WAKIX- pitolisant hydrochloride_tablet, film coated

The mechanism of action of pitolisant in excessive daytime sleepiness (EDS) in patients 6 years and older with narcolepsy or cataplexy in adult patients with narcolepsy is unclear. However, its efficacy could be mediated through its activity as an antagonist/inverse agonist at histamine-3 (H3) receptors. Pitolisant binds to H3 receptors with a high affinity (K i i Cardiac Electrophysiology WAKIX at the highest recommended dosage (i. 6 mg daily) led to a QTc increase of 4. Exposures 3. 8-fold higher than achieved at the highest recommended dose increased QTc 16 msec (mean) [see Warnings and Precautions ( 5. 1 Following oral administration of pitolisant 35. 6 mg once daily, the steady state C max max Absorption The median time to maximum plasma concentration (T max 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. Elimination After a single dose of 35. 6 mg, the median half-life of pitolisant is approximately 20 hours (7. 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 max 0-10h Patients with Hepatic Impairment Six subjects with mild hepatic impairment (Child-Pugh A), 6 subjects with moderate hepatic impairment (Child-Pugh 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 Figure 1: Effect of Hepatic Impairment on Pitolisant Pharmacokinetics inf max 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 m 2 2 2 2 Figure 2 Figure 2: Effect of Renal Impairment on Pitolisant Pharmacokinetics inf max 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 0-24 max 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 ( 2. 1 Figure 4: Effect of Concomitant Medications on Pitolisant inf max 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 ( 7. 3 Figure 5: Effect of Pitolisant on Concomitant Medications inf 0-24 max Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Approximately 3 to 10% of Caucasians and 2 to 7% of African Americans generally lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers. The AUC of pitolisant was approximately 2. 4 times higher in CYP2D6 poor metabolizers than in normal metabolizers and is similar to the exposure of pitolisant when WAKIX is administered concomitantly with a CYP2D6 inhibitor [see Dosage and Administration ( 2. 1 In CYP2D6 poor metabolizers, the C max.

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. WAKIX is a histamine-3 (H3) receptor antagonist/inverse agonist indicated for the: treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy ( 1 treatment of excessive daytime sleepiness (EDS) in pediatric patients 6 years of age and older with narcolepsy ( 1.

See Full Prescribing Information for complete dosage instructions ( 2. 2 Administer orally once daily in the morning upon wakening ( 2. 2 Dosage Recommendations: Adults: EDS or Cataplexy 2. 1 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 Pediatric Patients (6 years and older): EDS 2. 2 Week 1 Initiate with a dosage of 4. 45 mg once daily Week 2 Increase dosage to 8. 9 mg once daily Week 3 Increase dosage to 17. 8 mg once daily, the maximum recommended dosage Week 4 For patients weighing >=40 kg, may increase to the maximum Hepatic impairment ( 2. 3 Moderate hepatic impairment (Child-Pugh Class B): Adults: Pediatric Patients: Renal impairment (eGFR less than 60 mL/minute/1. 3 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 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 The recommended dosage range for WAKIX for the treatment of EDS or cataplexy in adult patients is 17. 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 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. 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 Dose may be adjusted based on tolerability. 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 ( 5. 3 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 ( 5. 3 Pediatric patients weighing >=40 kg: Initiate WAKIX at 4. 45 mg once daily and increase after 14 days to 8. May increase after another 14 days to a maximum recommended dosage of 17. 3 WAKIX is contraindicated in patients with severe hepatic impairment. WAKIX has not been studied in patients with severe hepatic impairment [see Contraindications ( 4 5. 3 Adult Patients with eGFR <60 mL/minute/1. 73 m 2 Initiate WAKIX at 8. 9 mg once daily and increase after 7 days to a maximum recommended dosage of 17. 3 Pediatric Patients (6 years and older) with eGFR <60 mL/minute/1. 73 m 2 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. 