Pitolisant

Histamine H3 receptor inverse agonist / antagonist, wake-promoting agent

Pitolisant

Wakix

Pitolisant (brand name Wakix) is a selective histamine H3 receptor inverse agonist FDA-approved in August 2019 for excessive daytime sleepiness and cataplexy in narcolepsy. Notable for being not a controlled substance, unique among approved wake-promoting medicines, all of which have abuse potential and DEA scheduling (modafinil IV, methylphenidate II, amphetamine II, solriamfetol IV, sodium oxybate III). Mechanism: H3 autoreceptors on histamine neurons in the tuberomammillary nucleus normally inhibit histamine release. Pitolisant blocks (or inverse-agonizes) these autoreceptors, disinhibiting histamine release and promoting wakefulness. Downstream effects on acetylcholine, norepinephrine, and dopamine pathways may also contribute. Slow titration required.

Experience

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Problems

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Titration strategies

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Effects

Headache, insomnia, anxiety, nausea, abdominal pain, decreased appetite, sleep disturbances. QT prolongation possible (caution with other QT-prolonging medicines). Can reduce hormonal contraceptive efficacy.

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Pharmacodynamics

High-affinity inverse agonist at human H3 receptor. Minimal binding at H1, H2, H4, monoamine transporters, or other monoamine receptors.

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Summary

Classes

Histamine H3 receptor inverse agonist / antagonist, wake-promoting agent

Common uses

Excessive daytime sleepiness or cataplexy in adults with narcolepsy (FDA-approved August 2019)

Pharmacy

Starting dose

Week 1: 8.9 mg PO once daily in the morning. Week 2: 17.8 mg. Week 3+: 35.6 mg (max). Titrate as needed.

Preparations

4.45 mg, 17.8 mg tablets

US FDA Max

35.6 mg/d

Pharmacology

Routes

Oral

Onset

Wake-promoting effect over weeks of titration

Duration

Daily morning dosing

Half-life

~20 hours

Bioavailability

Not formally established; oral once-daily adequate

Pregnancy

Limited data; pitolisant may reduce hormonal contraceptive efficacy

Legal status

Rx, not a controlled substance (unique among wake-promoting agents)

Purported mechanism

Selective inverse agonist (or antagonist depending on assay) at presynaptic histamine H3 autoreceptors. H3 receptors normally inhibit histamine release; blocking them disinhibits histamine release from tuberomammillary nucleus, promoting wakefulness. Also enhances acetylcholine, norepinephrine, dopamine release (downstream of histamine signaling).