Sleep Medicine 15 (2014) 681–687 Contents lists available at ScienceDirect Sleep Medicine journal homepage: www.elsevier.com/locate/sleep Original Article Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review ⇑ Smaranda Leu-Semenescu a,b,c, , Nandy Nittur b, Jean-Louis Golmard d, Isabelle Arnulf a,b,c a National Reference Centre for Narcolepsy and Idiopathic Hypersomnia, France b AP-HP, Hôpital Universitaire Pitié-Salpêtrière, Service des Pathologies du Sommeil, Paris, France c Pierre and Marie Curie University, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Inserm U 1127, CNRS UMR7225, Paris, France d Department of Biostatistics, Hôpital Universitaire Pitié-Salpêtrière, ER4, Pierre and Marie Curie University, Paris, France article info abstract Article history: Objective: To evaluate the benefits and risks of pitolisant (a wake-enhancing drug that increases the his- Received 13 September 2013 tamine release in the brain by blocking presynaptic H3 histamine reuptake) in patients with idiopathic Received in revised form 10 December 2013 (IH) and symptomatic (SH) hypersomnia plus sleepiness refractory to available stimulants (modafinil, Accepted 7 January 2014 methylphenidate, mazindol, sodium oxybate, and D-amphetamine). Available online 18 March 2014 Methods: Through retrospective analyses of patient files, the benefit (the score from the Epworth Sleep- iness Scale [ESS], authorization renewal) and tolerance (side-effects) of pitolisant were assessed. Keywords: Results: A total of 78 patients with IH (n = 65%, 78% women) and SH (n = 13%, 54% women) received pitol- Idiopathic hypersomnia isant 5–50 mg once per day over the course of five days to 37 months. The median (interquartile range) Pitolisant BF2.649 ESS scores of patients with IH decreased from 17 (15.5–18.5) to 14 (12–17). There were 36% responders H3 receptor antagonist (ESS fall of P3). The improvement in ESS score (À1.9 ± 2.6) was different from 0 in IH without long sleep Histamine time (P < 0.002) and in IH with a long sleep time (P < 0.0001), but not in SH. Forty-four (63%) patients Sleepiness with IH and 12 (77%) patients with SH stopped pitolisant, mostly due to a lack of efficacy. Side-effects included gastrointestinal pain (15.4%), increased appetite and weight gain (14.1%), headache (12.8%), insomnia (11.5%), and anxiety (9%), as well as exceptional reports of depression and persistent genital arousal. Conclusion: Pitolisant had a long-term favorable benefit/risk ratio in 23–38% of drug-resistant patients with IH and SH, suggesting that histamine neurons can be stimulated in severe idiopathic and symptom- atic hypersomnia. Ó 2014 Elsevier B.V. All rights reserved. 1. Introduction abnormally stimulated by an unknown endogenous substance in some cases [4]. Cerebrospinal fluid histamine levels are reduced Idiopathic hypersomnia (IH) is a rare (0.002–0.02% of the popu- [5,6] or unchanged in instances of IH [7], but they are also reduced lation) and disabling disease that affects mostly young subjects [1]. in narcolepsy with or without hypocretin deficiency, suggesting In addition to suffering from severe daytime sleepiness, most that low histamine levels signal rather than cause somnolence of patients report major sleep inertia, impaired daytime alertness a central origin. In addition to these idiopathic central hypersom- (the feeling of never being really awake), and altered cognition nias, some hypersomnias that are symptomatic of diencephalic with automatic behaviors [2,3]. Two forms of the disease are recog- lesions (e.g. neurolupus and craniopharyngioma) and medical dis- nized: one with and one without long (>10 h) night-time sleep. The eases have been described [1]. cause of this disease is unknown. The hypocretin system, which is Because IH is rare, no randomized controlled therapeutic trials deficient in narcolepsy/cataplexy, is unaffected in patients with IH, have been performed. As a consequence, no stimulant has received whereas the gamma-aminobutyric acid (GABA) system may be current approval from drug agencies for the purposes of treating IH. At present, clinicians treat IH-associated sleepiness with the same treatments as those used in narcolepsy [8]. Modafinil has a good benefit/risk ratio in IH with or without long sleep time, similar ⇑ Corresponding author at: Service des Pathologies du Sommeil, Hôpital Pitié Salpêtrière, 47-83 boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Tel.: +33 to its effects in narcolepsy/cataplexy [9]. However, modafinil and 142167702; fax: +33 1 42167700. methylphenidate provide, at best, only moderate improvement in E-mail address: [email protected] (S. Leu-Semenescu). sleepiness in patients with IH [10]. Reports of sodium oxybate use http://dx.doi.org/10.1016/j.sleep.2014.01.021 1389-9457/Ó 2014 Elsevier B.V. All rights reserved. 