pitolisant (Rx)

>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%)

Postmarketing Reports

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

Contraindications

Severe hepatic impairment

Hypersensitivity to pitolisant or any component of the formulation

Cautions

QT prolongation

• Use prolongs 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

Drug interaction overview

• 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

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

Pregnancy exposure registry

• Monitors pregnancy outcomes in women exposed to pitolisant during pregnancy
• Encourage patients to enroll in the registry if they become pregnancy
• To enroll or obtain information from the registry, contact 1-800-833-7460

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

The transfer of this drug into breastmilk is low based on data from lactation study; the mean infant dose was 0.009 mg/day, and relative infant dose was <1% of maternal weight-adjusted dose; there are no data on effects of the drug on breastfed infant, or 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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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

Absorption

Peak plasma level (steady-state): 73 ng/mL

AUC (steady-state): 812 ng⋅hr/mL

Peak plasma time: 3.5 hr

Distribution

Vd: ~700 L

Protein bound: ~91-96%

Blood-to-plasma ratio: 0.55-0.89

Metabolism

Primarily metabolized by CYP2D6 and CYP3A4 (lesser extent)

Metabolites are further metabolized or conjugated with glycine or glucuronic acid

None of the metabolites are pharmacologically active

Elimination

Half-life: ~20 hr

Clearance: 43.9L/hr (renal clearance accounts for <2%)

Excretion: Urine (~90%); feces (2.3%)

Oral Administration

Take orally in the morning upon wakening

Missed dose

• If a dose is missed, take next dose the following day in the morning upon wakening

Storage

Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)