Lemborexant - Uses, Mechanism of Action, Side Effects, and Precautions

Overview:

An orexin antagonist drug called Lemborexant, marketed under the trade name Dayvigo, is used to treat insomnia. It is specifically prescribed for individuals with insomnia, which manifests itself as problems in falling asleep, staying asleep, or maintaining sleep. The drug is consumed orally. It is thought that orexin signaling encourages periods of alertness. By attaching to both orexin receptor subtypes, Lemborexant blocks orexin signaling. The most frequent adverse effect associated with Lemborexant use is sleepiness. As a result, narcolepsy patients should not use Lemborexant.

Due to its potential for abuse or dependence, Lemborexant is a substance that is under federal regulation. To avoid misuse and abuse, store the medication safely. It is illegal to sell or give away the medication since it can potentially hurt other people. If someone has ever abused or been dependent on alcohol, prescription drugs, or illegal substances, they should let their doctor know about their history.

Insomnia is most likely caused by the brain's failure to "turn off" wake-promoting circuits and not being able to "switch on" sleep-related circuits, according to recent studies in the field of sleep disorders. Lemborexant and other orexin antagonists act to counteract unwarranted wakefulness, in contrast to historically well-liked pharmacologic therapies for insomnia (such as Zopiclone, Zolpidem, and benzodiazepines), which concentrate on improving sleep drive through modulation of melatonin and GABA receptors. This innovative method of action may herald the start of a new wave of therapy alternatives for individuals with insomnia, offering potential benefits over traditional hypnotic drugs, such as a more favorable negative effect profile and possibly higher efficacy.

How Does Lemborexant Work?

Many physiologic processes, including the regulation of sleep and wakefulness, are mediated by the orexin neuropeptide signaling system. Orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R) are present on neurons in the hypothalamus that project to various wake-controlling nuclei. Orexin-A and orexin-B activate these receptors. The activity of each receptor varies slightly; for example, activating the OX1R appears to prevent the development of rapid eye movement (REM) sleep, whereas activating the OX2R appears to prevent non-REM sleep.

OX1R and OX2R have Lemborexant as a competitive antagonist. Lemborexant lowers the wake drive and consequently encourages sleep by preventing the binding of the orexin-A and B that promotes waking at these receptors.

Lemborexant gets to work right away to aid in getting one to sleep. If someone takes Lemborexant with or right after a meal, it can take longer to start working. Only take the drug dose right before night because it wears off so quickly. It is advised to take Lemborexant only if someone has at least seven hours before they need to resume their normal activities.

Indications for Usage:

Lemborexant is used for the treatment of adult patients with insomnia who have trouble falling asleep or staying asleep.

Contraindications for the Usage of the Drug:

Lemborexant is contraindicated in patients suffering from narcolepsy.

Dosage of Lemborexant:

Lemborexant's recommended dosage is 5 milligrams, given as soon as possible before bed, no more than once per night, and at least seven hours before the intended time of waking up. On the basis of clinical response and tolerability, the dosage of the drug may be increased to 10 milligrams.

Warnings and Precautions:

1. Effects as CNS Depressants and Daytime Impairment:

   Even when taken as directed, the central nervous system (CNS) depressant Lemborexant may reduce daytime wakefulness. Some patients may experience CNS depressive side effects for several days after stopping the drug. Patients should be informed by their prescribers if somnolence on the next day is a possibility. Some patients using Lemborexant 10 mg reported having trouble driving. If Lemborexant is consumed with less than a full night of sleep remaining or if a higher dose is given than indicated, the risk of daytime impairment increases. Patients should be advised against driving and other tasks demanding total mental awareness if Lemborexant is used in these situations. The risk of central nervous system (CNS) depression, which can result in daytime impairment, is increased when other CNS depressants (such as benzodiazepines, opioids, and tricyclic antidepressants) are co-administered. Due to possible synergistic effects when taken concurrently, Lemborexant and concomitant CNS depressants may require dosage changes. It is not advised to combine Lemborexant with other medications to treat insomnia. Due to the cumulative effects, patients should be warned not to combine alcohol with the medication. Patients, particularly the aged, are at a higher risk of falling because Lemborexant can make them drowsy.

