ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in more detail in other sections of the labeling:QT Interval Prolongation [see Warnings and Precautions (5.1)] QT Interval Prolongation [see Warnings and Precautions (5.1)] The most common adverse reactions (>=5% and twice placebo) for WAKIX were insomnia, nausea, and anxiety (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Harmony Biosciences at 1-800-833-7460 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the clinical trials for narcolepsy, 172 patients were treated with WAKIX in placebo-controlled trials for up to weeks and in open-label extension trials for up to years. In trials in which WAKIX was directly compared to placebo, of the 152 patients (3.9%) who received WAKIX and of the 114 patients (3.5%) who received placebo discontinued because of an adverse event. Most Common Adverse ReactionsIn 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 presents the adverse reactions that occurred at rate of >=2% in patients treated with WAKIX and more frequently than in patients treated with placebo in the placebo-controlled clinical trials in narcolepsy.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: abdominal discomfort; abdominal pain; abdominal pain upperAnxiety includes: anxiety; nervousness; stress; stress at workHallucinations includes: hallucination; hallucination visual; hypnagogic hallucinationHeadache includes: cluster headache; headache; migraine; premenstrual headache; tension headacheHeart rate increased includes: heart rate increased; sinus tachycardia; tachycardiaInsomnia includes: initial insomnia; insomnia; middle insomnia; poor quality sleepMusculoskeletal pain includes: arthralgia; back pain; carpal tunnel syndrome; limb discomfort; musculoskeletal pain; myalgia; neck pain; osteoarthritis; pain in extremity; sciaticaRash includes: eczema; erythema migrans; rash; urticariaSleep disturbance includes: dyssomnia; sleep disorder; sleep paralysis; sleep talkingUpper respiratory infection includes: pharyngitis; rhinitis; sinusitis; upper respiratory tract infection; upper respiratory tract inflammation; viral upper respiratory tract infectionAdverse ReactionWAKIX(n=152)%Placebo(n=114)%Headache 1815Insomnia 62Nausea63Upper respiratory tract infection 53Musculoskeletal pain 53Anxiety 51Heart rate increased 30Hallucinations 30Irritability32Abdominal pain 31Sleep disturbance 32Decreased appetite30Cataplexy21Dry mouth21Rash 21. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of WAKIX. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure:General disorders and administration site conditions: fatigueImmune system disorders: hypersensitivity (anaphylaxis)Investigations: weight increasedNervous system disorders: epilepsyPsychiatric disorders: abnormal behavior, abnormal dreams, anhedonia, bipolar disorder, depression, depressed mood, nightmare, sleep disorder, suicide attempt, suicidal ideationSkin and subcutaneous tissue disorders: pruritus.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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 SummaryAvailable case reports from clinical trials and postmarketing reports with WAKIX use in pregnant women have not determined 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 (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.DataAnimal DataPitolisant 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 decreases in body weight, food consumption and convulsions. 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, and 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 times the MRHD. At the maternally toxic dose (8 times the MRHD), the incidence of pre-implantation loss and abortions increased with consequent decrease in both the number of implantations and live fetuses. Pitolisant was not teratogenic at doses up to 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 and times the MRHD based on mg/m2 body surface area, respectively.Pitolisant was administered orally to pregnant rats from gestation day 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. 