45 mg once daily and increase after 7 days to 8. May increase after another 7 days to a maximum recommended dosage of 17. 3 WAKIX is not recommended in patients with eGFR less than 15 mL/minute/1. 73 m 2 [see Warnings and Precautions ( 5. 3 Coadministration with Strong CYP2D6 Inhibitors Adult patients: Initiate WAKIX at 8. 8 mg once daily [see Drug Interactions ( 7. 3 Pediatric patients (6 years and older) weighing <40 kg: Initiate WAKIX at 4. 9 mg once daily [see Drug Interactions ( 7. 3 Pediatric patients (6 years and older) weighing >=40 kg: Initiate WAKIX at 4. 3 Adult and pediatric patients on a stable dose of WAKIX: Reduce the WAKIX dose by half upon initiating strong CYP2D6 inhibitors [see Drug Interactions ( 7. 3 Coadministration with Strong CYP3A4 Inducers Concomitant use of WAKIX with strong CYP3A4 inducers decreases pitolisant exposure by 50%. Assess for loss of efficacy after initiation of a strong CYP3A4 inducer. For adult and pediatric patients stable on WAKIX 8. 8 mg once daily, increase the dose of WAKIX to double the original daily dose (i. 6 mg, respectively) over 7 days. If concomitant dosing of a strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half [see Drug Interactions ( 7. 3 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 ( 8. 5 Pediatric patients Pediatric patients weighing <40 kg: Initiate WAKIX at 4. 9 mg once daily [see Use in Specific Populations ( 8. 5 Pediatric patients weighing >=40 kg: Initiate WAKIX at 4. 8 mg once daily [see Use in Specific Populations ( 8.

The following adverse reactions are discussed in more detail in other sections of the labeling: QT Interval Prolongation [see Warnings and Precautions ( 5. 1 Most common adverse reactions (>=5% and at least twice placebo) in adults: insomnia, nausea, and anxiety ( 6. 1 Most common adverse reactions (>=5% and greater than placebo) in pediatric patients 6 years and older: headache and insomnia ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Harmony Biosciences at 1-800-833-7460 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients with Narcolepsy In clinical trials for narcolepsy, 172 adult patients were treated with WAKIX in placebo-controlled trials for up to 8 weeks and in open-label extension trials for up to 5 years. In trials in which WAKIX was directly compared to placebo, 6 of the 152 patients (3. 9%) who received WAKIX and 4 of the 114 patients (3. 5%) who received placebo discontinued because of an adverse reaction. Most Common Adverse Reactions In the placebo-controlled clinical trials conducted in patients with narcolepsy with or without cataplexy, the most common adverse reactions (occurring in >=5% of patients and at least twice the rate of placebo) with the use of WAKIX were insomnia (6%), nausea (6%), and anxiety (5%). Table 1 Table 1: Adverse Reactions that Occurred in >=2% of WAKIX-Treated Patients and More Frequently than in Placebo-Treated Patients in Three Placebo-Controlled Narcolepsy Studies * The following terms were combined: Abdominal pain includes: Anxiety includes: Hallucinations includes: Headache includes: Heart rate increased includes: Insomnia includes: Musculoskeletal pain includes: Rash includes: Sleep disturbance includes: Upper respiratory tract infection includes: Adverse Reaction WAKIX Placebo Headache * 18 15 Insomnia * 6 2 Nausea 6 3 Upper respiratory tract infection * 5 3 Musculoskeletal pain * 5 3 Anxiety * 5 1 Heart rate increased * 3 0 Hallucinations * 3 0 Irritability 3 2 Abdominal pain * 3 1 Sleep disturbance * 3 2 Decreased appetite 3 0 Cataplexy 2 1 Dry mouth 2 1 Rash * 2 1 Pediatric Patients (6 years and older) with Narcolepsy In a clinical trial for narcolepsy, 73 pediatric patients 6 years and older were treated with WAKIX in the placebo-controlled phase for up to 8 weeks and 105 patients in the open-label extension phase for up to 6. Most Common Adverse Reactions In the placebo-controlled phase of the study, the most common adverse reactions (occurring in >=5% of patients and greater than the rate of placebo) with the use of WAKIX were headache (19%) and insomnia (7%). The overall adverse reaction profile of WAKIX in the pediatric clinical trial was similar to that seen in the adult clinical trial program. The following adverse reactions have been identified during post-approval use of WAKIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: General disorders and administration site conditions: Immune system disorders: Investigations: Nervous system disorders: Psychiatric disorders: Skin and subcutaneous tissue disorders:.

