In 2014, Kelty et al published a case report on the use of flumazenil given intravenously to a single patient for 96 hours and then implanted under the skin. The current paper from the group of Emory researchers includes information from additional patients who were treated with a compounded version of flumazenil.
What kind of a study was this?
This was a retrospective study, meaning that the researchers did not set out ahead of time to perform a research study with predetermined goals and questions. Instead, two neurologists prescribed the medication, flumazenil, as part of their routine practice to all appropriate patients who came to their clinic. Then, at a later date, they formulated their questions.
Who were the patients and what did they do?
One hundred fifty-three patients (92 women) were prescribed flumazenil by the physicians at Emory.
Who were the researchers and what did they do?
Dr. Trotti and her colleagues at Emory University reviewed the charts of their patients with hypersomnolence for whom they had prescribed flumazenil. They also reviewed the patients’ electronic correspondence and pharmacy records.
What were the results of the study?
Ninety-six of the 153 (63%) patients reported that they were less sleepy after taking flumazenil. On the other hand, 19 people reported that they were more sleepy after taking flumazenil. Among these 19 patients, nine continued taking flumazenil because the increased sleepiness was only temporarily worse right away after taking the medication or the sleepiness improved after the flumazenil dose was changed.
Before starting treatment, the average ESS score was 15.1, even among those who were taking wake-promoting agents. After starting treatment with flumazenil, the average ESS score dropped to 10.3 among the 40 people who reported improved sleepiness and who completed a second ESS.
Of the 96 patients who reported that their sleepiness improved in response to treatment with flumazenil, 59 continued to take the drug long term (average, 7.8 months at follow-up). Interestingly, 72% of women reported a positive response to the drug, whereas only 48% of men had a positive response. Similarly, people who reported having sleep inertia (difficulty waking up, including grogginess or disorientation immediately upon awakening) were more likely to respond to flumazenil, as compared with those without sleep inertia (72% vs 42%).
Seventy-nine participants (52%) reported experiencing an adverse event (the most common being dizziness, anxiety, and headache), with 17 people stopping the medicine because of adverse events. Two patients had serious adverse events, and another had changes in liver function tests that resolved after stopping the drug.
What were the researchers’ conclusions?
According to the authors of this study, “In summary, our clinical experience in a large group of patients with treatment-refractory hypersomnolence demonstrates meaningful and sustained clinical response in a substantial fraction of patients. Important questions remain about optimal formulation, dosing, long-term safety, and effectiveness. Prospective, controlled studies, ideally with measurement of plasma or cerebrospinal fluid flumazenil levels, are clearly needed. However, our experience suggests the possibility of clinical use of flumazenil in carefully selected, severely affected patients lacking other treatment options.”
Trotti LM, Saini P, Koola C, LaBarbera V, Bliwise DL, Rye DB. Flumazenil for the treatment of refractory hypersomnolence. J Clin Sleep Med 2016;ePub ahead of print.
Archive for 'Flumazenil'
We have continued to monitor the flumazenil shortage situation and now have some updates for you. We are offering this to you for information purposes only.
To the best of our knowledge, and until now, only one pharmacy in the United States, Pavilion Pharmacy in Atlanta, has been compounding flumazenil into a transdermal cream and sublingual lozenge. Just recently, a second pharmacy, Village Pharmacy, in Lynnfield, Massachusetts, has identified a source for flumazenil, received a very small shipment for testing, and been able to compound it into a transdermal cream.
As mentioned in last week’s SomnusNooze, according to information that we have received from Pavilion Pharmacy, the shipment of flumazenil that they ordered from the importer in Canada has cleared Canadian Health regulations and is awaiting approval from the US Food and Drug Administration before it can be sent to Pavilion. We have no timeframe for when that will occur. Pavilion Pharmacy has identified another source of flumazenil and, two weeks ago, ordered another batch of the drug from this new company. They anticipate receiving the drug from this new company within the next two to four weeks; however, no guarantees are in place.
Village Pharmacy imported a very small amount of flumazenil to test the drug for effectiveness and the drug was shown to be effective. They have currently dispensed the small amount that they ordered.
Because of state pharmacy regulations, Village Pharmacy can only fill prescriptions and send them to people within the state of Massachusetts. They can fill prescriptions for people from outside of Massachusetts, but those people, or their representatives, have to come to the pharmacy to pick up the drug. It cannot be shipped outside the state of Massachusetts. As mentioned above, they can only compound the cream, not the lozenges. Village Pharmacy does accept insurance from several carriers that cover compounded drugs.
Village Pharmacy has placed an order for more flumazenil, but, because of the cost, they have ordered only enough to fill prescriptions for people in Massachusetts. If you have a prescription for flumazenil cream and have a way to pick up the drug at Village Pharmacy, please call them and let them know so that they will order a larger quantity of flumazenil. They anticipate receiving the drug in the next three to four weeks.