Pharmacokinetics | WAKIX® (pitolisant) for HCPs

WAKIX had no clinically important PK interactions with modafinil or sodium oxybate

In a clinical PK study to evaluate the concomitant use of WAKIX with modafinil or sodium oxybate, WAKIX had no effect on the PK of modafinil or sodium oxybate, and these agents had no clinically relevant effect on the PK of WAKIX

Effect of WAKIX on the PK of Modafinil^1,*

Effect of WAKIX on the PK of Modafinil graph

Effect of WAKIX on the PK of Sodium Oxybate^1,†

Effect of WAKIX on the PK of Sodium Oxybate graph

*Seventeen healthy male subjects received treatment with a single dose of 35.6 mg WAKIX on Day 1, modafinil 200 mg/day from Day 5 to Day 25, and a single dose of 35.6 mg WAKIX plus 200 mg modafinil on Day 26.^{1 †}Sixteen healthy male subjects were randomized 1:1 to one of two treatment sequences: Treatment A (35.6 mg WAKIX) then Treatment B (sodium oxybate [two 2.25-g doses administered 3 hours apart] on Day 1, 35.6 mg WAKIX on Day 2, sodium oxybate [two 2.25-g doses administered 3 hours apart] on Day 3) or Treatment B then Treatment A. Treatment A and Treatment B were separated by 1 week.¹

Effect of Modafinil on the PK of WAKIX^1,*

Effect of Modafinil on the PK of WAKIX graph

Effect of Sodium Oxybate on the PK of WAKIX^1,†

Effect of Sodium Oxybate on the PK of WAKIX graph

Some medications have clinically important drug interactions with WAKIX

Medications That Have Clinically Important Drug Interactions With WAKIX
Effect of Other Drugs on WAKIX
Strong CYP2D6 Inhibitors	Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold
Strong CYP3A4 Inducers	Concomitant use of WAKIX with strong CYP3A4 inducers decreases exposure of pitolisant by 50%
Histamine 1 (H₁) Antagonists	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
Drugs Known to Prolong the QT Interval	Concomitant use of drugs that prolong the QT interval may add to the QT effects of WAKIX and increase the risk of cardiac arrhythmia
Effect of WAKIX on Other Drugs
Sensitive CYP3A4 Substrates	WAKIX is a borderline/weak inducer of CYP3A4; therefore, reduced effectiveness of sensitive CYP3A4 substrates may occur when used concomitantly with WAKIX 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

WAKIX is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy.

Contraindications

WAKIX is contraindicated in patients with known hypersensitivity to pitolisant or any component of the formulation. Anaphylaxis has been reported. WAKIX is also contraindicated in patients with severe hepatic impairment.

Warnings and Precautions

WAKIX prolongs the QT interval; avoid use of WAKIX in patients with known QT prolongation or in combination with other drugs known to prolong the QT interval. Avoid use 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 hepatic or renal impairment due to higher concentrations of pitolisant; monitor these patients for increased QTc. Dosage modification is recommended in patients with moderate hepatic impairment and moderate or severe renal impairment (see full prescribing information). WAKIX is not recommended in patients with end-stage renal disease (ESRD).

Adverse Reactions

In the placebo-controlled clinical trials conducted in patients with narcolepsy with or without cataplexy, the most common adverse reactions (≥5% and twice placebo) for WAKIX were insomnia (6%), nausea (6%), and anxiety (5%). Other adverse reactions that occurred at ≥2% and more frequently than in patients treated with placebo included headache, upper respiratory infection, musculoskeletal pain, heart rate increased, hallucinations, irritability, abdominal pain, sleep disturbance, decreased appetite, cataplexy, dry mouth, and rash.

Drug Interactions

Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold. Reduce the dose of WAKIX by half.
Concomitant use of WAKIX with strong CYP3A4 inducers decreases exposure of pitolisant by 50%. Dosage adjustments may be required (see full prescribing information).
H₁ receptor antagonists that cross the blood-brain barrier may reduce the effectiveness of WAKIX. Patients should avoid centrally acting H₁ receptor antagonists.
WAKIX is a borderline/weak inducer of CYP3A4. Therefore, reduced effectiveness of sensitive CYP3A4 substrates may occur when used concomitantly with WAKIX. The effectiveness of hormonal contraceptives may be reduced when used with WAKIX and effectiveness may be reduced for 21 days after discontinuation of therapy.

Use in Specific Populations

WAKIX may reduce the effectiveness of hormonal contraceptives. Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuing treatment.
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.
The safety and effectiveness of WAKIX have not been established in patients less than 18 years of age.
WAKIX is extensively metabolized by the liver. WAKIX is contraindicated in patients with severe hepatic impairment. Dosage adjustment is required in patients with moderate hepatic impairment.
WAKIX is not recommended in patients with end-stage renal disease. Dosage adjustment of WAKIX is recommended in patients with moderate or severe renal impairment.
Dosage reduction is recommended in patients known to be poor CYP2D6 metabolizers; these patients have higher concentrations of WAKIX than normal CYP2D6 metabolizers.

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.

Please see accompanying
Full Prescribing Information.

The Pharmacokinetic (PK) Profile of WAKIX Supports
Once-Daily Dosing

WAKIX had no clinically important PK interactions with modafinil or sodium oxybate

Some medications have clinically important drug interactions with WAKIX

Dosing WAKIX With Other Medications

AASM, American Academy of Sleep Medicine.
*	Clinical practice guideline on the treatment of central disorders of hypersomnolence, published in the Journal of Clinical Sleep Medicine, includes recommendations for treatment of narcolepsy in adults.

The Pharmacokinetic (PK) Profile of WAKIX SupportsOnce-Daily Dosing

WAKIX had no clinically important PK interactions with modafinil or sodium oxybate

Some medications have clinically important drug interactions with WAKIX

Dosing WAKIX With Other Medications

The Pharmacokinetic (PK) Profile of WAKIX Supports
Once-Daily Dosing