Summary Basis of Decision for Wakix
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Wakix is located below.
Recent Activity for Wakix
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Wakix
Date SBD issued: 2021-09-14
The following information relates to the new drug submission for Wakix.
Piltolisant hydrochloride
Drug Identification Number (DIN):
- DIN 02516268 - 20 mg pitolisant hydrochloride, tablets, oral administration
- DIN 02516241 - 5 mg pitolisant hydrochloride, tablets, oral administration
Endo Ventures Ltd.
New Drug Submission Control Number: 238175
On May 25, 2021, Health Canada issued a Notice of Compliance to Endo Ventures Ltd. for the drug product Wakix.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Wakix is favourable for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy.
1 What was approved?
Wakix, a wakefulness-promoting agent, was authorized for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy. It is the first member in the class of human histamine 3 (H3) receptor antagonists and inverse agonists that claim to enhance wakefulness by activating the histaminergic neurons.
This indication is based on pivotal studies of up to 8 weeks duration, in adults over 18 years of age.
Wakix is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available for this population.
The safety and efficacy of Wakix in patients 65 years of age or older have not been established. Caution should be used when treating geriatric patients, particularly in very elderly (≥75 years old) patients.
Wakix is contraindicated in patients who are hypersensitive to pitolisant hydrochloride or to any ingredient in the formulation, or component of the container. Wakix is also contraindicated in patients with severe hepatic impairment and in breastfeeding patients.
Wakix was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Wakix (5 mg and 20 mg pitolisant hydrochloride) is presented as tablets. In addition to the medicinal ingredient, the tablets contain colloidal anhydrous silica, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, polyvinyl alcohol, purified water, talc, and titanium dioxide.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Wakix Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Wakix approved?
Health Canada considers that the benefit-harm-uncertainty profile of Wakix is favourable for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy.
Narcolepsy is a rare and chronic neurological disease of the sleep-wake cycle. The International Classification of Sleep Disorder Criteria defines two types of narcolepsy:
- Type I – the patient has a low level of the hormone hypocretin or reports having excessive daytime sleepiness and cataplexy (sudden muscle weakness occurring while awake), and
- Type II – the patient has a normal level of hypocretin, excessive daytime sleepiness and the absence of cataplexy.
Narcolepsy often presents in adolescents and young adults, but a diagnosis is often delayed until a significant interruption in normal daily activities is observed, such as job loss, school disruption, acute injury while driving or other activities. Patients with narcolepsy may also experience waking intruding on nocturnal sleep leading to sleep paralysis, hypnogogic and hypnopompic hallucinations, and other disorders of their sleep including instability of the rapid eye movements and non-rapid eye movements associated with sleep. Patients with narcolepsy are at risk of acute injury as well as chronic co-morbidities such as depression, other psychiatric conditions, and cardiovascular disease. Narcolepsy can lead to significant and disabling social and occupational dysfunction.
The current Canadian standard of care for narcolepsy includes treatment with modafinil for excessive daytime sleepiness and treatment with sodium oxybate for cataplexy.
Wakix (pitolisant hydrochloride) is a histamine-3 receptor antagonist and inverse agonist that promotes wakefulness by blocking the normal histamine feedback system. Wakix regulates histamine synthesis and release, increasing its availability at the synapses of the neurons in the histaminergic system. This system has a contributory effect on the stabilization of the sleep wake cycle.
Wakix has been shown to be efficacious in reducing excessive daytime sleepiness in patients with narcolepsy. The market authorization was primarily based on the results of three pivotal studies which supported the efficacy and safety of Wakix: Study 07-03 (Harmony I), Study 09-15 (Harmony Ibis), and Study 11-05 (Harmony CTP). Harmony I and Harmony Ibis were 8-week, double-blind, randomized, controlled studies that compared treatment with Wakix, modafinil or a placebo. The maximum doses were 40 mg for the Harmony I study and 20 mg for the Harmony Ibis study. The primary endpoint for both studies was the reduction of excessive daytime sleepiness as assessed using the Epworth Sleepiness Scale (ESS), a validated scoring tool designed to assess the degree of sleepiness in everyday situations. When comparing treatment with Wakix to placebo, both studies demonstrated statistically and clinically significant differences in changes in the Epworth Sleepiness Scale score from baseline to the completion of treatment in the study. Despite these findings, neither study could demonstrate non-inferiority of Wakix to modafinil.
