达利雷生(Quviviq)详细说明书:适应症、用法用量、副作用、注意事项

As a fourth-generation anti-insomnia drug, Quviviq can effectively improve difficulty falling asleep and maintaining sleep by precisely regulating the sleep-wake pathway, with fewer side effects and no addiction.

1. Indications of Quviviq

Quviviq is suitable for the treatment of adult insomnia, characterized by difficulty falling asleep and/or sleep maintenance disorders.

The pictures are from public channels (such as the official website of the FDA, the official website of the original drug manufacturer, etc.) and are for reference only.

2. Usage and dosage of Quviviq

2.1 Recommended dosage

Take 25-50mg of the drug within 30 minutes before going to bed every day (it is best to wait at least 7 hours after taking the drug before planning to get up). If it is taken with or immediately after a meal, it may also delay the time to fall asleep.

2.2 Dose adjustment in combination with CYP3A4 inhibitors/inducers

Strong CYP3A4 inhibitors should be avoided in combination with Quviviq.

‌Moderate CYP3A4 inhibitors‌ It is recommended that the dose be adjusted to no more than 25 mg per night.

Strong or moderate CYP3A4 inducers should be avoided in combination with Quviviq.

2.3 Dose adjustment in patients with hepatic impairment

The maximum dose for moderate hepatic impairment (Child-Pugh score 7-9) is 25 mg/night.

Not recommended for severe hepatic insufficiency (Child-Pugh score ≥10).

2.4 Overdose

Clinical experience with overdose of Quviviq is limited. Clinical trials on healthy volunteers after a single oral administration of 200 mg (i.e., 4 times the recommended maximum dose of Quviviq) of Quviviq caused significant drowsiness, muscle weakness, cataplexy-like symptoms, sleep paralysis, significant attention impairment, fatigue, headache, constipation and other adverse reactions.

At present, there is no specific antidote and effective treatment for poisoning caused by Quviviq. In the event of overdose, symptomatic supportive treatment should be provided and gastric lavage should be performed immediately if appropriate, while the patient should be monitored closely. However, its dialysis effect may be greatly reduced due to its high degree of binding to proteins.

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3. Dosage forms and specifications of Quviviq

The 25 mg tablets are light purple, curved triangular film-coated tablets, with "25" engraved on one side and "i" (Idorsia company logo) engraved on the other side. Each tablet contains 25 mg of Quviviq.

‌50mg tablets‌ are light orange, curved triangular film-coated tablets, engraved with the word "50" on one side and "i" (Idorsia company logo) on the other side. Each tablet contains 50mg of DaliRasen.

4. Contraindications of Quviviq

(1) Patients with narcolepsy.

(2) Patients with a history of allergy to any component of Quviviq or Quviviq. Pharyngeal angioedema has been reported to occur.

5. Precautions for Quviviq

5.1 Central nervous system depressant effect and daytime functional impairment

Long-term or excessive use of Quviviq as prescribed may also have certain adverse effects on our waking state during the day. Some patients may have persistent CNS depressant effects for several days after stopping the drug. Prescribers should inform patients of the potential risk of next-day drowsiness.

Because DaliRazen may cause drowsiness, patients (especially the elderly) are at higher risk of falling.

5.2 Increased depression/suicidal ideation

Patients with mental disorders (including those with insomnia) are at increased risk of suicide. Clinical reports show that patients with depression treated with hypnotic drugs may experience worsening of depression and suicidal ideation and behavior. For patients with obvious depressive symptoms, the use of hypnotics as a hypnotic should be particularly cautious. In particular, the risk of suicide must be monitored and corresponding protective measures must be taken.

5.3 Sleep paralysis, sleep/awakening hallucinations and cataplexy-like symptoms

After receiving treatment with Quviviq, patients may experience a series of adverse reactions, such as sleep paralysis, making it difficult to move autonomously or speak during the process of waking up or falling asleep, and a series of sleep or waking hallucinations (particularly vivid and disturbing perceptions).

According to existing reports, long-term or acute orexin receptor antagonism may cause symptoms similar to mild cataplexy, such as transient lower limb weakness (lasting from seconds to minutes), which can mostly occur at night or during the day and often without clear triggers (such as laughter or surprise, etc.).

5.4 Complex sleep behaviors

When using hypnotic drugs, complex sleep behaviors may occur, such as sleepwalking, sleep driving, or engaging in other activities while not fully awake (such as preparing food, making phone calls, and having sex). When a patient develops complex sleep behaviors, we should immediately stop using long-term sleep hormone regulating drugs such as Quviviq.

5.5 Patients with impaired respiratory function

Considering the special respiratory function regulating effect of Quviviq, this should also be fully considered in the prescription of patients with inherently fragile respiratory functions. This drug has not been studied in people with mild or severe COPD.

