SUNOSI 75mg film-coated tablets medication leaflet

Sunosi 75 mg film-coated tablets

Sunosi 150 mg film-coated tablets

Sunosi 75 mg film-coated tablets

Each tablet contains solriamfetol hydrochloride equivalent to 75 mg of solriamfetol.

Sunosi 150 mg film-coated tablets

Each tablet contains solriamfetol hydrochloride, equivalent to 150 mg of solriamfetol.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Sunosi 75 mg film-coated tablets

Yellow to dark yellow oblong tablet, 7.6 mm x 4.4 mm, with “75” debossed on one side and a scoreline on the opposite side.

The tablet can be divided into equal doses.

Sunosi 150 mg film-coated tablets

Yellow oblong tablet, 9.5 mm x 5.6 mm, with “150” debossed on one side.

Sunosi is indicated to improve wakefulness and reduce excessive daytime sleepiness in adult patientswith narcolepsy (with or without cataplexy).

Sunosi is indicated to improve wakefulness and reduce excessive daytime sleepiness (EDS) in adultpatients with obstructive sleep apnoea (OSA) whose EDS has not been satisfactorily treated by primary

OSA therapy, such as continuous positive airway pressure (CPAP).

Treatment should be initiated by a healthcare professional experienced in the treatment of narcolepsyor OSA.

Sunosi is not a therapy for the underlying airway obstruction in patients with OSA. Primary OSAtherapy should be maintained in these patients.

Blood pressure and heart rate should be assessed before initiating treatment with solriamfetol andshould be monitored periodically during treatment, especially after increasing the dose. Pre-existinghypertension should be controlled before initiating treatment with solriamfetol and caution should beexercised in treating patients at higher risk of major adverse cardiac events (MACE), particularlypatients with pre-existing hypertension, patients with known cardiovascular or cerebrovascular diseaseand elderly patients.

The need for continued treatment with solriamfetol should be periodically assessed. If a patientexperiences increases in blood pressure or heart rate that cannot be managed with dose reduction ofsolriamfetol or other appropriate medical intervention, discontinuation of solriamfetol should beconsidered. Caution should be exercised when using other medicinal products that increase bloodpressure and heart rate (see section 4.5).

Narcolepsy

The recommended starting dose is 75 mg once daily, upon awakening. If clinically indicated inpatients with more severe levels of sleepiness, a starting dose of 150 mg may be considered.

Depending on clinical response, the dose can be titrated to a higher level by doubling the dose atintervals of at least 3 days, with a recommended maximum daily dose of 150 mg once daily.

OSA

The recommended starting dose is 37.5 mg once daily, upon awakening. Depending on clinicalresponse, the dose can be titrated to a higher level by doubling the dose at intervals of at least 3days, with a recommended maximum daily dose of 150 mg once daily.

Taking Sunosi less than 9 hours before bedtime should be avoided as it may affect night time sleep.

Long-term use

The need for continued treatment and the appropriate dose should be periodically assessed duringextended treatment in patients prescribed solriamfetol.

Elderly (> 65 years)

Limited data are available in elderly patients. Consideration should be given to the use of lower dosesand close monitoring in this population (see section 4.4). Solriamfetol is predominantly eliminated bythe kidney and since elderly patients are more likely to have decreased renal function, dosing mayneed to be adjusted based on creatinine clearance in these patients.

Mild renal impairment (creatinine clearance of 60-89 mL/min): No dose adjustment is required.

Moderate renal impairment (creatinine clearance of 30-59 mL/min): The recommended starting dose is37.5 mg once daily. Dose may be increased to a maximum of 75 mg once daily after 5 days.

Severe renal impairment (creatinine clearance of 15-29 mL/min): The recommended dose is 37.5 mgonce daily.

End stage renal disease (creatinine clearance <15 mL/min): Solriamfetol is not recommended for usein patients with end stage renal disease.

The safety and efficacy of Sunosi in children and adolescents (<18 years old) have not yet beenestablished. No data are available.

Sunosi is for oral use.

Sunosi can be taken with or without food.

Administration of a 37.5 mg dose can be achieved by halving a 75 mg tablet using the score line.

* Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

* Myocardial infarction within the past year, unstable angina pectoris, uncontrolled hypertension,serious cardiac arrhythmias and other serious heart problems.

* Concomitant use of monoamine oxidase inhibitors (MAOI) or within 14 days after MAOItreatment has been discontinued (see section 4.5).

Psychiatric symptoms

Solriamfetol has not been evaluated in patients with a history of or concurrent psychosis or bipolardisorders. Caution should be exercised when treating these patients due to psychiatric adversereactions that could exacerbate symptoms (e.g. manic episodes) of pre-existing psychiatric disorders.

Patients treated with solriamfetol should be carefully monitored for adverse reactions such as anxiety,insomnia and irritability. These adverse reactions were commonly observed during treatmentinitiation, but tended to resolve with continued treatment. If these symptoms persist or worsen, dosereduction or discontinuation should be considered.

Blood pressure and heart rate

Analyses of data from clinical trials showed that treatment with solriamfetol increases systolic bloodpressure, diastolic blood pressure, and heart rate in a dose dependent fashion.

Epidemiological data show that chronic elevations in blood pressure increase the risk of major adversecardiovascular event (MACE), including stroke, heart attack and cardiovascular death. The magnitudeof the increase in absolute risk is dependent on the increase in blood pressure and the underlying riskof MACE in the population being treated. Many patients with narcolepsy and OSA have multiple riskfactors for MACE, including hypertension, diabetes, hyperlipidemia and high body mass index (BMI).

Use in patients with unstable cardiovascular disease, serious heart arrhythmias and other serious heartproblems is contraindicated (see section 4.3).

Patients with moderate or severe renal impairment may be at a higher risk of increases in bloodpressure and heart rate because of the prolonged half-life of solriamfetol.

Abuse

Sunosi was assessed in a human abuse potential study and demonstrated low abuse potential. Resultsfrom this clinical study demonstrated that solriamfetol produced Drug Liking scores higher thanplacebo, but generally similar or lower than phentermine (a weak stimulant). Caution should beexercised when treating patients with a history of stimulant (e.g. methylphenidate, amphetamine) oralcohol abuse, and these patients should be monitored for signs of misuse or abuse of solriamfetol.

Angle closure glaucoma

Mydriasis may occur in patients taking solriamfetol. Caution is advised in patients with increasedocular pressure or at risk of angle closure glaucoma.

Women of childbearing potential or their partners

Women of childbearing potential or their male partners must use effective method of contraceptionwhile taking solriamfetol (see section 4.6).

No interaction studies have been performed (see section 5.2).

Solriamfetol must not be administered concomitantly with MAOIs or within 14 days after MAOItreatment has been discontinued because it may increase the risk of a hypertensive reaction (seesection 4.3).

Concomitant use of medicinal products that increase blood pressure and heart rate should be used withcaution (see section 4.4).

Medicinal products that increase levels of dopamine or that bind directly to dopamine receptors mightresult in pharmacodynamic interactions with solriamfetol. Concomitant use of such medicinalproducts should be used with caution.

There are no or limited amount of data from the use of solriamfetol in pregnant women. Animalstudies have shown reproductive toxicity (see section 5.3). Sunosi is not recommended duringpregnancy and in women of childbearing potential not using contraception.

Solriamfetol is excreted in human milk at approximately 4 % of the maternal dose on a weight-adjusted basis (see section 5.2). The effect of solriamfetol on newborns/infants or its impacts on milkproduction are unknown. A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Sunositherapy taking into account the benefit of breast feeding for the child and the benefit of therapy for thewomen.

The effects of solriamfetol in humans are unknown. Animal studies do not indicate direct or indirectharmful effects with respect to fertility (see section 5.3).

Minor influence on the ability to drive is expected in patients receiving stable solriamfetol doses.

Dizziness and disturbance in attention may occur following administration of solriamfetol (see section4.8).

Patients with abnormal levels of sleepiness who take solriamfetol should be advised that their level ofwakefulness may not return to normal. Patients with excessive daytime sleepiness, including thosetaking solriamfetol should be frequently reassessed for their degree of sleepiness and, if appropriate,advised to avoid driving or any other potentially dangerous activity, especially at the start of thetreatment or when the dose is changed.