WAKIX is contraindicated in patients with: known hypersensitivity to pitolisant or any component of the formulation. Anaphylaxis has been reported in patients treated with WAKIX [see Adverse Reactions ( 6. 2 severe hepatic impairment. WAKIX is extensively metabolized by the liver and there is a significant increase in WAKIX exposure in patients with moderate hepatic impairment [see Use in Specific Populations ( 8. 6 Known hypersensitivity to pitolisant or any component of the formulation ( 4 Severe hepatic impairment ( 4.

Pregnancy Exposure Registry 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. Risk Summary 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/m 2 2 (see Data 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. 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. Data Animal Data 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/m 2 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/m 2 2 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/m 2 2 1 1 2 Risk Summary The transfer of pitolisant into breastmilk is low based on data from a lactation study. The mean infant dose was 0. 009 mg/day, and the relative infant dose was less than 1% of the maternal weight-adjusted dose ( see Data The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WAKIX and any potential adverse effects on the breastfed infant from WAKIX or from the underlying maternal condition. Data An open-label study in 8 healthy lactating women who were 11 to 96 weeks post-partum evaluated the concentration of pitolisant in breast milk samples collected over 24 hours and serum samples collected over 120 hours after a single dose administration of 35. 6 mg of pitolisant. Pitolisant was present in breast milk with a mean C max max Contraception WAKIX may reduce the effectiveness of hormonal contraceptives. Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuing treatment [see Drug interactions ( 7. 3 The safety and effectiveness of WAKIX have been established for the treatment of excessive daytime sleepiness in pediatric patients 6 years of age and older with narcolepsy. Use of WAKIX in this age group is supported by one adequate and well-controlled study in 110 pediatric patients with narcolepsy ages 6 to less than 18 years of age [see Clinical Studies ( 14. 1 The safety and effectiveness of WAKIX have not been established for treatment of excessive daytime sleepiness in pediatric patients less than 6 years of age with narcolepsy. The safety and effectiveness of WAKIX have not been established for treatment of cataplexy in pediatric patients with narcolepsy. Juvenile Animal Toxicity Data In a juvenile animal study, male and female rats were administered pitolisant at 9, 21, or 48 mg/kg/day by oral gavage from postnatal day (PND) 7 to PND 70. Mortality occurred at the highest dose of 48 mg/kg/day; however, death was primarily related to aspiration/inhalation of food material. No adverse effects on growth and development up to the high dose were observed; however, plasma exposures at this dose were lower than those predicted to occur in pediatric patients at the maximum recommended human dose (MRHD) of 35. 6 mg due to low oral bioavailability in juvenile rats. In a second juvenile animal study, male and female rats were administered pitolisant at 15 or 30 mg/kg/day or 30 mg/kg/twice daily (60 mg/kg/day) by intraperitoneal injection from PND 7 to PND 70. Mortality and convulsions were observed at the top two doses of 30 and 60 mg/kg/day. Similar findings of convulsions and mortality were also observed in studies in adult rats at comparable doses. The no observed adverse effect level (NOAEL) is 15 mg/kg/day in juvenile animals administered pitolisant by intraperitoneal injection, which corresponds to plasma exposures that are approximately 4 times and 1 times the predicted pediatric exposures at the MRHD of 35. 