The third pivotal study, Harmony CTP, was distinct from the first two studies. Harmony CTP was a 7-week double-blind, randomized, controlled study that compared treatment with Wakix versus placebo. The primary endpoint was the ratio of reduction (improvement) in weekly cataplexy frequency rates compared to placebo. The results of this study demonstrated a statistically and clinically significant difference in the reduction of the frequency of weekly cataplexy events for Wakix when compared to placebo. Similar results were obtained for the secondary endpoint of the Harmony I Study which demonstrated a clinically and statistically significant reduction in daily (rather than weekly) cataplexy rates for Wakix compared to placebo.
The most common adverse events reported for Wakix in the pivotal double-blind placebo-controlled studies were headache (17.5%), nausea (6.0%), and insomnia (4.7%). Adverse events that led to discontinuation included adverse events of the gastrointestinal and nervous system, as well as psychiatric disorders.
The safety concerns identified in the pivotal studies with Wakix have all been addressed through appropriate labelling in the Wakix Product Monograph. The use of Wakix is contraindicated in patients with severe hepatic impairment and is not recommended in patients with end-stage renal disease. Patients treated with Wakix need to be monitored for increased exposure that could be due to hepatic or renal dysfunction, use with concomitant medications, or cytochrome P450 (CYP) 2D6 polymorphism. In addition, the results of two electrocardiogram studies indicated that Wakix causes a concentration-dependent prolongation of the QTc interval. This prolongation could potentially be greater if a patient is susceptible to increased Wakix exposure. Other safety concerns associated with Wakix include neurological events such as headache and insomnia. Wakix has been shown to have a potential pro-convulsive effect and should be used with caution in patients with a history of epilepsy. Further, Wakix should be used with caution in patients with a psychiatric history as cases of depression were reported in both long-term clinical studies and post-market surveillance from other jurisdictions. Safety issues regarding reproduction were identified in the non-clinical studies. These included fertility effects, and risk to the developing fetus from exposure to Wakix during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Wakix. This includes the use of reliable non-hormonal methods of birth control as Wakix may reduce the effectiveness of hormonal contraceptives. Based on the results of non-clinical studies, Wakix was present in the milk of lactating rats and milk production was also reduced at higher doses of Wakix. A risk to the breastfeeding child cannot be excluded and therefore breastfeeding is contraindicated.
A Risk Management Plan (RMP) for Wakix was submitted by Endo Ventures Ltd. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Wakix Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Wakix was accepted.
Wakix has been shown to have a favourable benefit-harm-uncertainty profile based on non-clinical and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Wakix Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Wakix?
Submission Milestones: Wakix
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2019-07-30 |
| Submission filed | 2020-04-06 |
| Screening | |
Screening Acceptance Letter issued | 2020-05-22 |
| Review | |
Request granted to pause review clock for 50 days (extension to clarifax response) | 2020-07-21 |
Request granted to pause review clock for 18 days (extension to clarifax response) | 2020-11-23 |
Review of Risk Management Plan complete | 2020-11-29 |
Biostatistics Evaluation complete | 2021-01-14 |
Biopharmaceutics Evaluation complete | 2021-04-06 |
Non-Clinical Evaluation complete | 2021-05-17 |
Quality Evaluation complete | 2021-05-21 |
Clinical/Medical Evaluation complete | 2021-05-25 |
Labelling Review complete | 2021-05-25 |
Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2021-05-25 |
The Canadian regulatory decision on the review of Wakix was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Pitolisant, the medicinal ingredient in Wakix, is a potent, highly selective, orally active antagonist/inverse agonist of the human histamine 3 (H3) receptor. By binding to presynaptic histaminergic H3 autoreceptors, pitolisant increases the synthesis and release of histamine, a wakefulness promoting neurotransmitter, as well as other neurotransmitters that promote wakefulness (e.g., acetylcholine, dopamine, norepinephrine). Histamine is important for stabilizing sleep/wake states via direct activation of wake-promoting brain regions and by directly and indirectly inhibiting rapid eye movement (REM) and non-REM sleep promoting brain regions.
