Wakix Drug Information
Generic name: PITOLISANT HYDROCHLORIDE
Uses of Wakix
WAKIX is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in patients 6 years of age and older with narcolepsy.
Dosage & Administration of Wakix
Recommendations Prior to WAKIX Initiation
Consider genotyping patients for CYP2D6 metabolizer status to determine the maximum recommended dosage.
Recommended Dosage in Adult Patients
The recommended dosage range for WAKIX for the treatment of EDS or cataplexy in adult patients is 17.8 mg to 35.6 mg administered orally once daily in the morning upon wakening. Titrate dosage as follows: Week 1: Initiate with a dosage of 8.9 mg (two 4.45 mg tablets) once daily Week 2: Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily Week 3: May increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily Dose may be adjusted based on tolerability.If a dose is missed, patients should take the next dose the following day in the morning upon wakening.It may take up to 8 weeks for some patients to achieve a clinical response.
Recommended Dosage in Pediatric Patients 6 Years and Older
The recommended starting dosage of WAKIX for the treatment of EDS or cataplexy in pediatric patients 6 years and older is 4.45 mg administered orally once daily in the morning upon wakening.
Dosage Recommendations in Patients with Hepatic Impairment Adult Patients with Moderate (Child-Pugh Class B) Hepatic Impairment Initiate WAKIX at 8.9 mg once daily and increase after 14 days to a maximum recommended dosage of 17.8 mg once daily. May increase after another 14 days to a maximum recommended dosage of 17.8 mg once daily. WAKIX is contraindicated in patients with severe hepatic impairment.
WAKIX has not been studied in patients with severe hepatic impairment.
Dosage Recommendations in Patients with Renal Impairment and End-Stage Renal Disease Adult Patients with eGFR <60 mL/minute/1.73 m 2 Initiate WAKIX at 8.9 mg once daily and increase after 7 days to a maximum recommended dosage of 17.8 mg once daily. WAKIX is not recommended in patients with eGFR less than 15 mL/minute/1.73 m 2.
Dosage Modifications for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers Coadministration with Strong CYP2D6 Inhibitors Adult patients: Initiate WAKIX at 8.9 mg once daily and increase after 7 days to a maximum recommended dosage of 17.8 mg once daily. Adult and pediatric patients on a stable dose of WAKIX: Reduce the WAKIX dose by half upon initiating strong CYP2D6 inhibitors. Coadministration with Strong CYP3A4 Inducers Concomitant use of WAKIX with strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Assess for loss of efficacy after initiation of a strong CYP3A4 inducer. If concomitant dosing of a strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half.
Dosage Recommendations in Patients Who Are CYP2D6 Poor Metabolizers Adult Patients Initiate WAKIX at 8.9 mg once daily and increase after 7 days to a maximum recommended dosage of 17.8 mg once daily.
| Adults ( 2.2 ) | |
| Week 1 | Initiate with a dosage of 8.9 mg once daily |
| Week 2 | Increase dosage to 17.8 mg once daily |
| Week 3 | May increase to the maximum recommended dosage of 35.6 mg once daily |
| Pediatric Patients (6 years and older) ( 2.3 ) | |
| Week 1 | Initiate with a dosage of 4.45 mg once daily |
| Week 2 | Increase dosage to 8.9 mg once daily |
| Week 3 | Increase dosage to 17.8 mg once daily, the maximum recommended dosage for patients weighing <40 kg |
| Week 4 | For patients weighing ≥40 kg, may increase to the maximum recommended dosage of 35.6 mg once daily |
Side Effects of Wakix
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients with Narcolepsy In clinical trials for narcolepsy, 172 adult patients were treated with WAKIX in placebo-controlled trials for up to 8 weeks and in open-label extension trials for up to 5 years. Most Common Adverse Reactions In the placebo-controlled clinical trials conducted in patients with narcolepsy with or without cataplexy, the most common adverse reactions (occurring in ≥5% of patients and at least twice the rate of placebo) with the use of WAKIX were insomnia (6%), nausea (6%), and anxiety (5%).