The most frequently reported adverse reactions were headache (11.1%), nausea (6.6%) and decreasedappetite (6.8%).

The frequency of adverse reactions is defined using the following MedDRA frequency convention:very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the availabledata).

System Organ Class Adverse reactions Frequency

Metabolism and nutrition disorders Decreased appetite Common

Psychiatric disorders Anxiety Common

Insomnia Common

Irritability Common

Bruxism Common

Agitation Uncommon

Restlessness Uncommon

Nervous system disorders Headache Very common

Dizziness Common

Disturbance in attention Uncommon

Tremor Uncommon

Cardiac disorders Palpitations Common

Tachycardia Uncommon

Vascular Disorders Hypertension Uncommon

Respiratory, thoracic and mediastinal disorders Cough Common

Dyspnoea Uncommon

Gastrointestinal disorders Nausea Common

Diarrhoea Common

Dry mouth Common

Abdominal pain Common

Constipation Common

Vomiting Common

Skin and subcutaneous tissue disorders Hyperhidrosis Common

General disorders and administration site conditions Feeling jittery Common

Chest discomfort Common

Chest pain Uncommon

Thirst Uncommon

Investigations Heart rate increased Uncommon

Blood pressure increased Common

Weight decreased Uncommon

Treatment initiation

The majority of the most frequently reported adverse reactions occurred within the first 2 weeks ofinitiating treatment and resolved for the majority of patients with a median duration of less than 2weeks.

In post-marketing experience, there have been reports of hypersensitivity reactions which have occurredwith one or more of the following: rash erythematous, rash, urticaria (see section 4.3).

Dose-dependent adverse reactions

In the 12-week clinical trials that compared doses of 37.5 mg, 75 mg and 150 mg/day of solriamfetolto placebo, the following adverse reactions were dose-related: headache, nausea, decreased appetite,anxiety, diarrhoea and dry mouth. The dose relationships were generally similar in OSA andnarcolepsy patients. Certain events such as anxiety, insomnia, irritability, and agitation werecommonly observed during treatment initiation, but tended to resolve with continued treatment. Ifthese symptoms persist or worsen, dose reduction or discontinuation should be considered (see section4.4).

In the 12-week placebo-controlled clinical trials, 11 of the 396 patients (3%) who receivedsolriamfetol discontinued due to an adverse reaction compared to 1 of the 226 patients (<1%) whoreceived placebo. The adverse reactions leading to discontinuation that occurred in more than onesolriamfetol-treated patients and at a higher rate than placebo were anxiety, palpitations andrestlessness, all of which occurred with a frequency less than 1%.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There have been no reports of overdose of solriamfetol in the clinical studies.

In healthy volunteers, there was one adverse reaction of mild tardive dyskinesia and one adversereaction of moderate akathisia that occurred at a supratherapeutic dose of 900 mg; symptoms resolvedafter treatment discontinuation.

There is no specific antidote. In the case of inadvertent overdose, symptomatic and supportive medicalcare should be provided and patients should be carefully monitored, as appropriate.

Pharmacotherapeutic group: psychoanaleptics, centrally acting sympathomimetics, ATC code:

N06BA14

The mechanism(s) of solriamfetol to improve wakefulness in patients with excessive daytimesleepiness associated with narcolepsy or obstructive sleep apnea has not been fully characterised.

However, its efficacy could be mediated through its activity as a dopamine and norepinephrinereuptake inhibitor (DNRI).

In vitro data

In radioligand-binding experiments with cells expressing cloned human receptors/transporters,solriamfetol showed affinity for the dopamine (replicate Ki=6.3 and 14.2 µM) and norepinephrinetransporter (replicate Ki= 3.7 and >10 µM) but no appreciable affinity to the serotonin transporter.

Solriamfetol inhibited the reuptake of dopamine (replicate IC50=2.9 and 6.4 µM) and norepinephrine(IC50= 4.4 µM) but not of serotonin by these cells.

In vivo animal data

In parenteral doses resulting in clear wake-promoting effects in rats, solriamfetol increased individualdopamine levels in the striatum and norepinephrine levels in the prefrontal cortex, and did not showappreciable binding to the rat dopamine and norepinephrine transporter in an autoradiographyexperiment.