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 times the MRHD, based on mg/m2 body surface area.. 8.2 Lactation. Risk SummaryThere are no data on the presence of pitolisant in human milk, the effects on the breastfed infant, or the effect of this drug on milk production.Pitolisant is present in the milk of lactating rats (see Data ). When drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for WAKIX and any potential adverse effects on the breastfed child from WAKIX or from the underlying maternal condition.DataRadiolabelled [14C]-pitolisant (30 mg/kg, free base; times the MRHD based on mg/m2) was administered to female rats during lactation on day 14 post-partum. Radioactivity in milk was first measured at 0.25 hours post-administration and reached maximum by hours post-administration. The level of radioactivity tended to be higher in milk compared to plasma, ranging from approximately to times higher in milk than plasma from 0.25 to hours post-administration.. 8.3 Females and Males of Reproductive Potential. ContraceptionWAKIX 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 (7.1), Clinical Pharmacology (12.3)].. 8.4 Pediatric Use. The safety and effectiveness of WAKIX in pediatric patients have not been established.Limited pharmacokinetic data from 24 pediatric patients with narcolepsy (ages to <18 years) receiving single dose of WAKIX suggest that pediatric patients have higher exposure to pitolisant than adults. The exposure (Cmax and AUC) of pitolisant was 2-fold higher in pediatric patients 12 to <18 years and 3-fold higher in pediatric patients to <12 years compared to adults. 8.5 Geriatric Use. Limited pharmacokinetic data are available in healthy elderly subjects. 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.. 8.6 Hepatic Impairment. 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 significant increase in WAKIX exposure in patients with moderate hepatic impairment [see Contraindications (4), Clinical Pharmacology (12.3)].Monitor patients with moderate hepatic impairment (Child-Pugh B) and adjust the dosage of WAKIX [see Dosage and Administration (2.2)].Monitor patients with mild hepatic impairment (Child-Pugh A). No dosage adjustment of WAKIX is recommended in patients with mild hepatic impairment.. 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 (12.3)]. Therefore, WAKIX is not recommended in patients with ESRD [see Dosage and Administration (2.3), Warnings and Precautions (5.1)]. Dosage adjustment of WAKIX is recommended in patients with moderate (eGFR 30 to 59 mL/minute/1.73 m2) and severe (eGFR 15 to 29 mL/minute/1.73 m2) renal impairment [see Dosage and Administration (2.3)].. 8.8 CYP2D6 Poor Metabolizers. 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 (2.5), Clinical Pharmacology (12.3, 12.5)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisPitolisant was not carcinogenic in mice or rats.Oral administration of pitolisant at 15, 30, and 75 mg/kg/day for months to CB6F1 TgrasH2 transgenic mice did not increase tumor incidence. These doses are 2, 4, and times the MRHD, respectively, based on mg/m2 body surface area.Oral administration of pitolisant at 5, 15, and 30 mg/kg/day for 105 weeks to Sprague-Dawley rats did not increase tumor incidence. MutagenesisPitolisant and its metabolites were not mutagenic in the in vitro bacterial reverse mutation assay (Ames), or clastogenic in the in vitro mammalian chromosomal aberration assay. Pitolisant was negative in the in vivo mouse micronucleus assay.Impairment of FertilityOral 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/m2 body surface area. dose-related increase in the percentage of post-implantation loss was observed compared to controls, leading to decrease in the percentage of live conceptuses, at doses 13 and 22 times the MRHD, based on mg/m2 body surface area. Pitolisant caused dose-related abnormalities in sperm morphology and decreased motility at doses that are 13 and 22 times the MRHD based on mg/m2 body surface area, without any significant effects on fertility indices in male rats. No effects on fertility were observed at 30 mg/kg/day (7 times the MRHD based on mg/m2 body surface area).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action of pitolisant in excessive daytime sleepiness (EDS) 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.. 12.2 Pharmacodynamics. Pitolisant binds to H3 receptors with high affinity (Ki 1 nM) and has no appreciable binding to other histamine receptors (H1, H2, or H4 receptors; Ki >=10 uM).Cardiac ElectrophysiologyWAKIX at the highest recommended dosage (i.e., 35.6 mg daily) led to QTc increase of 4.2 msec. Exposures 3.8-fold higher than achieved at the highest recommended dose increase QTc 16 msec (mean) [see Warnings and Precautions (5.1)].. 