2. Complicated Sleep Patterns:

   The use of hypnotics like Lemborexant has been documented to cause complex sleep behaviors, such as sleep-driving, sleep-walking, and engaging in other activities while not completely awake. These things can happen under hypnosis both in uninitiated and hypnotically skilled individuals. Patients typically do not recall these incidents. Following the initial or any future use of Lemborexant, complex sleep patterns may develop, with or without concurrent use of other CNS depressants and alcohol. In the event that a patient exhibits complex sleep behavior, stop taking Lemborexant right away.

3. Effect on Patients With Impaired Respiratory Function:

   If Lemborexant is recommended to individuals with impaired respiratory function, the medication's impact on respiratory health should be taken into account. Patients with mild to severe obstructive sleep apnea or those with chronic obstructive pulmonary disease (COPD) have not been examined with Lemborexant.

4. Hallucinations During Hypnagogic or Hypnopompic States, Sleep Paralysis, and Symptoms Similar to Cataplexy:

   With the usage of Lemborexant, it is possible to have hypnagogic or hypnopompic hallucinations, including vivid and unsettling perceptions, as well as sleep paralysis, an inability to move or talk for up to several minutes during sleep-wake transitions. When recommending Lemborexant to patients, prescribers should discuss the nature of these events with them. With Lemborexant, mild cataplexy-like symptoms are possible. These symptoms can include brief episodes of limb weakness that last a few minutes or longer, might happen throughout the day or night, and may not be linked to a specific trigger.

5. Need for Comorbid Diagnosis Evaluation:

   Treatment for insomnia should only begin after a thorough assessment of the patient, as sleep difficulties may be the presenting symptom of a medical or psychological disorder. After seven to ten days of treatment, if insomnia does not improve, it may be a sign of a primary psychiatric or medical disorder that needs to be assessed. A previously unidentified underlying psychiatric or medical problem may worsen insomnia or cause the emergence of new cognitive or behavioral abnormalities. This can happen when taking sleep aids like Lemborexant for therapy.

6. Depression or Suicidal Thoughts Getting Worse:

   The incidence of suicide ideation or any other suicidal conduct, as measured by a questionnaire in clinical investigations with Lemborexant in patients with insomnia, was greater in those getting Lemborexant than in those receiving placebo. Hypnotics have been used to treat mostly depressed individuals, and reports of worsened depression and increased suicidal ideation and behavior, including completed suicides, have been made. Such patients may exhibit suicidal tendencies, in which case safety precautions may be necessary. This particular patient population has a higher incidence of intentional overdose; as a result, the fewest amount of tablets that is technically possible should be provided at any given moment. Any new behavioral symptom or sign of concern should be carefully monitored and immediately evaluated.

Adverse Reactions to Lemborexant:

• Sleepiness lasts into the following day.

• Nightmares or strange dreams.

• Headache.

• Palpitations in the heart.

• Fluttering heartbeat sensation.

• Hammering feeling in the chest or neck.

• Hallucinations occur right before going to sleep or waking up.

• Abrupt limb or muscle weakness, lasting a few seconds to a few minutes.

• Changes in behavior or mood.

• Protracted sadness and losing interest in once-enjoyable activities.

• Waking paralysis.

• Unusual sleep habits, such as sleepwalking and excessive drowsiness.

• An allergic response.

• Suicidal ideas or actions.

For Patients

What Is Insomnia?

A common sleep issue known as insomnia can make it difficult to fall asleep, remain asleep, or lead people to wake up too early and have trouble falling back asleep. When one wakes up, one can still feel worn out. Health, productivity at work, and quality of life can all be negatively impacted by insomnia, in addition to energy level and mood. Individual needs for sleep vary, but most individuals need seven to eight hours per night. Many individuals eventually go through short-term or acute insomnia, which can endure for days or weeks. Typically, stress or a traumatic incident is the cause. However, some persons experience persistent long-term insomnia that lasts for a month or longer. The main issue can be insomnia, or it might be brought on by other illnesses or drugs.