Narcolepsy

Study 1, a 12-week, randomised, double-blind, placebo-controlled, parallel-group study, evaluatedthe efficacy of solriamfetol in adult patients with narcolepsy (with or without cataplexy).

For entry into this study patients had to have excessive daytime sleepiness (an Epworth Sleepiness

Scale [ESS] score greater than or equal to 10), and trouble maintaining wakefulness (mean sleeplatency less than 25 minutes) as documented by the mean of the first 4 trials of the 40-minute

Maintenance of Wakefulness Test (MWT) at baseline.

The measures of efficacy were change from baseline to Week 12 on: ability to stay awake as measuredby mean sleep latency on the MWT, excessive daytime sleepiness as measured by the ESS, andimprovement in overall clinical condition as assessed by the Patient Global Impression of Change(PGIc) scale. The ESS is an 8-item patient-reported measure of likelihood of falling asleep in usualdaily life activities. The PGIc is a 7-point scale ranging from “very much improved” to “very muchworse” which assesses the patient’s report of change in their clinical condition.

Patients with narcolepsy were characterised by impaired wakefulness and excessive daytimesleepiness, as indicated by baseline MWT mean sleep latency and ESS scores, respectively (Table 1).

Most patients had prior use of psychostimulants. Cataplexy was present in approximately half ofpatients overall; demographic and baseline characteristics were similar between patients withcataplexy and those without cataplexy.

In this study, patients with narcolepsy were randomised to receive solriamfetol 75 mg, 150 mg, or 300mg (two times the maximum recommended daily dose), or placebo once daily. At Week 12, patientsrandomised to the 150 mg dose showed statistically significant improvements on the MWT and ESS(co-primary endpoints), as well as on the PGIc (key secondary endpoint), compared with placebo.

Patients randomised to receive 75 mg showed statistically significant improvement on the ESS, butnot on the MWT or PGIc (Table 1). These effects were dose-dependent, observed at Week 1 andmaintained over the study duration (Figure 1). In general, at the same doses, a smaller magnitude ofeffect was observed in patients with more severe baseline levels of sleepiness relative to those whowere less severe. At Week 12, patients who were randomised to receive 150 mg of solriamfetoldemonstrated sustained improvements in wakefulness throughout the day that were statisticallysignificant compared to placebo for each of the 5 MWT trials, spanning approximately 9 hours afterdosing. Dose-dependent improvements in the ability to conduct daily activities were observed, asmeasured by the Functional Outcomes of Sleep Questionnaire Short Version (FOSQ-10). Dosagesabove 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-relatedadverse reactions.

Night-time sleep as measured with polysomnography was not affected by the use of solriamfetol.

Table 1. Overview of Efficacy Results at Week 12 in Patients with Narcolepsy in Study 1

Treatment Mean Baseline Mean Change Difference from P -

Groups (N) Score (SD) from Baseline Placebo (95% CI) Value

MWT Study 1 LS Mean (SE)(min) Placebo (58) 6.15 (5.68) 2.12 (1.29)

Sunosi 75 mg (59) 7.50 (5.39) 4.74 (1.34) 2.62 (-1.04, 6.28) 0.1595

Sunosi 150 mg (55) 7.85 (5.74) 9.77 (1.33) 7.65 (3.99, 11.31) <0.0001

Study 1 LS Mean (SE)

Placebo (58) 17.3 (2.86) -1.6 (0.65)

Sunosi 75 mg (59) 17.3 (3.53) -3.8 (0.67) -2.2 (-4.0, -0.3) 0.0211

Sunosi 150 mg (55) 17.0 (3.55) -5.4 (0.66) -3.8 (-5.6, -2.0) <0.0001

Percent age of Percentage P -

Patients Improved* Difference from Value

Placebo (95% CI)

PGIc Study 1

Placebo (58) 39.7%

Sunosi 75 mg (59) 67.8% 28.1 (10.8, 45.5) 0.0023†

Sunosi 150 mg (55) 78.2% 38.5 (21.9, 55.2) <0.0001

SD = Standard Deviation; SE = Standard Error; LS Mean = Least Square Mean; Difference From Placebo = LS Mean Differencebetween change from baseline between active drug and placebo. MWT results are derived from the first 4 trials of the MWT and apositive change from baseline represents improvement in the sleep latency time. On the ESS, a negative change from baselinerepresents improvement in excessive daytime sleepiness. *The percentage of patients improved on the PGIc includes those whoreported very much, much and minimal improvements;†Nominal p-value.

