Wakix

WAKIX is indicated for the:

• treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy.
• treatment of excessive daytime sleepiness (EDS) in pediatric patients 6 years of age and older with narcolepsy.

• See Full Prescribing Information for complete dosage instructions (
  2.1 Recommended Dosage in Adult Patients

  The recommended dosage range for WAKIX for the treatment of EDS or cataplexy in adult patients 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 (two 4.45 mg tablets) once daily
  
  Week 2: Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily
  
  Week 3: May increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily

  Dose may be adjusted based on tolerability.

  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.
  ,
  2.2 Recommended Dosage in Pediatric Patients 6 Years and Older

  The recommended starting dosage of WAKIX for the treatment of EDS in pediatric patients 6 years and older is 4.45 mg administered orally once daily in the morning upon wakening.

  Titrate dosage as follows:

  Week 1: Initiate with a dosage of 4.45 mg (one 4.45 mg tablet) once daily
  
  Week 2: Increase dosage to 8.9 mg (two 4.45 mg tablets) once daily
  
  Week 3: Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily, which is the maximum recommended dosage for patients weighing <40 kg
  
  Week 4: For patients weighing ≥40 kg, may increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily

  Dose may be adjusted based on tolerability. 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.
  )
• Administer orally once daily in the morning upon wakening (
  2.1 Recommended Dosage in Adult Patients

  The recommended dosage range for WAKIX for the treatment of EDS or cataplexy in adult patients 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 (two 4.45 mg tablets) once daily
  
  Week 2: Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily
  
  Week 3: May increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily

  Dose may be adjusted based on tolerability.

  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.
  ,
  2.2 Recommended Dosage in Pediatric Patients 6 Years and Older

  The recommended starting dosage of WAKIX for the treatment of EDS in pediatric patients 6 years and older is 4.45 mg administered orally once daily in the morning upon wakening.

  Titrate dosage as follows:

  Week 1: Initiate with a dosage of 4.45 mg (one 4.45 mg tablet) once daily
  
  Week 2: Increase dosage to 8.9 mg (two 4.45 mg tablets) once daily
  
  Week 3: Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily, which is the maximum recommended dosage for patients weighing <40 kg
  
  Week 4: For patients weighing ≥40 kg, may increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily

  Dose may be adjusted based on tolerability. 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.
  )
• Dosage Recommendations:

• Hepatic impairment (
  2.3 Dosage Recommendations in Patients with Hepatic Impairment

  Adult Patients with Moderate (Child-Pugh Class B) Hepatic Impairment

  • Initiate WAKIX at 8.9 mg once daily and increase after 14 days to a maximum recommended dosage of 17.8 mg once daily
    [see Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ]
    .

  Pediatric Patients (6 years and older) with Moderate (Child-Pugh Class B) Hepatic Impairment

  • Pediatric patients weighing <40 kg: Initiate WAKIX at 4.45 mg once daily and increase after 14 days to a maximum recommended dosage of 8.9 mg once daily

    [see Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ]

    .
  • Pediatric patients weighing ≥40 kg: Initiate WAKIX at 4.45 mg once daily and increase after 14 days to 8.9 mg once daily. May increase after another 14 days to a maximum recommended dosage of 17.8 mg once daily

    [see Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ]

    .

  WAKIX is contraindicated in patients with severe hepatic impairment. WAKIX has not been studied in patients with severe hepatic impairment

  [see Contraindications , Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ]

  .
  ,
  8.6 Hepatic Impairment

  WAKIX is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) as it has not been studied in this population. WAKIX is extensively metabolized by the liver and there is a significant increase in WAKIX exposure in patients with moderate hepatic impairment

  [see Contraindications , Clinical Pharmacology ]

  .

  Monitor patients with moderate hepatic impairment (Child-Pugh Class B) and adjust the dosage of WAKIX

  [see Dosage and Administration ]

  .

  Monitor patients with mild hepatic impairment (Child-Pugh Class A). No dosage adjustment of WAKIX is recommended in patients with mild hepatic impairment.
  ,
  12.3 Pharmacokinetics

  Following oral administration of pitolisant 35.6 mg once daily, the steady state C_maxand AUC are 73 ng/mL (range: 49.2 to 126 ng/mL) and 812 ng*hr/mL (range: 518 to 1468 ng*hr/mL), respectively. Pitolisant exposure (C_maxand AUC) increases proportionally with dose and steady state is reached by day 7.