Table 1 presents the adverse reactions that occurred at a rate of ≥2% in patients treated with WAKIX and more frequently than in patients treated with placebo in the placebo-controlled clinical trials in narcolepsy. Most Common Adverse Reactions In the placebo-controlled phase of the study, the most common adverse reactions (occurring in ≥5% of patients and greater than the rate of placebo) with the use of WAKIX were headache (19%) and insomnia (7%). The overall adverse reaction profile of WAKIX in the pediatric clinical trial was similar to that seen in the adult clinical trial program.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of WAKIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: General disorders and administration site conditions: fatigue Immune system disorders: hypersensitivity (anaphylaxis) Investigations: weight increased Nervous system disorders: dizziness, 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
| The following terms were combined: Abdominal pain includes: abdominal discomfort; abdominal pain; abdominal pain upper Anxiety includes: anxiety; nervousness; stress; stress at work Hallucinations includes: hallucination; hallucination visual; hypnagogic hallucination Headache includes: cluster headache; headache; migraine; premenstrual headache; tension headache Heart rate increased includes: heart rate increased; sinus tachycardia; tachycardia Insomnia includes: initial insomnia; insomnia; middle insomnia; poor quality sleep Musculoskeletal pain includes: arthralgia; back pain; carpal tunnel syndrome; limb discomfort; musculoskeletal pain; myalgia; neck pain; osteoarthritis; pain in extremity; sciatica Rash includes: eczema; erythema migrans; rash; urticaria Sleep disturbance includes: dyssomnia; sleep disorder; sleep paralysis; sleep talking Upper respiratory tract infection includes: pharyngitis; rhinitis; sinusitis; upper respiratory tract infection; upper respiratory tract inflammation; viral upper respiratory tract infection | ||
| Adverse Reaction | WAKIX (n=152) % | Placebo (n=114) % |
| Headache | 18 | 15 |
| Insomnia | 6 | 2 |
| Nausea | 6 | 3 |
| Upper respiratory tract infection | 5 | 3 |
| Musculoskeletal pain | 5 | 3 |
| Anxiety | 5 | 1 |
| Heart rate increased | 3 | 0 |
| Hallucinations | 3 | 0 |
| Irritability | 3 | 2 |
| Abdominal pain | 3 | 1 |
| Sleep disturbance | 3 | 2 |
| Decreased appetite | 3 | 0 |
| Cataplexy | 2 | 1 |
| Dry mouth | 2 | 1 |
| Rash | 2 | 1 |
Warnings & Cautions for Wakix
QT Interval Prolongation
WAKIX prolongs the QT interval. The use of WAKIX should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong the QT interval. WAKIX should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances 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.
The risk of QT prolongation may be greater in patients with higher concentrations of pitolisant (e.g., patients with hepatic or renal impairment). Monitor patients with hepatic or renal impairment for increased QTc. Dosage modification is recommended in patients with moderate hepatic impairment and moderate or severe renal impairment.
WAKIX is contraindicated in patients with severe hepatic impairment. WAKIX is not recommended in patients with end-stage renal disease (ESRD).
Drug Interactions with Wakix
- Drugs Having Clinically Important Interactions with WAKIX Table 2: Clinically Significant Drug Interactions with WAKIX Assess for loss of efficacy after initiation of a strong CYP3A4 inducer. If concomitant dosing of a strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half. Avoid the use of WAKIX in combination with other drugs known to prolong the QT interval. Effect of WAKIX on Other Drugs Sensitive CYP3A4 Substrates Clinical Implication: WAKIX is a borderline/weak inducer of CYP3A4. Therefore, reduced effectiveness of sensitive CYP3A4 substrates may occur when used concomitantly with WAKIX.
- Prevention or Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuation of treatment.