Figure 1: Co-Primary Efficacy Endpoints in Patients with Narcolepsy in Study 1

OSA

Study 2, a 12-week, randomised, double blind, placebo-controlled parallel-group study, evaluated theefficacy of solriamfetol in adult patients with OSA. The co-primary and key secondary endpoints inthis study were identical to Study 1. Study 3 was a 6-week, randomised-withdrawal, double-blind,placebo-controlled study of the efficacy of solriamfetol in adult patients with OSA. The measures ofefficacy in the randomised withdrawal period were change from the beginning to the end of therandomised-withdrawal period on the MWT, the ESS, and worsening in overall clinical condition asassessed by the PGIc.

For entry into both studies, patients had to have excessive daytime sleepiness (ESS score ≥10) andtrouble maintaining wakefulness (mean sleep latency <30 minutes as documented by the mean of thefirst 4 trials of the MWT) at baseline. Patients were eligible if they: 1) were currently using a primary

OSA therapy (at any level of adherence); 2) had previously used a primary therapy for at least onemonth with at least one documented adjustment to the therapy; or 3) had undergone a surgicalintervention in an attempt to treat the underlying obstruction. Patients were encouraged to stay ontheir current primary OSA therapy at the same level of use throughout the study. Patients wereexcluded only on the basis of their primary therapy use if they had refused to try a primary therapysuch as CPAP, an oral appliance, or a surgical intervention to treat their underlying obstruction.

In Study 2, patients with OSA were characterised by impaired wakefulness and excessive daytimesleepiness (EDS), as indicated by baseline MWT mean sleep latency and ESS scores, respectively(Table 2). Approximately 71% of patients were adherent (e.g. ≥4 hours per night on ≥70% of nights);demographic and baseline characteristics were similar between patients regardless of adherence toprimary OSA therapy. At baseline, primary OSA therapy was used by approximately 73% of patients;of these patients, 92% of patients were using positive airway pressure (PAP).

Patients were randomised to receive solriamfetol 37.5 mg, 75 mg, 150 mg, 300 mg (two times themaximum recommended daily dose), or placebo once daily. At Week 12, patients randomised to the 75mg and150 mg dose arms showed statistically significant improvements on the MWT and ESS (co-primary endpoints), as well as on the PGIc (key secondary endpoint), compared with placebo (Table 2).

Patients randomised to 37.5 mg solriamfetol showed statistically significant improvements based on the

MWT and ESS. These effects were observed at Week 1, maintained over the study duration and weredose-dependent (Figure 2). At Week 12, patients who were randomised to receive 75 mg and 150 mgof Sunosi demonstrated sustained improvements in wakefulness throughout the day that werestatistically significant compared to placebo for each of the 5 MWT trials, spanning approximately 9hours after dosing. Dose- dependent improvements in the ability to conduct daily activities wereobserved, as measured by the FOSQ-10. Dosages above 150 mg daily do not confer increasedeffectiveness sufficient to outweigh dose-related adverse reactions.

Night-time sleep as measured with polysomnography was not affected by the use of solriamfetol in

Study 2. No clinically meaningful changes in patient use of primary OSA therapy were observedacross the 12-week study period in any treatment group. Adherence/non-adherence to primary OSAtherapy did not suggest evidence of differential efficacy.

In Study 3, baseline demographics and disease characteristics were similar to the study population in

Study 2. The dose was initiated at 75 mg once daily and could be titrated up one dose level in intervalsno shorter than every 3 days, according to efficacy and tolerability, to 150 mg or 300 mg. Patientscould also titrate down to 75 mg or 150 mg. Patients treated with solriamfetol remained improved,whereas placebo-treated patients worsened (LS mean difference of 11.2 minutes on MWT and -4.6 on

ESS; both p<0.0001) during the randomised-withdrawal period after 4 weeks of open-label treatment.