The clinical pharmacology data provided included reports for 48 studies involving aspects of human pharmacodynamics, pharmacokinetics, and safety. These data support the use of Wakix for the recommended indication.
In healthy adults, repeat daily dosing for 14 days with the recommended maximum 40 mg dose of Wakix produced: a mean maximum concentration (Cmax) of 249.5 nM; a time to maximum concentration (Tmax) of approximately 3.5 hours; an area under the concentration time curve during a 24-hour period (AUC0-24) of 2,716.7 hr*nM; an apparent volume of distribution of approximately 538.6 L; an oral clearance of 41.3 L/hr; and a median plasma half-life of 9.5 hours. Steady state was achieved within 7 days of dosing. Renal excretion was determined to be the main route of elimination based on radiolabelling, with approximately 89% of radioactivity recovered in the urine.
Pitolisant is primarily metabolized by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4 in the liver. Primary human metabolites include BP2.951, BP1.8054, BP1.3484, and BP1.9733, which were determined to be inactive. The metabolites BP1.2525 and BP1.2526, previously shown to have convulsive actions in rats, were not detectable or found in low concentrations in humans, respectively.
Multi-dose studies demonstrated a clear dose-related trend, with respect to time-concentration profiles and pharmacokinetic parameters. However, exposures were modestly more than proportional (by approximately 17%) between 40 mg and 50 mg following 14 days of administration. Pitolisant exposure is significantly increased in poor metabolizers, patients with any degree of renal impairment, and patients with moderate hepatic impairment. Limited pharmacokinetic data were available from elderly subjects, however, a trend in the data raised concerns that elderly patients, particularly those who are very elderly (≥80 years old), may experience greater exposures due to compromised clearance.
Drug interaction studies showed increased exposure when pitolisant was administered concomitantly with CYP2D6 inhibitors. Contrastingly, CYP3A4 inducers and uridine 5’-diphospho (UDP)-glucuronosyltransferase (UGT) inhibitors appeared to reduce exposure. Data suggested that pitolisant acted as a weak inducer of CYP3A4 and may therefore reduce the efficacy of hormonal contraceptives.
Food delays Tmax and reduces the rate and extent of absorption of Wakix. Wakix should be taken with food. Grapefruit juice was found to have a mild inhibiting effect on the metabolism of Wakix and may impact exposure.
The 40 mg dose of pitolisant was well-tolerated in repeat-dose studies of up to 5 years duration. In these studies, pitolisant had positive effects on measures of excessive diurnal somnolence in narcoleptic patients that were sustained long-term. Beneficial effects were observed within 7 days of treatment, consistent with steady-state, but optimal response might take up to 8 weeks to achieve. Dose-related positive changes in electroencephalogram (EEG) parameters were also noted. Psychometric evaluations were inconclusive, however, positive effects were seen in quality of life assessments.
Although the results of a human abuse potential study suggest that pitolisant is unlikely to have abuse potential, there remains some uncertainty, particularly with higher doses. A statement has been included in the Product Monograph for Wakix regarding dependence/tolerance.
QT Prolongation
Pitolisant caused a concentration-dependent prolongation of the QTc interval that was characterized in two electrocardiogram (ECG) assessment studies (Studies P09-11 and P14-05).