5.6 Diagnostic assessment of comorbidities

Because sleep disturbances may be manifestations of underlying physical illnesses and/or mental disorders, insomnia treatment should be initiated only after careful evaluation of the patient. If insomnia symptoms do not resolve after 7 to 10 days of treatment, it may indicate a primary psychiatric or physical disorder that needs to be evaluated. Worsening insomnia symptoms or new cognitive/behavioral abnormalities may be manifestations of unrecognized mental or physical illnesses, which may occur during use of sleep-promoting drugs such as Quviviq.

6. Adverse reactions of Quviviq

‌Central nervous system depressant effects and daytime functional impairment, ‌exacerbation of depression/suicidal ideation, ‌sleep paralysis, sleep/wake hallucinations and cataplexy-like symptoms, ‌complex sleep behavior‌, and ‌patients with impaired respiratory function.

Since the launch of Quviviq, the following adverse reactions have been clinically exposed:

(1) Mental disorders: nightmares or abnormal dreams.

‌(2) Immune system diseases‌: hypersensitivity reactions (including angioedema, rash, urticaria).

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7. Drug interactions of Quviviq

7.1 Effects of other drugs on Quviviq Effects

(1) Strong or moderate CYP3A4 inhibitors‌

Combined use with strong or moderate CYP3A4 inhibitors will increase the exposure of daliradsin and may increase the risk of adverse reactions of daliradsin.

When used in combination with a moderate CYP3A4 inhibitor, the recommended dose of dalirasant is 25 mg. Concomitant use with strong CYP3A4 inhibitors is not recommended.

‌(2) Strong and moderate CYP3A4 inducers‌

Combined use with strong or moderate CYP3A4 inducers will reduce the exposure of daliradsin and may weaken the efficacy of daliradsin.

Concomitant use with strong or moderate CYP3A4 inducers is not recommended.

‌(3) Alcohol and other central nervous system depressants‌

Combined use with alcohol or other central nervous system depressants may lead to superimposed damage to psychomotor functions and increase the risk of central nervous system depression.

But please be sure to avoid alcohol as much as possible before taking DaliRasen to avoid the adverse effects of adverse drug interactions. However, special caution should be exercised when used in combination with central nervous system inhibitors, and the dosage of dalirasant and/or central nervous system inhibitors may even need to be adjusted appropriately based on the actual therapeutic effect.

7.2 Effects of Quviviq on other drugs

(1) ‌CYP3A4 substrate‌

Combined use with CYP3A4 substrates will increase the exposure of CYP3A4 substrates.

CYP3A4 substrates with narrow therapeutic windows should be used together with caution.

(2)‌P-gp substrate‌

Combined use with P-gp substrate will increase the exposure of P-gp substrate.

P-gp substrates with narrow therapeutic windows should be used together with caution.

8. Use of Quviviq in special populations

8.1 Pregnancy period‌

There are currently no available data on the use of Quviviq in pregnant women to assess drug-related risks of major birth defects, miscarriage or other adverse maternal and fetal outcomes. In animal reproduction studies, based on AUC (area under the curve), no fetal toxicity or malformations were observed at doses of 8 times and 10 times the maximum recommended human dose (MRHD) of 50 mg in pregnant rats and pregnant rabbits during the period of organogenesis. Based on AUC, no maternal or developmental toxicity was observed in pregnant and lactating rats at doses up to 9 times the MRHD.

The estimated background risk of major birth defects and miscarriage in this indicated population is unknown. All pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes. In the general U.S. population, the estimated background risks of major birth defects and miscarriage in clinically confirmed pregnancies are 2% to 4% and 15% to 20%, respectively.

8.2 Lactation period

Dalilaysan exists in human milk in low amounts. In a clinical lactation study, the test results of Dalirasin in human milk showed that based on the assumption that the infant weight was 6kg, the average daily infant dose was 0.0016mg/kg, and the relative infant dose was 0.22% of the mother's weight-adjusted dose. There are currently no data on the effects of DaliRazen on breastfed infants or on lactation.

Infants exposed to Quviviq through breast milk should be monitored for excessive sedation. The benefits of breastfeeding on infant development and health need to be weighed against the mother's clinical need for Quviviq and the potential adverse effects of Quviviq or the mother's underlying disease on the breastfed infant.

8.3 Pediatric Use

The safety and effectiveness of Quviviq in pediatric patients have not been established.

8.4 Geriatric use

No dose adjustment is required for patients aged 65 and above.

Because Quviviq may increase drowsiness and drowsiness, patients, especially older adults, are at higher risk of falls.

8.5 Hepatic Impairment

Quviviq has not been studied in patients with severe hepatic impairment (Child-Pugh score ≥ 10) and is not recommended for use in this population.

