Lemborexant

Registered South African indications: 

• Insomnia
  - Characterised by difficulties with sleep onset and/or sleep maintenance

Registered South African contraindications

• Hypersensitivity to lemborexant or to any of the excipients
• Contraindicated in patients with narcolepsy

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Hepatic impairment

Elderly

• Because lemborexant can cause drowsiness, patients, particularly the elderly, are at a higher risk of falls

CNS depressant effects and daytime impairment

• Lemborexant is a central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed
• CNS depressant effects may persist in some patients for up to several days after discontinuing lemborexant
• Medical practitioners should advise patients about the potential for next day somnolence
• Driving ability was impaired in some subjects taking lemborexant 10mg
• The risk of daytime impairment is increased if lemborexant is taken with less than a full night of sleep remaining or if a higher than recommended dose is taken
• If lemborexant is taken in these circumstances, patients should be cautioned against driving and other activities requiring complete mental alertness

Co-administration with other CNS depressants

• Increases the risk of CNS depression, which can cause daytime impairment
• Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects
• The use of lemborexant with other medicine to treat insomnia is not recommended
• Patients should be advised not to consume alcohol in combination with lemborexant because of additive effects

Sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy-like symptoms

• Sleep paralysis and hypnagogic/hypnopompic hallucinations can occur with the use of lemborexant
• Medical practitioners should explain the nature of these events to patients when prescribing lemborexant
• Symptoms similar to mild cataplexy can occur with lemborexant

Complex sleep behaviours

• Complex sleep behaviours, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake, have been reported with the use of hypnotics such as lemborexant
• These events can occur in hypnotic-naïve as well as in hypnotic-experienced persons
• Patients usually do not remember these events
• Discontinue lemborexant immediately if a patient experiences a complex sleep behaviour

Compromised respiratory function

• The effect of lemborexant on respiratory function should be considered if prescribed to patients with compromised respiratory function
• In a study of patients with mild obstructive sleep apnoea (OSA), lemborexant did not increase the frequency of apnoeic events or cause oxygen desaturation
• Lemborexant has not been studied in patients with chronic obstructive pulmonary disease (COPD) or moderate to severe OSA
• Clinically meaningful respiratory effects of lemborexant in COPD or moderate to severe OSA cannot be excluded

Worsening of depression/suicidal ideation

• In clinical studies of lemborexant in patients with insomnia, the incidence of suicidal ideation or any suicidal behaviour, as assessed by questionnaire, was higher in patients receiving lemborexant than in those receiving placebo
• In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported

Co-morbid diagnoses

• Because sleep disturbances may be the presenting manifestation of a medical and/or psychiatric disorder, treatment of insomnia should be initiated only after careful evaluation of the patient
• The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated
• Worsening of insomnia or the emergence of new cognitive or behavioural abnormalities may be the result of an unrecognized underlying psychiatric or medical disorder and can emerge during the course of treatment with sleep-promoting medicines such as lemborexant

Abuse

• Abuse is the intentional, non-therapeutic use of a drug or medicine, even once, for its desirable psychological or physiological effects. Abuse potential was analysed in a controlled trial that enrolled recreational hypnotic users, and the potential abuse of lemborexant 10mg was found to be greater than that of placebo in the comparative trial (p-value: 0.995 that lemborexant 10mg and placebo are not similar)

Dependence

• Physical dependence is a state that develops as a result of physiological adaptation in response to repeated medicine use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a medicine. In animal studies and clinical trials evaluating physical dependence, chronic administration of lemborexant did not produce withdrawal signs or symptoms upon medicine discontinuation
• This suggests that lemborexant does not produce physical dependence

Excipient cautions

• Lemborexant contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine

Effects on ability to drive and use machines

• Driving ability was impaired in some subjects taking lemborexant 10mg 
• The risk of daytime impairment is increased if lemborexant is taken with less than a full night of sleep remaining or if a higher than recommended dose is taken 
• If lemborexant is taken in these circumstances, patients should be cautioned against driving and other activities requiring complete mental alertness

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Insomnia
- Characterised by difficulties with sleep onset and/or sleep maintenance

• Oral (fct): Initial: 5mg, once per night, immediately before going to bed, with at least 7hrs remaining before the planned time of awakening; Dose may be increased to the maximum recommended dose of 10mg based on clinical response and tolerability