What Causes Insomnia?

The onset of insomnia can be caused by a variety of environmental, physiological, and psychological causes, such as:

• Life's stresses might come from a job, relationships, finances, and more.

• Unhealthy sleep and lifestyle choices.

• Depression, anxiety, and other mental health issues.

• Chronic illnesses, such as cancer.

• Chronic pain due to fibromyalgia, arthritis, or other diseases.

• Digestive illnesses, such as heartburn.

• Fluctuating hormone levels due to menstruation, menopause, thyroid disease, or other conditions.

• Neurological conditions like Parkinson's disease or Alzheimer's disease.

• Other sleep disorders such as restless leg syndrome and sleep apnea.

What Are the Symptoms of Insomnia?

• Difficulty sleeping at night.

• Having a night-time awakening.

• Early rise.

• Daytime drowsiness or fatigue.

• Anger, sadness, or irritability.

• Inability to concentrate, pay attention, or remember stuff.

• Increased mistakes or mishaps.

• Persistent concerns about sleep.

How Is Insomnia Diagnosed?

There is no particular test to identify insomnia. The doctor will perform a physical examination and ask the patient questions to find out more about their symptoms and sleep issues.

The doctor could advise the patient to get a blood test to rule out any disorders that could be impairing their sleep, like thyroid issues or low iron levels.

Patients could be requested to record their sleeping habits for one to two weeks (bedtime, wake time, naps, caffeine use, etc.). The healthcare professional may be able to discover patterns or actions that disrupt sleep using this information from the sleep journal.

Polysomnograms, or sleep tests, are not required to diagnose insomnia. One might be referred for the test if their doctor thinks sleep apnea or another sleep condition is to blame for their insomnia. These studies can either be conducted in a facility for sleep disorders or at home.

How to Treat Insomnia?

Most of the time, short-term insomnia gets better by itself. The healthcare practitioner might suggest these remedies for chronic insomnia:

Cognitive behavioral therapy for insomnia. With CBT-I, patients may quickly identify the thoughts and behaviors that are contributing to or making their insomnia worse while also replacing them with routines that encourage restful sleep. CBT-I, as opposed to sleeping drugs, aids in overcoming the root causes of sleep issues.

Changes in behavior and way of life are the most effective long-term sleep aids. But occasionally, taking sleeping medications for a brief period of time will help patients fall asleep. Doctors advise just occasionally or for a brief period of time using sleep aids. For the treatment of persistent insomnia, they are not the first option.

Before taking Lemborexant, a patient should inform their healthcare practitioner about all of their medical conditions, especially if they:

• Have past drug or alcohol abuse or addiction.

• Experience rapid onset of muscle weakness (cataplexy).

• Experience sadness, mental disease, or suicidal thoughts.

• Experience daytime sleepiness.

• Have breathing or lung issues, including sleep apnea.

• Have a liver disease condition.

• Are breastfeeding or intend to breastfeed.

• Are trying to get pregnant.

All of the medications that patients use, including prescribed and over-the-counter medications, vitamins, and herbal supplements, should be disclosed to the healthcare physician. Serious adverse effects may result from using Lemborexant with specific medications. Both Lemborexant and other medications have the potential to influence how they function.

Unless the doctor specifically instructs the patient to avoid using Lemborexant with other drugs that may cause drowsiness.

Avoidances Patients Should Follow While Taking Lemborexant:

When using Lemborexant, avoid drinking alcohol. The likelihood of experiencing severe adverse effects may increase. If a patient takes Lemborexant and has not had a full night's sleep (at least 7 hours), or if they have taken more Lemborexant than recommended by their healthcare practitioner, avoid driving, operating heavy machinery, engaging in risky activities, and other tasks that call for alert judgment. Lemborexant may leave the patient feeling sleepy the next day. Until they feel fully awake, refrain from driving or engaging in other risky activities.