6 mg, based on C max Limited pharmacokinetic data are available in healthy elderly subjects. A pharmacokinetic study that compared 12 elderly subjects (age 68 to 82 years) to 12 healthy adults (age 18 to 45 years) did not reveal any significant differences in drug exposure [see Clinical Pharmacology ( 12. 3 Of the total number of patients with narcolepsy in clinical studies of WAKIX, 14 patients (5%) were >=65 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients in these clinical trials, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy. WAKIX is contraindicated in patients with severe hepatic impairment (Child-Pugh 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 ( 4 12. 3 Monitor patients with moderate hepatic impairment (Child-Pugh B) and adjust the dosage of WAKIX [see Dosage and Administration ( 2. 3 Monitor patients with mild hepatic impairment (Child-Pugh A). No dosage adjustment of WAKIX is recommended in patients with mild hepatic impairment. The pharmacokinetics of WAKIX in patients with end-stage renal disease (ESRD) (eGFR of <15 mL/minute/1. 73 m 2 [see Clinical Pharmacology ( 12. 3 [see Dosage and Administration ( 2. 1 Dosage adjustment of WAKIX is recommended in patients with eGFR <60 mL/minute/1. 73 m 2 [see Dosage and Administration ( 2. 4 Dosage reduction is recommended in patients known to be poor CYP2D6 metabolizers because these patients have higher pitolisant concentrations than normal CYP2D6 metabolizers [see Dosage and Administration ( 2.

Strong CYP2D6 Inhibitors: Maximum recommended dosage is 17. 8 mg once daily ( 2. 1 Strong CYP3A4 Inducers: Decreased exposure of WAKIX; consider dosage adjustment ( 2. 1 Sensitive CYP3A4 Substrates (including hormonal contraceptives): WAKIX may reduce effectiveness of sensitive CYP3A4 substrates. Use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuation of treatment ( 7. 3 Table 2: Clinically Significant Drug Interactions with WAKIX Effect of Other Drugs on WAKIX Strong CYP2D6 Inhibitors Clinical Implication: Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure by 2. Prevention or Management: Reduce the dose of WAKIX by half [see see Dosage and Administration ( 2. 3 Strong CYP3A4 Inducers Clinical Implication: Concomitant use of WAKIX with strong CYP3A4 inducers decreases exposure of pitolisant by 50%. Prevention or Management: Assess for loss of efficacy after initiation of a strong CYP3A4 inducer. For patients stable on WAKIX 8. 8 mg once daily, increase the dose of WAKIX to reach double the original daily dose (i. 6 mg, respectively) over 7 days. If concomitant dosing of a strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half [see see Dosage and Administration ( 2. 3 Histamine-1 (H1) Receptor Antagonists Clinical Implication: 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. Prevention or Management: Avoid centrally acting H1 receptor antagonists. QT Interval Prolongation Clinical Implication: Concomitant use of drugs that prolong the QT interval may add to the QT effects of WAKIX and increase the risk of cardiac arrhythmia. Prevention or Management: Avoid the use of WAKIX in combination with other drugs known to prolong the QT interval [see Warnings and Precautions ( 5. 1 Effect of WAKIX on Other Drugs Sensitive CYP3A4 Substrates Clinical Implication: WAKIX is a borderline/weak inducer of CYP3A4. Therefore, reduced effectiveness of sensitive CYP3A4 substrates may occur when used concomitantly with WAKIX [see Clinical Pharmacology ( 12. 3 Prevention or Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuation of treatment [see Use in Specific Populations ( 8. 3 A clinical study was conducted to evaluate the concomitant use of WAKIX with modafinil or sodium oxybate. This study demonstrated no clinically relevant effect of modafinil or sodium oxybate on the pharmacokinetics of WAKIX and no effect of WAKIX on the pharmacokinetics of modafinil or sodium oxybate [see Clinical Pharmacology ( 12. 3 A clinical study showed that strong CYP3A4 inhibitors (e. , ketoconazole, grapefruit juice) have no effect on the pharmacokinetics of WAKIX [see Clinical Pharmacology ( 12.

