Pitolisant (Wakix) Package Insert

RECENT MAJOR CHANGES

1 INDICATIONS AND USAGE

Pitolisant Tablets are indicated for the treatment of excessive daytime sleepiness (EDS) in patients with narcolepsy.

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations Prior to Pitolisant Tablets Initiation

Consider genotyping patients for CYP2D6 metabolizer status to determine the maximum recommended dosage [see Dosage and Administration (2.7)].

2.2 Recommended Dosage in Adult Patients

The recommended dosage range for pitolisant tablets for the treatment of EDS 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.

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

2.4 Dosage Recommendations in Patients with Hepatic Impairment

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

• Initiate pitolisant tablets 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 (5.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Pitolisant tablets are contraindicated in patients with severe hepatic impairment. Pitolisant tablets have 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 )].

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information

2.5 Dosage Recommendations in Patients with Renal Impairment and End-Stage Renal Disease

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

• Initiate pitolisant tablets 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 (5.1), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Pitolisant Tablets is not recommended in patients with eGFR less than 15 mL/minute/1.73 m² [see Warnings and Precautions (5.1), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information

2.6 Dosage Modifications for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers

Coadministration with Strong CYP2D6 Inhibitors

• Adult patients: Initiate Pitolisant Tablets at 8.9 mg once daily and increase after 7 days to a maximum recommended dosage of 17.8 mg once daily [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
• Adult patients on a stable dose of pitolisant tablets: Reduce the pitolisant tablets dose by half upon initiating strong CYP2D6 inhibitors [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Coadministration with Strong CYP3A4 Inducers

Concomitant use of pitolisant tablets with strong CYP3A4 inducers decreases pitolisant exposure by 50 %. Assess for loss of efficacy after initiation of a strong CYP3A4 inducer.

For adult patients stable on pitolisant tablets 8.9 mg or 17.8 mg once daily, increase the dose of pitolisant tablets to double the original daily dose (i.e., 17.8 mg or 35.6 mg, respectively) over 7 days.

If concomitant dosing of a strong CYP3A4 inducer is discontinued, decrease pitolisant tablets dosage by half [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information

2.7 Dosage Recommendations in Patients Who Are CYP2D6 Poor Metabolizers

Adult Patients

• Initiate pitolisant tablets at 8.9 mg once daily and increase after 7 days to a maximum recommended dosage of 17.8 mg once daily [see Use in Specific Populations (8.8), Clinical Pharmacology (12.5)].

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information

3 DOSAGE FORMS AND STRENGTHS

• Pitolisant tablets, 4.45 mg: White to off white, round, film-coated, biconvex tablets debossed with "L" on one side and "T2" on the other side. Each film-coated tablet contains 5 mg of pitolisant hydrochloride equivalent to 4.45 mg of pitolisant.
• Pitolisant tablets, 17.8 mg: White to off white, round, film-coated, biconvex tablets debossed with "L" on one side and "T3" on the other side. Each film-coated tablet contains 20 mg of pitolisant hydrochloride equivalent to 17.8 mg of pitolisant.

4 CONTRAINDICATIONS

Pitolisant tablets are contraindicated in patients with:

• known hypersensitivity to pitolisant or any component of the formulation. Anaphylaxis has been reported in patients treated with pitolisant tablets [see Adverse Reactions (6.2)].
• severe hepatic impairment. Pitolisant tablets are extensively metabolized by the liver and there is a significant increase in pitolisant tablets exposure in patients with moderate hepatic impairment [see Use in Specific Populations (8.6)].