12.3 Pharmacokinetics. Following oral administration of pitolisant 35.6 mg once daily, the steady state Cmax and AUC are 73 ng/mL (range: 49.2 to 126 ng/mL) and 812 nghr/mL (range: 518 to 1468 nghr/mL), respectively. Pitolisant exposure (Cmax and AUC) increases proportionally with dose and steady state is reached by day 7.AbsorptionThe median time to maximum plasma concentration (Tmax) of pitolisant is 3.5 hours (2 to hours).The oral absorption of WAKIX is around 90%.Food EffectNo clinically significant differences in the pharmacokinetics of pitolisant were observed following administration with high-fat meal.DistributionThe apparent volume of distribution of pitolisant is approximately 700 (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.EliminationAfter 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. MetabolismPitolisant is primarily metabolized by CYP2D6 and to lesser extent by CYP3A4; these metabolites are further metabolized or conjugated with glycine or glucuronic acid. None of these metabolites are pharmacologically active. ExcretionAfter 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 PopulationsNo 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.Patients with Hepatic ImpairmentSix subjects with mild hepatic impairment (Child-Pugh A), subjects with moderate hepatic impairment (Child-Pugh B), and 12 healthy subjects matched for age, sex, body mass index and ethnicity received 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 PharmacokineticsDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUCinf area under the curve from time to time infinity; Cmax maximum plasma concentration.Patients with Renal ImpairmentA single dose of WAKIX 17.8 mg was administered to subjects with mild renal impairment (eGFR of 60 to 89 mL/min/1.73 m2), subjects with moderate renal impairment (eGFR of 30 to 59 mL/min/1.73 m2), 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 PharmacokineticsDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUCinf area under the curve from time to time infinity; Cmax maximum plasma concentration.CYP2D6 Poor MetabolizersThe pharmacokinetics of pitolisant were evaluated in subjects who were CYP2D6 poor metabolizers (PMs) and subjects who were CYP2D6 extensive metabolizers (EMs). All subjects received WAKIX 17.8 mg daily for days. Exposure of pitolisant in CYP2D6 PMs is summarized in Figure 3.Figure 3: Pitolisant Pharmacokinetics in CYP2D6 Poor MetabolizersDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUC0-24 area under the curve from time to 24 hours post-dose; Cmax maximum plasma concentration.Drug-Drug InteractionsEffect of Other Drugs on the Pharmacokinetics of WAKIXThe effect of other drugs on the pharmacokinetics of pitolisant is presented in Figure [see Dosage and Administration (2.4), Drug Interactions (7.1)]. Figure 4: Effect of Concomitant Medications on PitolisantDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUCinf area under the curve from time to time infinity; Cmax maximum plasma concentration.Effect of WAKIX on the Pharmacokinetics of Other DrugsThe effect of pitolisant on the pharmacokinetics of other drugs is presented in Figure [see Drug Interactions (7.1)].Figure 5: Effect of Pitolisant on Concomitant MedicationsDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUCinf area under the curve from time to time infinity; AUC0-24 area under the curve from time to 24 hours; Cmax maximum plasma concentration.Administration of WAKIX concomitantly with oral contraceptives may reduce their effectiveness [see Drug Interactions (7.1), Use in Specific Populations (8.3)]. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. 12.5 Pharmacogenomics Approximately to 10% of Caucasians and 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 CYP2D6 inhibitor [see Dosage and Administration (2.5), Drug Interactions (7.1)].In CYP2D6 poor metabolizers, the Cmax of pitolisant is 153 (151 to 157) ng/mL and the AUC is 1920 (1854 to 2000) nghr/mL after steady state dosing with 35.6 mg once daily.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Excessive Daytime Sleepiness (EDS) in 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-text questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities. Each of the texts on the ESS is rated from (would never doze) to (high chance of dozing); the maximum score is 24. Study and Study included an 8-week treatment period: 3-week dose titration phase followed by 5-week stable dose phase. These studies compared WAKIX to both 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 17.8 mg or 35.6 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 5-week stable dose phase. 