  Absorption

  The median time to maximum plasma concentration (T_max) of pitolisant is 3.5 hours (2 to 5 hours).
  
  The oral absorption of WAKIX is around 90%.

  Food Effect

  No clinically significant differences in the pharmacokinetics of pitolisant were observed following administration with a high-fat meal.

  Distribution

  The apparent volume of distribution of pitolisant is approximately 700 L (5 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

  After a single dose of 35.6 mg, the median half-life of pitolisant is approximately 20 hours (7.5 to 24.2 hours). The apparent oral clearance (CL/F) of pitolisant is 43.9 L/hr 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 with glycine or glucuronic acid. None of these metabolites are pharmacologically active.

  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.

  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). The effects of end-stage renal disease and severe hepatic impairment on the pharmacokinetics of pitolisant are unknown.

  Pediatric Patients

  Pharmacokinetic data from 24 pediatric patients with narcolepsy (ages 7 to 17 years) receiving a single dose of WAKIX suggest that pediatric patients have higher exposure to pitolisant than adults. The geometric mean C_maxand AUC_0-10hof pitolisant were 2.2 and 2.0-fold higher, respectively, in pediatric patients 12 to 17 years and 3.4 and 3.6-fold higher, respectively, in pediatric patients 7 to 11 years compared to adults.

  Patients with Hepatic Impairment

  Six subjects with mild hepatic impairment (Child-Pugh Class A), 6 subjects with moderate hepatic impairment (Child-Pugh Class B), and 12 healthy subjects matched for age, sex, body mass index and ethnicity received a single dose of WAKIX 17.8 mg to assess the pharmacokinetics of WAKIX in patients with hepatic impairment. Exposure of pitolisant in patients with mild or moderate hepatic impairment is summarized in Figure 1. No studies have been conducted in patients with severe hepatic impairment.

  
  
  

  Figure 1: Effect of Hepatic Impairment on Pitolisant Pharmacokinetics

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_inf= area under the curve from time 0 to time infinity; C_max= maximum plasma concentration.

  
  
  

  Patients with Renal Impairment

  A single dose of WAKIX 17.8 mg was administered to 4 subjects with mild renal impairment (eGFR of 60 to 89 mL/min/1.73 m²), 4 subjects with moderate renal impairment (eGFR of 30 to 59 mL/min/1.73 m²), 4 subjects with severe renal impairment (eGFR of 15 to 29 mL/min/1.73 m²), and 12 subjects with normal renal function (i.e., eGFR >90 mL/min/1.73 m²) to assess the pharmacokinetics of WAKIX in patients with renal impairment. Exposure of pitolisant in patients with mild, moderate, and severe renal impairment is summarized in Figure 2. No studies have been conducted in patients with ESRD.

  
  
  

  Figure 2: Effect of Renal Impairment on Pitolisant Pharmacokinetics

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_inf= area under the curve from time 0 to time infinity; C_max= maximum plasma concentration.

  
  
  

  CYP2D6 Poor Metabolizers

  The pharmacokinetics of pitolisant were evaluated in 3 subjects who were CYP2D6 poor metabolizers (PMs) and 5 subjects who were CYP2D6 extensive metabolizers (EMs). All subjects received WAKIX 17.8 mg daily for 7 days. Exposure of pitolisant in CYP2D6 PMs is summarized in Figure 3.

  
  
  

  Figure 3: Pitolisant Pharmacokinetics in CYP2D6 Poor Metabolizers

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_0-24= area under the curve from time 0 to 24 hours post-dose; C_max= maximum plasma concentration.

  
  
  

  Drug-Drug Interactions

  Effect of Other Drugs on the Pharmacokinetics of WAKIX

  The effect of other drugs on the pharmacokinetics of pitolisant is presented in Figure 4

  [see Dosage and Administration , Drug Interactions ]

  .

  
  
  

  Figure 4: Effect of Concomitant Medications on Pitolisant

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_inf= area under the curve from time 0 to time infinity; C_max= maximum plasma concentration.

  
  
  

  Effect of WAKIX on the Pharmacokinetics of Other Drugs

  The effect of pitolisant on the pharmacokinetics of other drugs is presented in Figure 5

  [see Drug Interactions ]

  .