Fewer patients treated with solriamfetol reported worsening on the PGIc (percentage difference of30%; p=0.0005).

Table 2. Overview of Efficacy Results at Week 12 in Patients with OSA in Study 2

Treatment Group Mean Baseline Mean Change Difference from P -(N) Score (SD) from Baseline Placebo (95% CI) Value

LS Mean (SE)

MWT Placebo (114) 12.58 (7.14) 0.21 (1.0) - -(min) Sunosi 37.5 mg (56) 13.6 (8.15) 4.74 (1.42) 4.53 (1.16, 7.90) 0.0086

Sunosi 75 mg (58) 12.44 (6.91) 9.08 (1.36) 8.87 (5.59, 12.14) <0.0001

Sunosi 150 mg (116) 12.54 (7.18) 10.96 (0.97) 10.74 (8.05, 13.44) <0.0001

LS Mean (SE)

Placebo (114) 15.6 (3.32) -3.3 (0.45) - -

ESS Sunosi 37.5 mg (56) 15.1 (3.53) -5.1 (0.64) -1.9 (-3.4, -0.3) 0.0161

Sunosi 75 mg (58) 15.0 (3.51) -5.0 (0.62) -1.7 (-3.2, -0.2) 0.0233

Sunosi 150 mg (116) 15.1 (3.37) -7.7 (0.44) -4.5 (-5.7, -3.2) <0.0001

Percentage of Patients Percentage P -

Improved* Difference from Value

Placebo (95% CI)

Placebo (114) 49.1% - -

PGIc Sunosi 37.5 mg (56) 55.4% 6.2 (-9.69, 22.16) 0.4447

Sunosi 75 mg (58) 72.4% 23.3 (8.58, 38.01) 0.0035

Sunosi 150 mg (116) 89.7% 40.5 (29.81, 51.25) <0.0001

SD = Standard Deviation; SE = Standard Error; LS Mean = Least Square Mean; Difference From Placebo = LS Mean Difference onchange from baseline between active drug and placebo. MWT results are derived from the first 4 trials of the MWT and a positivechange from baseline represents improvement in the sleep latency time. On the ESS, a negative change from baseline representsimprovement in excessive daytime sleepiness. *The percentage of patients improved on the PGIc includes those who reported verymuch, much and minimal improvements.

Figure 2: Co-Primary Efficacy Endpoints in Patients with OSA in Study 2

Long-term efficacy in narcolepsy and OSA

Study 4 was a long-term safety and maintenance of efficacy study for up to a year of treatment withsolriamfetol, including a 2-week randomised-withdrawal, placebo-controlled period after at least 6months of treatment with solriamfetol, in adult patients with narcolepsy or OSA who had completeda prior trial.

The measures of efficacy in the randomised withdrawal period were change from the beginning tothe end of the randomised-withdrawal period on the ESS and worsening in overall clinical conditionas assessed by the PGIc. Dose initiation and titration was identical to Study 3.

Patients treated with solriamfetol remained improved, whereas placebo-treated patients worsened (LSmean difference of -3.7 on ESS; p<0.0001) during the randomised-withdrawal period after at least 6months of open-label treatment. Fewer patients treated with solriamfetol reported worsening on the

PGIc (percentage difference of -36.2%; p<0.0001). These results demonstrate long-term maintenanceof efficacy with continued solriamfetol treatment, and a reversal of treatment benefit upondiscontinuation of that treatment.

For patients who were using a primary OSA therapy at the beginning of the study, primary OSAtherapy use did not change over the course of the long-term study.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Sunosi in one or more subsets of the paediatric population from 6 to less than 18 years of age insymptomatic treatment of excessive daytime sleepiness in narcolepsy (see section 4.2 for informationon paediatric use).

The oral bioavailability of solriamfetol is approximately 95% with peak plasma concentrationsoccurring at a median Tmax of 2 hours (range 1.25 to 3 hours) under fasted conditions.

Ingestion of solriamfetol with a high-fat meal resulted in minimal changes in Cmax and AUC; however,a delay of approximately 1 hour was observed in Tmax. The results show that solriamfetol can be takenwithout regard to food.

