Wakix

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

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 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) 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: 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

2.1Recommendations Prior to

WAKIX Initiation Consider genotyping patients for CYP2D6 metabolizer status to determine the maximum recommended dosage .

2.2Recommended 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.

2.3Recommended 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.

2.4Dosage 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 . 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 . 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 . WAKIX is contraindicated in patients with severe hepatic impairment. WAKIX has not been studied in patients with severe hepatic impairment .

2.5Dosage 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 . 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 . 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 . WAKIX is not recommended in patients with eGFR less than 15 mL/minute/1.73 m 2 .

2.6Dosage Modifications for Concomitant Use with Strong

CYP2D6 Inhibitors and Strong CYP3A4 Inducers Coadministration with Strong CYP2D6 Inhibitors Adult patients: Initiate WAKIX at 8.9 mg once daily and increase after 7 days to a maximum recommended dosage of 17.8 mg once daily . Pediatric patients (6 years and older) 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 . Pediatric patients (6 years and older) 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 . Adult and pediatric patients on a stable dose of WAKIX: Reduce the WAKIX dose by half upon initiating strong CYP2D6 inhibitors . Coadministration with Strong CYP3A4 Inducers Concomitant use of WAKIX with strong CYP3A4 inducers decreases pitolisant exposure by 50%. Assess for loss of efficacy after initiation of a strong CYP3A4 inducer. For adult and pediatric patients stable on WAKIX 8.9 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 7 days.

If concomitant dosing of a strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half .

2.7Dosage Recommendations in Patients Who Are

CYP2D6 Poor Metabolizers Adult Patients Initiate WAKIX at 8.9 mg once daily and increase after 7 days to a maximum recommended dosage of 17.8 mg once daily . Pediatric patients Pediatric patients (6 years and older) 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 . Pediatric patients (6 years and older) 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 .

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

5.1QT 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 . 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 . 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 . WAKIX is contraindicated in patients with severe hepatic impairment . WAKIX is not recommended in patients with end-stage renal disease (ESRD) .

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 . 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 . Known hypersensitivity to pitolisant or any component of the formulation Severe hepatic impairment

8.1Pregnancy 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 . 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.

The following adverse reactions are discussed in more detail in other sections of the labeling: QT Interval Prolongation Most common adverse reactions (≥5% and at least twice placebo) in adults: insomnia, nausea, and anxiety. Most common adverse reactions (≥5% and greater than placebo) in pediatric patients 6 years and older: headache and insomnia. 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 .

6.1Clinical 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.

6.2Postmarketing 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