Pitolisant

Indications

Pitolisant is used for: Narcolepsy

Adult Dose

Narcolepsy Indicated for treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy Week 1: Initiate with 8.9 mg (two 4.45-mg tablets) PO qDay Week 2: Increase to 17.8 mg (one 17.8-mg tablet) PO qDay Week 3: May increase to maximum of 35.6 mg (two 17.8-mg tablets) qDay Adjust dose based on tolerability May take up to 8 weeks to achieve clinical response Hepatic impairment Mild (Child Pugh A): No dosage adjustment necessary; monitor Moderate (Child Pugh B): Initiate at 8.9 mg qDay; increase after 14 days to up to maximum of 17.8 mg qDay Severe (Child Pugh C): Not studied; contraindicated

Child Dose

<18 years: Safety and efficacy not established

Renal Dose

Renal impairment Mild (eGFR ?60 mL/min/1.73m2): No dosage adjustment necessary Moderate-to-severe (eGFR 15-59 mL/min/1.73m2): Initiate at 8.9 mg qDay and increase after 7 days to up to maximum of 17.8 mg qDay End-stage renal disease (eGFR <15 mL/min/1.73m2): Not recommended; pharmacokinetics unknown

Administration

Contra Indications

Severe liver impairment

Precautions

QT prolongation Use prolongs the QT interval Avoid with history of cardiac arrhythmias, as well as other circumstances that may increase risk of torsade de pointes or sudden death, including symptomatic bradycardia, hypokalemia, or hypomagnesemia, and the presence of congenital QT prolongation Patients with hepatic or renal impairment have greater risk of QT prolongation due to higher pitolisant concentrations Monitor patients with hepatic or renal impairment for increased QT interval

Pregnancy-Lactation

Pregnancy Available case reports from clinical trials and postmarketing reports with use in pregnant women have not determined a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes Animal data In animal reproductive studies, administration of pitolisant during organogenesis caused maternal and embryofetal toxicity in rats and rabbits at doses ?13 and >4 times the maximum recommended human dose (MRHD) of 35.6 mg based on mg/m2 body surface area Oral administration of pitolisant to female rats during pregnancy and lactation adversely affected maternal and fetal health and produced developmental delay at doses >13 times the MRHD, based on mg/m2 body surface area and increased the incidence of major malformations at 22 times the MRHD Contraception Pitolisant may reduce effectiveness of hormonal contraception owing to it being a weak CYP3A4 inducer Advise patients using hormonal contraception to use an alternative nonhormonal contraceptive method during treatment and for at least 21 days after discontinuing treatment Lactation No data available on the presence of pitolisant in human milk, the effects on the breastfed infant, or the effect of this drug on milk production Pitolisant is present in milk of lactating rats When a drug is present in animal milk, it is likely that the drug will be present in human milk Consider developmental and health benefits of breastfeeding along with the mother’s clinical need and any potential adverse effects on the breastfed child or from the underlying maternal condition

Interactions

Pitolisant is a CYP2D6 and CYP3A4 substrate; weak CYP3A4 inducer Strong CYP2D6 inhibitors Coadministration with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold Strong CYP3A4 inducers Concomitant use with strong CYP3A4 inducers decreases exposure of pitolisant by 50%. Sensitive CYP3A4 substrates Concomitant use with sensitive CYP3A4 may reduce the efficacy of these sensitive CYP3A4 substrates Effectiveness of hormonal contraceptives (eg, ethinyl estradiol) may be reduced when used with pitolisant and reduction in efficacy may last for 21 days after discontinuation of therapy Drugs that prolong QT interval Avoid coadministration with drugs known to prolong QT interval, owing to increased risk of serious cardiac arrhythmias Histamine-1 (H1) antagonists Avoid centrally acting H1 antagonists Pitolisant increases histamine levels in the brain; therefore, H1 antagonists that cross the blood-brain barrier may reduce pitolisant effectiveness

Adverse Effects

Side effects of Pitolisant : >10% Headache (18%) 1-10% Insomnia (6%) Nausea (6%) Upper respiratory tract infection (5%) Musculoskeletal pain (5%) Anxiety (5%) Heart rate increased (3%) Hallucinations (3%) Irritability (3%) Abdominal pain (3%) Sleep disturbance (3%) Decreased appetite (3%) Cataplexy (2%) Dry mouth (2%) Rash (2%)

Mechanism of Action

Selective histamine 3 (H3) receptor antagonist/inverse agonist Mechanism of action for EDS in patients with narcolepsy is unclear Efficacy could be mediated through its activity as an antagonist/inverse agonist at histamine-3 (H3) receptors