The apparent volume of distribution of solriamfetol is approximately 198.7 L, indicating extensivetissue distribution beyond the vascular compartment. Plasma protein binding ranged from 13.3% to19.4% over the solriamfetol concentration range of 0.059 to 10.1 µg/mL in human plasma. The meanblood-to-plasma concentration ratio ranged from 1.16 to 1.29, suggesting a small extent of binding ofsolriamfetol to blood cells.

Solriamfetol is minimally metabolised in humans.

With the exception of weak inhibition of CYP2D6 (IC50 of 360 µM), solriamfetol is not a substrate orinhibitor of any of the major CYP enzymes and does not induce CYP1A2, 2B6, 3A4 or UGT1A1enzymes at clinically relevant concentrations. Solriamfetol does not appear to be a substrate orinhibitor of membrane transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1 or OAT3. Solriamfetolis primarily excreted unchanged in the urine and is a low-affinity substrate of multiple renal cationicactive substance transporters, without strong affinity for any individual transporter tested (OCT2,

MATE1, OCTN1 and OCTN2). Solriamfetol is not an inhibitor of renal transporters OCT1,

MATE2K, OCTN1 or OCTN2 but is a weak inhibitor of OCT2 (IC50 of 146 µM) and MATE1 (IC50 of211 µM). Taken together, these results show that clinically relevant PK drug interactions are unlikelyto occur in patients taking solriamfetol.

The apparent mean elimination half-life of solriamfetol is 7.1 hours, and the apparent total clearance isapproximately 19.5 L/h. Renal clearance for solriamfetol is approximately 18.2 L/h.

In a human mass-balance study, approximately 95% of the dose was recovered in urine as unchangedsolriamfetol and 1% or less of the dose was recovered as the minor inactive metabolite N-acetylsolriamfetol. Renal clearance represented the majority of apparent total clearance and exceededcreatinine clearance by approximately 3-fold, indicating that active tubular secretion of the parent drugis likely the major elimination pathway.

Solriamfetol exhibits linear pharmacokinetics over the clinical dose range. Steady state is reached in 3days, and once-daily administration of 150 mg is expected to result in minimal solriamfetolaccumulation (1.06 times single-dose exposure).

Compared to subjects with normal renal function (eGFR≥90 mL/min/1.73 m2), AUC of solriamfetolwas higher by approximately 1.5-, 2.3-, and 4.4-fold, and t1/2 increased approximately 1.2-, 1.9-, and3.9- fold in patients with mild (eGFR 60-89 mL/min/1.73 m2), moderate (eGFR30-59 mL/min/1.73 m2), or severe (eGFR<30 mL/min/1.73 m2) renal impairment, respectively. Ingeneral, mean Cmax and median Tmax values were not affected by renal impairment.

Compared to subjects with normal renal function (eGFR≥90 mL/min/1.73 m2), AUC of solriamfetolwas higher by approximately 6.2- and 4.6-fold, respectively, in patients with ESRD withouthemodialysis and in patients with ESRD undergoing hemodialysis, and t1/2 increased at least 13-fold.

Solriamfetol is not recommended for use in patients with ESRD. In patients with ESRD, an average of21% of solriamfetol was removed by hemodialysis.

Lactation and Breast-feeding

A single-dose milk and plasma lactation study was conducted in 6 healthy adult lactating women whowere between 15 and 37 weeks postpartum and were administered a single oral 150 mg dose of

Sunosi. The cumulative mean amount excreted in breast milk was 0.59 mg over 24 hours, which isabout 4% of the maternal dose on a weight-adjusted basis. Of the total amount of solriamfetolexcreted in breast milk over 72 hours, approximately 78% and 98% were excreted by 8 and 24 hours,respectively, with an apparent mean elimination half-life in breast milk of about 5 hours.

Population PK analysis indicated that the intrinsic covariates of age, gender, and race do not haveclinically relevant effects on the pharmacokinetics of solriamfetol.

Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity,and male and female fertility.

