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Pitolisant
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Initially, 8.9 mg PO once daily in the morning upon waking for 1 week. Then, increase dosage to 17.8 mg PO once daily for 1 week. After that, the dose may be adjusted based on efficacy response and tolerability. Max: 35.6 mg/day PO; limit to 17.8 mg/day PO in CYP2D6 poor metabolizers. Up to 8 weeks may be necessary for clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[64562]
Initially, 4.45 mg PO once daily in the morning upon waking for 1 week. Then, increase dosage to 8.9 mg PO once daily for 1 week. After that, increase dosage to 17.8 mg PO once daily for 1 week. Dosage may be increased at week 4 to 35.6 mg PO once daily. Max: 35.6 mg/day PO; limit to 17.8 mg/day PO in CYP2D6 poor metabolizers. Up to 8 weeks may be necessary for clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[64562]
Initially, 4.45 mg PO once daily in the morning upon waking for 1 week. Then, increase dosage to 8.9 mg PO once daily for 1 week. After that, increase dosage to 17.8 mg PO once daily. Max: 17.8 mg/day PO; limit to 8.9 mg/day PO in CYP2D6 poor metabolizers. Up to 8 weeks may be necessary for clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[64562]
35.6 mg/day PO.
35.6 mg/day PO.
weighing 40 kg or more: 35.6 mg/day PO
weighing less than 40 kg: 17.8 mg/day PO
6 to 12 years weighing 40 kg or more: 35.6 mg/day PO
6 to 12 years weighing less than 40 kg: 17.8 mg/day PO
1 to 5 years: Safety and efficacy have not been established.
Safety and efficacy have not been established.
Adults
Mild hepatic impairment (Child-Pugh A): No dosage adjustment needed.
Moderate hepatic impairment (Child-Pugh B): 8.9 mg PO once daily initially, then increase after 14 days to a maximum of 17.8 mg PO once daily.
Severe hepatic impairment (Child-Pugh C): Use is contraindicated.[64562]
Pediatrics (6 to 17 years)
Mild hepatic impairment (Child-Pugh A): No dosage adjustment needed.
Moderate hepatic impairment (Child-Pugh B):
Weighing 40 kg or more: 4.45 mg PO once daily initially, then increase after 14 days to 8.9 mg PO once daily. May increase after another 14 days to a maximum of 17.8 mg PO once daily.
Weighing less than 40 kg: 4.45 mg PO once daily initially, then increase after 14 days to a maximum of 8.9 mg PO once daily.
Severe hepatic impairment (Child-Pugh C): Use is contraindicated.[64562]
Adults
eGFR 60 mL/minute/1.73 m2 or more (Mild renal impairment): No dose adjustment needed.
eGFR 15 to 59 mL/minute/1.73 m2 (Moderate to Severe renal impairment): 8.9 mg PO once daily initially, then increase dose after 7 days to a maximum of 17.8 mg PO once daily.
eGFR less than 15 mL/minute/1.73 m2: Use is not recommended in end-stage renal disease (ESRD); no studies are available in these patients.[64562]
Pediatrics (6 to 17 years)
eGFR 60 mL/minute/1.73 m2 or more (Mild renal impairment): No dose adjustment needed.
eGFR 15 to 59 mL/minute/1.73 m2 (Moderate to Severe renal impairment):
Weighing 40 kg or more: 4.45 mg PO once daily initially, then increase dose after 7 days to 8.9 mg PO once daily. May increase after another 7 days to a maximum of 17.8 mg PO once daily.
Weighing less than 40 kg: 4.45 mg PO once daily initially, then increase dose after 7 days to a maximum of 8.9 mg PO once daily.