682 S. Leu-Semenescu et al. / Sleep Medicine 15 (2014) 681–687 in IH are exceptional [10]. Plus, some patients have a severe sleepi- 2010 to March 2013 and who used the drug for at least a single ness refractory to these drugs and require another therapeutic day. To be eligible for an individual ATU of pitolisant, delivered option. Dextroamphetamine has been approved by the US Food by the French Drug Agency (Agence Nationale de Sécurité du and Drug Administration for the treatment of narcolepsy and is also Médicament et des produits de santé), the patients must have suf- used in patients with IH in the UK and the USA [10,11]. Pemoline has fered symptoms resistant to stimulants that were approved for been withdrawn from the market due to concerns about the risk of narcolepsy given at the highest tolerable dosage. In France, modafi- liver toxicity [10,12]. Mazindol and D-amphetamine can be obtained nil, methylphenidate and sodium oxybate are marketed for narco- in rare cases in France on a named patient basis after approval by the lepsy and can be used by analogy in primary and secondary French Drug Agency [13]. Although all of these treatments are active, hypersomnias of central origin. Mazindol [13] and D-amphetamine further medication improvements are needed in terms of efficacy, are imported on an individual basis and are delivered by the hos- ease of use, and safety. pital pharmacy after the ATU has been obtained. These criteria Pitolisant (BF 2.649, previously named tiprolisant; Bioprojet for eligibility are strict and must be approved by two anonymous Ltd., Paris, France) is a new histaminergic stimulant. This inverse experts in the field after they have reviewed the medical case. agonist of the histamine H3 autoreceptor increases histamine The individual ATU procedure is aimed at making some drugs release in the hypothalamus and cortex. Pitolisant increases wake- that are currently absent from the national market available to a fulness and decreases narcoleptic episodes in orexin knockout limited number of patients with resistant, severe and orphan dis- mice. In a single-blind trial, it reduced excessive daytime sleepi- eases for the sake of human compassion. This procedure requires ness in patients with narcolepsy/cataplexy [14]. In a recent large, the treating physician (who should be experienced in the field randomized controlled study of pitolisant (versus modafinil and and a member of a sleep center in a university hospital) to com- versus placebo) in 95 patients with narcolepsy, the Epworth Sleep- plete a detailed, anonymous form listing the patient’s age, sex, iness Scale (ESS) score improved by À5.8 with pitolisant, a weight, diagnosis, medical history, severity of the disease, and list decrease which was non-inferior to modafinil [15]. We first of maximum dosages and effects (benefit and side-effects) of drugs reviewed the charts of four teenagers with resistant narcolepsy already used to alleviate sleepiness along with the reason for who benefited from pitolisant treatment [16]. Since 2010, because requesting the authorization. The form is sent to the drug agency the drug had been tested in phase III trials and one long-term via the local hospital pharmacy and examined by two anonymous open-extension trial for narcolepsy, it was available on a named expert referees (one physician and one pharmacist) who decide patient basis to patients with IH experiencing severe sleepiness whether to authorize the administration of the drug for three refractory to available stimulants after individual authorization months. In particular, they require the knowledge of whether the from the French Drug Agency. We studied the benefits and risks maximum stimulant dosages have been tried in these patients of pitolisant in our patients with IH and symptomatic hypersomnia and whether intolerable side-effects were observed. Their decision over the long term using a chart review process. is based on a major resistance to marketed drugs given at the high- est tolerated dosage. If refractory sleepiness is the motive for requesting pitolisant, then the symptoms should be refractory to 2. Methods modafinil 600 mg/day, methylphenidate 80 mg/day, and sodium oxybate 9 g/day alone or in combination. The liability is shared 2.1. Subjects between the French Drug Agency and the physician prescribing the non-marketed drug (who engages his or her liability with a The files of all patients diagnosed with IH and symptomatic written signature). Every three months, the physician must report hypersomnia at the University Hospital of Pitié-Salpêtrière (Paris) on the benefits and side-effects of the drug to the agency through a and treated with pitolisant were retrospectively collected. The form and dependening on this information, can obtain a renewal of study was approved by the local institutional review board. All of the authorization for use. The hospital pharmacy buys the drug the patients had undergone an attended nocturnal polysomnogra- from the pharmaceutical company and sells it directly to the phy followed by five multiple sleep latency tests (MSLTs) the next patient, and the price is paid by the national health insurance.