Study P09-11 was a randomized, double-blind, placebo- and positive-controlled, four-period, four-arm, single-dose crossover study performed in 56 healthy subjects. Single 40 mg (therapeutic dose) and 120 mg (3-times the therapeutic dose) doses of pitolisant resulted in QTcF prolongation. In the 40 mg treatment arm, the 90% confidence interval (CI) for the difference from placebo in mean change from baseline QTcF interval excluded zero only at the 2 hrs time point: 3.69 ms (90% CI: 1.43, 5.94). In the 120 mg treatment arm, the 90% CI for the difference from placebo in mean change from baseline QTcF excluded zero from 1 hr to 12 hrs post-dose, inclusive, and at 24 hrs. The maximum difference from placebo was 9.91 ms (90% CI: 7.63, 12.18) at 2 hrs post-dosing. A major limitation of this study was that the single-dose regimen did not achieve serum concentrations substantially beyond the therapeutic range.
Study P14-05 was a double-blind, placebo- and positive-controlled study designed to characterize the effects of pitolisant at higher concentrations. Single doses of 160 mg, 200 mg, and 240 mg doses of pitolisant were administered to healthy male subjects (n = 6 per treatment arm) according to a parallel group design. The maximum difference from placebo in mean change from baseline QTcF interval was 11.9 ms (90% CI: 6.7, 17.1) at 2 hrs post-dosing for the 160 mg dose, 13.3 ms (90% CI: 8.1, 18.5) at 2 hrs post-dosing for the 200 mg dose, and 9.9 ms (90% CI: 4.7, 15.1) at 1.5 hrs post-dosing for the 240 mg dose. The slope of the concentration-effect relationship was positive and statistically significant. On the basis of the pharmacokinetic-pharmacodynamic model, the placebo-adjusted mean change from baseline QTcF is predicted to be 3.6 ms (90% CI: 2.40, 4.79) at a concentration of 73 ng/mL (the mean steady-state Cmax of pitolisant administered at 40 mg once daily for 14 days in healthy subjects) and 7.17 ms (90% CI: 5.56, 8.79) at 153 ng/mL (expected steady-state Cmax for the 40 mg once-daily dose in CYP2D6 poor metabolizers).
Dosing Considerations
Wakix dosing needs to be carefully initiated and monitored. Wakix dosing is typically titrated over three weeks, although the range may be two to four weeks depending on the target dose. The maximal dose varies for patients who may have increased exposure. The metabolism of pitolisant has been shown to be different in patients who have a CYP2D6 genetic polymorphism (slow metabolizers). Additionally, the exposure of pitolisant can be elevated in patients who take concomitant medication or who have a co-morbidity that increases exposure such as hepatic or renal impairment (hepatic and renal monitoring is required). The increased exposure may potentially increase the risk of adverse events.
Wakix is contraindicated in patients with severe hepatic dysfunction and is not recommended in patients with end-stage renal disease. Pitolisant should be used with caution in patients with seizure risk, a history of psychiatric conditions and in patients with a history of or risk factors for QT prolongation.
For further details, please refer to the Wakix Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Wakix was demonstrated in three pivotal studies. Study 07-03 (Harmony I) and Study 09-15 (Harmony Ibis) provided support for the efficacy of Wakix in reducing daytime sleepiness. Study 11-05 (Harmony CTP) provided support for the efficacy of Wakix in reducing the weekly rate of cataplexy in enrolled patients with narcolepsy type I compared to placebo.
Harmony I and Harmony Ibis
Harmony I and Harmony Ibis were 8-week, multicentre, double-blind, randomized, controlled studies to assess the effect of Wakix in the treatment of excessive daytime sleepiness. Patients ≥18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy and who had an Epworth Sleepiness Scale (ESS) score ≥14 were eligible to enroll in the studies. The ESS is a self-administered questionnaire developed as a tool to differentiate patients with excessive daytime sleepiness (EDS) from alert individuals. Both Harmony I and Harmony Ibis included patients with or without cataplexy (Narcolepsy type 1 or Narcolepsy type 2) and compared Wakix to both a placebo and an active control (modafinil).
In the Harmony I Study, there were 94 patients in one of three treatment arms: Wakix (number of patients [n] = 31), placebo (n = 30) or modafinil (n = 33). The median age of the patients included in the intent-to-treat (ITT) population ranged from 33 to 40 years of age in each of the three treatment groups. Approximately 50% of the ITT population was male and >90% of the study population was Caucasian. Approximately 80% of patients took at least one chronic medication for treatment of narcolepsy during the three-month period prior to the study. Thirty-three patients with severe cataplexy were permitted to remain on their anti-cataplectic medications at stable doses for the duration of the study.