5 WARNINGS AND PRECAUTIONS

5.1 QT Interval Prolongation

Pitolisant tablets prolong the QT interval. The use of pitolisant tablets should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong the QT interval [see Drug Interactions (7.1)]. Pitolisant tablets should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval [see Clinical Pharmacology (12.2)]. The risk of QT prolongation may be greater in patients with higher concentrations of pitolisant (e.g., patients with hepatic or renal impairment). Monitor patients with hepatic or renal impairment for increased QTc. Dosage modification is recommended in patients with moderate hepatic impairment and moderate or severe renal impairment [see Dosage and Administration (2.4, 2.5)]. Pitolisant tablets are contraindicated in patients with severe hepatic impairment [see Contraindications (4)]. Pitolisant tablets are not recommended in patients with end-stage renal disease (ESRD) [see Dosage and Administration (2.5), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

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)]

6.1 Clinical Trials Experience

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 pitolisant tablets in placebo-controlled trials for up to 8 weeks and in open-label extension trials for up to 5 years. In trials in which pitolisant tablets was directly compared to placebo, 6 of the 152 patients (3.9 %) who received pitolisant tablets 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 pitolisant tablets were insomnia (6 %), nausea (6 %), and anxiety (5 %).

Table 1 presents the adverse reactions that occurred at a rate of ≥2 % in patients treated with pitolisant tablets 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 Pitolisant Tablets-Treated Patients and More Frequently than in Placebo-Treated Patients in Three Placebo-Controlled Narcolepsy Studies

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pitolisant tablets. 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: Fatigue

Immune system disorders: hypersensitivity (anaphylaxis)

Investigations: weight increased

Nervous system disorders: dizziness, Epilepsy

Psychiatric disorders: abnormal behavior, abnormal dreams, anhedonia, bipolar disorder, depression, depressed mood, nightmare, sleep disorder, suicide attempt, suicidal ideation

Skin and subcutaneous tissue disorders: Pruritus

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Pitolisant Tablets

Table 2: Clinically Significant Drug Interactions with Pitolisant Tablets

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available case reports from clinical trials and postmarketing reports with pitolisant tablets 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 (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. 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.

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 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, 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.

8.2 Lactation

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). There are no data on the effects of pitolisant on the breastfed infant, or the effect of this drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pitolisant tablets and any potential adverse effects on the breastfed infant from pitolisant tablets 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 of 47.5 ng/mL, while the mean C_max of pitolisant in serum was 61.4 ng/mL. Following a single dose of pitolisant 35.6 mg, approximately 50 % of the amount of pitolisant measured in breast milk occurred during the first 4 hours post dose. Based on single dose data, the mean infant dosage of pitolisant was calculated to be 0.009 mg/day, which represented a mean of 0.564 % of the maternal dose received.

8.3 Females and Males of Reproductive Potential

Contraception

Pitolisant tablets 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 pitolisant tablets 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 pitolisant tablets have not been established for the treatment of excessive daytime sleepiness in pediatric patients less than 6 years of age 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 Cmax and AUC, respectively.

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use

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 adult patients with narcolepsy in clinical studies of pitolisant tablets, 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

Pitolisant tablets are contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) as it has not been studied in this population. Pitolisant tablets are extensively metabolized by the liver and there is a significant increase in pitolisant tablets exposure in patients with moderate hepatic impairment [see Contraindications (4), Clinical Pharmacology (12.3)].

Monitor patients with moderate hepatic impairment (Child-Pugh Class B) and adjust the dosage of pitolisant tablets [see Dosage and Administration ( 2.4)].

Monitor patients with mild hepatic impairment (Child-Pugh Class A). No dosage adjustment of pitolisant tablets is recommended in patients with mild hepatic impairment.

8.7 Renal Impairment

The pharmacokinetics of pitolisant tablets in patients with end-stage renal disease (ESRD) (eGFR of <15 mL/minute/1.73 m²) is unknown [see Clinical Pharmacology (12.3)]. Therefore, pitolisant tablets are not recommended in patients with ESRD [see Dosage and Administration (2.5), Warnings and Precautions (5.1)].

Dosage adjustment of pitolisant tablets is recommended in patients with eGFR <60 mL/minute/1.73 m² [see Dosage and Administration (2.5)].

8.8 Use in Genomic Subgroups

The maximum recommended dosage is lower in patients who are CYP2D6 poor metabolizers because these patients have higher pitolisant concentrations than CYP2D6 normal metabolizers and may have increased risk of adverse events [see Dosage and Administration (2.7), Warnings and Precautions (5.1), Clinical Pharmacology (12.5)].

