Daridorexant - Uses, Side Effects, Dosage, Warning and Precautions, and Drug Interactions

Overview:

Daridorexant acts as an antagonist for both orexin type 1 and type 2 (OX1 and OX2) receptors and is used for the treatment of insomnia in adults. It has demonstrated efficacy in reducing insomnia symptoms, enhancing daytime functioning, and improving sleep quality overall. Daridorexant is an alternative treatment option for insomnia patients that circumvents the harsh side effects and dependence risks of conventional remedies such as benzodiazepines and sedatives.

Insomnia is a multifaceted sleep disorder that impacts numerous individuals across the globe. This disorder is frequently observed in conjunction with other comorbidities, making it a complex condition that necessitates a multidimensional approach to treatment. Cognitive-behavioral therapy for insomnia (CBT-I) is the first-line therapy for insomnia. The pharmacotherapy options for insomnia can be categorized into four classes according to their mechanism of action, which include benzodiazepine receptor agonists (BZRAs), histamine receptor antagonists, melatonin receptor agonists, and dual orexin receptor antagonists (DORAs).

How Does Daridorexant Work?

Daridorexant works as a dual antagonist for both orexin type 1 (OX1) and type 2 (OX2) receptors in the brain. The sleep-wake cycle is regulated by the orexin system, and orexin receptor antagonists like Daridorexant act by blocking the activation of these receptors by orexin neuropeptides, thereby reducing the arousal state and promoting sleep. By blocking both OX1 and OX2 receptors, Daridorexant has a more potent and sustained effect on sleep promotion than selective antagonists for either receptor alone. Daridorexant has demonstrated efficacy in improving sleep onset latency, total sleep time, and sleep maintenance in clinical trials, making it a promising treatment option for insomnia.

Uses:

Insomnia: Daridorexant is a US FDA (Food and Drug Association)-approved medication for the treatment of insomnia in adults. It is a dual antagonist for both orexin type 1 and type 2 (OX1 and OX2) receptors in the brain, and it works by reducing the arousal state and promoting sleep. Daridorexant has demonstrated efficacy in improving sleep onset latency, total sleep time, and sleep maintenance in clinical trials.

Dosage: Daridorexant is prescribed for individuals with insomnia, individuals having trouble staying asleep throughout the night, or falling asleep. The recommended dose for Daridorexant is 25 to 50 milligrams, taken orally once per night.

Warning:

• Daridorexant may impair daytime wakefulness. It may occur if there is less than a full night of sleep or with a higher-than-recommended dose.

• Co-administration with other CNS (central nervous system) depressants, such as benzodiazepines, opioids, tricyclic antidepressants, or alcohol, can increase the risk of CNS depression, leading to daytime impairment.

• Dosage adjustments of Daridorexant and concomitant CNS depressants may be necessary when administered together due to potentially additive effects. The use of Daridorexant with other drugs for insomnia is not recommended, and alcohol consumption during therapy is also not recommended.

• Patients, especially elderly individuals, may be at a higher risk of falls due to the potential for drowsiness. Orexin receptor antagonists such as Daridorexant may cause symptoms similar to mild cataplexy.

• These symptoms can occur at night or during the day and may not be related to a triggering event, such as laughter or surprise.

For Patients:

Learn About Insomnia

What Is Insomnia?

Insomnia negatively impacts an individual's sleep patterns and quality of life. Patients with insomnia struggle to initiate sleep, maintain sleep, or return to sleep after waking up early in the morning, leading to fatigue, mood changes, impaired memory, and reduced attentiveness. The International Classification of Sleep Disorders (ICSD-3) reclassified insomnia into short-term, chronic, and other subtypes for ease of diagnosis. Insomnia is often associated with coexisting comorbidities, necessitating a multifaceted approach to treatment.

Why Does Insomnia Occurs?

Insomnia is a complex disorder that lacks a universally accepted model for its pathophysiology, which can be attributed to its heterogeneity and co-occurrence with other conditions. Various models, including cognitive, neurobiological, behavioral, and emotional, are used to describe insomnia's manifestations. Despite differences in models, researchers agree that insomnia arises from an imbalance in brain centers that regulate sleep and wakefulness, such as those responsible for circadian rhythm and homeostasis. The ascending reticular activation system (ARAS) controls wakefulness, whereas the ventrolateral preoptic region (VLPR) is responsible for inducing sleep. The flip-flop switch, regulated by neurotransmitters GABA (gamma-aminobutyric acid) and galanin, demonstrates how sleep and wakefulness are mutually exclusive. Insomnia is now understood as a disorder of hyperarousal, characterized by excessive worrying, racing thoughts, elevated metabolic rate and blood pressure, high-frequency brain activity during sleep, and elevated cortisol levels. The 3P model, which considers predisposing, precipitating, and perpetuating factors, is the best way to describe insomnia's progression from acute to chronic stages.

Who Is at Risk of Developing Insomnia?

