Conference Coverage

Flumazenil effective in refractory hypersomnolence


 

AT SLEEP 2016

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DENVER – Transdermal or sublingual flumazenil is well worth considering for treatment of carefully selected patients with hypersomnolence refractory to conventional wake-promoting medications, Lynn Marie Trotti, MD, said at the annual meeting of the Associated Professional Sleep Societies.

Her retrospective chart review of 153 consecutive patients treated with flumazenil (Romazicon) showed that 63% derived symptomatic benefit, and 39% of patients remained on the drug at the end of the review period, which averaged 6.8 months, reported Dr. Trotti, a neurologist and sleep scientist at Emory University in Atlanta.

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Make no mistake: This is off-label therapy. Flumazenil’s approved indication is as intravenous therapy for benzodiazepine sedation. Given orally, the drug is almost entirely eliminated on first-pass metabolism, so she and her coinvestigators had flumazenil compounded at a pharmacy in two formulations: a 6-mg sublingual lozenge and a transcutaneous lotion in a dispenser providing 3 mg of flumazenil per click of the device.

This novel therapy is supported by a plausible mechanistic rationale. Dr. Trotti and colleagues have previously shown that most patients with central hypersomnolence have abnormal potentiation of GABA-A receptors in their cerebrospinal fluid (CSF).

“Functionally speaking, it’s as though they’re producing an endogenous benzodiazepinelike substance,” she explained.

The investigators showed further that the macrolide antibiotic clarithromycin, a negative allosteric modulator of GABA-A receptors, reduced sleepiness in patients with central hypersomnolence syndromes in a randomized, double-blind, crossover trial (Ann Neurol. 2015 Sep;78[3]:454-65).

“It’s not great to use an antibiotic to treat people who don’t have a bacterial infection, so it would be really lovely if we had a GABA antagonist or negative allosteric modulator of GABA-A receptors that was not clarithromycin. And that’s where flumazenil comes into the picture,” according to Dr. Trotti.

As a requirement for receiving flumazenil at the Emory sleep disorders center, patients had to have been refractory to all conventional therapies. Indeed, they had been refractory to an average of 4.6 medications for excessive sleepiness. Also, their hypersomnolence had to have a serious impact on their daily life, for example a job at risk because of inability to drive to and from work safely. Initially, it was further required as a condition for treatment that patients had to show abnormal CSF potentiation of GABA-A receptors; however, the investigators quit requiring a CSF sample after roughly the first 100 candidates proved positive.

Dosing of the sublingual flumazenil lozenges began at one 6-mg lozenge four times daily, titrating up by adding an extra lozenge every 4-5 days until reaching a maximum of 12 per day. The lotion is rubbed on the inside of the forearm at a dose of 3 mg on each arm up to four times per day.

Among the 40 treatment responders who completed the Epworth Sleepiness Scale at baseline and after an average of 6.8 months on flumazenil, the average score improved from 15 to 10.3.

Fifty-seven patients obtained no benefit from flumazenil, 10 stopped the drug because of side effects, 3 quit because they preferred clarithromycin, 8 stopped owing to the cost, and the rest dropped the drug for an assortment of reasons, including planned pregnancy.

The most common treatment-emergent adverse events included dizziness in 13% of subjects, anxiety in 7%, and other mood disturbances in 6%.

Two serious adverse events occurred. One patient with a history of atrial fibrillation experienced a transient ischemic attack. And a patient with systemic lupus erythematous developed asymptomatic CNS lupus vasculopathy. It’s not possible to say whether these events were treatment related because the experience with chronic flumazenil therapy is so limited. After all, the drug is given for its approved indication for no longer than a few days, Dr. Trotti observed.

“This is all clinical data. Obviously I’m not suggesting that everybody should start prescribing flumazenil. That being said, we really need better treatment options,” she said.

The long-term treatment continuation rate with modafinil for hypersomnolence is about 50%, anywhere from 29% to 66% for amphetamines, 38% for clarithromycin, and 37% for pitolisant.

“If you look globally at how likely people with idiopathic hypersomnolence or narcolepsy are to get a satisfactory response to conventional therapies, probably 15%-20% do not get satisfactorily treated with what we currently have available. Prospective controlled studies of flumazenil for treatment of hypersomnolence are certainly needed, but in the absence of those data there’s at least a rationale for people who are severely affected and have nowhere else to turn to consider flumazenil,” Dr. Trotti concluded.

She reported having no financial conflicts regarding her study, supported by the National Institutes of Health.

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