Pitolisant (Wakix) is a selective antagonist (or inverse agonist) of the H3 (histamine) receptors in the brain that improves wakefulness. It is used in the management of patients with narcolepsy similar to modafinil (but with a unique mechanism of action)

Pitolisant Uses:

• Narcolepsy:

  • It is used to treat excessive daytime sleepiness in adult patients with narcolepsy.

Pitolisant (Wakix) Dose in Adults:

The recommended dose is 17.8 to 35.6 mg orally once a day administered early in the morning before meals. The dose is then titrated based on the patients' response and tolerance as follows:

• Week 1: Initiate at a dose of 8.9 mg or two tablets of 4.45 mg daily.
• Week 2: Increase the dose to 17.8 mg as a single tablet of 17.8 mg daily.
• Week 3: The dose may be increased to the maximum daily recommended dose of 35.6 mg daily or two tablets of 17.8 mg daily administered early in the morning.

In case a dose is missed, administering a double dose that day is not recommended. The dose should be taken at the next scheduled time.

Dosage recommendations with concomitant medications:

Coadministration with strong CYP2D6 inhibitors:

• Initiate treatment at a dose of 8.9 mg per day and increase the dose after 7 days to 17.8 mg per day.
• If the patient is on a stable dose of Wakix before initiating CYP2D6, the dose of the treatment should be reduced by half.

Coadministration with strong CYP3A4 inducers:

• CYP3A4 reduces the efficacy of the drug by 50%. For patients who are on 8.9 mg or 17.8 mg stable dose before initiating CYP3A4 treatment initiation, the dose should be double by 50% after 7 days.
• Similarly, if the CYP3A4 treatment is discontinued, the dose should of Wakx should be doubled.

Use in patients who are are known CYP2d6 poor metabolizers:

• Poor CYP2D6 metabolizers should be started on a lower initial dose of 8.9 mg. The dose should be increased after 7 days to a maximum of 17.8 mg per day.

Pitolisant (Wakix) Dose in Children:

Not indicated

Pregnancy Risk Category:

• It has not been tested in human or animal pregnancies. 
• There are no case reports that have shown drug-related adverse pregnancy outcomes in fetuses or mothers.
• Manufacturer recommends that pregnant women who have been exposed to the drug in pregnancy be registered on the drug registry Also, hormonal contraceptives may be less effective due to the drug. 
• It is recommended that both males and females of reproductive age be instructed to use alternative methods of contraception while on the drug and for 21 days following the last dose.

Use during Lactation:

• It is unknown if the drug is found in breastmilk. 
• It was detected in breastmilk in animal studies. 
• It is possible that the drug may also be excreted in human breastmilk, which could affect the infant's health.
• Before initiating treatment in lactating mothers, the manufacturer suggests that you weigh the benefits and risks of drug therapy for the mother against the potential dangers to the infant.

Dose in Kidney disease:

In mild to moderate renal dysfunction, a lower initial dose of 8.9 mg is recommended that should be titrated to the maximum dose of 17.8 mg per day after a week. It should be avoided in severe kidney dysfunction.

Dose in Liver disease:

In mild to moderate hepatic dysfunction, a lower initial dose of 8.9 mg is recommended that should be titrated to the maximum dose of 17.8 mg per day after two weeks. It should be avoided in severe hepatic dysfunction. 

Common Side Effects of Pitolisant (Wakix):

• Central Nervous System:

  • Headache

Less Common Side Effects Of Pitolisant (Wakix):

• Cardiovascular:

  • Increased Heart Rate

• Central Nervous System:

  • Insomnia
  • Anxiety
  • Hallucination
  • Irritability
  • Sleep Disturbance
  • Cataplexy

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Nausea
  • Abdominal Pain
  • Decreased Appetite
  • Xerostomia

• Neuromuscular & Skeletal:

  • Musculoskeletal Pain

• Respiratory:

  • Upper Respiratory Tract Infection

Frequency of side effects Not Defined:

• Cardiovascular:

  • Prolonged QT Interval On ECG
  • Tachycardia

• Central Nervous System:

  • Migraine
  • Sleep Paralysis
  • Sleep Talking

Contraindications to Pitolisant (Wakix):

Severe hepatic dysfunction (It is extensively processed in the liver, and drug toxicity can be possible).

Warnings and precautions

• Longer QT interval
  • The QT interval may be prolonged by the drug. 
  • Patients at high risk for QT interval prolongation due to pre-existing cardiac conditions, concomitant medication that may prolong QT interval, patients who have hypokalemia or hypomagnesemia and patients with hypocalcemia should be advised to avoid the drug.
  • Higher doses of medication and patients with renal or liver dysfunction are at greater risk for QT-interval prolongation, and cardiac arrhythmias.

Pitolisant: Drug Interaction

Monitoring Parameters:

Monitor liver function tests, renal function tests, ECG (QT interval), heart rate, and central nervous system side effects.

How to administer Pitolisant (Wakix)?

It is administered in the early morning as a once-daily oral medicine.

Mechanism of action of Pitolisant (Wakix):

• Pitolisant, a medicine that increases wakefulness through its unique mechanism of action, is known as a medicine. 
• It acts as a selective antagonist (or inverted agonist) of H3 (histamine), receptors in the brain. 
• It enhances the brain's histaminergic transmission without affecting H1,H2, or H4 receptors.
• Orexins, which are excitatory neurotransmitters, project to histaminergic cells. 
• Presynaptic inhibitory (H3 receptors) receptors that promote histamine uptake are known as H3 receptors. 
• The drug blocks the uptake histamine at H3 receptors and enhances activity. It also promotes wakefulness.
• It is a competitive antagonist with high affinity (Ki 0.16 nM), and an inverse agonist at the human H3 receptor (EC50 1.5 nM). 
• It is also thought to modulate the release of norepinephrine, acetylcholine, and dopamine, however, it has little effect on dopamine in the striatal pathway [Ref].

Absorption:

• It is absorbed rapidly when administered orally. 90% of the drug is absorbed after oral administration.

Bioavailability:

• Not determined.

Distribution:

• It can cross the blood-brain barrier.

Steady-state concentration:

• After repeated dosing, it takes about 5 - 6 days to reach a steady-state concentration.

Protein binding:

• 91 - 96% of the drug is bound to proteins, primarily to albumin and alpha-1 glycoprotein.

Metabolism:

• It is primarily metabolized in the liver by CYP2D6 and to a lesser extent by CYP3A4.

Excretion:

• After it is metabolized in the liver, 63% is excreted via kidneys as inactive non-conjugated metabolites.
• 25% is excreted as expired air and less than 3% is excreted in feces.

Half-life elimination:

• It has a half-life elimination of about 10 - 12 hours.

International Brand Names of Pitolisant:

• Wakix

Pitolisant Brand Names in Pakistan:

No Brands Available in Pakistan.