Insomnia has several predisposing factors, such as older age, female sex, previous episodes of insomnia, and family history. A genetic basis for insomnia has also been identified in a genome-wide association study that found several loci. Psychiatric comorbidities, such as anxiety, substance use disorders, and post-traumatic stress disorder, are present in 50 percent of patients with insomnia. Moreover, approximately 80 percent of individuals with major depressive disorder experience insomnia, and in almost half of the cases, insomnia precedes mood disorder.

Patients with insomnia is commonly present with difficulty initiating sleep, waking up too early without being able to fall back asleep, or staying asleep. This lack of sleep can negatively impact daily activities, including concentration, fatigue, work performance, and even driving safety. One hallmark of insomnia is the persistence of symptoms despite having ample opportunities for sleep.

Learn More About Daridorexant

Before Starting Daridorexant

• Prior to taking Daridorexant, inform the physician and pharmacist about any allergies to Daridorexant, other medications, or any ingredients present in the tablet.

• It is also necessary to inform about medications that are being taken or planned to be taken, including Amoxapine, Aprepitant, Clomipramine (Anafranil), and Clonazepam.

• The physician may need to adjust medication doses or monitor carefully for side effects.

• Certain medications may also interact with Daridorexant, so inform the physician about all medications being taken.

• Inform the physician about any herbal products.

• Additionally, informing the physician about having narcolepsy (excessive daytime sleepiness) as a Daridorexant may not be advised.

• Also, inform the physician about a history of alcohol or drug abuse, depression, mental illness, chronic obstructive pulmonary disease (COPD) (chronic lung disease that primarily affects the airways), sleep apnea (pauses in breathing or shallow breathing during sleep), any other lung or breathing problems, sudden muscle weakness, or liver disease.

• Inform the physician if pregnant, planning to become pregnant, or breastfeeding.

• If planning a surgery, including dental surgery, inform the doctor or dentist about taking Daridorexant.

Things to Tell Physicians Before They Prescribe Daridorexant:

• If narcolepsy is a condition that one has, it is not advisable to take Daridorexant.

• In addition, providing one's medical history to their healthcare provider, including any instances of mental illness, depression, suicidal ideation, drug or alcohol abuse or addiction, cataplexy (sudden and temporary loss of muscle tone), daytime sleepiness, breathing issues like sleep apnea, or liver problems, is important.

• The effect of Daridorexant on an unborn child is uncertain; therefore, informing one's physician if they are pregnant or planning to conceive is necessary. The name may be added to a pregnancy registry if pregnant to monitor the impact of Daridorexant on the fetus.

• Before using Daridorexant, checking with a physician if it is safe to breastfeed is recommended.

Starting Daridorexant

How to Take Daridorexant?

• Daridorexant is an orally administered tablet that should be taken once daily, as needed, at least 30 minutes prior to going to bed. The medication is more effective when taken on an empty stomach.

• Read the directions on the prescription label. If there are any unclear instructions, ask the doctor or pharmacist to explain them. One tablet per day is the recommended dose, and it should not be exceeded even if experiencing difficulty falling or staying asleep.

• Symptoms should start improving within seven to ten days of starting Daridorexant.

• The whole tablet should be swallowed and should never be split, chewed, or crushed. Daridorexant may be habit-forming, so it should not be taken in larger doses, more frequently, or for a longer period than prescribed by a doctor.

Look Out for the Side Effects:

Inform the doctor if any of these symptoms are severe or persistent:

• Headache.

• Fatigue.

• Daytime sleepiness.

• Dizziness.

• Nausea.

While some side effects may not be serious, others can be. These include:

• Inability to speak or inability to move for up to several minutes while falling asleep or waking up temporarily.

• Hallucinations while falling asleep or waking up.

• Weakness in the leg.

For Doctors

Indication:

Daridorexant is used to treat insomnia in adults suffering from the inability to fall asleep or stay asleep.

Pharmacology:

• Mechanism of Action- Daridorexant is a medication designed to target orexin receptors OX1 and OX2, inhibiting their effects and promoting sleep. This drug, also known as ACT-541468, has been recently approved by the FDA to treat insomnia and belongs to a novel class of drugs called DORAs, as it selectively and potently acts on both OX1 and OX2 receptors. Orexinergic neurons located in the hypothalamus are known to project their axons to various wake-promoting regions of the brain, such as dorsal raphe, ventral tegmental area, locus coeruleus, tuberomammillary nucleus centers, and laterodorsal tegmental nuclei, where serotonergic, dopaminergic, noradrenergic, histaminergic, and cholinergic neuronal projections are found. While traditional hypnotics that target these receptors, including GABA-A, have been used in the past to treat insomnia, the development of specific DORA agents like Daridorexant offers a unique approach that leads to fewer side effects and does not interfere with the sleep-wake architecture.

