solriamfetol: prescribing information – dosing, contraindications, interactions, side effects

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

Sunosi is indicated to improve wakefulness and reduce excessive daytime sleepiness (EDS) in adult patients 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 narcolepsy or OSA.

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

Blood pressure and heart rate should be assessed before initiating treatment with solriamfetol and should be monitored periodically during treatment, especially after increasing the dose. Pre-existing hypertension should be controlled before initiating treatment with solriamfetol and caution should be exercised in treating patients at higher risk of major adverse cardiac events (MACE), particularly

patients with pre-existing hypertension, patients with known cardiovascular or cerebrovascular disease and elderly patients.

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

Posology

Narcolepsy
The recommended starting dose is 75 mg once daily, upon awakening. If clinically indicated in patients 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 at intervals 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 clinical response, the dose can be titrated to a higher level by doubling the dose at intervals of at least 3 days, 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 during extended treatment in patients prescribed solriamfetol.

Special populations

Elderly (> 65 years)
Limited data are available in elderly patients. Consideration should be given to the use of lower doses and close monitoring in this population (see section 4.4). Solriamfetol is predominantly eliminated by the kidney and since elderly patients are more likely to have decreased renal function, dosing may need to be adjusted based on creatinine clearance in these patients.

Renal impairment
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 is 37.5 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 mg once daily.

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

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

Method of administration

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 MAOI treatment has been discontinued (see section 4.5).

Summary of the safety profile

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

Tabulated list of adverse reactions

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 available data).

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

Description of selected adverse reactions

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

Hypersensitivity reactions
In post-marketing experience, there have been reports of hypersensitivity reactions which have occurred with 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 solriamfetol to 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 and narcolepsy patients. Certain events such as anxiety, insomnia, irritability, and agitation were commonly observed during treatment initiation, but tended to resolve with continued treatment. If these symptoms persist or worsen, dose reduction or discontinuation should be considered (see section 4.4).

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Psychiatric symptoms

Solriamfetol has not been evaluated in patients with a history of or concurrent psychosis or bipolar disorders. 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 treated with solriamfetol should be carefully monitored for adverse reactions such as anxiety, insomnia and irritability. These adverse reactions were commonly observed during treatment initiation, but tended to resolve with continued treatment. If these symptoms persist or worsen, dose reduction or discontinuation should be considered.

Blood pressure and heart rate

Analyses of data from clinical trials showed that treatment with solriamfetol increases systolic blood pressure, 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 adverse cardiovascular event (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 (BMI).

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

Patients with moderate or severe renal impairment may be at a higher risk of increases in blood pressure 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. Results from this clinical study demonstrated that solriamfetol produced Drug Liking scores higher than placebo, but generally similar or lower than phentermine (a weak stimulant). Caution should be exercised when treating patients with a history of stimulant (e.g. methylphenidate, amphetamine) or alcohol 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 increased ocular 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 contraception while 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 MAOI treatment has been discontinued because it may increase the risk of a hypertensive reaction (see section 4.3).

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

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

Pregnancy

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

Breast-feeding

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 milk production 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 Sunosi therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the women.

Fertility

The effects of solriamfetol in humans are unknown. Animal studies do not indicate direct or indirect harmful 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 section 4.8).

Patients with abnormal levels of sleepiness who take solriamfetol should be advised that their level of wakefulness may not return to normal. Patients with excessive daytime sleepiness, including those taking 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 the treatment or when the dose is changed.

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 adverse reaction of moderate akathisia that occurred at a supratherapeutic dose of 900 mg; symptoms resolved after treatment discontinuation.

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

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: psychoanaleptics, centrally acting sympathomimetics, ATC code:
N06BA14

Mechanism of action

The mechanism(s) of solriamfetol to improve wakefulness in patients with excessive daytime sleepiness 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 norepinephrine reuptake inhibitor (DNRI).

Pharmacodynamic effects

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 norepinephrine transporter (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 individual dopamine levels in the striatum and norepinephrine levels in the prefrontal cortex, and did not show appreciable binding to the rat dopamine and norepinephrine transporter in an autoradiography experiment.

Clinical efficacy and safety

Narcolepsy
Study 1, a 12-week, randomised, double-blind, placebo-controlled, parallel-group study, evaluated the 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 sleep latency 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 measured by mean sleep latency on the MWT, excessive daytime sleepiness as measured by the ESS, and improvement 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 usual daily life activities. The PGIc is a 7-point scale ranging from “very much improved” to “very much worse” which assesses the patient’s report of change in their clinical condition.

Patients with narcolepsy were characterised by impaired wakefulness and excessive daytime sleepiness, 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 of patients overall; demographic and baseline characteristics were similar between patients with cataplexy and those without cataplexy.

Absorption

The oral bioavailability of solriamfetol is approximately 95% with peak plasma concentrations occurring 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 taken without regard to food.

Distribution

The apparent volume of distribution of solriamfetol is approximately 198.7 L, indicating extensive tissue distribution beyond the vascular compartment. Plasma protein binding ranged from 13.3% to 19.4% over the solriamfetol concentration range of 0.059 to 10.1 µg/mL in human plasma. The mean blood-to-plasma concentration ratio ranged from 1.16 to 1.29, suggesting a small extent of binding of solriamfetol to blood cells.

Biotransformation

Solriamfetol is minimally metabolised in humans.

Interactions
With the exception of weak inhibition of CYP2D6 (IC50 of 360 µM), solriamfetol is not a substrate or inhibitor of any of the major CYP enzymes and does not induce CYP1A2, 2B6, 3A4 or UGT1A1 enzymes at clinically relevant concentrations. Solriamfetol does not appear to be a substrate or inhibitor of membrane transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1 or OAT3. Solriamfetol is primarily excreted unchanged in the urine and is a low-affinity substrate of multiple renal cationic

active 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 of 211 µM). Taken together, these results show that clinically relevant PK drug interactions are unlikely to occur in patients taking solriamfetol.

Elimination