Wakix (pitolisant)

The following adverse reactions are discussed in more detail in other sections of the labeling:

• QT Interval Prolongation

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.

In the clinical trials for narcolepsy, 172 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 pitolisant 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 event.

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 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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Wakix outside of the United States. 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
• Investigations: weight increased
• Nervous system disorders: 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

Recommended Dosage

The recommended dosage range for Wakix is 17.8 mg to 35.6 mg administered orally once daily in the morning upon wakening. Titrate dosage as follows:

• Week 1: Initiate with 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.

Dosage Modification And Recommendations In Patients With Hepatic Impairment

• In patients with moderate hepatic impairment, initiate Wakix at 8.9 mg once daily and increase after 14 days to a maximum 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.

Dosage Modification And Recommendations In Patients With Renal Impairment And End Stage Renal Disease

• In patients with moderate and severe renal impairment, initiate Wakix at 8.9 mg once daily and increase after 7 days to a maximum dosage of 17.8 mg once daily.
• Wakix is not recommended in patients with end stage renal disease (ESRD).

Dosage Recommendations For Concomitant Use With Strong CYP2D6 Inhibitors And Strong CYP3A4 Inducers

Coadministration With Strong CYP2D6 Inhibitors

• For patients receiving strong CYP2D6 inhibitors, initiate Wakix at 8.9 mg once daily and increase after 7 days to a maximum dosage of 17.8 mg once daily.
• For 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 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.

Use In Patients Who Are Known CYP2D6 Poor Metabolizers (PMs)

• In patients known to be poor CYP2D6 metabolizers, initiate Wakix at 8.9 mg once daily and titrate to a maximum dose of 17.8 mg once daily after 7 days.

Drugs Having Clinically Important Interactions With Wakix

Table 2: Clinically Significant Drug Interactions with Wakix

Drugs Having No Clinically Important Interactions With Wakix

A clinical study was conducted to evaluate the concomitant use of Wakix with modafinil or sodium oxybate. This study demonstrated no clinically relevant effect of modafinil or sodium oxybate on the pharmacokinetics of Wakix and no effect of Wakix on the pharmacokinetics of modafinil or sodium oxybate.

A clinical study showed that strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) have no effect on the pharmacokinetics of Wakix.

• 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.
• There are no data on the presence of pitolisant in human milk, the effects on the breastfed infant, or the effect of this drug on milk production.
• 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 child from Wakix or from the underlying maternal condition.