Serious Negative Effects of Lemborexant Include:

1. Sleep paralysis- The momentary incapacity to speak or move for a few minutes as you are falling asleep or waking up.

2. Momentary weakness in the legs occurs during the day or at night.

3. Complicated sleep behaviors include sleep-driving, sleep-walking, making and eating meals, making phone calls, having sex, or engaging in other activities that you might not recall the next morning.

4. Suicidal thoughts and worsened depression occur while receiving treatment with Lemborexant.

5. Sleepiness is one of Lemborexant's most frequent side effects.

These are not all of Lemborexant's potential negative effects. If a patient needs medical advice, or if any of their adverse effects have changed or gotten worse, they should call their doctor.

How Should Lemborexant Be Taken?

• Take Lemborexant precisely as directed by your healthcare professional.

• Lemborexant should only be used once each night, just before bed.

• Only use Lemborexant if you can spend the entire night in bed (at least 7 hours).

• If you take Lemborexant with or right after a meal, it can take longer to take effect.

• Do not raise your Lemborexant dosage without first consulting your doctor. If insomnia (sleep issue) worsens or does not get better within 7 to 10 days, contact your healthcare professional. This could imply that another condition is causing your sleep issue.

• If you take too much Lemborexant, contact your doctor or head to the emergency room of the closest hospital.

How Should Lemborexant Be Kept?

Store Lemborexant between 68 and 77 degrees Fahrenheit (20 and 25 degrees Celsius).

Keep Lemborexant and all medications away from kids.

For Doctors

Chemical Taxonomy:

Kingdom- Organic Compounds.

Super Class- Organic Nitrogen Compounds.

Class- Organonitrogen Compounds.

Sub Class- N-aryl amides.

Direct Parent- N-aryl amides.

Mechanism of Action:

Control over sleep and wakefulness is one of the many physiologic processes in which the orexin neuropeptide signaling system is involved. Orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R), which are present on neurons in the hypothalamus and project to various wake-controlling nuclei, are activated by orexin-A and orexin-B. Rapid eye movement (REM) sleep appears to be suppressed when the OX1R receptor is activated, whereas non-REM sleep appears to be suppressed when the OX2R receptor is activated.

OX1R and OX2R's competitive antagonist is Lemborexant. Lemborexant inhibits orexin-A and orexin-B's ability to bind to these receptors, hence suppressing the wake drive and promoting sleep.

Pharmacodynamics:

By opposing the effects of wake-promoting substances in the brain, Lemborexant encourages sleep. Lemborexant users have reported five episodes of sophisticated sleep activities, including eating, having sex, and making phone calls; these events may occur in both hypnotic-naive and hypnotic-experienced users and users are unlikely to recall these experiences. Patients displaying complicated sleep patterns should stop using Lemborexant right away. Lemborexant may have some misuse potential; thus, individuals with a history of alcohol or drug addiction should use it with caution. The Drug Enforcement Administration is currently reviewing its controlled substance schedule.

Pharmacokinetics:

AUC0-24h and geometric mean Cmax increased slightly less than in proportion to dose after single doses of Lemborexant 2.5 to 75 mg. Lemborexant accumulates 1.5 to 3 times as much at a steady state across this dosing range.

Metabolism:

Lemborexant is predicted to be substantially metabolized given that less than 1 % of an injected dose is recovered unchanged in the urine, which has been validated in rat and monkey models, but its metabolism in humans has not been thoroughly described. According to the prescribing information, CYP3A4 is primarily responsible for its metabolism, with CYP3A5 having a minor role. Lemborexant's metabolite, which is pharmacologically active and binds to the orexin receptors with a similar affinity to the parent drug, is the main circulating metabolite. The M10 metabolite is a substrate of P-gp transporters, has the ability to stimulate CYP3A and CYP2B6 enzymes, and only faintly inhibits CYP3A enzymes.

