Summary Basis of Decision for Sunosi

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Sunosi is located below.

Recent Activity for Sunosi

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.

The following table describes post-authorization activity for Sunosi, a product which contains the medicinal ingredient solriamfetol (supplied as solriamfetol hydrochloride). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Updated: 2023-02-21

Drug Identification Number (DIN) :

  • DIN 02515814 - 75 mg solriamfetol, tablet, oral administration
  • DIN 02515822 - 150 mg solriamfetol, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DINs 02515814, 02515822) market notification Not applicable Date of first sale: 2022-11-17 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 266452 2022-07-26 Issued NOC 2022-08-25 Submission filed to transfer ownership of the drug product from Jazz Pharmaceuticals Ireland Limited to Axsome Malta Ltd. An NOC was issued.
Drug product (DINs 02515814, 02515822) market notification Not applicable Date of first sale: 2021-08-03 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 237511 2020-03-30 Issued NOC 2021-05-13 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Sunosi

Date SBD issued: 2021-09-10

The following information relates to the new drug submission for Sunosi.

Solriamfetol (supplied as solriamfetol hydrochloride)

Drug Identification Number (DIN):

  • DIN 02515814 - 75 mg solriamfetol, tablet, oral administration
  • DIN 02515822 - 150 mg solriamfetol, tablet, oral administration

Jazz Pharmaceuticals Ireland Ltd.

New Drug Submission Control Number: 237511

 

On May 13, 2021, Health Canada issued a Notice of Compliance to Jazz Pharmaceuticals Ireland Limited for the drug product Sunosi.

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 Sunosi is favourable for:

  • the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy.
  • the treatment of excessive daytime sleepiness in adult patients with obstructive sleep apnea (OSA).

Sunosi is not indicated to treat the underlying airway obstruction in patients with OSA. A maximal effort to treat the underlying airway obstruction with a primary OSA therapy (e.g., with continuous positive airway pressure), for an adequate period of time should be made, prior to initiating treatment with Sunosi for excessive sleepiness. Primary OSA therapy for the underlying airway obstruction should be maintained during treatment with Sunosi. Sunosi is not a substitute for primary OSA therapy.

1 What was approved?

Sunosi, a psychoanaleptic, was authorized for:

  • the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy.
  • the treatment of excessive daytime sleepiness in adult patients with obstructive sleep apnea (OSA).

Sunosi is not indicated to treat the underlying airway obstruction in patients with OSA. A maximal effort to treat the underlying airway obstruction with a primary OSA therapy (e.g., with continuous positive airway pressure) for an adequate period of time should be made prior to initiating treatment with Sunosi for excessive sleepiness. Primary OSA therapy for the underlying airway obstruction should be maintained during treatment with Sunosi. Sunosi is not a substitute for primary OSA therapy.

Sunosi is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available for this population.

There are limited data available for geriatric patients (≥65 years of age). Physicians who choose to treat geriatric patients with Sunosi should consider treatment in the context of greater frequency of reduced renal function, other concomitant diseases and concomitant drug therapies, which may necessitate dose adjustments and additional or more frequent monitoring.

Sunosi is contraindicated in patients:

  • who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container;
  • who are receiving concomitant treatment with monoamine oxidase inhibitors or within 14 days after MAOI treatment has been discontinued, due to the risk of hypertensive crisis;
  • with myocardial infarction within the past year, unstable angina pectoris, uncontrolled hypertension, serious cardiac arrhythmias and other serious heart problems;
  • who have end-stage renal disease.

Sunosi 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.

Sunosi (75 mg and 150 mg solriamfetol, supplied as solriamfetol hydrochloride) is presented as a tablet. In addition to the medicinal ingredient, the tablet also contains the non-medicinal ingredients hydroxypropyl cellulose and magnesium stearate. The film coating on the tablet contains iron oxide yellow, polyethylene glycol (Macrogol), polyvinyl alcohol, 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 Sunosi Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Sunosi approved?

Health Canada considers that the benefit-harm-uncertainty profile of Sunosi is favourable for:

  • the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy.
  • the treatment of excessive daytime sleepiness in adult patients with obstructive sleep apnea (OSA).

Sunosi is not indicated to treat the underlying airway obstruction in patients with OSA. A maximal effort to treat the underlying airway obstruction with a primary OSA therapy (e.g., with continuous positive airway pressure), for an adequate period of time should be made, prior to initiating treatment with Sunosi for excessive sleepiness. Primary OSA therapy for the underlying airway obstruction should be maintained during treatment with Sunosi. Sunosi is not a substitute for primary OSA therapy.