| Effect of Other Drugs on WAKIX | |
| Strong CYP2D6 Inhibitors | |
| Clinical Implication: | Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold. |
| Prevention or Management: | Reduce the dose of WAKIX by half [see see Dosage and Administration ( 2.6 ), Clinical Pharmacology ( 12.3 )]. |
| Strong CYP3A4 Inducers | |
| Clinical Implication: | Concomitant use of WAKIX with strong CYP3A4 inducers decreases exposure of pitolisant by 50%. |
| Prevention or Management: | Assess for loss of efficacy after initiation of a strong CYP3A4 inducer. For patients stable on WAKIX 8.9 mg or 17.8 mg once daily, increase the dose of WAKIX to reach double the original daily dose (i.e., 17.8 mg or 35.6 mg, respectively) over 7 days. If concomitant dosing of a strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half [see see Dosage and Administration ( 2.6 ), Clinical Pharmacology ( 12.3 )]. |
| Histamine-1 (H1) Receptor Antagonists | |
| Clinical Implication: | WAKIX increases the levels of histamine in the brain; therefore, H1 receptor antagonists that cross the blood-brain barrier may reduce the effectiveness of WAKIX. |
| Prevention or Management: | Avoid centrally acting H1 receptor antagonists. |
| QT Interval Prolongation | |
| Clinical Implication: | Concomitant use of drugs that prolong the QT interval may add to the QT effects of WAKIX and increase the risk of cardiac arrhythmia. |
| Prevention or Management: | Avoid the use of WAKIX in combination with other drugs known to prolong the QT interval [see Warnings and Precautions ( 5.1 )]. |
| Effect of WAKIX on Other Drugs | |
| Sensitive CYP3A4 Substrates | |
| Clinical Implication: | WAKIX is a borderline/weak inducer of CYP3A4. Therefore, reduced effectiveness of sensitive CYP3A4 substrates may occur when used concomitantly with WAKIX [see Clinical Pharmacology ( 12.3 )]. The effectiveness of hormonal contraceptives (e.g., ethinyl estradiol) may be reduced when used with WAKIX and effectiveness may be reduced for 21 days after discontinuation of therapy. |
| Prevention or Management: | Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuation of treatment [see Use in Specific Populations ( 8.3 )]. |
Pregnancy Safety for Wakix
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to WAKIX during pregnancy. Patients should be encouraged to enroll in the WAKIX pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call 1-800-833-7460.
Risk Summary Available case reports from clinical trials and postmarketing reports with WAKIX 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 and >4 times the maximum recommended human dose (MRHD) of 35.6 mg based on mg/m 2 body surface area, respectively. 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/m 2 body surface area and increased the incidence of major malformations at 22 times the MRHD (see Data ).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.
Data Animal Data Pitolisant was administered orally to pregnant rats during the period of organogenesis at doses of mg/kg/day, which are approximately times the MRHD, based on mg/m2 body surface area, respectively. Maternal toxicity occurred at >22 times the MRHD and included convulsions and decreases in body weight and food consumption. At these maternally toxic doses, no adverse effects on embryofetal development were noted and the no observed-adverse-effect-level for embryofetal toxicity is 27 times the MRHD based on mg/m 2 body surface area.
Maternal toxicity occurred at ≥4 times the MRHD and included significant body weight loss and decreased food consumption. Mortality (1 animal) and convulsions (2 animals) occurred at 8 times the MRHD. At the maternally toxic dose (8 times the MRHD), the incidence of pre-implantation loss and abortions increased with a consequent decrease in both the number of implantations and live fetuses.
Pitolisant was not teratogenic at doses up to 8 times the MRHD; however, delayed skeletal development (incomplete ossification and supernumerary ribs) was observed. The no-observed-adverse-effect-level for maternal toxicity and embryofetal development is 2 and 4 times the MRHD based on mg/m 2 body surface area, respectively. Maternal toxicity included death, CNS signs including convulsions, and significant decrease in body weight and food consumption at 22 times the MRHD based on mg/m 2 body surface area.
At the maternally toxic dose (22 times the MRHD), fetal toxicity included stillbirths, postnatal pup mortality (due to lack of milk and/or failure to nurse), and decreased pup length and weight. A single female at the mid dose (13 times the MRHD) also failed to produce milk resulting in pup mortality. At the maternally toxic dose (22 times the MRHD), pitolisant was teratogenic causing major malformations (cleft palate, abnormal limb flexure).
F 1 toxicity included delay in postnatal development (decrease in body weight and length, delay in incisor eruption, and delay in testes descent), which occurred at ≥13 times the MRHD; however, there was no effect on sexual maturation or reproductive capacity of the F 1 generation. The no-observed-adverse-effect-level for developmental toxicity is approximately 7 times the MRHD, based on mg/m 2 body surface area.
Pediatric Use of Wakix
Pediatric Use The safety and effectiveness of WAKIX have been established for the treatment of excessive daytime sleepiness or cataplexy in pediatric patients 6 years of age and older with narcolepsy. Use of WAKIX in this age group is supported by one adequate and well-controlled study in 110 pediatric patients with narcolepsy ages 6 to less than 18 years of age. Mortality occurred at the highest dose of 48 mg/kg/day; however, death was primarily related to aspiration/inhalation of food material.
No adverse effects on growth and development up to the high dose were observed; however, plasma exposures at this dose were lower than those predicted to occur in pediatric patients at the maximum recommended human dose (MRHD) of 35.6 mg due to low oral bioavailability in juvenile rats. Mortality and convulsions were observed at the top two doses of 30 and 60 mg/kg/day. Similar findings of convulsions and mortality were also observed in studies in adult rats at comparable doses.
