Pronunciation: pi TOL i sant / way kicks
Mascot: “Wacky Pitstop”
Available since: 2019
Cost: $7,200–$8,800 / mo
Mechanism: Histamine-3 antagonist/ inverse agonist
Available doses: Tablets: 4.45 mg, 17.8 mg
FDA-approved for: ❖ Excessive daytime sleepiness (EDS) with narcolepsy
❖ Cataplexy with narcolepsy
❖ Idiopathic hypersomnia
Pitolisant (Wakix) debuted in 2019 as the first approved histamine-3 (H3) antagonist, more accurately described as an inverse agonist. It is highly selective for H3 receptors, with no appreciable binding H1, H2, or H4 receptors. Unlike other narcolepsy medications it is not a controlled substance and has no apparent potential for abuse/misuse.
H3 autoreceptors regulate histaminergic activity in the central nervous system by inhibiting histamine synthesis as a negative feedback mechanism. When histamine binds an H3 receptor in the CNS, less histamine is synthesized. As an inverse agonist, pitolisant produces a response opposite to that of endogenous histamine at the receptor, increasing histamine neurotransmission in the brain.
What’s the mechanism of pitolisant? The least convoluted answer may be “central histaminergic effect via H3 receptors”. “Central” refers to central nervous system, i.e., in the brain.
Diphenhydramine (Benadryl) may decrease effectiveness of pitolisant as a pharmacodynamic interaction. Diphenhydramine is an antihistaminergic agent which opposes the histaminergic action of pitolisant. However, diphenhydramine is selective for H1 receptors and does not bind H3 receptors.
What's the mechanism of diphenhydramine in the brain? “Central antihistaminergic effect via H1 receptors” which is the opposite effect of pitolisant but not a precisely opposite mechanism.
Compared to modafinil (Provigil), pitolisant had similar efficacy but better tolerability (Romigi et al, 2018).
It may take up to 8 weeks for some patients to achieve a clinical response.
In 2023 the FDA granted Orphan Drug designation to pitolisant for the treatment of idiopathic hypersomnia.
Pitolisant appears to be a great treatment option for idiopathic hypersomnia other than being extremely expensive. Patients with commercial insurance may be eligible for low copays through a patient-assistance program. Medicare and Medicaid prohibit patient-assistance programs directly affiliated with a drug manufacturer from covering patient co-pays due to anti-kickback concerns.
Side effects of pitolisant may include insomnia, headache, nausea, and anxiety. It possibly may suppress appetite. Pitolisant prolongs QT interval.
Tmax is 3.5 hours and half-life is 20 hours. It is 90% excreted in urine, <2% unchanged. It is contraindicated for patients with severe hepatic or renal impairment (eGFR < 15).
Pharmacodynamic dynamic interactions:
❖ Central histaminergic effects
❖ QT prolongation
No interactions with other medications for narcolepsy, including:
❖ Sodium oxybate (Xyrem) ❖ Modafinil (Provigil)
❖ Armodafinil (Nuvigil)
❖ 2D6 substrate (beach ball)
For individuals with a 2D6 poor metabolizer (PM) genotype (10% of population), do not exceed 17.8 mg
Do not exceed 17.8 mg if taking a strong 2D6 inHibitor (fluoxetine, paroxetine bupropion)
Contraindicated with quinidine (strong 2D6 inHibitor that also prolongs QT interval)
❖ 3A4 inDucer (weak) -- anvil
May make hormonal contraception ineffective
Dosing: Start 8.9 mg QD x 1 week, then 17.8 mg QD which can be the target dose, or on week three may increase to the maximum dose of 35.6 mg QD; Do not exceed 17.8 QD if 2D6 poor metabolizer genotype, concomitant use of a strong 2D6 inHibitor, or moderate hepatic/renal insufficiency; May take with or without food.
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