Excessive daytime sleepiness is defined in the International Classification of Sleep Disorders, 3rd edition 2014 as “difficulty in maintaining wakefulness and alertness during the major waking episodes of the day, with sleep occurring unintentionally or at inappropriate times almost daily for at least 3 months”. Individuals with EDS are unable to stay awake, alert and optimally functional throughout the day. Estimates of EDS in the general population are 10% to 25% but are highly dependent on the measures used to classify sleepiness as EDS. There are numerous causes of EDS including insufficient sleep, medications, and various neurological, psychiatric and medical conditions. Narcolepsy and OSA are among the neurological and medical conditions that have EDS as a prominent symptom.

Narcolepsy is a chronic, debilitating neurological disorder that affects the brain’s ability to control sleep-wake cycles, which is characterized primarily by EDS with or without cataplexy. Cataplexy is the sudden transient loss of muscle tone (ranging from seconds to 3-5 minutes) due to weakness or paralysis, usually in response to strong emotions such as laughter, surprise, anger, fright, or anticipation of reward. It is a rare disease, with an estimated prevalence of 0.03% to 0.056% (3.1 to 5.6 per 10,000 people) in the United States of America. Narcolepsy typically has onset in childhood or adolescence/young adulthood and is equally common in males and females. Excessive daytime sleepiness is usually the first symptom of narcolepsy to manifest; it is the most prominent and frequently reported symptom and, is often the most disabling symptom. Cataplexy is the most specific symptom of the disease. Narcolepsy has a substantial clinical burden because EDS is associated with lapses into sleep at times when an individual should be awake, as well as fatigue, neurocognitive impairment, mood changes, poor attention, and slow reaction times. All of these impairments can affect school and work performance, relationships, mental health, and quality of life.

There is no cure for narcolepsy, and EDS associated with narcolepsy is managed with non-pharmacologic and pharmacologic interventions. Non -pharmacologic interventions include a regular nighttime sleep schedule, scheduled daytime naps, and psychosocial support. In Canada, pharmacologic treatments that are indicated for patients with narcolepsy are central nervous system stimulant drugs including methylphenidate (Ritalin) and dextroamphetamine (Dexedrine), which are indicated for treatment of narcolepsy, or modafinil (Alertec), which is indicated specifically for treatment of EDS associated with narcolepsy. Modafinil is considered a first-line therapy among these drugs because it is generally well-tolerated and may have fewer sympathomimetic effects than other stimulant drugs, which can cause hypertension and serious cardiovascular events (e.g., myocardial infarction, stroke). In addition, modafinil is considered to have less abuse potential than other stimulant drugs. Cataplexy is managed with other drugs such as sodium oxybate (Xyrem), which is indicated in Canada for the treatment of cataplexy in narcolepsy patients.

Obstructive sleep apnea is characterized by repetitive episodes of complete (apnea) or partial (hypopnea) upper airway obstruction occurring during sleep, which often result in reductions in blood oxygen saturation and are usually terminated by brief arousals from sleep. The apnea/hypopnea events in OSA are caused by poor muscle tone of the tongue and/or upper airway dilator muscles, which leads to repeated arousals secondary to partial/complete obstruction of the upper airway during sleep and consequently sleep fragmentation. As a consequence of sleep fragmentation, EDS is a major presenting complaint in many patients with OSA. In contrast to narcolepsy, OSA is a relatively common sleep-related disorder. General population-based studies from several countries indicate that OSA associated with EDS occurs in 3% to 7% of adult males and 2% to 5% of adult females. In addition to EDS, other daytime symptoms of OSA can include daytime fatigue, cognitive deficits, decreased vigilance, personality and mood alterations, as well as morning confusion, gastroesophageal reflux, hypertension and sexual dysfunction, some of which may be related to EDS.

Treatment of OSA is primarily non-pharmacologic, with the goal of reducing apnea/hypopnea events during sleep, to reduce sleep fragmentation. Continuous positive airway pressure (CPAP) is considered the first-line therapy for OSA but other non-pharmacologic therapies such as oral appliances and upper airway surgery may be used for patients who cannot tolerate or adhere to use of a CPAP device. For patients whose OSA is managed successfully with CPAP or other non-pharmacologic therapies with respect to reducing/preventing respiratory events during sleep, but who continue to have EDS, pharmacological therapies may be used adjunctively. Modafinil is the only pharmacotherapy indicated in Canada for treatment of EDS in patients with OSA, as an adjunct to a primary OSA therapy (e.g., CPAP).

For both narcolepsy and OSA patients, EDS decreases the quality of life, particularly when it is severe. In addition, both disorders are associated with similar comorbidities including psychiatric comorbidity (depression, anxiety), cardiovascular comorbidity (higher than expected rates of hypertension, coronary artery disease, heart failure, stroke, and increased mortality), increased rates of obesity, and diabetes mellitus.

