Wakix (Pitolisant Hydrochloride): Uses, Dosage, Side Effects & Warnings

Uses

1 INDICATIONS AND USAGE WAKIX is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in 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 patients 6 years of age and older with narcolepsy ( 1 )

Dosage and administration

See Full Prescribing Information for complete dosage instructions ( 2.2 , 2.3 ) Administer orally once daily in the morning upon wakening ( 2.2 , 2.3 ) Dosage Recommendations: Adults ( 2.2 ) 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) ( 2.3 ) 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 for patients weighing <40 kg Week 4 For patients weighing ≥40 kg, may increase to the maximum recommended dosage of 35.6 mg once daily Hepatic impairment ( 2.4 , 8.6 , 12.3 ): Moderate hepatic impairment (Child-Pugh Class B): Adults: Initial dosage is 8.9 mg once daily. Increase to a maximum dosage of 17.8 mg once daily after 14 days Pediatric Patients: Initial dosage is 4.45 mg once daily. Increase to 8.9 mg once daily after 14 days; for patients weighing ≥40 kg, may increase to 17.8 mg once daily after another 14 days Renal impairment (eGFR less than 60 mL/minute/1.73 m 2 ) ( 2.5 , 8.7 , 12.3 ): Adults: Initial dosage is 8.9 mg once daily. Increase to a maximum dosage of 17.8 mg once daily after 7 days Pediatric Patients: Initial dosage is 4.45 mg once daily.Increase 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 ( 2.7 ): 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 2.1 Recommendations Prior to WAKIX 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 WAKIX for the treatment of EDS or cataplexy in adult patients is 17.8 mg to 35.6 mg administered orally once daily in the morning upon wakening. Titrate dosage as follows: Week 1: Initiate with a dosage of 8.9 mg (two 4.45 mg tablets) once daily Week 2: Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily Week 3: May increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily Dose may be adjusted based on tolerability.If a dose is missed, patients should take the next dose the following day in the morning upon wakening.It may take up to 8 weeks for some patients to achieve a clinical response. 2.3 Recommended Dosage in Pediatric Patients 6 Years and Older The recommended starting dosage of WAKIX for the treatment of EDS or cataplexy in pediatric patients 6 years and older is 4.45 mg administered orally once daily in the morning upon wakening. Titrate dosage as follows: Week 1: Initiate with a dosage of 4.45 mg (one 4.45 mg tablet) once daily Week 2: Increase dosage to 8.9 mg (two 4.45 mg tablets) once daily Week 3: Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily, which is the maximum recommended dosage for patients weighing <40 kg Week 4: For patients weighing ≥40 kg, may increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily Dose may be adjusted based on tolerability. If a dose is missed, patients should take the next dose the following day in the morning upon wakening. It may take up to 8 weeks for some patients to achieve a clinical response. 2.4 Dosage Recommendations in Patients with Hepatic Impairment Adult Patients with Moderate (Child-Pugh Class B) Hepatic Impairment Initiate WAKIX at 8.9 mg once daily and increase after 14 days to a maximum recommended dosage of 17.8 mg once daily [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . 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 ( 5.1 ), Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . Pediatric patients weighing ≥40 kg: Initiate WAKIX at 4.45 mg once daily and increase after 14 days to 8.9 mg once daily. May increase after another 14 days to a maximum recommended dosage of 17.8 mg once daily [see Warnings and Precautions ( 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 )] . 2.5 Dosage Recommendations in Patients with Renal Impairment and End-Stage Renal Disease 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 17.8 mg once daily [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] . Pediatric Patients (6 years and older) with eGFR <60 mL/minute/1.73 m 2 (using the Schwartz equation, eGFR (mL/min/1.73 m2)=(0.413*height in cm)/serum creatinine in mg/dL) Pediatric patients weighing <40 kg: Initiate WAKIX at 4.45 mg once daily and increase after 7 days to a maximum recommended dosage of 8.9 mg once daily [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] . Pediatric patients weighing ≥40 kg: Initiate WAKIX at 4.45 mg once daily and increase after 7 days to 8.9 mg once daily. May increase after another 7 days to a maximum recommended dosage of 17.8 mg once daily [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] .

Dosage forms and strengths

4.45 mg tablets: white, round, biconvex film-coated tablet, marked with “S” on one side and plain on the other side. Each tablet contains 5 mg of pitolisant hydrochloride equivalent to 4.45 mg of pitolisant. WAKIX 17.8 mg tablets: white, round, biconvex film-coated tablet, marked with “H” on one side and plain on the other side. Each tablet contains 20 mg of pitolisant hydrochloride equivalent to 17.8 mg of pitolisant. Tablets: 4.45 mg and 17.8 mg ( 3 )

Contraindications

4 CONTRAINDICATIONS 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 )

Warnings and precautions

Interval Prolongation : Increases in QT interval. Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. Monitor patients with hepatic or renal impairment for increased QTc ( 5.1 ) 5.1 QT Interval Prolongation WAKIX prolongs the QT interval. The use of WAKIX 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 )]. WAKIX 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 )] . WAKIX is contraindicated in patients with severe hepatic impairment [see Contraindications ( 4 )] . WAKIX is 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 )] .