The prevalence of CYP2D6 poor metabolizers is approximately 7% in White populations, 2% in Asian populations, and 2% in Black or African American populations.

10 OVERDOSAGE

Human Experience

In premarketing clinical studies, overdosage of pitolisant tablets was identified in one patient who ingested 320.4 mg of pitolisant tablets (9 times the maximum recommended daily dose). The patient experienced nystagmus and twitching, reported generalized pain, and had QT prolongation. The patient was monitored in the hospital, received supportive care, and was discharged the following day without sequelae.

There have been postmarketing reports of overdoses of pitolisant tablets. The most frequently reported symptoms with overdoses up to 71.2 mg (twice the maximum recommended daily dose) were headache, nausea, and hallucinations.

Management of Overdosage

No specific antidote for pitolisant tablets is known. In managing acute overdosage, provide general symptomatic and supportive care including close medical supervision and monitoring of vital signs and cardiac rhythm. Specifically, continuous cardiovascular monitoring should be initiated to detect possible arrhythmias [see Warnings and Precautions (5.1)]. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

11 DESCRIPTION

Pitolisant tablets contain pitolisant hydrochloride. Pitolisant is an antagonist/inverse agonist of the histamine-3 (H3) receptor. Pitolisant hydrochloride is a white to white powder with a molecular formula of C₁₇H₂₇Cl₂NO and a molecular weight of 332.3. Pitolisant hydrochloride is freely soluble in methanol and water. The chemical name of pitolisant hydrochloride is 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride and its structural formula is:

The molecular formula of the pitolisant free base is C₁₇H₂₆ClNO and its molecular weight is 295.85.

Pitolisant tablets are for oral administration and each film-coated tablet contains 5 mg or 20 mg of pitolisant hydrochloride (equivalent to 4.45 mg or 17.8 mg of pitolisant free base, respectively) and the following inactive ingredients: crospovidone, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, silicon dioxide, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of pitolisant in excessive daytime sleepiness (EDS) 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.

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

12.2 Pharmacodynamics

Pitolisant binds to H3 receptors with a high affinity (K_i = 1 nM) and has no appreciable binding to other histamine receptors (H1, H2, or H4 receptors; K_i >10 mcM).

Cardiac Electrophysiology

Pitolisant tablets at the highest recommended dosage (i.e., 35.6 mg daily) led to a QTc increase of 4.2 msec. Exposures 3.8-fold higher than achieved at the highest recommended dose increased 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 C_max and 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_max and 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 pitolisant tablets is around 90 %.

Food Effect

No clinically significant differences in the pharmacokinetics of pitolisant were observed following administration with a high-fat meal (approximately 950 calories, 62% fat).

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.

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 pitolisant tablets 17.8 mg to assess the pharmacokinetics of pitolisant tablets 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 pitolisant tablets 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 pitolisant tablets 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.

Drug-Drug Interactions

Effect of Other Drugs on the Pharmacokinetics of Pitolisant Tablets:

The effect of other drugs on the pharmacokinetics of pitolisant is presented in Figure 3 [see Dosage and Administration (2.6), Drug Interactions (7.1)].

Figure 3: 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 Pitolisant Tablets on the Pharmacokinetics of Other Drugs:

The effect of pitolisant on the pharmacokinetics of other drugs is presented in Figure 4 [see Drug Interactions (7.1) Use in Specific Populations (8.3)].

Figure 4: 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 to 24} = area under the curve from time 0 to 24 hours;

C_max = maximum plasma concentration.

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

12.5 Pharmacogenomics

Pitolisant is metabolized by CYP2D6 [see Clinical Pharmacology (12.3)]. The gene encoding CYP2D6 has variants that affect CYP2D6 metabolic function. CYP2D6 poor metabolizers are individuals with two nonfunctional alleles (e.g., CYP2D6*5/*5), and as a result have no CYP2D6 enzyme activity.

Administration of Pitolisant Tablets 17.8 mg daily for 7 days resulted in 2.4 times higher AUC and 2.1 times higher Cmax in CYP2D6 poor metabolizers (n=3) compared to CYP2D6 normal metabolizers (n=5). [see Dosage and Administration (2.7), Use in Genomic Subgroups (8.8)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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/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. These doses are 1.4, 4, and 8 times the MRHD based on mg/m² body surface area.