NONCLINICAL TOXICOLOGY
Carcinogenesis Pitolisant was not carcinogenic in mice or rats. Oral administration of pitolisant at 15, 30, and 75 mg/kg/day for 6 months to CB6F1 TgrasH2 transgenic mice did not increase tumor incidence. These doses are 2, 4, and 9 times the MRHD, respectively, based on mg/m 2 Oral administration of pitolisant at 5, 15, and 30 mg/kg/day for 105 weeks to Sprague-Dawley rats did not increase tumor incidence. These doses are 1. 4, 4, and 8 times the MRHD based on mg/m 2 Mutagenesis Pitolisant and its metabolites were not mutagenic in the in vitro in vitro in vivo Impairment of Fertility Oral administration of pitolisant at 30, 52, and 90 mg/kg/day to male and female rats prior to and throughout mating and continuing in females through early gestation resulted in adverse effects at the mid and high doses. These doses are 13 and 22 times the MRHD, respectively, based on mg/m 2 2 2 2 Adverse CNS-related clinical signs including tremors and convulsions occurred after single and repeated oral administration of pitolisant across multiple species. In a 9-month repeat-dose toxicity study in adult monkeys, sporadic incidences of convulsions occurred at doses corresponding to exposures approximately 3 times the MRHD based on C max max max.
CLINICAL STUDIES
Adult Patients with Narcolepsy The efficacy of WAKIX for the treatment of excessive daytime sleepiness in adult patients with narcolepsy was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (Study 1; NCT01067222 and Study 2; NCT01638403). Patients >=18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy (with or without cataplexy) 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. Each of the 8 items on the ESS is rated from 0 (would never doze) to 3 (high chance of dozing); the maximum score is 24. Study 1 and Study 2 included an 8-week treatment period: a 3-week dose titration phase followed by a 5-week stable dose phase. These studies compared WAKIX to both a placebo and an active control. In Study 1, 95 patients were randomized to receive WAKIX, placebo, or active control. The dose of WAKIX was initiated at 8. 9 mg once daily and could be increased at weekly intervals to 17. 6 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 5-week stable dose phase. 61% of patients reached a stable dose of 35. Median age in the study was 37 years. More than 90% of patients in the WAKIX and placebo groups were Caucasian and 54% were male. Approximately 80% of the population had a history of cataplexy. WAKIX demonstrated statistically significantly greater improvement on the primary endpoint, the least square mean final ESS score compared to placebo ( Table 3 In Study 2, 166 patients were randomized to receive WAKIX, placebo, or active control. The dose of WAKIX was initiated at 4. 45 mg and could be increased at weekly intervals to 8. 8 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 5-week stable-dose phase. 76% of patients reached a stable dose of 17. Median age in the study was 40 years. In the WAKIX and placebo groups, approximately 50% of patients were male, 90% of patients were Caucasian, and 75% of patients had a history of cataplexy. WAKIX demonstrated statistically significantly greater improvement on the primary endpoint, the least square mean final ESS score compared to placebo ( Table 3 Examination of demographic subgroups by sex did not suggest differences in response. The efficacy results from Study 1 and Study 2 are shown in Table 3 Table 3: Efficacy Results for Epworth Sleepiness Scale in Adult Patients with Narcolepsy (Study 1 and Study 2) CI = confidence interval; LS Mean = least square mean; SD = standard deviation; SE = standard error a b c d Study Treatment Baseline ESS Score Final ESS Score c Placebo Subtracted d Study 1 a WAKIX (n=31) 17. 46] Placebo (n=30) 18. 03) Study 2 b WAKIX (n=66) 18. 22] Placebo (n=32) 18. 