Elimination:

Following oral administration, 29.1 % of the dosage is excreted in the urine, and 57.4 % is detected in the feces. Less than 1 % of the dose retrieved in the urine is the parent drug in its unmodified form, indicating significant metabolism.

Toxicity:

There is little clinical evidence of a Lemborexant overdose. It is expected that overdose symptoms will be consistent with the side effect profile of Lemborexant, given that the healthy patients receiving doses up to 10 times the authorized maximum dose observed dose-dependent increases in the frequency of adverse events such as somnolence. Implement supportive measures and consult your local poison control center for the most recent management techniques in the event of an overdose. Hemodialysis is likely to be ineffective in cases of overdose since Lemborexant is largely protein-bound.

Non-clinical Toxicology: Mutagenesis, Carcinogenesis, and Fertility Impairment

Carcinogenesis: In rats treated for two years at oral doses, which are >80 times the MRHD based on AUC, Lemborexant did not increase the occurrence of tumors.

Mutagenesis: Lemborexant was not mutagenic or clastogenic in the in vivo rat micronucleus assay, in vitro mouse lymphoma thymidine kinase assay, or in the bacterial reverse mutation experiment.

Impairment of Fertility: Lemborexant was given orally to female rats at doses before, during, and after mating, as well as until day six of pregnancy. At 60 times, irregular estrous cycles and a decreased pregnancy rate were seen, while at >500 times, fewer corpora lutea, implantations, and viable embryos were seen. When given orally to male rats prior to and during mating, Lemborexant did not influence fertility.

Experience With Clinical Trials:

Because adverse reaction rates in clinical trials are determined under a variety of different circumstances, they cannot be directly compared to adverse reaction rates in clinical trials of other drugs and may not accurately represent rates seen in actual clinical practice.

1418 adult patients with insomnia disorders (aged 18 to 88 years) from two controlled effectiveness trials had their safety with Lemborexant assessed (study 1 and study 2). A 6-month parallel-group extension period followed study 1's 6-month placebo-controlled trial evaluating Lemborexant 5 or 10 mg once nightly. During this time, patients who had previously been prescribed Lemborexant continued to take that dosage, while those who had previously received a placebo were re-randomized to receive Lemborexant 5 or 10 mg once nightly.

Patients on Lemborexant 10 mg and 5 mg experienced discontinuation rates of 8.3 percent and 4.1 percent, respectively, over the 6-month placebo-controlled phase of study 1, compared to patients taking placebo, who experienced a discontinuation rate of 3.8 percent. Sleepiness, nightmares, and palpitations were the most frequent causes of discontinuation of the Lemborexant.

Dosage and Administration:

The dosage for Lemborexant is 5 mg, given as soon as possible before bed, no more than once per night, and at least 7 hours before the intended time of awakening. On the basis of the clinical response and tolerability, the dose may be increased to the maximum advised dose of 10 mg if taken with a meal or immediately after a meal; the time until sleep onset may be delayed. The use of Lemborexant together with strong or moderate CYP3A inhibitors should be avoided. When co-administered with mild CYP3A inhibitors, the maximum recommended dosage of Lemborexant is 5 mg, no more than once per night. Avoid using Lemborexant concurrently with CYP3A inducers that are strong or moderate. In patients with mild hepatic impairment, the maximum recommended dose of Lemborexant is 5 mg, administered no more than once per night. Patients having severe hepatic impairment should not use Lemborexant.

Dosage Form and Strength:

Lemborexant tablets come in the following dosage forms and strengths: 5 mg tablets, which are pale yellow, biconvex, round, film-coated tablets debossed with "5" on one side and "LM" on the other. 10 mg pills, which are orange, round, biconvex, and film-coated tablets debossed with "10" and "LM," respectively.