  
  
  

  Figure 5: Effect of Pitolisant on Concomitant Medications

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_inf= area under the curve from time 0 to time infinity; AUC_0-24= area under the curve from time 0 to 24 hours; C_max= maximum plasma concentration.

  
  
  

  Figure 1

  Figure 2

  Figure 3

  Figure 4

  Figure 5

  ):
  
  • Moderate hepatic impairment (Child-Pugh Class B):
    
    
    Adults:
    Initial dosage is 8.9 mg once daily. Titrate to a maximum dosage of 17.8 mg once daily after 14 days
    
    
    Pediatric Patients:
    Initial dosage is 4.45 mg once daily. Titrate to 8.9 mg once daily after 14 days; for patients weighing ≥40 kg, may increase to 17.8 mg once daily after another 14 days
• Renal impairment (eGFR less than 60 mL/minute/1.73 m²) (
  2.4 Dosage Recommendations in Patients with Renal Impairment and End-Stage Renal Disease

  Adult Patients with eGFR <60 mL/minute/1.73 m²

  • Initiate WAKIX at 8.9 mg once daily and increase after 7 days to a maximum recommended dosage of 17.8 mg once daily
    [see Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ]
    .

  Pediatric Patients (6 years and older) with eGFR <60 mL/minute/1.73 m²

  (using the Schwartz equation, eGFR (mL/min/1.73 m2)=(0.413*height in cm)/serum creatinine in mg/dL)

  • Pediatric patients weighing <40 kg: Initiate WAKIX at 4.45 mg once daily and increase after 7 days to a maximum recommended dosage of 8.9 mg once daily

    [see Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ]

    .
  • Pediatric patients weighing ≥40 kg: Initiate WAKIX at 4.45 mg once daily and increase after 7 days to 8.9 mg once daily. May increase after another 7 days to a maximum recommended dosage of 17.8 mg once daily

    [see Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ]

    .

  WAKIX is not recommended in patients with eGFR less than 15 mL/minute/1.73 m²

  [see Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ]

  .
  ,
  8.7 Renal Impairment

  The pharmacokinetics of WAKIX in patients with end-stage renal disease (ESRD) (eGFR of <15 mL/minute/1.73 m²) is unknown

  [see Clinical Pharmacology ]

  . Therefore, WAKIX is not recommended in patients with ESRD

  [see Dosage and Administration , Warnings and Precautions ]

  .

  Dosage adjustment of WAKIX is recommended in patients with eGFR <60 mL/minute/1.73 m²

  [see Dosage and Administration ]

  .
  ,
  12.3 Pharmacokinetics

  Following oral administration of pitolisant 35.6 mg once daily, the steady state C_maxand AUC are 73 ng/mL (range: 49.2 to 126 ng/mL) and 812 ng*hr/mL (range: 518 to 1468 ng*hr/mL), respectively. Pitolisant exposure (C_maxand AUC) increases proportionally with dose and steady state is reached by day 7.

  Absorption

  The median time to maximum plasma concentration (T_max) of pitolisant is 3.5 hours (2 to 5 hours).
  
  The oral absorption of WAKIX is around 90%.

  Food Effect

  No clinically significant differences in the pharmacokinetics of pitolisant were observed following administration with a high-fat meal.

  Distribution

  The apparent volume of distribution of pitolisant is approximately 700 L (5 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

  After a single dose of 35.6 mg, the median half-life of pitolisant is approximately 20 hours (7.5 to 24.2 hours). The apparent oral clearance (CL/F) of pitolisant is 43.9 L/hr 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 with glycine or glucuronic acid. None of these metabolites are pharmacologically active.

  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.

  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). The effects of end-stage renal disease and severe hepatic impairment on the pharmacokinetics of pitolisant are unknown.

  Pediatric Patients

  Pharmacokinetic data from 24 pediatric patients with narcolepsy (ages 7 to 17 years) receiving a single dose of WAKIX suggest that pediatric patients have higher exposure to pitolisant than adults. The geometric mean C_maxand AUC_0-10hof pitolisant were 2.2 and 2.0-fold higher, respectively, in pediatric patients 12 to 17 years and 3.4 and 3.6-fold higher, respectively, in pediatric patients 7 to 11 years compared to adults.