32) Figure 6 Figure 6: Epworth Sleepiness Scale Score (mean +/- SEM) from Baseline to Week 8 in Study 1 Pediatric Patients (6 years of age and older) with Narcolepsy The efficacy of WAKIX for the treatment of excessive daytime sleepiness in pediatric patients 6 years of age and older with narcolepsy was evaluated in one multicenter, randomized, double-blind, placebo-controlled study (Study 4; NCT02611687). Pediatric patients 6 to 17 years who met the International Classification of Sleep Disorders (ICSD-3) criteria for narcolepsy (with or without cataplexy) and who had a Pediatric Daytime Sleepiness Scale (PDSS) score >=15 were eligible to enroll in the study. EDS was assessed with the PDSS, an 8-item questionnaire in which patients report their frequency of EDS-related symptoms. Each of the 8 items on the PDSS is rated from 0 (never) to 4 (very often, always); the maximum score is 32, with higher scores representing greater severity of symptoms. The study included an 8-week treatment period: a 4-week dose titration phase followed by a 4-week stable dose phase. In Study 4, 110 pediatric patients 6 to 17 years were randomized to receive WAKIX or placebo. 45 mg once daily and could be increased at weekly intervals to 17. 8 mg for patients weighing <40 kg or 35. 6 mg for patients weighing>=40 kg, based on clinical response and tolerability. No dose adjustments were permitted during the 4-week stable dose phase. 69% of patients weighing <40 kg reached a stable dose of 17. 8 mg and 72% of patients weighing >=40 kg reached a stable dose of 35. Median age in the study was 13 years, 56% of the patients were male, and 82% of the population had a history of cataplexy. Race and ethnicity were not collected in this study. WAKIX demonstrated statistically significantly greater improvement on the least square mean change from baseline to the end of treatment in final PDSS total score compared to placebo, of -3. 41 points (95% CI: -5. Study 4 included global assessments, which showed positive trends supporting PDSS total score of improvement in favor of WAKIX. Figure 6 The efficacy of WAKIX for the treatment of cataplexy in adult patients with narcolepsy was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (Study 3; NCT01800045 and Study 1; NCT01067222). Patients >=18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy with cataplexy with at least 3 cataplexy attacks per week and an ESS score of >=12 were eligible to enroll in Study 3; patients meeting the ICSD-2 criteria for narcolepsy (with or without cataplexy) and an ESS score of >=14 were eligible to enroll in Study 1. Study 3 included a 7-week treatment period: a 3-week dose titration phase followed by a 4-week stable dose phase. 105 patients were randomized to receive WAKIX or placebo. 45 mg once daily for the first week, increased to 8. 9 mg for the second week, and could remain the same or be decreased or increased at the next two weekly intervals to a maximum of 35. 65% of patients reached a stable dose of 35. Median age in the study was 37 years and 51% of the patients were male. Race was not collected in this study. WAKIX demonstrated statistically significantly greater improvement on the primary endpoint, the change in geometric mean number of cataplexy attacks per week from baseline to the average of the 4 week stable dosing period for WAKIX compared to placebo ( Table 4 Study 1 was described in Section 14. In the subset of patients with a history of cataplexy (n=49), WAKIX demonstrated statistically significantly greater improvement on the secondary endpoint, the change from baseline in geometric mean daily rate of cataplexy at Week 8 for WAKIX compared to placebo ( Table 4 In both Study 3 and Study 1, examination of demographic subgroups by sex did not suggest differences in response. Table 4: Efficacy Results for Cataplexy in Adult Patients with Narcolepsy (Study 3 and Study 1) CI = confidence interval; SD = standard deviation a b c Study Endpoint Treatment Baseline Rate a Final Rate a Rate Ratio b Study 3 Final Mean Weekly Rate of Cataplexy Over 4-Week Stable Dosing Period WAKIX 9. 60] Placebo 7. 8) Study 1 Final Mean Daily Rate of Cataplexy at Week 8 WAKIX c 0. 36] Placebo c 0.

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WAKIX- pitolisant hydrochloride_tablet, film coated Product manual source documgent