Wakix (pitolisant)

What is Wakix, and how does it work?

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

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

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

Adverse ReactionWakix
(n=152) %Placebo
(n=114) %Headache*1815Insomnia*62Nausea63Upper respiratory tract infection*53Musculoskeletal pain*53Anxiety*51Heart rate increased*30Hallucinations*30Irritability32Abdominal pain*31Sleep disturbance*32Decreased appetite30Cataplexy21Dry mouth21Rash*21* 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
Sleep disturbance includes: dyssomnia; sleep disorder; sleep paralysis; sleep talking
Rash includes: eczema, erythema migrans, rash, urticaria
Upper respiratory infection includes: pharyngitis; rhinitis; sinusitis; upper respiratory tract infection; upper respiratory tract inflammation; viral upper respiratory tract infection

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

What is the dosage for Wakix?

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.

What drugs interact with Wakix?

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.

Examples:
paroxetine, fluoxetine, bupropion

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.

Examples:
rifampin, carbamazepine, phenytoin

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.

Examples:
pheniramine maleate, diphenhydramine, promethazine (anti-histamines) imipramine, clomipramine, mirtazapine (tri or tetracyclic antidepressants)

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.

Examples:
Class 1A antiarrhythmics: quinidine, procainamide, disopyramide; Class 3 antiarrhythmics: amiodarone, sotalol; Antipsychotics: ziprasidone, chlorpromazine, thioridazine; Antibiotics: moxifloxacin

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.

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.

Examples:
midazolam, hormonal contraceptives, cyclosporine

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.

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Is Wakix safe to use while pregnant or breastfeeding?

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.