Patients with moderate hepatic impairment (patients with Child-Pugh score 7-9) should have their Quviviq dose reduced by half. Moderate hepatic impairment may result in clinically relevant increases in systemic exposure to dalirasin, which may increase the frequency or severity of adverse reactions.

8.6 Patients with impaired respiratory function

‌Obstructive sleep apnea‌: Due to the limitations of the study (such as the short study time), it cannot be ruled out that Quviviq has a clinically significant respiratory impact on OSA, including long-term treatment.

9. Storage method of Quviviq

Store at a stable storage temperature of 20°C to 25°C (i.e. 68°F to 77°F).

10. Clinical pharmacology of Quviviq

10.1 Mechanism of action

The mechanism of action of DaliRazen in treating insomnia is speculated to be through antagonizing orexin receptors. The orexin neuropeptide signaling system plays an important role in the wakeful state, and blocking the binding of the wake-promoting neuropeptides orexin A and orexin B to the receptors OX1R and OX2R is thought to inhibit wakefulness drive.

10.2 Pharmacodynamics

Dalirasan binds to orexin receptors OX1R and OX2R and inhibits their activity (Ki values ​​are 0.47 and 0.93nM respectively).

(1)‌Cardiac Electrophysiology‌

In the clinical trials of Quviviq, there was no clinically significant prolongation of the QT interval at a dose of 4 times the recommended maximum dose (200mg).

(2)‌Alcohol interaction‌

The combined use of a single dose of 50 mg Quviviq and alcohol with a blood concentration of 0.6g/L will cause a superimposed effect of impairment of psychomotor function (postural stability and alertness). DaliRazen does not affect alcohol concentration, and alcohol does not affect DaliRazen concentration.

(3) ‌Citalopram Interactions‌

Concomitant administration of 50 mg of Quviviq with 20 mg of citalopram failed to observe any significant clinical effects on psychomotor performance in healthy, steady-state subjects.

10.3 Pharmacokinetics

The plasma exposure of Dalirasin is dose proportional in the range of 25-50 mg. The pharmacokinetic characteristics of multiple doses and single doses are similar, and there is no accumulation phenomenon.

(1)‌Absorption‌

The peak (Tmax) of DaliRazen is 1-2 hours, and the absolute bioavailability is 62%.

(2)‌Food Effect‌

The intake of healthy subjects with high-fat and high-calorie meals caused a delay of Tmax by 1.3 hours and a decrease of Cmax by 16%, but had no significant impact on the total exposure (AUC).

(3)‌Distribution‌

The apparent distribution volume is 31L, the plasma protein binding rate is 99.7%, and the blood/plasma ratio is 0.64.

(4)‌Elimination‌

The terminal half-life is about 8 hours.

(5) Metabolism

Daliramin is extensively metabolized, mainly by CYP3A4 (89%), and the contribution of other CYP enzymes to metabolic clearance is less than 3%.

(6) Excretion

The main excretion route of dalireson is feces (about 57%), followed by urine (about 28%), all of which are excreted in the form of metabolites. Only trace amounts of unchanged drug were found in feces and urine.

11. Non-clinical toxicology of Quviviq

11.1 Carcinogenicity, mutagenicity and reproductive toxicity

(1) Carcinogenicity

Dalilayson did not increase the incidence of tumors in a 2-year oral administration test in rats (15, 50, 150mg/kg/day). The highest dose is 150 mg/kg/day (approximately 4 times the maximum recommended human dose [MRHD] of 50 mg based on AUC). In the 26-week test in Tg.rasH2 mice (males 100, 300, 1000mg/kg/day; females 100, 200, 1000mg/kg/day), there was no increase in tumor incidence.

(2)‌Mutagenicity‌

DaliRasen did not show mutagenicity in the following tests:

Bacterial reverse mutation test (Ames test);

Human lymphocyte in vitro mammalian chromosome aberration test;

Rat in vivo micronucleus test (non-clastogenic).

(3)‌Reproductive toxicity‌

‌Female rats‌:

Orally administered (30, 100, 300 mg/kg/day, approximately 0.5, 3, and 9 times the MRHD based on AUC) before mating to the 6th day of pregnancy. The 300 mg/kg/day dose group increased pre-implantation loss and reduced implantation sites, but did not affect mating or fertility. The no-observed adverse effect level (NOAEL) for female fertility is 100 mg/kg/day (approximately 3 times the MRHD).

‌Male Rat‌:

Oral administration before and during mating (50, 150, and 450 mg/kg/day, approximately 1, 3, and 7 times the MRHD based on AUC, respectively) did not affect fertility.

11.2 Animal Toxicology/Pharmacology

When dogs take daily oral administration of dalirasin ≥ 30mg/kg/day, they will develop cataplexy-like behavioral characteristics under positive stimulation. The no-observed effect level (NOEL) for cataplexy is 20 mg/kg/day (approximately 3 times the MRHD based on Cmax and AUC).