  Patients with Hepatic Impairment

  Six subjects with mild hepatic impairment (Child-Pugh Class A), 6 subjects with moderate hepatic impairment (Child-Pugh Class B), and 12 healthy subjects matched for age, sex, body mass index and ethnicity received a single dose of WAKIX 17.8 mg to assess the pharmacokinetics of WAKIX in patients with hepatic impairment. Exposure of pitolisant in patients with mild or moderate hepatic impairment is summarized in Figure 1. No studies have been conducted in patients with severe hepatic impairment.

  
  
  

  Figure 1: Effect of Hepatic Impairment on Pitolisant Pharmacokinetics

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_inf= area under the curve from time 0 to time infinity; C_max= maximum plasma concentration.

  
  
  

  Patients with Renal Impairment

  A single dose of WAKIX 17.8 mg was administered to 4 subjects with mild renal impairment (eGFR of 60 to 89 mL/min/1.73 m²), 4 subjects with moderate renal impairment (eGFR of 30 to 59 mL/min/1.73 m²), 4 subjects with severe renal impairment (eGFR of 15 to 29 mL/min/1.73 m²), and 12 subjects with normal renal function (i.e., eGFR >90 mL/min/1.73 m²) to assess the pharmacokinetics of WAKIX in patients with renal impairment. Exposure of pitolisant in patients with mild, moderate, and severe renal impairment is summarized in Figure 2. No studies have been conducted in patients with ESRD.

  
  
  

  Figure 2: Effect of Renal Impairment on Pitolisant Pharmacokinetics

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_inf= area under the curve from time 0 to time infinity; C_max= maximum plasma concentration.

  
  
  

  CYP2D6 Poor Metabolizers

  The pharmacokinetics of pitolisant were evaluated in 3 subjects who were CYP2D6 poor metabolizers (PMs) and 5 subjects who were CYP2D6 extensive metabolizers (EMs). All subjects received WAKIX 17.8 mg daily for 7 days. Exposure of pitolisant in CYP2D6 PMs is summarized in Figure 3.

  
  
  

  Figure 3: Pitolisant Pharmacokinetics in CYP2D6 Poor Metabolizers

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_0-24= area under the curve from time 0 to 24 hours post-dose; C_max= maximum plasma concentration.

  
  
  

  Drug-Drug Interactions

  Effect of Other Drugs on the Pharmacokinetics of WAKIX

  The effect of other drugs on the pharmacokinetics of pitolisant is presented in Figure 4

  [see Dosage and Administration , Drug Interactions ]

  .

  
  
  

  Figure 4: Effect of Concomitant Medications on Pitolisant

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_inf= area under the curve from time 0 to time infinity; C_max= maximum plasma concentration.

  
  
  

  Effect of WAKIX on the Pharmacokinetics of Other Drugs

  The effect of pitolisant on the pharmacokinetics of other drugs is presented in Figure 5

  [see Drug Interactions ]

  .

  
  
  

  Figure 5: Effect of Pitolisant on Concomitant Medications

  
  
  Dots = Geometric least squares mean ratios, Error bars = 90% CI; reference dashed lines are 0.8 and 1.25.
  
  AUC_inf= area under the curve from time 0 to time infinity; AUC_0-24= area under the curve from time 0 to 24 hours; C_max= maximum plasma concentration.

  
  
  

  Figure 1

  Figure 2

  Figure 3

  Figure 4

  Figure 5

  ):
  
  • Adults: Initial dosage is 8.9 mg once daily. Titrate to a maximum dosage of 17.8 mg once daily after 7 days
  • Pediatric Patients: Initial dosage is 4.45 mg once daily. Titrate to 8.9 mg once daily after 7 days; for patients weighing ≥40 kg, may increase to 17.8 mg once daily after another 7 days
  • End-stage renal disease (ESRD): Not recommended
• Poor Metabolizers of CYP2D6 (
  2.6 Dosage Recommendations in Patients Who Are Known CYP2D6 Poor Metabolizers (PMs)

  Adult Patients

  • Initiate WAKIX at 8.9 mg once daily and titrate to a maximum recommended dosage of 17.8 mg once daily after 7 days
    [see Use in Specific Populations , Clinical Pharmacology ]
    .