Sunosi contains the medicinal ingredient solriamfetol which is a psychoanaleptic. Solriamfetol has an affinity for the dopamine and norepinephrine transporters. The precise mechanism of action by which solriamfetol has its therapeutic effect in the treatment of EDS has not been fully characterized, but the effect may be mediated by its activity to inhibit both dopamine and norepinephrine reuptake in the brain.

Sunosi was shown to be efficacious for the treatment of EDS primarily in two pivotal Phase III clinical trials in adult patients with narcolepsy (Study 14 -002) or OSA (Study 14-003). Both trials were 12 weeks in duration and had a similar study design (randomized, double-blind, placebo controlled, parallel group) that compared Sunosi 37.5 mg/day (Study 14-003, OSA patients only), 75 mg/day, 150 mg/day or 300 mg/day to a placebo. Both trials had the same two co-primary efficacy endpoints, which were the change in total score from baseline to Week 12 on the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS). A key secondary endpoint in both trials was the percentage of patients who rated their overall condition at Week 12 as improved (minimally, much, or very much) relative to baseline using the Patient Global Impression of Change (PGI-C).

In both trials, results obtained at Week 12 showed a statistically significant treatment difference in the co-primary and key secondary endpoints favoring Sunosi over a placebo. These results included increases in the MWT mean sleep latency, decreases in ESS total score, and greater percentages of patients with improved overall condition. Both trials showed an increase in the MWT mean sleep latency with Sunosi remaining relatively constant for approximately 9 hours, after the dose was administered upon awakening in the morning. Because the 300 mg dose did not confer additional benefit over the 150 mg dose to outweigh the dose-related adverse events the maximum recommended dose in both patient populations is 150 mg/day, with titration.

Efficacy results obtained in the two pivotal trials were further supported in two supportive studies, Study 14-004 and Study 14-005. Both supportive studies were Phase III clinical trials that used a randomized withdrawal design to evaluate the long-term maintenance of Sunosi. Results from the supportive studies demonstrated that EDS was reduced during open-label treatment with Sunosi, similar to what was observed in the 12-week pivotal trials based on the same efficacy endpoints. For patients that continued to receive Sunosi, there was essentially no change in the efficacy endpoints from the beginning to the end of the trial (i.e., the effect of Sunosi on EDS was maintained). For those randomized to a placebo, the effect of Sunosi on EDS was partially lost and the differences between the Sunosi and placebo groups were statistically significant. The abrupt discontinuation of Sunosi for the patients randomized to a placebo did not result in EDS that was worse than the baseline level of EDS.

The overall pharmacological activity of Sunosi is similar to other drugs used to manage EDS associated with narcolepsy (e.g., amphetamines, methylphenidate, modafinil) or OSA (e.g., modafinil). This activity includes sympathomimetic effects which can lead to treatment emergent increases in blood pressure and heart rate, gastrointestinal effects, effects on appetite and weight (decreases both), and psychiatric adverse events. The most common treatment emergent adverse events (TEAEs) reported in narcolepsy or OSA patients treated with Sunosi (>5%) in the 12-week pivotal trials included headache, nausea, decreased appetite, anxiety, and insomnia. Other commonly reported TEAEs in patients treated with Sunosi (>1%) included palpitations, feeling jittery, chest discomfort, diarrhea, constipation, dry mouth, dizziness, hyperhidrosis, hypertension, and increased blood pressure. Several of the commonly reported TEAEs showed a dose relationship to Sunosi. The long-term safety data from 172 narcolepsy patients and 359 OSA patients treated with Sunosi for >6 months and 95 narcolepsy patients and 186 OSA patients treated for >12 months were generally consistent with the safety data from the 12-week clinical trials.

A Risk Management Plan (RMP) for Sunosi was submitted by Jazz Pharmaceuticals Ireland 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 Sunosi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name was performed. During review, the sponsor requested that the brand name be changed to Sunosi to align with international approvals. The new brand name was reviewed, which included testing for look-alike sound-alike attributes, the name Sunosi was accepted. A complete review of the package labels was also conducted. All issues identified were communicated to and satisfactorily addressed by the sponsor.

Overall, the therapeutic benefits of Sunosi demonstrated in the two pivotal trials and supportive studies are considered to outweigh the potential harms. Based on the non-clinical data and clinical studies, Sunosi has an acceptable safety profile, when used as described in the approved Product Monograph. Appropriate warnings, precautions and monitoring recommendations are in place in the Sunosi Product Monograph to manage 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 Sunosi?

