Pitolisant

Oral
Narcolepsy

Patients taking strong CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, bupropion): For those currently on strong CYP2D6 inhibitor and starting pitolisant treatment: Initially, 9 mg once daily for 1 week, then may be increased up to Max 18 mg once daily. For individuals on stable pitolisant treatment and starting a strong CYP2D6 inhibitor: Reduce pitolisant dose by 50%.

Patients taking strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin): For those on stable pitolisant treatment and starting a strong CYP3A4 inducer: Increase pitolisant dose to twice the original dose given for 1 week (e.g. from 9 mg once daily to 18 mg once daily, or from 18 mg once daily to 36 mg once daily). Assess for loss of pitolisant efficacy after initiation of strong CYP3A4 inducer. If the strong CYP3A4 inducer is discontinued: Reduce pitolisant dose by 50%.

Pharmacogenomics:

Pitolisant is primarily metabolised by CYP2D6 isoenzyme, and to a lesser extent by CYP3A4 isoenzyme into multiple, inactive, nonconjugated and conjugated metabolites.

Individuals who lack CYP2D6 activity, known as CYP2D6 poor metabolisers, may experience higher pitolisant plasma concentrations as compared to normal CYP2D6 metabolisers. The prevalence of CYP2D6 poor metabolisers is estimated at approx 3-10% in Caucasians and 2-7% in African American population.

A research conducted in the U.S. indicated that CYP2D6 poor metabolisers have approx 2.4-fold higher pitolisant exposure compared to normal CYP2D6 metabolisers (known as extensive metabolisers) after receiving 18 mg pitolisant daily dose for 7 days. However, the EMA requested that further study may be required to determine the pharmacokinetics and metabolism at steady state in CYP2D6 poor metabolisers.

CYP2D6 poor metabolisers
Recommended dosage adjustment: Initially, 9 mg once daily, may be further increased up to Max 18 mg once daily after 1 week according to individual response and tolerability.

Max: 18 mg once daily. ESRD: Not recommended.

Moderate (Child-Pugh class B): Initially, 9 mg once daily, may be increased up to Max 18 mg daily after 2 weeks of initiating treatment. Severe (Child-Pugh class C): Contraindicated.

May be taken with or without food. Take in the morning upon wakening.

Severe hepatic impairment (Child-Pugh class C). Lactation.

Patients with history of psychiatric disorders (e.g. severe anxiety, severe depression with suicidal ideation risk), acid-related gastric disorders, severe obesity, severe anorexia, epilepsy, known QT interval prolongation, history of cardiac arrhythmias, conditions that increase risk of torsades de pointes or sudden death (e.g. symptomatic bradycardia, hypokalaemia, hypomagnesaemia, congenital QT interval prolongation). Patients taking strong CYP2D6 inhibitors or strong CYP3A4 inducers. CYP2D6 poor metabolisers. Renal and mild to moderate hepatic impairment. Pregnancy.

Significant: Mild to moderate QT interval prolongation, convulsions.
Cardiac disorders: Bradycardia, extrasystoles.
Ear and labyrinth disorders: Vertigo, tinnitus.
Eye disorders: Reduced visual acuity, blepharospasm.
Gastrointestinal disorders: Nausea, vomiting, dyspepsia, dry mouth, abdominal pain, diarrhoea, constipation, gastritis, GERD.
General disorders and admin site conditions: Fatigue, asthenia, chest pain.
Investigations: Weight decreased, elevated hepatic enzymes, increased heart rate.
Metabolism and nutrition disorders: Decreased or increased appetite, fluid retention.
Musculoskeletal and connective tissue disorders: Arthralgia, back pain, myalgia.
Nervous system disorders: Headache, dizziness, tremor, somnolence, migraine.
Psychiatric disorders: Insomnia, anxiety, irritability, depression, sleep disorder.
Renal and urinary disorders: Pollakiuria.
Reproductive system and breast disorders: Metrorrhagia.
Respiratory, thoracic and mediastinal disorders: Yawning, upper respiratory tract infections.
Skin and subcutaneous tissue disorders: Rash, pruritus, erythema, hyperhidrosis.
Vascular disorders: Hot flush, hypertension, hypotension.

This drug may not immediately return your level of wakefulness to normal, if you still experience excessive daytime sleepiness, do not drive or operate machinery.

Monitor renal and liver function at baseline and as clinically indicated; QTc interval in patients at risk.

Symptoms: Headache, insomnia, irritability, nausea and abdominal pain. Management: Hospitalisation and vital function monitoring.

Histamine-1 receptor antagonist antihistamines (e.g. pheniramine maleate, chlorphenamine, diphenhydramine, promethazine, mepyramine) and antidepressants (e.g. imipramine, clomipramine, mirtazapine) may impair the efficacy of pitolisant. Increased risk of cardiac arrhythmia with known QT-prolonging agents (e.g. disopyramide, procainamide, amiodarone, sotalol, thioridazine, moxifloxacin). Significantly decreased exposure with strong CYP3A4 inducers (e.g. rifampicin, phenobarbital, phenytoin, carbamazepine). Significantly increased exposure with strong CYP2D6 inhibitors (e.g. paroxetine, venlafaxine, fluoxetine, bupropion, quinidine, terbinafine, cinacalcet). May reduce the effectiveness of hormonal contraceptives (e.g. ethinylestradiol).

Plasma concentration may be reduced by St. John’s wort.

Description:
Mechanism of Action: Pitolisant is a potent histamine H₃-receptor antagonist or inverse agonist. It blocks the histamine auto-receptors, thereby enhancing the activity of brain histaminergic neurons, a major arousal system with widespread projections to the brain. Pitolisant also modulates various neurotransmitter systems such as increasing the release of acetylcholine, norepinephrine, and dopamine in the brain; however, no dopamine increase is evident in the striatal complex including the nucleus accumbens.
Synonym: Tiprolisant
Onset: Treatment of narcolepsy: Up to 8 weeks.
Pharmacokinetics:
Absorption: Rapidly and well absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 3.5 hours.
Distribution: Volume of distribution: 700 L (5-10 L/kg). Plasma protein binding: 91-96%.
Metabolism: Extensively metabolised in the liver primarily by CYP2D6 isoenzyme and to a lesser extent by CYP3A4 isoenzyme into inactive metabolites.
Excretion: Mainly via urine (approx 90%, <2% as unchanged drug); faeces (2.3%). Elimination half-life: Approx 20 hours.

Source: National Center for Biotechnology Information. PubChem Database. Pitolisant, CID=9948102, https://pubchem.ncbi.nlm.nih.gov/compound/Pitolisant (accessed on Jan. 22, 2020)

Store between 20-25°C.

Thuốc TKTW khác & thuốc trị rối loạn tăng động giảm chú ý

N07XX11 - pitolisant ; Belongs to the class of other nervous system drugs.

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Anon. Pitolisant. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 11/10/2019.

Anon. Pitolisant. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 11/10/2019.

Buckingham R (ed). Pitolisant. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 11/10/2019.

Joint Formulary Committee. Pitolisant. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 11/10/2019.

Wakix Tablet, Film Coated (Harmony Biosciences, LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 11/10/2019.

Wakix Tablets (Harmony Biosciences, LLC). U.S. FDA. https://www.fda.gov/. Accessed 11/10/2019.