Repeated dose toxicity studies with daily oral application were conducted in mice (duration 3 months,

NOAEL 17 mg/kg/day), rats (duration 6 months with a 3-month recovery period, NOAEL notestablished, LOAEL 29 mg/kg/day) and dogs (duration 12 months with a 3-month recovery period,

NOAEL not established, LOAEL 8 mg/kg/day). AUC-based safety factors for solriamfetol derivedfrom these studies (based on comparison with clinical AUC at the maximum recommended human doseof 150 mg/day) were <1 for mice (based on NOAEL) and <2 for rats and dogs (based on LOAEL),mainly due to exaggerated pharmacological effects of solriamfetol on CNS activity.

Long-term carcinogenicity studies have been performed in mice, treated with oral solriamfetol dosesof 20, 65 and 200 mg/kg/day for up to 104 weeks, and in rats, treated with oral solriamfetol doses of35, 80 and 200 mg/kg/day for up to 101 weeks. Solriamfetol did not increase the incidence ofneoplastic findings in these lifetime carcinogenicity assays. AUC-based safety margins at the highdose to the maximal recommended human dose (MRHD, 150 mg/day) were about 7.8 in mice andabout 20.7 in rats. In the light of negative genotoxicity and no increase of tumour incidence in bothcarcinogenicity studies, it can be concluded that solriamfetol does not pose a carcinogenic risk tohumans. Compared to controls, survival rate was decreased in solriamfetol-treated (male) mice,maximal at a dose of 65 mg/kg/day (AUC-based safety margin to MRHD about 2.9), but not insolriamfetol-treated rats.

Embryofoetal development

Possible effects on embryofoetal development were investigated in pregnant rats and rabbits.

Embryofoetal toxicity (increased postimplantation loss in rats, increased incidence of skeletalalterations that included sternebrae malalignment in rats and rabbits, hindlimb rotation and bent bonesin rats, and decreased foetal weights in both species) and situs inversus in rats was only evident in thepresence of maternal toxicity (decreased body weights). Whether embryotoxicity was a consequenceof maternal toxicity or a direct effect of solriamfetol cannot be determined. In a distribution study inpregnant rats 14C-solriamfetol was detected in foetal membrane (around twice as high as in blood),placenta and whole foetus (nearly similar to blood concentration) and thus a direct toxic effect on thefoetus cannot be excluded. In rats the exposure margins at the maternal and developmental NOAELare below the human exposure (0.6 - 0.7 based on AUC) at the MRHD, while in rabbits the exposuremargins at the maternal and developmental NOAEL is < 6 (based on mg/m2 body surface area).

Prenatal and postnatal Development

In rats exposure levels (AUC) above 0.6 - 0.7 times the human exposure (AUC) at the MRHD duringpregnancy and lactation resulted in maternal toxicity and adverse effects on growth and developmentin the offspring. At exposure levels (AUC) 8 to 12 times the human exposure (AUC) at the MRHD nolong-term effects on learning and memory were observed, but mating and pregnancy indices of theoffspring were decreased.

Hydroxypropyl cellulose

Magnesium stearate

Poly(vinyl alcohol)

Macrogol

Talc

Titanium dioxide (E 171)

Iron oxide yellow (E 172)

Not applicable.

5 years

Bottles after first opening: 120 days

Blisters: This medicinal product does not require any special storage conditions.

Bottles: Once opened, use within 4 months. Keep the container tightly closed in order to protect frommoisture.

7 x 1 film coated tablets in PVC/PCTFE/Aluminium perforated unit dose blisters.

PVC/PCTFE/Aluminium blister.

Packs containing 7, 28 or 56 film-coated tablets.

High density polyethylene (HDPE) bottle with polypropylene (PP) child-resistant cap with integratedsilica gel desiccant. Each bottle contains 30 or 100 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

Atnahs Pharma Netherlands B. V.

Copenhagen Towers

Ørestads Boulevard 108, 5.tv

DK-2300 København S

Denmark

EU/1/19/1408/001

EU/1/19/1408/002

EU/1/19/1408/003

EU/1/19/1408/004

EU/1/19/1408/005

EU/1/19/1408/006

EU/1/19/1408/007

EU/1/19/1408/008

EU/1/19/1408/009

EU/1/19/1408/010

Date of first authorisation: 16 January 2020

Date of latest renewal: 13 January 2025

MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.