A meeting was held between Health Canada and Jazz Pharmaceuticals Ireland Ltd. on March 26, 2019 to discuss the planned filing of the New Drug Submission (NDS) for Sunosi. The NDS was filed at Health Canada on March 30, 2020 and on May 15, 2020 the sponsor received a Screening Deficiency Notice. Following an acceptable response to the Screening Deficiency Notice, the NDS was accepted for review on July 17, 2020. On May 13, 2021, the review was completed and a Notice of Compliance was issued to Jazz Pharmaceuticals Ireland Ltd. for Sunosi.

Submission Milestones: Sunosi

Submission Milestone Date
Pre-submission meeting 2019-03-26
Submission filed 2020-03-30
Screening  
Screening Deficiency Notice issued
 2020-05-15
Response filed
 2020-06-03
Screening Acceptance Letter issued
 2020-07-17
Review  
Review of Risk Management Plan complete
 2021-02-26
Biopharmaceutics Evaluation complete
 2021-03-07
Quality Evaluation complete
 2021-05-12
Non-Clinical Evaluation complete
 2021-05-12
Clinical/Medical Evaluation complete
 2021-05-12
Biostatistics Evaluation complete
 2021-03-31
Labelling Review complete
 2021-05-12
Notice of Compliance issued by Director General, Therapeutic Products Directorate
 2021-05-13

The Canadian regulatory decision on the review of Sunosi was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency and the United States Food and Drug Administration 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.

5 What post-authorization activity has taken place for Sunosi?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (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. The PAAT will continue to be updated during the product life cycle.

The PAAT for Sunosi is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

Clinical Pharmacology

Solriamfetol (the medicinal ingredient in Sunosi) is a phenylalanine derivative in the same class as other centrally acting sympathomimetic drugs that have similar pharmacological activities (e.g., methylphenidate, amphetamines, modafinil). The exact mechanism of action by which solriamfetol increases sleep latency in patients with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) has not been fully characterized. Given solriamfetol is a selective dopamine and norepinephrine reuptake inhibitor; its efficacy is thought to be mediated by inhibiting dopamine and norepinephrine transporters. By inhibiting the reuptake of both neurotransmitters, this enhances dopamine and norepinephrine signaling in the brainstem arousal system.

Solriamfetol exposure and half-life were significantly increased with moderate and severe renal impairment and in patients with end-stage renal disease (ESRD). Therefore, there is the potential for greater increases in blood pressure and heart rate in these patients than what was observed in the two pivotal trials, which excluded these patients. To mitigate this potential harm, dose adjustments and close monitoring of blood pressure and heart rate are recommended for patients with moderate and severe renal impairment and a contraindication has been included in the product’s labelling for patients with ESRD.

The main study assessing the abuse potential of solriamfetol evaluated single supratherapeutic doses of Sunosi 300 mg, 600 mg and 1200 mg compared to placebo and phentermine 45 mg and 90 mg, in subjects with a history of alcohol and drug/stimulant abuse. On average, the peak Drug Liking (on a visual analog scale; VAS) scores (primary endpoint) with all three doses of solriamfetol were statistically significantly greater than with placebo, similar to phentermine 45 mg and lower than phentermine 90 mg dose. All three solriamfetol doses had lower Overall Drug Liking scores compared to both phentermine doses. Based on a scale, interpreted as a measure of euphoric effects, both doses of phentermine and all doses of solriamfetol showed statistically significant greater effects compared to placebo. Therefore, it is recommended that patients be carefully screened for a history of alcohol and/or drug abuse prior to prescribing Sunosi and are observed for signs of misuse/abuse (e.g., incrementation of doses or drug-seeking behavior) during treatment.

For further details, please refer to the Sunosi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The market authorization for Sunosi was primarily based on evidence from two pivotal Phase III clinical trials, Study 14-002 and Study 14-003. Additional supportive data was also provided from Study 14-004 and Study 14-005.

Pivotal Studies

The efficacy of Sunosi for the treatment of EDS was evaluated in two 12-week pivotal Phase III, multicentre, randomized, double-blind, placebo-controlled clinical trials in adults diagnosed with narcolepsy (Study 14-002; number of patients [n] = 239) or OSA (Study 14-003; number of patients n = 476). In Study 14-002 patients were randomized to placebo, or 75, 150, 300 mg/day Sunosi. In Study 14-003 patients were randomized to placebo, or 37.5, 75, 150, 300 mg/day Sunosi. Because the 300 mg/day dose did not confer additional efficacy that was sufficient to outweigh the dose-related treatment emergent adverse events at this dose, final efficacy results are presented only for doses up to 150 mg/day.