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Method of administration
Lemborexant tablets are intended for oral administration. Time to sleep onset may be delayed if taken with or soon after a meal

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Dosage recommendations for coadministration with CYP3A inhibitors or CYP3A inducers
- Avoid concomitant use of lemborexant with strong or moderate CYP3A inhibitors
- The maximum recommended dosage of lemborexant is 5mg no more than once per night when co administered with weak CYP3A inhibitors
- Avoid concomitant use of lemborexant with strong or moderate CYP3A inducers

Safety and effectiveness have not been established in paediatric patients

Pregnancy

South African recommendations

• Caution; not recommended
• Lemborexant is not recommended in pregnancy. There are no available data on use in pregnant women to evaluate for medicine-associated risks of major birth defects, miscarriage or adverse maternal or foetal outcomes
• In animal reproduction studies, oral administration of lemborexant to pregnant rats and rabbits during the period of organogenesis caused toxicities only at high multiples of the human exposure at the maximum recommended human dose (MRHD) based on AUC
• The no observed adverse effect levels (NOAEL) are approximately >100 and 23 times the MRHD based on AUC in rats and rabbits, respectively. Similarly, oral administration of lemborexant to pregnant and lactating rats caused toxicities only at high multiples of the human exposure at the MRHD based on AUC. The NOAEL is 93 times the MRHD based on AUC
• Safety during pregnancy has not been established

Breastfeeding

South African recommendations

• Caution
• There are no data on the presence of lemborexant in human milk, the effects on the breastfed infant, or the effects on milk production
• Lemborexant and its metabolites are present in the milk of lactating rats at concentrations higher than in maternal plasma. When a medicine is present in animal milk, it is likely that the medicine will be present in human milk
• The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lemborexant and any potential adverse effects on the breastfed infant from lemborexant or from the underlying maternal condition
• Safety during breastfeeding has not been established

Fertility

South African recommendations

• No information available

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Lemborexant exposure (AUC) was increased in patients with severe renal impairment. Patients with severe renal impairment may experience an increased risk of somnolence

South African recommendations

• Mild (Child-Pugh class A): Caution; no dose adjustment recommended
  Patients with mild hepatic impairment may experience an increased risk of somnolence
• Moderate (Child-Pugh class B): Caution; dose adjustment recommended
  Lemborexant exposure (AUC and C_max) and terminal half-life were increased in patients with moderate hepatic impairment
• Severe: Caution; not recommended
  Lemborexant has not been studied in patients with severe hepatic impairment. Use in this population is not recommended

South African recommendations

• Caution; no dose adjustment recommended
  Higher risk of falls

Nervous system disorders
Common

• Somnolence or fatigue (combines preferred terms somnolence, lethargy, fatigue, sluggishness)
• Headache

Psychiatric disorders
Common

• Nightmare or abnormal dreams

Others

• CNS depressant effects and daytime impairment
• Sleep paralysis
• Hypnagogic/hypnopompic hallucinations, and cataplexy-like symptoms
• Complex sleep behaviours
• Compromised respiratory function
• Worsening of depression/suicidal ideation

Adverse reactions observed during clinical trials (Studies 1 and 2)

Adverse reactions of <2% incidence but greater than placebo

• Sleep paralysis
• Hypnagogic hallucinations
• Complex sleep behaviour 

• Strong CYP3A inhibitors
• Itraconazole
• Clarithromycin
• Moderate CYP3A inhibitors
• Fluconazole
• Verapamil
• Weak CYP3A inhibitors
• Ranitidine
• Strong CYP3A inducers
• Rifampin
• Carbamazepine
• Moderate CYP3A inducers
• Efavirenz
• Modafinil
• CYP2B6 substrates
• Bupropion
• Methadone

Other interactions

• Alcohol
• St. John’s wort

• Renal function (baseline and as clinically indicated)
• Hepatic function (baseline and as clinically indicated)

Additional observations

• Worsening depression
• Suicidality
• Mental alertness

Lemborexant is a competitive antagonist of both orexin receptors, OX1R and OX2R, with a higher affinity for OX2R. It belongs to the pharmacologic class of orexin receptor antagonists. The orexin neuropeptide signalling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive. Antagonism of orexin receptors may also underlie potential adverse effects such as signs of narcolepsy/cataplexy. Lemborexant administered to mice at oral doses greater than 10mg/kg resulted in behaviour characteristic of cataplexy when presented with chocolate.