  Pediatric patients

  • Pediatric patients weighing <40 kg: Initiate WAKIX at 4.45 mg once daily and increase after 7 days to a maximum recommended dosage of 8.9 mg once daily

    [see Use in Specific Populations , Clinical Pharmacology ]

    .
  • Pediatric patients weighing ≥40 kg: Initiate WAKIX at 4.45 mg once daily and increase after 7 days to 8.9 mg once daily. May increase after another 7 days to a maximum recommended dosage of 17.8 mg once daily

    [see Use in Specific Populations , Clinical Pharmacology ]

    .
  ):
  
  • Adults: Maximum recommended dosage is 17.8 mg once daily
  • Pediatric Patients: Maximum recommended dosage is 8.9 mg once daily for patients weighing <40 kg and 17.8 mg for patients weighing ≥40 kg

• WAKIX 4.45 mg tablets: white, round, biconvex film-coated tablet, marked with “S” on one side and plain on the other side. Each tablet contains 5 mg of pitolisant hydrochloride equivalent to 4.45 mg of pitolisant.
• WAKIX 17.8 mg tablets: white, round, biconvex film-coated tablet, marked with “H” on one side and plain on the other side. Each tablet contains 20 mg of pitolisant hydrochloride equivalent to 17.8 mg of pitolisant.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to WAKIX during pregnancy. Patients should be encouraged to enroll in the WAKIX pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call 1-800-833-7460.

Available case reports from clinical trials and postmarketing reports with WAKIX use in pregnant women have not determined a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproductive studies, administration of pitolisant during organogenesis caused maternal and embryofetal toxicity in rats and rabbits at doses ≥13 and >4 times the maximum recommended human dose (MRHD) of 35.6 mg based on mg/m² body surface area, respectively. Oral administration of pitolisant to female rats during pregnancy and lactation adversely affected maternal and fetal health and produced developmental delay at doses ≥13 times the MRHD, based on mg/m² body surface area and increased the incidence of major malformations at 22 times the MRHD

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Pitolisant was administered orally to pregnant rats during the period of organogenesis at doses of 30, 52, 90 and 110 mg/kg/day, which are approximately 7, 13, 22 and 27 times the MRHD, based on mg/m2 body surface area, respectively. Maternal toxicity occurred at >22 times the MRHD and included convulsions and decreases in body weight and food consumption. At these maternally toxic doses, no adverse effects on embryofetal development were noted and the no observed-adverse-effect-level for embryofetal toxicity is 27 times the MRHD based on mg/m² body surface area.

Pitolisant was administered intramuscularly to pregnant rabbits during the period of organogenesis at doses of 4, 8, and 16 mg/kg/day, which are approximately 2, 4 and 8 times the MRHD, based on mg/m² body surface area, respectively. Maternal toxicity occurred at ≥4 times the MRHD and included significant body weight loss and decreased food consumption. Mortality (1 animal) and convulsions (2 animals) occurred at 8 times the MRHD. At the maternally toxic dose (8 times the MRHD), the incidence of pre-implantation loss and abortions increased with a consequent decrease in both the number of implantations and live fetuses. Pitolisant was not teratogenic at doses up to 8 times the MRHD; however, delayed skeletal development (incomplete ossification and supernumerary ribs) was observed. The no-observed-adverse-effect-level for maternal toxicity and embryofetal development is 2 and 4 times the MRHD based on mg/m² body surface area, respectively.

Pitolisant was administered orally to pregnant rats from gestation day 7 through lactation day 20 post-partum at doses of 30, 52, and 90 mg/kg/day, which are 7, 13 and 22 times the MRHD, based on mg/m² body surface area, respectively. Maternal toxicity included death, CNS signs including convulsions, and significant decrease in body weight and food consumption at 22 times the MRHD based on mg/m² body surface area. At the maternally toxic dose (22 times the MRHD), fetal toxicity included stillbirths, postnatal pup mortality (due to lack of milk and/or failure to nurse), and decreased pup length and weight. A single female at the mid dose (13 times the MRHD) also failed to produce milk resulting in pup mortality. At the maternally toxic dose (22 times the MRHD), pitolisant was teratogenic causing major malformations (cleft palate, abnormal limb flexure). F₁ toxicity included delay in postnatal development (decrease in body weight and length, delay in incisor eruption, and delay in testes descent), which occurred at ≥13 times the MRHD; however, there was no effect on sexual maturation or reproductive capacity of the F₁ generation. The no-observed-adverse-effect-level for developmental toxicity is approximately 7 times the MRHD, based on mg/m² body surface area.