Both pivotal trials had an identical set of co-primary and key secondary efficacy endpoints. Co-primary efficacy endpoints were the change from baseline to Week 12 on the:

  • Maintenance of Wakefulness Test (MWT) mean sleep latency, which is an objective (polysomnography) measure of the time to sleep onset when a patient is instructed to remain awake for as long as possible under soporific conditions during five 40-minute test sessions (over a 9 to 10 hour period). Mean sleep latency of <8 minutes measured by the MWT is considered abnormal.
  • Epworth Sleepiness Scale (ESS) total score, which is a subjective measure of the patient’s perception of their sleepiness during normal situations of low activity. The ESS is a validated 8-item questionnaire by which patients rate their perceived likelihood of falling asleep in usual daily life activities. The total score ranges from 0 to 24, with higher scores reflecting greater sleepiness. An ESS total score >10 (maximum score 24) is considered abnormal.

The key secondary efficacy endpoint was the percentage of patients who rated their overall condition at Week 12 as improved relative to study baseline, using the Patient Global Impression of Change (PGI-C). The PGI-C is a 7-point scale ranging from “very much improved” to “very much worse,” which is the patient’s rating of their overall condition relative to the start of the study.

For both studies, concomitant medications that could confound interpretation of the treatment effect or safety profile of Sunosi were not permitted and were discontinued prior to enrollment. These medications included drugs commonly used to treat EDS (e.g., methylphenidate, amphetamines, modafinil) and/or cataplexy in patients with narcolepsy (e.g., sodium oxybate and other medications).

Study 14-002 for Narcolepsy

Patients enrolled in this study were diagnosed with narcolepsy (with or without cataplexy) according to the International Classification of Sleep Disorders 3rd edition criteria or the Diagnostic and Statistical Manual of Mental Disorders 5th edition criteria. The mean age (34 years; age range 18 to 70 years) and gender distribution (65% female and 35% male) was representative of a narcolepsy patient population. Approximately 51% of patients had cataplexy. Most patients reported prior use of psychostimulants. At baseline MWT mean sleep latency was <10 minutes and mean ESS score was approximately 17.

The study included 239 patients randomized in a 1:1:1:1 ratio to receive either Sunosi 75, 150, or 300 mg/day (two times the maximum recommended dose) or a placebo orally once daily for 12 weeks. Patients randomized to the 150 mg dose received 75 mg once daily for the first three days before increasing to 150 mg/day. Efficacy was assessed by the co-primary endpoints, the change from baseline in MWT and ESS at Week 12.

At Week 12, patients randomized to Sunosi 150 mg/day showed statistically significant improvements on the co-primary endpoints of MWT (treatment effect difference: 7.7 minutes increase in mean sleep latency) and ESS (treatment effect difference: 3.8 points decrease in total score), as well as on the PGI-C (treatment difference: 38.5% more with improved overall condition), compared to the placebo group. Patients randomized to receive the 75 mg/day dose did show a statistically significant treatment effect difference in the ESS total score but this was not shown for the co-primary endpoint MWT mean sleep latency. As for the PGI-C at Week 12, a greater percentage of patients treated with Sunosi (75 mg and 150 mg) showed improvement, compared to patients who received a placebo. These observed effects were noted to be dose-dependent, observed at Week 1, and maintained over the trial duration.

Sunosi had no meaningful effect on cataplexy episodes. Nighttime sleep as measured with polysomnography was also not affected by the use of Sunosi.

Study 14-003 for Obstructive Sleep Apnea

Patients enrolled in this study were diagnosed with OSA according to the International Classification of Sleep Disorders 3rd edition criteria. The majority of patients used a primary OSA therapy (mostly continuous positive airway pressure [CPAP]) and had moderate to severe EDS at baseline, according to the mean baseline values for the co-primary endpoints (~12.5 to 13 minutes MWT mean sleep latency; ESS total score ~15). The mean age and gender distribution of the study population was representative of an OSA patient population.

Patients were randomized to be treated with Sunosi (37.5, 75, 150, or 300 mg/day) or a placebo orally once daily for 12 weeks. The benefit of Sunosi was assessed by determining the difference in ESS scores and MWT times before and during treatment.

Study results for OSA patients showed statistically significant increases in the MWT mean sleep latency and statistically significant decreases in the ESS total score compared to a placebo. Greater percentages of patients treated with Sunosi (75 mg and 150 mg doses, but not the 37.5 mg dose) were improved on the PGI-C at Week 12, compared to patients who received a placebo.

In both clinical trials, the magnitude of change from baseline at Week 12 for both co-primary endpoints was similar to what was observed at Week 1 (i.e., maintained through the 12 weeks of each study). The observed increase in the MWT mean sleep latency with Sunosi remained relatively constant for approximately 9 hours, after dose administration upon awakening in the morning.

In terms of a risk-benefit analysis, it was determined that the maximum recommended dose in both patient populations (narcolepsy and OSA) is 150 mg/day, with titration.