Usage of the Drug in a Specific Population:

1. Patients With Hepatic Impairment:

   Patients with significant hepatic impairment have not been studied when taking Lemborexant. It is not advised to use the drug in this population. Patients with moderate hepatic impairment had higher Lemborexant exposure as well as terminal half-life. Patients with mild hepatic impairment should have their dosage adjusted. They had higher Lemborexant exposure, but there was no change in the terminal half-life. An increased risk of somnolence may be present in patients with modest hepatic impairment.

2. Patients With Renal Impairment:

   In patients with mild to severe renal impairment, there is no need to alter the dose. Patients with severe renal impairment had higher Lemborexant exposure, and an increased risk of somnolence may be seen in them.

3. Patients With Impairment of Respiratory Function:

   Lemborexant did not raise the frequency of apneic events or lead to oxygen desaturation in a study of participants with mild OSA (apnea-hypopnea index less than 15 occurrences per hour of sleep). Lemborexant has not been evaluated in patients with chronic obstructive pulmonary disease (COPD) or moderate to severe OSA. It cannot be ruled out that Lemborexant will have clinically significant respiratory effects in those with COPD or moderate to severe OSA.

4. Pregnant Patients:

   Outcomes in women exposed to Lemborexant during their pregnancy are tracked via a pregnancy exposure registry. There are currently no data available on the use of Lemborexant during pregnancy that can be used to assess the drug's potential risks for serious birth abnormalities, miscarriage, or other undesirable maternal or fetal outcomes.

5. Lactating Patients:

   There is no data on Lemborexant's presence in breast milk, its effects on nursing infants, or its impact on milk production. The nursing rats' milk contains Lemborexant and its metabolites. If a medication is found in animal milk, it is likely to be found in human milk as well. Lemborexant exposure in breastfed infants should be watched for signs of severe sedation. Along with the mother's clinical requirement for Lemborexant and any potential negative effects from the drug or from the underlying maternal disease on the breastfed newborn, it is important to weigh the developmental and health benefits of breastfeeding.

6. Pediatric Patients:

   For pediatric patients, Lemborexant's efficacy and safety have not been proven.

7. Geriatric Patients:

   With Lemborexant 5 mg, somnolence was equally common in individuals under 65 and over 65 years old. Regardless of age, 2 % or less of patients receiving placebo experienced somnolence. Patients, especially the elderly, are more likely to fall because Lemborexant can make them drowsy and somnolent. When administering amounts greater than 5 mg to people under 65 years, use them with caution.

Drug Abuse and Dependence:

The purposeful, non-therapeutic use of a drug, even just once, for its pleasurable psychological or physiological benefits is known as abuse. Lemborexant 10 mg, 20 mg, and 30 mg produce responses on positive subjective measures like "drug liking," "overall drug liking," "take drug again," and "good drug effects" that were statistically comparable to those produced by the sedatives Zolpidem and Suvorexant, and statistically greater than those produced by the sedatives Phenobarbital and Suvorexant because those who have a history of alcoholism or drug addiction may be more susceptible to abuse and addiction, hence follow such patients carefully.

Physical dependency is a condition that arises through physiological adaptation in response to recurrent drug use and is characterized by withdrawal signs and symptoms following sudden cessation of drug usage or a considerable dose reduction. Lemborexant was chronically administered to animals in experiments and clinical trials examining physical dependence; however, there were no withdrawal signs or symptoms after the drug was stopped. Lemborexant may not cause physical dependence, according to this.

Overdose:

Clinical knowledge of Lemborexant overdose is minimal. Healthy patients who received numerous doses of Lemborexant up to 75 mg in clinical pharmacology trials demonstrated dose-dependent increases in the frequency of somnolence. An overdose of Lemborexant has no specific antidote currently on the market. In the case of an overdose, regular medical procedures for managing overdoses should be followed. When treating an overdose, give supportive care, pay attention to the possibilities of multiple drug involvement, and provide close medical supervision and monitoring. Lemborexant's value in the management of overdosage has not been established. Hemodialysis is not expected to help remove Lemborexant because it is highly protein-bound.