In the Harmony Ibis Study, there were 164 patients in one of three treatment arms: Wakix (n = 67), placebo (n = 32) or modafinil (n = 65). Between 75% and 81% of patients in each group were cataplectic.
The maximal doses were 40 mg for the Harmony I Study and 20 mg for the Harmony Ibis Study.
The primary endpoint was reduction of excessive daytime sleepiness assessed using the Epworth Sleepiness Scale (ESS), a validated scoring tool designed to assess the degree of sleepiness in everyday situations. A key secondary endpoint was the reduction in daily cataplexy attacks.
Both studies demonstrated statistically and clinically significant reductions in excessive daytime sleepiness in adult patients with narcolepsy when treated with Wakix compared to placebo. Harmony I demonstrated a -3.1 point difference in scores (95% confidence interval [CI]: -5.73; -0.46, p = 0.022) between Wakix and placebo for reduction in excessive daytime sleepiness measured by the Epworth Sleepiness Scale. In Harmony Ibis, there was a reduction of -2.19 (95% CI: -4.17; -0.22, p = 0.030) difference between Wakix and placebo.
The pre-specified analysis for both studies indicated that if superiority for Wakix versus placebo was demonstrated, a second comparison could be conducted with the standard of care active-comparator, modafinil. Neither pivotal study was able to demonstrate the non-inferiority of Wakix compared to modafinil.
Harmony CTP
The third pivotal trial, Harmony CTP (Study 11-05), was distinct from Harmony I and Harmony Ibis in that it had a different primary endpoint and had two treatment arms rather than three. This double-blind, randomized, controlled trial enrolled adult narcoleptic patients with a high weekly frequency cataplexy rate at baseline. There were 51 patients in the placebo arm and 54 patients in the Wakix treatment arm.
The primary endpoint was the ratio of reduction (improvement) in weekly cataplexy frequency rates compared to placebo. The rate ratio for the Wakix to placebo arm for the reduction in cataplexy weekly rates was 0.49 (95% CI: 0.36; 0.66, p <0.0001). This endpoint represented a statistically and clinically significant difference in reduction of the frequency of weekly cataplexy events in Wakix-treated patients when compared to placebo.
Although there was no second confirmatory study for the primary endpoint, a secondary endpoint of the Harmony I Study demonstrated a clinically and statistically significant reduction in the Wakix-treatment arm compared to placebo with a demonstrated rate ratio of 0.38 (95% CI: 0.15; 0.03, p = 0.034). This finding supports the primary endpoint of the Harmony CTP Study. The superiority of Wakix over placebo for these primary and secondary endpoints was statistically and clinically significant for doses of Wakix up to 40 mg. This supports a benefit for Wakix treatment for the reduction of cataplexy episodes in patients with narcolepsy and cataplexy.
Indication
The New Drug Submission for Wakix was filed by the sponsor with the following indication:
Wakix (pitolisant hydrochloride tablets) is indicated for:
- The improvement of wakefulness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy
- The treatment of cataplexy in patients with narcolepsy.
Health Canada approved the following indication:
Wakix (pitolisant hydrochloride tablets) is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy.
This indication is based on pivotal trials of up to 8 weeks duration, in adults over 18 years of age.
For more information, refer to the Wakix Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Wakix was evaluated in the pivotal studies described in the Clinical Efficacy section above. In addition, the Harmony Ibis Study provided data from an open-label long-term period following patients for up to 5 years. Further data was evaluated from additional longer-term sources of safety data including a European sponsored post-authorization safety study (PASS).