The no-observed-adverse-effect-level (NOAEL) is 15 mg/kg/day in juvenile animals administered pitolisant by intraperitoneal injection, which corresponds to plasma exposures that are approximately 4 times and 1 times the predicted pediatric exposures at the MRHD of 35.6 mg, based on C max and AUC, respectively.
Contraindications for Wakix
WAKIX is contraindicated in patients with: known hypersensitivity to pitolisant or any component of the formulation. Anaphylaxis has been reported in patients treated with WAKIX. severe hepatic impairment. WAKIX is extensively metabolized by the liver and there is a significant increase in WAKIX exposure in patients with moderate hepatic impairment.
Known hypersensitivity to pitolisant or any component of the formulation Severe hepatic impairment
Clinical Studies of Wakix
Excessive Daytime Sleepiness (EDS) in Patients with Narcolepsy Adult Patients with Narcolepsy The efficacy of WAKIX for the treatment of excessive daytime sleepiness in adult patients with narcolepsy was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (Study 1; NCT01067222 and Study 2; NCT01638403). Patients ≥18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy (with or without cataplexy) and who had an Epworth Sleepiness Scale (ESS) score ≥14 were eligible to enroll in the studies. EDS was assessed using the ESS, an 8-item questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities.
Study 1 and Study 2 included an 8-week treatment period: a 3-week dose titration phase followed by a 5-week stable dose phase. These studies compared WAKIX to both a placebo and an active control. In Study 1, 95 patients were randomized to receive WAKIX, placebo, or active control.
The dose of WAKIX was initiated at 8.9 mg once daily and could be increased at weekly intervals to 17.8 mg or 35.6 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 5-week stable dose phase. 61% of patients reached a stable dose of 35.6 mg. Median age in the study was 37 years.
More than 90% of patients in the WAKIX and placebo groups were Caucasian and 54% were male. Approximately 80% of the population had a history of cataplexy. WAKIX demonstrated statistically significantly greater improvement on the primary endpoint, the least squares mean final ESS score compared to placebo ( Table 3 ).
In Study 2, 166 patients were randomized to receive WAKIX, placebo, or active control. No dose adjustments were permitted during the 5-week stable-dose phase. 76% of patients reached a stable dose of 17.8 mg. Median age in the study was 40 years.
In the WAKIX and placebo groups, approximately 50% of patients were male, 90% of patients were Caucasian, and 75% of patients had a history of cataplexy. Examination of demographic subgroups by sex did not suggest differences in response. The efficacy results from Study 1 and Study 2 are shown in Table 3.
Figure 5: Epworth Sleepiness Scale Score (mean ± SEM) from Baseline to Week 8 in Study 1 SEM = standard error of the mean (raw mean scores) ESS scores range from 0 to 24, with 0 being the best score and 24 being the worst score Pediatric Patients (6 years of age and older) with Narcolepsy The efficacy of WAKIX for the treatment of excessive daytime sleepiness in pediatric patients 6 years of age and older with narcolepsy was evaluated in one multicenter, randomized, double-blind, placebo-controlled study (Study 4; NCT02611687). Pediatric patients 6 to 17 years who met the International Classification of Sleep Disorders (ICSD-3) criteria for narcolepsy (with or without cataplexy) and who had a Pediatric Daytime Sleepiness Scale (PDSS) score ≥15 were eligible to enroll in the study. EDS was assessed with the PDSS, an 8-item questionnaire in which patients report their frequency of EDS-related symptoms.
The study included an 8-week treatment period: a 4-week dose titration phase followed by a 4-week stable dose phase. Median age in the study was 13 years, 56% of the patients were male, and 86% of the population had a history of cataplexy. Race and ethnicity were not collected in this study.
WAKIX demonstrated statistically significantly greater improvement on the least squares mean change of -3.41 points (95% CI: -5.52, -1.31) from baseline to the end of treatment in final PDSS total score compared to placebo. Study 4 included global assessments, which showed positive trends supporting PDSS total score of improvement. Figure 5
Cataplexy in Patients with Narcolepsy Adult Patients with Narcolepsy The efficacy of WAKIX for the treatment of cataplexy in adult patients with narcolepsy was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (Study 3; NCT01800045 and Study 1; NCT01067222). Patients ≥18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy with cataplexy with at least 3 cataplexy attacks per week and an ESS score of ≥12 were eligible to enroll in Study 3; patients meeting the ICSD-2 criteria for narcolepsy (with or without cataplexy) and an ESS score of ≥14 were eligible to enroll in Study 1. Study 3 included a 7-week treatment period: a 3-week dose titration phase followed by a 4-week stable dose phase. 105 patients were randomized to receive WAKIX or placebo.
