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Medication Highlight: Wakix

In the field of narcolepsy treatment, a limited number of options are available, which include modafinil and methylphenidate. Here, we highlight a novel first-in-class antihistamine agent called Wakix (pitolisant).


Pitolisant is known as a H3 receptor antagonist/inverse agonist. H3 receptors are present on presynaptic neurons which regulate the release of histamine. Histamine then stimulates H1 receptors on the postsynaptic neuron involved in wakefulness. The blockade of H3 receptors by pitolisant causes an increase in histamine production, which leads to an increase in neurotransmitters such as dopamine, serotonin, acetylcholine and norepinephrine. As a result, patients experience more wakefulness and a downregulation of sleep neurons.

Pitolisant is taken in the morning with food, starting at a dose of 10 mg/day in the first week. The dose can be doubled to 20 mg/day in the second week, and then again to the maximum dose of 40 mg/day in the third week.

The most common adverse effects of pitolisant is insomnia (hence taken first thing in the morning), nausea (hence taken with food) and headache. Caution should be advised when prescribed in patients with psychiatric disorders or epilepsy. Pitolisant may prolong the QT interval as well.

Pitolisant is a CYP2D6 and CYP3A4 substrate. Specifically, dose adjustments are required when taken with CYP2D6 inhibitors and CYP3A4 inducers. One important interaction is that pitolisant itself is a weak CYP3A4 inducer, so it may affect oral contraceptives.

Another important interaction is the use of H1 receptor antagonists, which may counter the effectiveness of pitolisant since H1 receptor antagonists block the histamine activity. This interaction is more important with CENTRALLY acting antihistamine such as diphenhydramine and pheniramine.

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