FDA Approves WAKIX (Pitolisant) for the Treatment of Excessive Daytime Sleepiness (EDS) in Adult Patients with Narcolepsy


On August 14, 2019, the U.S. Food and Drug Administration (FDA) approved WAKIX (pitolisant) for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. The approved recommended dosage of WAKIX is 17.8 mg to 35.6 mg administered orally once daily in the morning upon wakening. Titrate dosage as follows:

  • Week 1: Initiate with a dosage of 8.9 mg once daily
  • Week 2: Increase dosage to 17.8 mg once daily
  • Week 3: May increase to the maximum recommended dosage of 35.6 mg once daily

If a dose is missed, patients should take the next dose the following day in the morning upon wakening.

It may take up to 8 weeks for some patients to achieve a clinical response.

WAKIX is contraindicated in patients with severe (Child Pugh C) hepatic impairment. Additionally, there is also a significant increase in pitolisant exposure in patients with moderate (Child Pugh B) hepatic impairment. WAKIX prolongs the QT interval. Avoid use of WAKIX in patients with known QT prolongation or with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes or sudden death. The risk of QT prolongation may be greater in patients with hepatic or renal impairment. Monitor patients with hepatic or renal impairment for increased QTc.

Additional information regarding dosage and administration and warnings and precautions can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: WAKIX is a histamine-3 (H3) receptor antagonist/inverse agonist. The mechanism of action of pitolisant in excessive daytime sleepiness (EDS) in adult patients with narcolepsy is unclear.
  • General PK: The steady state Cmax and AUC of pitolisant at a dosage of 35.6 mg once daily are 73 ng/mL (range: 49.2 ng/mL to 126 ng/mL) and 812 ng*hr/mL (range: 518 ng*hr/mL to 1468 ng*hr/mL), respectively. The exposure (Cmax and AUC) of pitolisant increases proportionally with dose and steady state is reached by day 7.
  • Absorption: The oral absorption of pitolisant is around 90%. The median time to maximum plasma concentration of pitolisant is 3.5 hours (2 hours to 5 hours).
  • Distribution: The apparent volume of distribution of pitolisant is approximately 700 L (5 L/kg to 10 L/kg). Serum protein binding is approximately 91% to 96%. The blood to plasma ratio of pitolisant is 0.55 to 0.89.
  • Elimination: The median half-life of pitolisant is approximately 20 hours (7.5 hours to 24.2 hours). The apparent clearance (CL/F) of pitolisant is 43.9 L/hour and renal clearance accounts for < 2% of the total clearance of pitolisant.
  • Metabolism: Pitolisant is primarily metabolized by CYP2D6 and to a lesser extent by CYP3A4; these metabolites are further metabolized or conjugated.
  • Excretion: After a single oral radiolabeled pitolisant 17.8 mg dose, approximately 90% of the dose was excreted in urine (< 2% unchanged) and 2.3% in feces.
  • Cardiac Electrophysiology: At the maximum approved recommended dosage, WAKIX led to a QTc increase of 4.2 msec. Exposures 3.8-fold higher than achieved at the maximum approved recommended dosage increase QTc 16 msec (mean).

Drug Interactions

  • Strong CYP2D6 Inhibitors: Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure. For patients receiving strong CYP2D6 inhibitors, initiate WAKIX at 8.9 mg once daily and increase after 7 days to a maximum dosage of 17.8 mg once daily. For patients on a stable dose of WAKIX, reduce the WAKIX dose by half upon initiating strong CYP2D6 inhibitors.
  • Strong CYP3A4 Inducers: Concomitant use of WAKIX with strong CYP3A4 inducers decreases pitolisant exposure. Assess for loss of efficacy after initiation of a strong CYP3A4 inducer. For patients stable on WAKIX 8.9 mg or 17.8 mg once daily, increase the dose of WAKIX to double the original daily dose (i.e., 17.8 mg or 35.6 mg, respectively) over 7 days. If concomitant use of a strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half.
  • Histamine-1 (H1) Receptor Antagonists: WAKIX increases the levels of histamine in the brain; therefore, H1 receptor antagonists that cross the blood-brain barrier may reduce the effectiveness of WAKIX. Avoid concomitant use of WAKIX with centrally acting H1 receptor antagonists.
  • QT Interval Prolongation: Concomitant use of drugs that prolong the QT interval may add to the QT effects of WAKIX and increase the risk of cardiac arrhythmia. Avoid concomitant use of WAKIX with other drugs known to prolong the QT interval.
  • Sensitive CYP3A4 Substrates: WAKIX may reduce effectiveness of sensitive CYP3A4 substrates. The effectiveness of hormonal contraceptives (e.g., ethinyl estradiol) may be reduced when used with WAKIX and effectiveness may be reduced for 21 days after discontinuation of therapy. Advise patients using hormonal contraception to use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuation of treatment.

Use in Specific Populations

  • No clinically significant differences in the pharmacokinetics of pitolisant were observed based on age (18 to 82 years old), sex, race/ethnicity (Caucasians or Blacks), or body weight (48 to 103 kg).
  • Renal Impairment: The exposure of pitolisant increases in patients with moderate to severe (eGFR 15 to 59 mL/minute/1.73 m2) renal impairment. The pharmacokinetics of WAKIX in patients with end stage renal disease (ESRD) (eGFR of <15 mL/minute/1.73 m2) is unknown. Monitor patients with renal impairment for increased QTc. In patients with moderate to severe renal impairment, initiate WAKIX at 8.9 mg once daily and increase after 7 days to a maximum dosage of 17.8 mg once daily. WAKIX is not recommended in patients with ESRD.
  • Hepatic Impairment: The exposure of pitolisant increases in patients with moderate (Child Pugh B) hepatic impairment. WAKIX has not been studied in patients with severe (Child Pugh C) hepatic impairment. Monitor patients with hepatic impairment for increased QTc. No dosage adjustment of WAKIX is recommended in patients with mild (Child Pugh A) hepatic impairment. In patients with moderate hepatic impairment, initiate WAKIX at 8.9 mg once daily and increase after 14 days to a maximum dosage of 17.8 mg once daily. WAKIX is contraindicated in patients with severe hepatic impairment.
  • Poor CYP2D6 Metabolizers: Patients known to be poor CYP2D6 metabolizers have higher pitolisant concentrations than normal CYP2D6 metabolizers. Initiate WAKIX at 8.9 mg once daily and titrate to a maximum dose of 17.8 mg once daily after 7 days.

Additional information regarding use in specific populations can be found in the full prescribing information linked below.

Efficacy and Safety

Efficacy of WAKIX for the treatment of EDS in adult patients with narcolepsy was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies. Patients ≥ 18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy and who had an Epworth Sleepiness Scale (ESS) score ≥ 14 were eligible to enroll in the studies. EDS was assessed using the ESS, an 8-item questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities. The primary endpoint for both studies was the least square mean final ESS score compared to placebo. Additional information regarding efficacy trials can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 5% and twice placebo) for WAKIX were insomnia, nausea, and anxiety.


Full prescribing information is available at https://go.usa.gov/xVawA.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.