The most common adverse events reported for Wakix in the pivotal studies were headache (17.5%), nausea (6.0%), and insomnia (4.7%). Based on the total available dataset, the most frequently reported moderate treatment-emergent adverse events (TEAEs) reported in >1% of Wakix patients were headache, nausea, insomnia, and depression. The adverse events most frequently associated with Wakix as compared to placebo were: headache (18.4% versus [vs.] 14.7%), insomnia (5.9% vs. 1.8%), nausea (5.9% vs. 3.6%), upper respiratory tract infection (5.3% vs. 2.6%), musculoskeletal pain (4.5% vs. 2.6%), anxiety (4.6% vs. 2.6%), increased heart rate/tachycardia (3.7% vs. 0%), hallucinations (3.3% vs. 0%), irritability (3.3% vs. 1.8%), dizziness/light headedness (3.3 % vs. 2.6%), abdominal pain (3.3% vs. 1%), decreased appetite (2.6% vs. 0%), and sleep disturbance (2.6% vs. 1.8%).
In the pivotal studies, the frequency of serious adverse events (SAEs) and adverse events leading to discontinuations were low. One patient in the Harmony Ibis Study reported an SAE of depression. In the Harmony I Study, there was one SAE of severe abdominal pain and one SAE of hemorrhoids and pyelonephritis. Adverse events that led to discontinuation included adverse events of the gastrointestinal and nervous systems, as well as psychiatric disorders. During the single-blind studies and open-label studies (n = 137), depression (2.2%) was reported as SAEs, sometimes leading to discontinuation (1.5%).
Symptoms of withdrawal were formally evaluated in the pivotal studies during a one-week washout. There was no evidence of withdrawal syndrome noted. Based on the non-clinical data suggesting abuse potential and a theoretical role of sigma receptors on reinforcement, cautionary text has been added to the Wakix Product Monograph.
Additional safety data was available from the United States Food and Drug Administration (FDA) expanded access program and a European sponsored post-authorization safety study (PASS). These data included reports of hospitalizations for depression and suicidal ideation, relapse of psychiatric disorders such as Bipolar I and alcohol disorder (reported from the FDA expanded access program), and reports of depression (from the uncontrolled long-term extension Harmony III Study).
Depression can be a co-morbidity of narcolepsy, however, given that depression could be a side effect of Wakix and that additional cases of depression were described in post-market reports, precautionary text was added to the Wakix Product Monograph, especially for use in patients with a history of psychiatric conditions.
Post-market use for Wakix is based on experience in Europe since 2016 and in the United States since 2018 and other additional countries where it is approved for use. Post-market reports arise from post-market spontaneous cases, ongoing safety clinical studies such as compassionate use, and post-authorization safety studies. Wakix Periodic Safety Update Reports (PSURs) provided cumulative post-market reports of possible safety signals which included cumulative post-market reports of depression.
Safety issues related to increased pitolisant exposure exist for the following identified groups: slow metabolizers of Wakix (genetic polymorphism), patients with hepatic impairment, patients with renal impairment and patients with concomitant medications including CYP2D6 inhibitors and CYP 3A4 inducers. These patients could potentially be at increased risk of QTc prolongation and other potential side effects from increased exposure to pitolisant therapy. Wakix is contraindicated in patients with severe hepatic impairment and is not recommended in patients with end stage renal disease. The Product Monograph includes statements regarding dosing in patients with hepatic or renal impairment.
Based on animal toxicity studies, it is not recommended that Wakix be used in pregnancy. Women of childbearing age who use hormonal contraception should use an additional non-hormonal method during treatment with Wakix and for up to 21 days after discontinuation. Wakix is contraindicated for breastfeeding women.
Missing information include the absence of controlled long-term efficacy and safety clinical study data as the double-blind, controlled, pivotal studies were only seven weeks in duration. Data on the use of Wakix in patients with concomitant psychiatric or concomitant physical co-morbidities was not available.
Based on available safety data from the pivotal clinical studies and the additional safety data sources, there were no safety concerns that precluded the authorization of Wakix. Appropriate warnings and precautions are in place in the approved Wakix Product Monograph to address the identified safety concerns.