61% of patients reached stable dose of 35.6 mg. 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 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 8.9 mg or 17.8 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 5-week stable-dose phase. 76% of patients reached stable dose of 17.8 mg. 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 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 and Study are shown in Table 3.Table 3: Efficacy Results for Epworth Sleepiness Scale in Patients with Narcolepsy (Study and Study 2)SD standard deviation; SE standard error; LS Mean least square mean; CI confidence intervalaMaximum dose randomized to was 35.6 mgbMaximum dose randomized to was 17.8 mgcA lower score on the ESS represents improvement; scores range from (no symptoms) to 24 (worst symptoms)dA negative value for the placebo subtracted difference represents improvementStudyTreatmentGroup (N)Baseline ESS ScoreMean (SD)Final ESS Scorec LS Meanat Week (SE)Placebo SubtractedDifference [95% CI]at Week 8d Study 1a WAKIX (n=31)17.8 (2.5)12.4 (1.01)-3.1 [-5.73; -0.46]Placebo (n=30)18.9 (2.5)15.5 (1.03)Study 2b WAKIX (n=66)18.3 (2.4)13.3 (1.19)-2.2 [-4.17; -0.22]Placebo (n=32)18.2 (2.3)15.5 (1.32)Figure shows the ESS score from baseline to Week in Study 1.Figure 6: Epworth Sleepiness Scale Score (mean +- SEM) from Baseline to Week in Study 1SEM standard error of the mean (raw mean scores)ESS scores range from to 24, with being the best score and 24 being the worst score. Figure 6. 14.2 Cataplexy in Patients with Narcolepsy. 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 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 included 7-week treatment period: 3-week dose titration phase followed by 4-week stable dose phase. 105 patients were randomized to receive WAKIX or placebo. The dose of WAKIX was initiated at 4.45 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 maximum of 35.6 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 4-week stable dose phase. 65% of patients reached stable dose of 35.6 mg. 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 week stable dosing period for WAKIX compared to placebo (Table 4).Study was described in Section 14.1. In the subset of patients with 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 for WAKIX compared to placebo (Table 4).In both Study and Study 1, examination of demographic subgroups by sex did not suggest differences in response.Table 4:Efficacy Results for Cataplexy in Patients with Narcolepsy (Study and Study 1) SD standard deviation; CI confidence interval The mean refers to geometric mean, which was used because values for weekly rate of cataplexy were not normally distributed; the geometric mean takes the average of the logs of the individual values and exponentiates that average back to an arithmetic scale. The rate ratio is derived from Poisson regression model. Patients with history of cataplexy. StudyEndpointTreatmentGroup (N)Baseline RateMeana [SD][95% CI]Final RateMeana [SD][95% CI]Rate Ratiob (WAKIX to placebo)[95% CI] Study 3Final Mean Weekly Rate of Cataplexy Over 4-Week Stable Dosing Period(primary endpoint)WAKIX(n=54)9.1 (2.0)[7.6, 11.0]2.3 (4.4)[1.5, 3.4]0.51 [0.44, 0.60]Placebo(n=51)7.3 (2.0)[6.0, 8.9]4.5 (4.8)[2.9, 7.0] Study 1Final Mean Daily Rate of Cataplexy at Week 8(secondary endpoint)WAKIX(n=25)c 0.4 (4.0)[0.2, 0.7]0.1 (2.8)[0.1, 0.2]0.07 [0.01, 0.36]Placebo(n=24) 0.3 (3.6)[0.1, 0.4]0.2 (4.3)[0.1, 0.5].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer once daily in the morning upon wakening.The recommended dosage range is 17.8 mg to 35.6 mg daily. Titrate dosage as follows: Week 1: Initiate with 8.9 mg once daily Week 2: Increase dosage to 17.8 mg once dailyWeek 3: May increase to the maximum recommended dosage of 35.6 mg once daily (2.1) Hepatic impairment (2.2, 8.6, 12.3): Moderate hepatic impairment: Initial dosage is 8.9 mg once daily. Titrate to maximum dosage of 17.8 mg once daily after 14 days Renal impairment (2.3, 8.7, 12.3): Moderate and severe impairment: Initial dosage is 8.9 mg once daily. Titrate to maximum dosage of 17.8 mg once daily after daysEnd-stage renal disease (ESRD): Not recommended Poor Metabolizers of CYP2D6: Maximum recommended dosage is 17.8 mg once daily (2.5). Administer