A main issue related to the assessment of efficacy was the inclusion of “to improve wakefulness” in the sponsor’s proposed wording of the indication. Excessive daytime sleepiness is generally understood to be an inability to stay awake, alert and optimally function throughout the day, and the “to improve wakefulness” component of the indication could be interpreted as improved alertness/vigilance or being awake enough to be optimally functional throughout the day. The co-primary and key secondary endpoints used in the pivotal trials did not evaluate whether alertness or vigilance improved, or whether the increases in MWT mean sleep latency meant patients were awake enough to be optimally functional throughout the day. The sponsor considered the wording “to improve wakefulness” in the indication to reflect the statistically significant increases in the MWT mean sleep latency. However, without a clear demonstration of whether the observed increases in mean sleep latency on the MWT resulted in improved alertness or functional capability, the potential for this wording in the indication to be misinterpreted was a concern. Therefore, the recommended indication for Sunosi is limited to the treatment of EDS in adult patients with narcolepsy or OSA. 

Indication

The New Drug Submission for Sunosi was filed by the sponsor with the following indication:

  • Sunosi (solriamfetol) is indicated to improve wakefulness and reduce excessive daytime sleepiness (EDS) in adult patients with narcolepsy or obstructive sleep apnea (OSA).

To promote safe and effective use of Sunosi, Health Canada revised the proposed indication to include clarifying statements regarding its use in treating OSA. Accordingly, Health Canada approved the following indication:

Sunosi (solriamfetol) is indicated for:

  • the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy.
     
  • the treatment of excessive daytime sleepiness in adult patients with obstructive sleep apnea (OSA).

Sunosi is not indicated to treat the underlying airway obstruction in patients with OSA. A maximal effort to treat the underlying airway obstruction with a primary OSA therapy (e.g., with continuous positive airway pressure [CPAP]), for an adequate period of time should be made prior to initiating treatment with Sunosi for excessive sleepiness. Primary OSA therapy for the underlying airway obstruction should be maintained during treatment with Sunosi. Sunosi is not a substitute for primary OSA therapy.

Supportive Studies

The long-term maintenance of effect of Sunosi in the treatment of EDS in adult patients with narcolepsy and OSA was assessed in two supportive studies, Study 14-004 and Study 14-005. Both studies were Phase III clinical trials that used a similar design, which incorporated a 2-week randomized withdrawal period. After being stabilized on open-label treatment with Sunosi at the maximum tolerated dose that was effective (75 mg/day, 150 mg/day, or 300 mg/day) for a protocol-specified period of time, patients were randomized 1:1 to continue the stable dose of Sunosi or to switch to a placebo for a 2-week, double-blind, randomized withdrawal period for evaluating maintenance of efficacy. Study 14-004 included OSA patients only and was 6 weeks in duration (including a 2-week randomized withdrawal period). Study 14-005 included narcolepsy and OSA patients who had completed other clinical studies in the Sunosi clinical program (mainly Studies 14-002 and 14-003) and was up to 40 weeks or 52 weeks in duration (including a 2-week randomized withdrawal period), depending on the parent studies from which patients were entering. Results from both supportive studies demonstrated that EDS was reduced during open-label treatment with Sunosi, similar to what was observed in the 12-week pivotal trials based on the same efficacy endpoints. For patients that continued to receive Sunosi, there was essentially no change in the efficacy endpoints from the beginning to the end of the 2-week randomized withdrawal period (i.e., the effect of Sunosi on EDS was maintained). For those randomized to a placebo, the effect of Sunosi on EDS was partially lost and the differences between the Sunosi and placebo groups were statistically significant. The abrupt discontinuation of Sunosi for the patients randomized to placebo did not result in EDS that was worse than the baseline level of EDS.

Both supportive studies, like the two pivotal trials, also showed that doses above 150 mg/day did not confer additional efficacy that was sufficient to outweigh the dose-related treatment emergent adverse events. Therefore, the maximum recommended dose for the treatment of EDS in adult patients with narcolepsy or OSA is 150 mg/day, with titration.

Overall Analysis of Efficacy

Overall, efficacy of Sunosi has been demonstrated for the treatment of EDS in adult patients with narcolepsy or OSA. The pivotal trials (Study 14‑002 and Study 14-003) assessed the efficacy and safety of Sunosi and the supportive studies (Study 14-004 and Study 14-005) evaluated the maintenance of efficacy in both populations. Collectively the results show that Sunosi is efficacious for the treatment of EDS in adult patients with narcolepsy or OSA.

For more information, refer to the Sunosi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Sunosi for the proposed indication was primarily characterized in two pivotal Phase III clinical trials, Study 14-002 and Study 14-003 previously described in the Clinical Efficacy section. Additional safety information was also obtained from two supportive studies, Study 14‑004 and Study 14-005.