Side effects

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.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 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 presents the adverse reactions that occurred at a 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 upper Anxiety includes: anxiety; nervousness; stress; stress at work Hallucinations includes: hallucination; hallucination visual; hypnagogic hallucination Headache includes: cluster headache; headache; migraine; premenstrual headache; tension headache Heart rate increased includes: heart rate increased; sinus tachycardia; tachycardia Insomnia includes: initial insomnia; insomnia; middle insomnia; poor quality sleep Musculoskeletal pain includes: arthralgia; back pain; carpal tunnel syndrome; limb discomfort; musculoskeletal pain; myalgia; neck pain; osteoarthritis; pain in extremity; sciatica Rash includes: eczema; erythema migrans; rash; urticaria Sleep disturbance includes: dyssomnia; sleep disorder; sleep paralysis; sleep talking Upper respiratory tract infection includes: pharyngitis; rhinitis; sinusitis; upper respiratory tract infection; upper respiratory tract inflammation; viral upper respiratory tract infection Adverse Reaction WAKIX (n=152) % Placebo (n=114) % 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 8 years. 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. 6.2 Postmarketing Experience 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: 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

Drug interactions

Strong CYP2D6 Inhibitors: Increased exposure of WAKIX; reduce the maximum recommended dose of WAKIX by half ( 2.6 , 7.1 ) Strong CYP3A4 Inducers: Decreased exposure of WAKIX; consider dosage adjustment of WAKIX ( 2.6 , 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 WAKIX Effect of Other Drugs on WAKIX Strong CYP2D6 Inhibitors Clinical Implication: Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold. Prevention or Management: Reduce the dose of WAKIX by half [see see Dosage and Administration ( 2.6 ), Clinical Pharmacology ( 12.3 )] . 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 8.9 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 7 days. If concomitant dosing of a strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half [see see Dosage and Administration ( 2.6 ), Clinical Pharmacology ( 12.3 )] . 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 )] . 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 )].

Use in specific populations

8.1 Pregnancy 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 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/m 2 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 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 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/m 2 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/m 2 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/m 2 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/m 2 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). F 1 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 F 1 generation. The no-observed-adverse-effect-level for developmental toxicity is approximately 7 times the MRHD, based on mg/m 2 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 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 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 WAKIX may reduce the effectiveness of hormonal contraceptives.

Pregnancy

8.1 Pregnancy 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 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/m 2 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 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 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/m 2 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/m 2 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/m 2 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/m 2 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). F 1 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 F 1 generation. The no-observed-adverse-effect-level for developmental toxicity is approximately 7 times the MRHD, based on mg/m 2 body surface area.

Pediatric use

8.4 Pediatric Use The safety and effectiveness of WAKIX have been established for the treatment of excessive daytime sleepiness or cataplexy 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 the treatment of excessive daytime sleepiness or cataplexy 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 C max and AUC, respectively.

Geriatric use

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 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.

Description

11 DESCRIPTION WAKIX tablets contain pitolisant hydrochloride. Pitolisant is an antagonist/inverse agonist of the histamine-3 (H3) receptor. Pitolisant hydrochloride is a white or almost white crystalline powder with a molecular formula of C 17 H 26 ClNO·HCl and a molecular weight of 332.31. Pitolisant hydrochloride is soluble in water, ethanol, and methylene chloride and practically insoluble in cyclohexane. 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 C 17 H 26 ClNO and its molecular weight is 295.85. WAKIX 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: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. chemical structure

Mechanism of action

12.1 Mechanism of Action The mechanism of action of pitolisant in excessive daytime sleepiness (EDS) or cataplexy in patients 6 years and older with narcolepsy is unclear. However, its efficacy could be mediated through its activity as an antagonist/inverse agonist at histamine-3 (H3) receptors.

How supplied

16.1 How Supplied WAKIX (pitolisant) tablets are available as: 4.45 mg: white, round, biconvex film-coated tablet, 3.7 mm diameter, marked with “S” on one side and plain on the other side. NDC 72028-045-03 – Bottles of 30 17.8 mg: white, round, biconvex film-coated tablet, 7.5 mm diameter, marked with “H” on one side and plain on the other side. NDC 72028-178-03 – Bottles of 30 16.2 Storage and Handling Store at 20° C to 25° C (68° F to 77° F); excursions permitted between 15° C to 30° C (59° F to 86° F) [see USP Controlled Room Temperature]. 16.1 How Supplied WAKIX (pitolisant) tablets are available as: 4.45 mg: white, round, biconvex film-coated tablet, 3.7 mm diameter, marked with “S” on one side and plain on the other side. NDC 72028-045-03 – Bottles of 30 17.8 mg: white, round, biconvex film-coated tablet, 7.5 mm diameter, marked with “H” on one side and plain on the other side. NDC 72028-178-03 – Bottles of 30

Storage

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

Patient 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 WAKIX before any new drug is taken. Contraception Advise patients that use of WAKIX 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 )]. Pregnancy Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to WAKIX during pregnancy [see Use in Specific Populations ( 8.1 )]. 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 WAKIX and other drugs [see Drug Interactions ( 7 )]. Distributed by: Harmony Biosciences, LLC, Plymouth Meeting, PA 19462 USA WAKIX is a registered trademark of Bioprojet Europe, Ltd. Protected by US Patent Numbers 8,207,197 and 8,486,947 Harmony Biosciences name and logo are trademarks of Harmony Biosciences Management, Inc. and are used herein by permission. Label #100.10

Active ingredients

Pitolisant Hydrochloride in 2 products

Wakix NDC products (2)

NDC	Strength & form	Labeler	Type
72028-045	Pitolisant Hydrochloride 4.45 mg/1 Tablet, Film Coated	Harmony Biosciences, LLC	NDA
72028-178	Pitolisant Hydrochloride 17.8 mg/1 Tablet, Film Coated	Harmony Biosciences, LLC	NDA

Frequently asked questions

What is Wakix used for?

1 INDICATIONS AND USAGE WAKIX is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in 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 patients 6 years of age and older with narcolepsy ( 1 )

What are the side effects of Wakix?

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 (… See the full label for the complete list.

Who makes Wakix?

Wakix is listed by 1 labeler in the FDA NDC directory, including Harmony Biosciences, LLC.