once daily in the morning upon wakening.. The recommended dosage range is 17.8 mg to 35.6 mg daily. Titrate dosage as follows: Week 1: Initiate with 8.9 mg once daily Week 2: Increase dosage to 17.8 mg once dailyWeek 3: May increase to the maximum recommended dosage of 35.6 mg once daily (2.1) Week 1: Initiate with 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 (2.1). Hepatic impairment (2.2, 8.6, 12.3): Moderate hepatic impairment: Initial dosage is 8.9 mg once daily. Titrate to maximum dosage of 17.8 mg once daily after 14 days Moderate hepatic impairment: Initial dosage is 8.9 mg once daily. Titrate to maximum dosage of 17.8 mg once daily after 14 days. Renal impairment (2.3, 8.7, 12.3): Moderate and severe impairment: Initial dosage is 8.9 mg once daily. Titrate to maximum dosage of 17.8 mg once daily after daysEnd-stage renal disease (ESRD): Not recommended Moderate and severe impairment: Initial dosage is 8.9 mg once daily. Titrate to maximum dosage of 17.8 mg once daily after days. End-stage renal disease (ESRD): Not recommended. Poor Metabolizers of CYP2D6: Maximum recommended dosage is 17.8 mg once daily (2.5). 2.1 Recommended Dosage. The recommended dosage range for 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 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 dailyDose may be adjusted based on tolerability.If dose is missed, patients should take the next dose the following day in the morning upon wakening.It may take up to weeks for some patients to achieve clinical response.. 2.2 Dosage Modification and Recommendations in Patients with Hepatic Impairment In patients with moderate hepatic impairment, initiate WAKIX at 8.9 mg once daily and increase after 14 days to maximum dosage of 17.8 mg once daily [see Warnings and Precautions (5.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. WAKIX is contraindicated in patients with severe hepatic impairment. WAKIX has not been studied in patients with severe hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].. 2.3 Dosage Modification and Recommendations in Patients with Renal Impairment and End-Stage Renal Disease In patients with moderate (eGFR of 30 to 59 mL/minute/1.73 m2) and severe renal impairment (eGFR of 15 to 29 mL/minute/1.73 m2), initiate WAKIX at 8.9 mg once daily and increase after days to maximum dosage of 17.8 mg once daily [see Warnings and Precautions (5.1), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. WAKIX is not recommended in patients with end-stage renal disease (ESRD) (eGFR of <15 mL/minute/1.73 m2)[see Warnings and Precautions (5.1), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. 2.4 Dosage Recommendations for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers Coadministration with Strong CYP2D6 InhibitorsFor patients receiving strong CYP2D6 inhibitors, initiate WAKIX at 8.9 mg once daily and increase after days to maximum dosage of 17.8 mg once daily.For patients on stable dose of WAKIX, reduce the WAKIX dose by half upon initiating strong CYP2D6 inhibitors [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Coadministration with Strong CYP3A4 InducersConcomitant use of WAKIX with strong CYP3A4 inducers decreases pitolisant exposure by 50%. Assess for loss of efficacy after initiation of 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 days. If concomitant dosing of strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].. 2.5 Use in Patients Who Are Known CYP2D6 Poor Metabolizers (PMs). In patients known to be poor CYP2D6 metabolizers, initiate WAKIX at 8.9 mg once daily and titrate to maximum dose of 17.8 mg once daily after days [see Use in Specific Populations (8.8), Clinical Pharmacology (12.5)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP2D6 Inhibitors: Maximum recommended dosage is 17.8 mg once daily (2.4, 7.1)Strong CYP3A4 Inducers: Decreased exposure of WAKIX; consider dosage adjustment (2.4, 7.1)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 (7.1, 8.3). Strong CYP2D6 Inhibitors: Maximum recommended dosage is 17.8 mg once daily (2.4, 7.1). Strong CYP3A4 Inducers: Decreased exposure of WAKIX; consider dosage adjustment (2.4, 7.1). 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 (7.1, 8.3). 