The most common treatment emergent adverse events (TEAEs) reported in patients with narcolepsy or OSA treated with Sunosi (>5%) in the 12‑week pivotal studies included headache, nausea, decreased appetite, anxiety, and insomnia. Other commonly reported TEAEs in patients treated with Sunosi (>1%) included palpitations, feeling jittery, chest discomfort, diarrhea, constipation, dry mouth, dizziness, hyperhidrosis, hypertension, and increased blood pressure. Several of the commonly reported TEAEs showed a relationship to the dose of Sunosi administered. The long-term safety data from 172 narcolepsy patients and 359 OSA patients treated with Sunosi for >6 months and 95 narcolepsy patients and 186 OSA patients treated for >12 months were generally consistent with the safety data from the 12-week studies.

Other notable safety issues identified during the review of Sunosi included sympathomimetic effects, prolonged Sunosi exposure for patients with renal impairment, the potential for abuse, and lack of safety data for pregnant women.

Sympathomimetic Effects

Solriamfetol (the medicinal ingredient in Sunosi) has its main pharmacological activity at dopamine and norepinephrine transporters where it acts to inhibit reuptake and increase the post-synaptic concentrations of these neurotransmitters. Other drugs used in the treatment of EDS associated with narcolepsy or OSA also increase the availability of dopamine and/or norepinephrine via either reuptake inhibition, neurotransmitter release, or a combination of these activities. Given its pharmacological activity, Sunosi also has sympathomimetic effects, which can lead to treatment emergent increases in blood pressure and heart rate, gastrointestinal effects (effects on appetite and weight), and may promote/exacerbate psychiatric symptoms.

Increase in blood pressure and heart rate

Increases in blood pressure and heart rate were observed with Sunosi treatment, with the greatest increases primarily observed at the 300 mg/day dose. Maximal mean increases in blood pressure (up to 2-3 mmHg greater than with a placebo) and heart rate (up to 2.6 bpm greater than with a placebo) with 37.5 mg, 75 mg, or 150 mg Sunosi were generally observed at 1 to 4 hours post-dose. Chronic increases in blood pressure and heart rate can lead to the risk of major cardiovascular events (MACE), including stroke, heart attack, and cardiovascular death. The magnitude of the increase in absolute risk is dependent on the increase in blood pressure and the underlying risk of MACE in the population being treated. Many patients with narcolepsy and OSA have multiple risk factors for MACE, including hypertension, diabetes, hyperlipidemia, and high body mass index, and these patients were included in the pivotal trials. However, the pivotal trials excluded patients with significant cardiovascular disease, including but not limited to: myocardial infarction within the previous year, unstable angina pectoris, uncontrolled hypertension, serious cardiac arrhythmias, and other serious cardiovascular conditions. Since the effects of Sunosi on blood pressure and heart rate in patients with significant cardiovascular conditions have not been evaluated, a contraindication for patients with significant cardiovascular conditions was deemed necessary. Prior to initiating treatment with Sunosi, blood pressure and heart rate should be assessed and pre-existing hypertension should be controlled. Monitoring of blood pressure and heart rate during dose titration and periodically during treatment is also recommended.

Concomitant use of Sunosi with other drugs which increase blood pressure and/or heart rate was not evaluated in the Phase III clinical trials or in any pharmacodynamic interaction studies in healthy subjects. Drugs commonly used for treatment of EDS and certain drugs used for the treatment of cataplexy all cause increases in blood pressure and are frequently prescribed in these patient populations. Use of these medications was prohibited in the Phase III clinical trials. Therefore, the safety of concomitant use of these medications with Sunosi is not known and caution is recommended for concomitant use. Concomitant use of monoamine oxidase inhibitors (MAOIs) was also prohibited in the clinical trials and, due to the risk of hypertensive crisis, concomitant use of MAOIs is contraindicated.

Gastrointestinal Effects

Gastrointestinal adverse events were reported more frequently with the use of Sunosi compared to placebo in both the narcolepsy and OSA patient populations. Decreased appetite and nausea were more commonly noted, while constipation, decreased weight, diarrhea, stomach pain, and vomiting were less commonly noted.

Psychiatric Symptoms

Psychiatric adverse reactions were observed in the Phase III clinical trials with use of Sunosi. Noted adverse reactions included anxiety, insomnia, and irritability.

Use of Sunosi has not been evaluated in patients with a history of or concurrent psychosis or bipolar disorders. Therefore, caution should be exercised when treating these patients due to psychiatric adverse reactions that could exacerbate symptoms (e.g., manic episodes) of pre-existing psychiatric disorders.