• Pharmacodynamics- Daridorexant is a medication taken orally with a half-life of approximately eight hours when administered at a 25 mg (milligrams) dosage. It is metabolized in the liver by the cytochrome P450 3A4 enzyme, with metabolites excreted in both urine (28 percent) and feces (57 percent). In in-vitro experiments, Daridorexant has inhibition constants (Kb) of 0.52 nM and 0.78 nM on human orexin receptors OX1 and OX2, respectively. During human trials, the medication's effects declined to baseline levels after three to six hours and six to eight hours for dosages of 25 mg and 50 milligrams, respectively, with its maximum effective capacity reaching approximately 1.5 to two hours after administration for dosages up to 100 mg. A double-blind clinical trial assessing human abuse potential in users with a history of sedative addiction (n=63) showed that Daridorexant had drug-liking visual analog scale (VAS) Emax values of 73.2, 79.1, and 81.3 at 50, 100, and 150 mg, respectively, with a lower VAS Emax than zolpidem 30 mg and suvorexant 150 mg at the 50 mg dosage (p ≤ 0.0007). Additionally, QT intervals did not prolong with dosages between 25 to 200 mg.

• Absorption- Within one to two hours of administration, Daridorexant achieves its maximum plasma concentration. The drug has an absolute bioavailability of 62 percent. A high-fat or high-calorie meal can postpone the time to reach maximum plasma concentration (Tmax) by 1.3 hours and reduce the maximum plasma concentration (Cmax) by 16 percent, but it did not affect the overall exposure (AUC).

• Metabolism- To a great extent, Daridorexant is metabolized through oxidative transformations, primarily by the CYP3A4 enzyme, accounting for approximately 89 percent of its metabolic clearance. Other CYP enzymes have a minor role, with less than a three percent contribution to the metabolic clearance of Daridorexant.

• Elimination- Approximately five to seven percent of the drug excretion occurs through feces, while around 28 percent is excreted through urine, mainly in the form of metabolites. Minimal quantities of the parent drug were detected in both urine and feces.

What Are the Warnings and Precautions for the Drug?

• When prescribing Daridorexant, it is important to be cautious of patients exhibiting symptoms of depression, as worsening depression or suicidal ideation may occur.

• Signs and symptoms of suicide should be monitored, and protective measures should be provided.

• Sleep paralysis and hypnagogic or hypnopompic hallucinations can occur, so it is necessary to explain the nature of these events when prescribing.

• There have been reports of cognitive and behavioral changes, such as amnesia, anxiety, hallucinations, and other neuropsychiatric symptoms, associated with hypnotics.

• If complex sleep behavior occurs, therapy should be discontinued immediately. Daridorexant's effects on respiratory function should be considered in patients with compromised respiratory function. The drug has not been studied in patients with moderate obstructive sleep apnea (OSA) requiring continuous positive airway pressure, severe OSA, or severe chronic obstructive pulmonary disease.

• The patients should be reevaluated for comorbid conditions.

Dosage Strength and Forms:

Daridorexant is available in tablet form and is classified as a Schedule IV controlled substance. It comes in two strengths: 25 mg and 50 mg.

Considerations for Administration:

CYP3A4 Inducers:

Concomitant use of Daridorexant with moderate or strong CYP3A4 inducers should be avoided.

CYP3A4 Inhibitors:

It is recommended to avoid using strong CYP3A4 inhibitors concurrently with Daridorexant. In the case of moderate CYP3A4 inhibitors, the dose of Daridorexant should not exceed 25 mg per night.

Renal Impairment:

Dosage modification is not necessary for patients with any severity of renal impairment.

Hepatic Impairment:

For patients with moderate hepatic impairment (Child-Pugh score of 7 to 9), the dose of Daridorexant should not exceed 25 mg per night. It should be avoided in patients with hepatic impairment (Child-Pugh score ≥10).

Drug Interactions:

Daridorexant can increase the risk or severity of CNS depression when combined with 1,2-Benzodiazepine, Acetazolamide, Acetophenazine, Agomelatine, Alfentanil, Alimemazine, Almotriptan, Alosetron, or Alprazolam. Additionally, the serum concentration of Daridorexant can be increased when combined with Abametapir.

When combined with Baclofen, Benperidol, Benzocaine, Benzphetamine, Benzyl alcohol, or Boceprevir, Daridorexant can increase the risk or severity of CNS depression, while the metabolism of Daridorexant can be affected by Berotralstat, Bexarotene, or Bosentan.

Other Specifications:

• Daridorexant During Pregnancy- The safety of Daridorexant during pregnancy has not been established.

• Breastfeeding and Daridorexant- It is not known if Daridorexant is excreted in human milk, and the effects of the drug on breastfed infants are unknown, so caution should be exercised when Daridorexant is administered to a breastfeeding woman.

• Daridorexant in Geriatric Patients- The safety and effectiveness of Daridorexant in geriatric patients is not fully established; therefore, care should be taken while using it in this population.