7.1 Drugs Having Clinically Important Interactions with WAKIX. Table 2: Clinically Significant Drug Interactions with WAKIXEffect of Other Drugs on WAKIXStrong CYP2D6 InhibitorsClinical Implication:Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold. Prevention or Management:Reduce the dose of WAKIX by half [see see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].Examples:paroxetine, fluoxetine, bupropionStrong CYP3A4 InducersClinical 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 strong CYP3A4 inducer. For patients stable on WAKIX 8.9 mg or 17.8 mg once daily, increase the dose of WAKIX to reach double the original daily dose (i.e., 17.8 mg or 35.6 mg, respectively) over days. If concomitant dosing of strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half [see see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].Examples:rifampin, carbamazepine, phenytoinHistamine-1 (H1) Receptor AntagonistsClinical 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.Examples:pheniramine maleate, diphenhydramine, promethazine (anti-histamines) imipramine, clomipramine, mirtazapine (tri or tetracyclic antidepressants) QT Interval ProlongationClinical 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)].Examples:Class 1A antiarrhythmics: quinidine, procainamide, disopyramide;Class antiarrhythmics: amiodarone, sotalol;Antipsychotics: ziprasidone, chlorpromazine, thioridazine;Antibiotics: moxifloxacinEffect of WAKIX on Other DrugsSensitive CYP3A4 SubstratesClinical Implication:WAKIX is borderline/weak inducer of CYP3A4. Therefore, reduced effectiveness of sensitive CYP3A4 substrates may occur when used concomitantly with WAKIX [see Clinical Pharmacology (12.3)]. 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.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)]. Examples:midazolam, hormonal contraceptives, cyclosporine. 7.2 Drugs Having No Clinically Important Interactions with WAKIX. 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.g., ketoconazole, grapefruit juice) have no effect on the pharmacokinetics of WAKIX [see Clinical Pharmacology (12.3)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisPitolisant was not carcinogenic in mice or rats.Oral administration of pitolisant at 15, 30, and 75 mg/kg/day for months to CB6F1 TgrasH2 transgenic mice did not increase tumor incidence. These doses are 2, 4, and times the MRHD, respectively, based on mg/m2 body surface area.Oral administration of pitolisant at 5, 15, and 30 mg/kg/day for 105 weeks to Sprague-Dawley rats did not increase tumor incidence. MutagenesisPitolisant and its metabolites were not mutagenic in the in vitro bacterial reverse mutation assay (Ames), or clastogenic in the in vitro mammalian chromosomal aberration assay. Pitolisant was negative in the in vivo mouse micronucleus assay.Impairment of FertilityOral 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/m2 body surface area. dose-related increase in the percentage of post-implantation loss was observed compared to controls, leading to decrease in the percentage of live conceptuses, at doses 13 and 22 times the MRHD, based on mg/m2 body surface area. Pitolisant caused dose-related abnormalities in sperm morphology and decreased motility at doses that are 13 and 22 times the MRHD based on mg/m2 body surface area, without any significant effects on fertility indices in male rats. No effects on fertility were observed at 30 mg/kg/day (7 times the MRHD based on mg/m2 body surface area).. 13.2 Animal Toxicology and/or Pharmacology. Adverse CNS-related clinical signs including tremors and convulsions occurred after single and repeated oral administration of pitolisant across multiple species. In 9-month repeat-dose toxicity study in monkeys, sporadic incidences of convulsions occurred at doses corresponding to exposures approximately times the MRHD based on Cmax and times the MRHD, based on AUC. Convulsions were first observed close to Tmax and resolved by hours after dosing. Convulsions were not observed after discontinuation of dosing and were not associated with microscopic findings in the brain. Safety margins at the no-observed-adverse-effect-level (NOAEL) correspond to times the MRHD based on Cmax and 0.4 times based on AUC.