For more information, refer to the Wakix Product Monograph approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
In vitro studies demonstrated the activity of pitolisant on its pharmacological target. In Chinese hamster ovary cells stably expressing the human histamine 3 (H3) receptor, pitolisant inhibited binding with a median effective dose (EC50) of 1.5 nM. This finding suggests that pitolisant is an inverse agonist of the H3 receptor. Moreover, pitolisant was able to reverse the imetit (a histamine 3 reference agonist)-induced increase in functional binding, suggesting that pitolisant behaves as a competitive H3 receptor antagonist.
Neuropharmacologically relevant doses of pitolisant were tested in several experimental models predictive of drug abuse potential. In general, no liability could be established. However, some uncertainty remains regarding inconclusive results from a self-administration study in monkeys and a theoretical role of sigma receptors on reinforcement.
Safety pharmacology studies evaluated impacts to central nervous system, respiratory, and gastrointestinal function. The results indicated that pitolisant displays satisfactory safety margins when comparing the plasma levels at the no-observed-adverse-effect level (NOAEL) doses in these studies with plasma levels in humans receiving chronic therapeutic doses.
Following oral administration to mice, rats, rabbits, dogs, and monkeys, pitolisant was rapidly absorbed across all species, with time to maximum concentration (Tmax) values observed between 0.25 h and 1.0 h. Bioavailability was 1.5% in rats and 27% in monkeys. Results from in vivo distribution studies demonstrated that high tissue exposure occurred in the brain and metabolizing organs. Across all species, the metabolism of pitolisant is highly complex.
In vitro, pitolisant showed inhibition towards organic cation transporter 1 (OCT1) with a half-maximal inhibitory concentration (IC50) of 0.795 µM. This suggests a possible OCT1 drug interaction when pitolisant is administered with a substrate of OCT1 (e.g., metformin). The major metabolites of pitolisant appear to be produced under the action of cytochrome P450 (CYP) 2D6 and CYP3A4. Pitolisant caused direct inhibition of CYP2D6 with moderate potency (IC50 = 2.6 µM).
In single- and repeat-dose toxicology studies, rats and monkeys experienced convulsions after receiving high doses of pitolisant administered intravenously and orally. One of the metabolites of pitolisant, BP1.2526, was shown to elicit pro-convulsive effects; however, since its detection in humans represents a small fraction of pitolisant, this metabolite’s effect does not raise serious concerns, and the risk of convulsions in humans is considered limited. Overall, the repeat-dose studies in rats and monkeys provided a safety margin near or below the expected therapeutic exposure.
Pitolisant did not show genotoxic or carcinogenic potential.
Reproductive and developmental toxicity studies in rats and rabbits demonstrated serious adverse effects for both mother and fetus. Studies have demonstrated that pitolisant crosses the blood-brain barrier and placenta, and has been found in fetal tissue and in the milk of nursing rats. Fetal blood and tissue levels of pitolisant and its metabolites were comparable to maternal blood concentrations. Rats treated with high doses of pitolisant (30, 52, or 90 mg/kg/day) demonstrated dose-related abnormalities in sperm morphology and motility, with limited effects on fertility indices in males, and with increased post-implantation loss and fewer live conceptuses in females. Milk production and nursing were affected at doses ≥52 mg/kg/day. A number of females presented with agalactorrhea and failed to nurse, leading to the death of their pups. Malformations (cleft palate, abnormal limb flexure) and developmental delays (physical, motor and behavioural) were noted in pups at maternally toxic doses. The NOAEL for fertility was established at 30 mg/kg/day (7.3-times the maximum recommended human dose based on mg/m2 body surface area). The risks for fertility and pregnancy have been mitigated by including appropriate warnings in the Product Monograph. Breastfeeding has been contraindicated.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Wakix Product Monograph. In view of the intended use of Wakix, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Wakix Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Wakix has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
None of the excipients used in the formulation of Wakix is of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| WAKIX | 02516268 | ENDO OPERATIONS LTD. | PITOLISANT HYDROCHLORIDE 20 MG |
| WAKIX | 02516241 | ENDO OPERATIONS LTD. | PITOLISANT HYDROCHLORIDE 5 MG |