WAKIX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for WAKIX (WAKIX).
WAKIX (pitolisant) is a histamine-3 (H3) receptor antagonist/inverse agonist. It enhances the activity of histaminergic neurons in the brain by blocking the H3 autoreceptor, thereby increasing histamine release. This promotes wakefulness and reduces excessive daytime sleepiness in narcolepsy.
| Metabolism | Pitolisant is primarily metabolized by CYP2D6 and CYP3A4. It is also a substrate for CYP2B6 and CYP2C19. The major metabolic pathways include oxidation and glucuronidation. |
| Excretion | Primarily renal (≥80% as unchanged drug and metabolites); minor biliary/fecal elimination (<20%). |
| Half-life | Terminal half-life approximately 11 hours (range 8–15 h) in patients with narcolepsy; steady state achieved within 5 days. |
| Protein binding | ~83% bound primarily to serum albumin. |
| Volume of Distribution | Approximately 0.43 L/kg, suggesting distribution into total body water. |
| Bioavailability | Oral bioavailability is approximately 60–70% due to moderate first-pass metabolism. |
| Onset of Action | Oral: Onset of clinical effect (improved wakefulness) within 1–2 hours after dosing. |
| Duration of Action | Duration of action is approximately 9–12 hours, supporting twice-daily dosing; sustained wakefulness throughout the day with morning and midday doses. |
17.8 mg orally once daily in the morning upon awakening. The starting dose is 4.45 mg once daily for the first week, then increased to 8.9 mg once daily for the second week, and then to the maintenance dose of 17.8 mg once daily thereafter.
| Dosage form | TABLET |
| Renal impairment | For severe renal impairment (eGFR 15-29 mL/min/1.73m2): 8.9 mg orally once daily. Not recommended in end-stage renal disease (eGFR <15 mL/min/1.73m2). |
| Liver impairment | For moderate hepatic impairment (Child-Pugh B): 8.9 mg orally once daily. Not recommended in severe hepatic impairment (Child-Pugh C). |
| Pediatric use | Not approved for pediatric patients. Safety and efficacy in patients <18 years have not been established. |
| Geriatric use | No specific dose adjustment recommended. However, due to potential age-related renal impairment, dose adjustment should be considered based on renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for WAKIX (WAKIX).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. However, pitolisant and its metabolites are present in rat milk. M/P ratio unknown. Caution advised; consider developmental and health benefits of breastfeeding alongside mother's clinical need and potential adverse effects on infant. Consider alternative agents during lactation. |
| Teratogenic Risk | Based on animal studies, WAKIX (pitolisant) caused increased fetal loss and reduced fetal body weight at maternal doses ≥ 4 times the maximum recommended human dose (MRHD). In rabbits, no adverse fetal effects were observed at up to 6 times MRHD. There are no adequate and well-controlled studies in pregnant women. Risk cannot be ruled out; use only if potential benefit justifies potential risk. For trimester-specific risks: first trimester – potential for embryofetal toxicity; second and third trimesters – monitor fetal growth given reduced fetal weight in animals. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Severe hepatic impairment (Child-Pugh class C)","Concomitant use with monoamine oxidase inhibitors (MAOIs)","Known hypersensitivity to pitolisant or any component of the formulation"]
| Precautions | ["QTc prolongation: Avoid use in patients with known QT interval prolongation, electrolyte disturbances, or those taking other QT-prolonging drugs","Hepatic impairment: Contraindicated in severe hepatic impairment (Child-Pugh class C); use with caution in moderate impairment","Renal impairment: Not recommended in severe renal impairment (CrCl <30 mL/min)","Depression/suicidality: Monitor for emergent depression or suicidal ideation","Insomnia: Can cause difficulty sleeping if taken too close to bedtime"] |
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| Fetal Monitoring | Monitor for maternal adverse effects: insomnia, headache, nausea, anxiety, and QT prolongation (ECG monitoring recommended). Fetal monitoring: serial ultrasound for fetal growth assessment (due to animal data showing reduced fetal weight). No specific fetal monitoring required beyond routine prenatal care. |
| Fertility Effects | In animal studies, no impairment of male or female fertility at doses up to 6 times MRHD. No human data on fertility effects. Consider potential for hormonal interactions (histamine H3 receptor antagonist may affect neuroendocrine regulation). Conclude: no significant fertility impairment expected based on animal data, but human data lacking. |