Mutagenesis

Pitolisant 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 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/m² body surface area (BSA). A dose-related increase in the percentage of post-implantation loss was observed compared to controls, leading to a decrease in the percentage of live conceptuses, at doses 13 and 22 times the MRHD, based on mg/m² BSA. 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 BSA, 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 BSA).

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 a 9-month repeat-dose toxicity study in monkeys, sporadic incidences of convulsions occurred at doses corresponding to exposures approximately 3 times the MRHD based on C_max and 1 times the MRHD, based on AUC. Convulsions were first observed close to T_max and resolved by 2 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 1 times the MRHD based on C_max and 0.4 times based on AUC.

14 CLINICAL STUDIES

14.1 Excessive Daytime Sleepiness (EDS) in Patients with Narcolepsy

Adult Patients with Narcolepsy

The efficacy of pitolisant tablets 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 pitolisant tablets to both a placebo and an active control.

In Study 1, 95 patients were randomized to receive pitolisant tablets, placebo, or active control. The dose of pitolisant tablets 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 a stable dose of 35.6 mg. Median age in the study was 37 years. More than 90 % of patients in the pitolisant tablets and placebo groups were Caucasian and 54 % were male. Approximately 80 % of the population had a history of cataplexy.

Pitolisant tablets demonstrated statistically significantly greater improvement on the primary endpoint, the least squares mean final ESS score compared to placebo (Table 3).

In Study 2, 166 patients were randomized to receive pitolisant tablets, placebo, or active control. The dose of pitolisant tablets 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 a stable dose of 17.8 mg. Median age in the study was 40 years. In the pitolisant tablets and placebo groups, approximately 50 % of patients were male, 90 % of patients were Caucasian, and 75 % of patients had a history of cataplexy.

Pitolisant tablets demonstrated statistically significantly greater improvement on the primary endpoint, the least squares 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 Patients with Narcolepsy (Study 1 and Study 2)

Figure 5 shows the ESS score from baseline to Week 8 in Study 1.

Figure 5: Epworth Sleepiness Scale Score (mean ± SEM) from Baseline to Week 8 in Study 1

SEM = standard error of the mean (raw mean scores)

ESS scores range from 0 to 24, with 0 being the best score and 24 being the worst score

Pediatric use information is approved for Harmony Biosciences Management Inc.'s WAKIX (pitolisant) tablets. However, due to Harmony Biosciences Management Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Pitolisant tablets are available as:

4.45 mg: White to off white, round, film-coated, biconvex tablets debossed with "L" on one side and "T2" on the other side.

NDC 70748-386-01: Bottles of 30 Tablets

17.8 mg: White to off white, round, film-coated, biconvex tablets debossed with "L" on one side and "T3" on the other side.

NDC 70748-387-01: Bottles of 30 Tablets

16.2 Storage and Handling

Store at 20° C to 25^oC (68° F to 77^o F); excursions permitted between 15° C and 30° C (59° F and 86° F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Prolongation of the QT Interval

Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations [see Warnings and Precautions (5.1)]. Advise patients to inform their healthcare provider that they are taking pitolisant tablets before any new drug is taken.

Contraception

Advise patients that use of pitolisant tablets may reduce the efficacy of hormonal contraceptives. Advise patients using a hormonal contraceptive to use an alternative non-hormonal contraceptive method of contraception during treatment and for at least 21 days after discontinuing treatment [see Drug Interactions (7.1), Use in Specific Populations (8.3)].

Concomitant Medication

Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs, because of the potential for interactions between pitolisant tablets and other drugs [see Drug Interactions (7)].

LUPIN and the are registered trademarks of Lupin Pharmaceuticals, Inc.

The brands listed are trademarks of their respective owners and are not trademarks of Lupin Limited. The makers of these brands are not affiliated with and do not endorse Lupin Limited or its products.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Naples, FL 34108United States

Manufactured by:

Lupin Limited

Nagpur - 441 108

India

August 2026 ID#: 284828