eGFR less than 15 mL/minute/1.73 m2: Use is not recommended in end-stage renal disease (ESRD); no studies are available in these patients.[64562]
† Off-label indication
Pitolisant is an oral histamine-3 (H3) receptor antagonist/inverse agonist, the first in its class. Pitolisant is indicated for the treatment of excessive daytime sleepiness (EDS) in adults and pediatric patients 6 years and older with narcolepsy. It is also approved for treatment of cataplexy in adult patients with narcolepsy. The efficacy of pitolisant for the treatment of EDS was established in 2 placebo-controlled, active control trials of 8 weeks duration. In both trials, pitolisant-treated patients had significantly improved EDS during activities of daily living as measured using the least-squares mean final Epworth Sleepiness Scale (ESS) vs. ESS scores for patients receiving placebo. The use of pitolisant in pediatric patients was established in a placebo-controlled, 8-week trial of 110 patients with narcolepsy and a Pediatric Daytime Sleepiness Scale (PDSS) score of 15 or more. Patients receiving pitolisant had a statistically significant improvement in the least squares mean change from baseline to end of treatment in final PDSS total score compared to placebo (-3.41 points; 95% CI: -5.52, -1.31). During studies for cataplexy, treated patients had a significant change in the geometric mean number of cataplexy attacks per week from baseline vs. placebo. The drug may cause QT prolongation and it is contraindicated in patients with severe hepatic impairment. Pitolisant was FDA approved in August 2019.[64562]
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In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, nausea was a common adverse reaction that occurred in 6% of pitolisant-treated patients compared to 3% of placebo-treated patients. Other gastrointestinal adverse reactions that occurred more frequently with pitolisant treatment than placebo treatment include abdominal pain including abdominal discomfort (3%), decreased appetite (3%), and xerostomia (2%). Weight gain has been observed during postmarketing experience.[64562]
In placebo-controlled trials of pitolisant in adult patients with narcolepsy with and without cataplexy, insomnia (inclusive of initial and middle insomnia, insomnia, and poor quality sleep) was a common adverse reaction that occurred in 6% of pitolisant-treated patients compared to 2% of placebo-treated patients. Insomnia was also reported in 7% of pediatric patients in clinical trials. Anxiety (inclusive of nervousness, stress, stress at work, and anxiety) occurred in 5% of pitolisant-treated adult patients compared to 1% of placebo-treated patients. Hallucinations (inclusive of visual hallucination, hypnagogic hallucination, and hallucinations) occurred in 3% of pitolisant-treated adult patients compared to no placebo-treated patients. Sleep disturbances (inclusive of dyssomnia, sleep disorder, sleep paralysis, and sleep talking) occurred in 3% of pitolisant-treated adult patients compared to 2% of placebo-treated patients. Other adverse reactions that occurred more frequently with pitolisant treatment than placebo treatment include irritability (3%) and cataplexy (2%). Abnormal behavior, abnormal dreams, anhedonia, bipolar disorder, depression, depressed mood, nightmares, unspecified sleep disorder, suicide attempt, and suicidal ideation have been observed during postmarketing experience.[64562]
In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, headache was a common adverse reaction that occurred in 18% of pitolisant-treated adult patients compared to 15% of placebo-treated patients. Headache was also one of the most common adverse reactions reported in a pediatric clinical trial, affecting 19% of patients. Cluster headache, migraine, headache, premenstrual headache, and tension headaches were observed. Epilepsy, dizziness, and seizures have been observed during postmarketing experience.[64562]
In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, musculoskeletal pain (inclusive of arthralgia, back pain, carpal tunnel syndrome, limb discomfort, myalgia, neck pain, osteoarthritis, musculoskeletal pain, extremity pain, and sciatica) occurred in 5% of pitolisant-treated patients and at incidences higher than with placebo.[64562]
In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, upper respiratory tract infections, (inclusive of pharyngitis, rhinitis, sinusitis, upper respiratory tract inflammation, upper respiratory tract infection, and viral upper respiratory tract infection) occurred in 5% of pitolisant-treated patients and at rates higher than with placebo.[64562]
In placebo-controlled trials of pitolisant in patients with narcolepsy with and without cataplexy, rash (inclusive of eczema or atopic dermatitis, rash, erythema migrans, and urticaria) occurred in 2% of pitolisant-treated patients and at incidence rates higher than with placebo. Hypersensitivity (anaphylaxis, anaphylactoid reactions) and pruritus have been observed during postmarketing experience.[64562]
Fatigue has been observed during postmarketing experience with pitolisant.[64562]
Pitolisant is contraindicated in patients with known hypersensitivity to pitolisant or any component of the formulation. Anaphylaxis has been reported with use of the drug.[64562]
Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C). Pitolisant has not been studied in this population. Pitolisant is extensively metabolized by the liver, and a significant increase in drug exposure occurs in patients with moderate hepatic disease (Child-Pugh B). Specific dosage adjustments are available for patients with moderate hepatic impairment. Monitor hepatic function in patients and adjust the dosage as necessary. No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh A). Dosage reduction is recommended in patients known to be CYP2D6 poor metabolizers (CYP2D6 PMs) because these patients have higher pitolisant concentrations than normal CYP2D6 metabolizers.[64562]
Pitolisant use is not recommended in patients with end-stage renal disease (i.e., renal failure; eGFR less than 15 mL/minute/1.73 m2), as pitolisant has not been studied in this population. Specific dosage adjustments are available for patients with moderate (eGFR 30 to 59 mL/minute/1.73 m2) or severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2). No dosage adjustment is needed for patients with mild renal impairment.[64562]
Pitolisant prolongs the QT interval. Avoid the use of pitolisant in patients with known QT prolongation, receiving medications known to prolong the QT interval, with a history of cardiac arrhythmias, or who have other conditions that may increase the risk of the occurrence of torsade de pointes or sudden death (including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval such as congenital long QT syndrome). Use pitolisant with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. The risk of QT prolongation may be greater in patients with renal or hepatic impairment due to a decrease in drug elimination with a subsequent increase in drug exposure. A QTc increase of 4.2 milliseconds occurred at the highest recommended dosage of pitolisant (35.6 mg daily). Exposures 3.8-fold higher than that achieved at the highest recommended dose increased mean QTc 16 milliseconds.[28432] [28457] [56592] [65180] [64562]
There are no adequate data on the developmental risk associated with pitolisant use during human pregnancy. Available case reports from clinical trials and postmarketing reports with pitolisant use in pregnant women have not determined a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproductive studies, administration of pitolisant during organogenesis caused maternal and embryofetal toxicity in rats and rabbits at doses 13 or greater and 4 times or greater the maximum recommended human dose (MRHD) of 35.6 mg based on mg/square meter body surface area, respectively. The no observed adverse effect dose for maternal toxicity and embryofetal development were 2 and 4 times the MRHD based on body surface area, respectively. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pitolisant during pregnancy. To enroll or obtain information, patients can call 1-800-833-7460. The effects of pitolisant during labor and obstetric delivery are unknown.[64562]
Contraception requirements are suggested for pitolisant. Pitolisant may reduce the effectiveness of hormonal contraceptives. Female patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuing treatment.[64562]
Use pitolisant with caution during lactation; consider the developmental and health benefits of breast-feeding along with the mother's clinical need for pitolisant and any potential adverse effects on the breastfed infant from pitolisant or the underlying maternal condition. Pitolisant was found to pass into breast milk at low levels in an open-label study of 8 healthy lactating women who were 11 to 96 weeks postpartum. The concentration of pitolisant was evaluated in breast milk samples collected over 24 hours and serum samples were collected over 120 hours after a single dose of 35.6 mg of pitolisant was administered. Approximately 50% of the amount of pitolisant measured in breast milk occurred during the first 4 hours post dose. Based on the study, the mean infant dose was 0.009 mg/day, less than 1% of the maternal weight-adjusted dose. There are no data on the effects of pitolisant on the breastfed infant or the effect of pitolisant on milk production.[64562]
Pitolisant is a selective antagonist/inverse agonist of the histamine-3 (H3) receptor. HIstamine H3 receptors are mainly located in the brain. Activation of histaminergic neurons increases histamine release that promotes wakefulness, attention, and memory. Pitolisant regulates the release of other neurotransmitters involved in wake promotion, including dopamine, noradrenaline, and acetylcholine.[64562][64569]
Revision Date: 08/06/2024, 03:12:00 AMPitolisant is administered orally. The approximate apparent volume of distribution of pitolisant is 700 L (5 to 10 L/kg). Serum protein binding is 91% to 96%. The blood to plasma ratio of pitolisant is 0.55 to 0.89. Metabolism primarily occurs by CYP2D6 and to a lesser extent by CYP3A4. Metabolites are not pharmacologically active and they are further metabolized or conjugated with glycine or glucuronic acid. Approximately 90% of a single 17.8 mg dose is excreted in urine (less than 2% unchanged) and 2.3% is excreted in the feces. The median half-life of pitolisant is approximately 20 hours (7.5 to 24.2 hours) following administration of a single 35.6 mg dose.[64562]
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP3A4