Patients with moderate or severe renal impairment may be at a higher risk of psychiatric symptoms because of the prolonged half-life of Sunosi.

Patients treated with Sunosi should be carefully observed for possible adverse reactions or exacerbation of psychiatric symptoms, such as anxiety, insomnia, and irritability. These adverse reactions were commonly observed during treatment initiation but tended to resolve with continued treatment. If psychiatric symptoms develop in association with the administration of Sunosi, a dose reduction or discontinuation should be considered.

Renal Impairment

Sunosi exposure and half-life were significantly increased with moderate and severe renal impairment and in patients with end-stage renal disease. Therefore, there is the potential for greater increases blood pressure and heart rate in such patients than what was observed in the pivotal trials, which excluded these patients. Dose adjustments and close monitoring of blood pressure and heart rate were recommended for patients with moderate and severe renal impairment, and a contraindication was deemed necessary for patients with end-stage renal disease.

Potential for Abuse

Sunosi showed greater abuse potential than a placebo and similar or greater abuse potential than phentermine 45 mg in Study 14-001 (human abuse liability study), which included subjects who were recreational drug users with recent use of stimulants. Results from a validated scale for assessing euphoria and other similar effects (marker of psychological dependence), used in Study 14-001, demonstrated that single doses of Sunosi (supratherapeutic doses) could lead to development of euphoria and similar effects. However, it is not known whether therapeutic doses could also produce these effects in some patients. Based on the results observed in the abuse liability study, the labelling for Sunosi includes a recommendation to evaluate patients carefully for a history of drug abuse prior to prescribing the drug.

Use in Pregnant Women

There are no data for the use of Sunosi in pregnant women, with regard to fetal or maternal outcomes. In the Sunosi clinical studies, the mean age of patients with narcolepsy was approximately 38 years and the mean age of OSA patients was approximately 54 years. Therefore, female narcolepsy patients may be of childbearing age. The non-clinical embryo-fetal development studies showed that Sunosi caused developmental toxicity, with uncertainty about the relationship to maternal toxicity, and there was potential teratogenicity in at least one of the two species evaluated. The sponsor has established a Sunosi Pregnancy Registry as part of the post-marketing requirements associated with approval of Sunosi in the United States of America (USA), which also include conducting two studies to evaluate maternal, fetal, and infant outcomes in pregnant women who are exposed to Sunosi. The sponsor has committed to including Canadian patients in the USA-based registry (Risk Management Plan). The warning for pregnant women included in the Sunosi Product Monograph summarizes the available non-clinical data, and recommends not using Sunosi in pregnant women, or women of childbearing potential who are not using effective methods of contraception. The Sunosi Product Monograph also provides information on how to enroll in the Sunosi pregnancy registry.

Overall Analysis of Safety

At the recommended doses, Sunosi was generally well-tolerated in narcolepsy patients with severe EDS and in OSA patients with moderate to severe EDS. Many of the treatment emergent adverse events were predicted by the pharmacological activity of Sunosi. In the context of the known comorbidities in narcolepsy and OSA patient populations, the identified harms and uncertainties associated with Sunosi necessitate careful evaluation of patients prior to prescribing and monitoring during treatment. These harms and uncertainties are clearly described in the Sunosi Product Monograph with recommendations for mitigating and managing these effects. The benefit-harm-uncertainty profile for Sunosi is considered acceptable under the conditions of use recommended in the approved Sunosi Product Monograph.

For more information, refer to the Sunosi Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non-clinical component of the Sunosi New Drug Submission was comprehensive. In the safety pharmacology studies there were no significant liabilities identified at therapeutic doses. The toxicology studies showed that there was no indication of carcinogenicity in rats and mice at any dose. Additionally, no significant effects were observed in pharmacology models for neurotoxicity, including no effects on learning and memory and no central nervous system histopathologic effects.

The main finding from the non-clinical studies was that Sunosi caused maternal and developmental toxicity in rats and rabbits. It could not be determined if the developmental toxicity was a result of maternal toxicity or a direct effect. Based on the maximum recommended human dose (MRHD) and body surface area (mg/m2) comparison, the no-observed-adverse-effect level (NOAEL) in the rat was approximately at the MRHD. Maternal and developmental toxicity occurred at >4 times the MRHD, and potential teratogenicity (increase in skeletal malformation) occurred at 19 times the MRHD. Based on the MRHD and body surface area (mg/m2) comparison, the NOAEL in rabbits was 2 times the MRHD. Developmental toxicity in rabbits occurred at 5 times the MRHD, and maternal toxicity and developmental toxicity occurred at 10 times the MRHD.

For more information, refer to the Sunosi 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 Sunosi 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 is acceptable when the drug product is stored at room temperature between 15º C to 30º C.

Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation 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.

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