Race was not collected in this study. WAKIX demonstrated statistically significantly greater improvement on the primary endpoint, the change in geometric mean number of cataplexy attacks per week from baseline to the average of the 4 week stable dosing period for WAKIX compared to placebo ( Table 4 ). Study 1 was described in Section 14.1.
In the subset of patients with a history of cataplexy (n=49), WAKIX demonstrated statistically significantly greater improvement on the secondary endpoint, the change from baseline in geometric mean daily rate of cataplexy at Week 8 for WAKIX compared to placebo ( Table 4 ). Table 4: Efficacy Results for Cataplexy in Adult Patients with Narcolepsy Baseline Rate Mean a (SD) Final Rate Mean a (SD) Rate Ratio b (WAKIX to placebo) 0.3 0.2 Pediatric Patients (6 years of age and older) with Narcolepsy The efficacy of WAKIX for the treatment of cataplexy in pediatric patients 6 years of age and older with narcolepsy was evaluated in one multicenter, randomized, double-blind, placebo-controlled study (Study 4; NCT02611687). In the subset of patients with a history of cataplexy (n=95), WAKIX demonstrated statistically significantly greater improvement on the least squares mean from baseline to the end of treatment for the average number of cataplexy attacks per week (weekly rate of cataplexy ) compared with placebo (2.2 in the WAKIX group and 5.6 in the placebo group).
The rate ratio, defined as the WRC ratio of the WAKIX group to the placebo group adjusted for baseline value, was
| CI = confidence interval; LS Mean = least squares mean; SD = standard deviation; SE = standard error a Maximum dose randomized to was 35.6 mg b Maximum dose randomized to was 17.8 mg c A lower score on the ESS represents improvement; scores range from 0 (no symptoms) to 24 (worst symptoms) d A negative value for the placebo subtracted difference represents improvement | ||||
| Study | Treatment Group (N) | Baseline ESS Score Mean (SD) | Final ESS Score c LS Mean at Week 8 (SE) | Placebo Subtracted Difference [95% CI] at Week 8 d |
| Study 1 a | WAKIX (n=31) | 17.8 (2.5) | 12.4 (1.01) | -3.1 [-5.73; -0.46] |
| Placebo (n=30) | 18.9 (2.5) | 15.5 (1.03) | ||
| Study 2 b | WAKIX (n=66) | 18.3 (2.4) | 13.3 (1.19) | -2.2 [-4.17; -0.22] |
| Placebo (n=32) | 18.2 (2.3) | 15.5 (1.32) | ||
| CI = confidence interval; SD = standard deviation a The mean refers to geometric mean, which was used because values for weekly rate of cataplexy were not normally distributed; the geometric mean takes the average of the logs of the individual values and exponentiates that average back to an arithmetic scale. b The rate ratio is derived from a Poisson regression model. c Patients with a history of cataplexy. | |||||
| Study | Endpoint | Treatment Group (N) | Baseline Rate Mean a (SD) [95% CI] | Final Rate Mean a (SD) [95% CI] | Rate Ratio b (WAKIX to placebo) [95% CI] |
|---|---|---|---|---|---|
| Study 3 | Final Mean Weekly Rate of Cataplexy Over 4-Week Stable Dosing Period (primary endpoint) | WAKIX (n=54) | 9.1 (2.0) [7.6, 11.0] | 2.3 (4.4) [1.5, 3.4] | 0.51 [0.44, 0.60] |
| Placebo (n=51) | 7.3 (2.0) [6.0, 8.9] | 4.5 (4.8) [2.9, 7.0] | |||
| Study 1 | Final Mean Daily Rate of Cataplexy at Week 8 (secondary endpoint) | WAKIX (n=25) c | 0.4 (4.0) [0.2, 0.7] | 0.1 (2.8) [0.1, 0.2] | 0.07 [0.01, 0.36] |
| Placebo (n=24) c | 0.3 (3.6) [0.1, 0.4] | 0.2 (4.3) [0.1, 0.5] | |||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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