Pitolisant is predominately metabolized by CYP2D6 and to a lesser extent by CYP3A4. Concomitant administration of pitolisant with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold, and dose reductions of pitolisant are needed. Strong CYP3A4 inducers decrease exposure of pitolisant by 50%; dose adjustments may be necessary in some patients, as long as the usual maximum dosage is not exceeded. Pitolisant is a borderline/weak inducer of CYP3A4. Therefore, reduced effectiveness of sensitive CYP3A4 substrates, such as hormonal contraceptives, may occur when used concomitantly with the drug.[64562]
Oral absorption of pitolisant is approximately 90%. The Cmax and AUC of pitolisant are 73 ng/mL (range: 49.2 to 126 ng/mL) and 821 ng x hour/mL (range: 518 to 1,468 ng x hour/mL), respectively, following administration of 35.6 mg once daily. The Cmax and AUC increase proportionally with the dose. The Tmax of pitolisant is 3.5 hours (range 2 to 5 hours). Steady-state is reached by day 7 of treatment. No significant differences in the pharmacokinetics of pitolisant were observed following administration with a high-fat meal.[64562]
The AUC of pitolisant was increased by an approximate factor of 3 among 6 subjects with moderate hepatic impairment (Child-Pugh B) compared to 12 healthy subjects following receipt of a single 17.8 mg dose. The Cmax increased by an approximate factor of 1.5 of among 6 subjects with moderate hepatic impairment; however, the increase was not statistically significant. Among 6 subjects with mild hepatic impairment (Child-Pugh A) there were no significant changes in Cmax or AUC compared to healthy subjects. The effects of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of pitolisant are unknown.[64562]
The Cmax of pitolisant increased by an approximate factor of 3 among 4 subjects with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2) compared to 12 healthy subjects following receipt of a single 17.8 mg dose. AUC increased by an approximate factor 2 of among patients with severe renal impairment. In 4 subjects with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m2), AUC and Cmax increased by approximate factors of 2 and 1.5, respectively; the increase in Cmax was not statistically significant. In 4 subjects with mild renal impairment (eGFR 60 mL/minute/1.73 m2 or more), AUC and Cmax increased by an approximate factor of 2; the increases in AUC were not statistically significant. The effects of end-stage renal disease (eGFR less than 15 mL/minute/1.73 m2) on the pharmacokinetics of pitolisant are unknown.[64562]
Data from a single dose pharmacokinetic study of pediatric patients (7 to 17 years) with narcolepsy suggest that pediatric patients have an increased exposure to pitolisant compared to adults. The Cmax and AUC of pitolisant were 2.2- and 2-fold higher, respectively, in patients 12 to 17 years when compared with the adult population. In patients 7 to 11 years, the Cmax and AUC were 3.4- and 3.6-fold higher, respectively.[64562]
The pharmacokinetics of pitolisant were not affected by age.[64562]
The pharmacokinetics of pitolisant were not affected by gender.[64562]
The pharmacokinetics of pitolisant were not affected by race.[64562]
The pharmacokinetics of pitolisant were not affected by body weight (48 to 103 kg).[64562]
CYP2D6 Poor Metabolizers
The Cmax and AUC of pitolisant increased approximately 2-fold among 3 CYP2D6 poor metabolizers compared to 5 CYP2D6 extensive (normal) metabolizers following receipt of pitolisant 17.8 mg for 7 days.[64562]
There are no adequate data on the developmental risk associated with pitolisant use during human pregnancy. Available case reports from clinical trials and postmarketing reports with pitolisant use in pregnant women have not determined a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproductive studies, administration of pitolisant during organogenesis caused maternal and embryofetal toxicity in rats and rabbits at doses 13 or greater and 4 times or greater the maximum recommended human dose (MRHD) of 35.6 mg based on mg/square meter body surface area, respectively. The no observed adverse effect dose for maternal toxicity and embryofetal development were 2 and 4 times the MRHD based on body surface area, respectively. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pitolisant during pregnancy. To enroll or obtain information, patients can call 1-800-833-7460. The effects of pitolisant during labor and obstetric delivery are unknown.[64562]
Use pitolisant with caution during lactation; consider the developmental and health benefits of breast-feeding along with the mother's clinical need for pitolisant and any potential adverse effects on the breastfed infant from pitolisant or the underlying maternal condition. Pitolisant was found to pass into breast milk at low levels in an open-label study of 8 healthy lactating women who were 11 to 96 weeks postpartum. The concentration of pitolisant was evaluated in breast milk samples collected over 24 hours and serum samples were collected over 120 hours after a single dose of 35.6 mg of pitolisant was administered. Approximately 50% of the amount of pitolisant measured in breast milk occurred during the first 4 hours post dose. Based on the study, the mean infant dose was 0.009 mg/day, less than 1% of the maternal weight-adjusted dose. There are no data on the effects of pitolisant on the breastfed infant or the effect of pitolisant on milk production.[64562]
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