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following oral administration of pitolisant 35.6 mg once daily, the steady state Cmax and AUC are 73 ng/mL (range: 49.2 to 126 ng/mL) and 812 nghr/mL (range: 518 to 1468 nghr/mL), respectively. Pitolisant exposure (Cmax and AUC) increases proportionally with dose and steady state is reached by day 7.AbsorptionThe median time to maximum plasma concentration (Tmax) of pitolisant is 3.5 hours (2 to hours).The oral absorption of WAKIX is around 90%.Food EffectNo clinically significant differences in the pharmacokinetics of pitolisant were observed following administration with high-fat meal.DistributionThe apparent volume of distribution of pitolisant is approximately 700 (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.EliminationAfter 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. MetabolismPitolisant is primarily metabolized by CYP2D6 and to lesser extent by CYP3A4; these metabolites are further metabolized or conjugated with glycine or glucuronic acid. None of these metabolites are pharmacologically active. ExcretionAfter 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 PopulationsNo 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.Patients with Hepatic ImpairmentSix subjects with mild hepatic impairment (Child-Pugh A), subjects with moderate hepatic impairment (Child-Pugh B), and 12 healthy subjects matched for age, sex, body mass index and ethnicity received 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 PharmacokineticsDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUCinf area under the curve from time to time infinity; Cmax maximum plasma concentration.Patients with Renal ImpairmentA single dose of WAKIX 17.8 mg was administered to subjects with mild renal impairment (eGFR of 60 to 89 mL/min/1.73 m2), subjects with moderate renal impairment (eGFR of 30 to 59 mL/min/1.73 m2), 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 PharmacokineticsDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUCinf area under the curve from time to time infinity; Cmax maximum plasma concentration.CYP2D6 Poor MetabolizersThe pharmacokinetics of pitolisant were evaluated in subjects who were CYP2D6 poor metabolizers (PMs) and subjects who were CYP2D6 extensive metabolizers (EMs). All subjects received WAKIX 17.8 mg daily for days. Exposure of pitolisant in CYP2D6 PMs is summarized in Figure 3.Figure 3: Pitolisant Pharmacokinetics in CYP2D6 Poor MetabolizersDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUC0-24 area under the curve from time to 24 hours post-dose; Cmax maximum plasma concentration.Drug-Drug InteractionsEffect of Other Drugs on the Pharmacokinetics of WAKIXThe effect of other drugs on the pharmacokinetics of pitolisant is presented in Figure [see Dosage and Administration (2.4), Drug Interactions (7.1)]. Figure 4: Effect of Concomitant Medications on PitolisantDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUCinf area under the curve from time to time infinity; Cmax maximum plasma concentration.Effect of WAKIX on the Pharmacokinetics of Other DrugsThe effect of pitolisant on the pharmacokinetics of other drugs is presented in Figure [see Drug Interactions (7.1)].Figure 5: Effect of Pitolisant on Concomitant MedicationsDots Geometric LSM ratios, Error bars 90% CI; reference dashed lines are 0.8 and 1.25.AUCinf area under the curve from time to time infinity; AUC0-24 area under the curve from time to 24 hours; Cmax maximum plasma concentration.Administration of WAKIX concomitantly with oral contraceptives may reduce their effectiveness [see Drug Interactions (7.1), Use in Specific Populations (8.3)]. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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 SummaryAvailable case reports from clinical trials and postmarketing reports with WAKIX use in pregnant women have not determined 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 (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.DataAnimal DataPitolisant 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 decreases in body weight, food consumption and convulsions. 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, and 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 times the MRHD. At the maternally toxic dose (8 times the MRHD), the incidence of pre-implantation loss and abortions increased with consequent decrease in both the number of implantations and live fetuses. Pitolisant was not teratogenic at doses up to 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 and times the MRHD based on mg/m2 body surface area, respectively.Pitolisant was administered orally to pregnant rats from gestation day 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. 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 times the MRHD, based on mg/m2 body surface area.