DRUG INTERACTIONS- (summary)

­ • Strong CYP3A4 inhibitors: Avoid concomitant use.

 • Moderate CYP3A4 inhibitors: Maximum recommended dose is 25 mg.

 • Moderate or Strong CYP3A4 inducers: Avoid concomitant use.

DRUG INTERACTIONS-(Details)-

Drugs Having Clinically Important Interactions with QUVIVIQ-

Clinically Important Drug Interactions with QUVIVIQ Strong or Moderate CYP3A4 Inhibitors Clinical Implications:

1.Concomitant use with a strong or moderate CYP3A4 inhibitor increases exposure to daridorexant], which may increase the risk of QUVIVIQ adverse reactions.

Prevention or Management: The recommended dose of QUVIVIQ is 25 mg when used with a moderate CYP3A4 inhibitor .

Concomitant use of QUVIVIQ with a strong inhibitor of CYP3A4 is not recommended

2. Strong and Moderate CYP3A4 Inducers Clinical Implications:                         Concomitant use with a strong or moderate CYP3A4 inducer decreases exposure to daridorexant, which may reduce the efficacy of QUVIVIQ.

Prevention or Management: Concomitant use of QUVIVIQ with a strong or moderate inducer of CYP3A4 is not recommended .

3.Alcohol and Other CNS Depressants Clinical Implications:                         Concomitant use of alcohol or other CNS depressants with QUVIVIQ may lead to additive impairment of psychomotor performance and risk of CNS depression

Prevention or Management: Avoid alcohol consumption with QUVIVIQ

4. Use with caution in patients receiving CNS depressants. -                             Consider dose adjustment of QUVIVIQ and/or the CNS depressant(s) if used concomitantly

BRIEF SUMMARY

DARIDOREXANT-(Jan 2022)

Indicn- To treat Insomnia   

Comp- Tablets: 25 mg, 50 mg.The recommended dosage is 25 mg to 50 mg once per night, taken orally within 30 minutes before going to bed, with at least 7 hours remaining prior to planned awakening.

ADR- ­ The most common adverse reactions (reported in = 5% of patients treated with the drug and at an incidence = than placebo) were headache and somnolence or fatigue.

CI-­  is contraindicated in patients with narcolepsy.

WARNINGS -

­  CNS-Depressant Effects and Daytime Impairment: Impairs alertness and motor coordination including morning impairment. Risk increases when used with other central nervous system (CNS) depressants.

Pat inform -

Advise patients to take only in the evening within 30 minutes before going to bed and only if they can stay in bed for a full night (at least 7 hours) before being active again 

Advise patients that the effect of the drug may be delayed if taken with or soon after a meal

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U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 1

Name of the Drug-    QUVIVIQ

Active Ingredient -   Daridorexant

Pharmacological Classification- To treat Insomnia                                                                                                                                                                                                    Date of Approval-          1/7//22                                                                    

HIGHLIGHTS OF PRESCRIBING INFORMATION-

 These highlights do not include all the information needed to use                                   QUVIVIQ safely and effectively.                                                                                     See full prescribing information for QUVIVIQ. QUVIVIQ (daridorexant) tablets, for oral use, [controlled substance schedule pending]

Initial U.S. Approval: [pending controlled substance scheduling]

INDICATIONS AND USAGE-

­ QUVIVIQ is an orexin receptor antagonist indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

DOSAGE AND ADMINISTRATION-

­ • The recommended dosage is 25 mg to 50 mg once per night, taken orally within 30 minutes before going to bed, with at least 7 hours remaining prior to planned awakening.

 • Time to sleep onset may be delayed if taken with or soon after a meal.

• Hepatic Impairment:                                                                                                       o Moderate hepatic impairment: Maximum recommended dosage is 25 mg no more than once per night. o Severe hepatic impairment: Not recommended.

DOSAGE FORMS AND STRENGTHS-                                                                             ­ Tablets: 25 mg, 50 mg.

ADVERSE REACTIONS

­ The most common adverse reactions (reported in = 5% of patients treated with QUVIVIQ and at an incidence = than placebo) were headache and somnolence or fatigue.

CONTRAINDICATIONS-

­ QUVIVIQ is contraindicated in patients with narcolepsy.

WARNINGS AND PRECAUTIONS-

­ • CNS-Depressant Effects and Daytime Impairment: Impairs alertness and motor coordination including morning impairment. Risk increases when used with other central nervous system (CNS) depressants.

For patients taking QUVIVIQ, caution against next-day driving and other activities requiring complete mental alertness.Worsening of depression or suicidal thinking may occur.

• Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms: May occur with use of QUVIVIQ.

 • Complex Sleep Behaviors: Behaviors including sleepwalking, sleepdriving, and engaging in other activities while not fully awake may occur. Discontinue immediately if complex sleep behavior occurs.

 • Compromised Respiratory Function: Effect on respiratory function should be considered.

• Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days

DOSAGE AND ADMINISTRATION-

­ • The recommended dosage is 25 mg to 50 mg once per night, taken orally within 30 minutes before going to bed, with at least 7 hours remaining prior to planned awakening.

 • Time to sleep onset may be delayed if taken with or soon after a meal.

• Hepatic Impairment:                                                                                                       o Moderate hepatic impairment: Maximum recommended dosage is 25 mg no more than once per night.                                                                                                            o Severe hepatic impairment: Not recommended.

DOSAGE FORMS AND STRENGTHS-                                                                             ­ Tablets: 25 mg, 50 mg.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Administration-                                                                                                         Instructions -Advise patients to take QUVIVIQ only in the evening within 30 minutes before going to bed and only if they can stay in bed for a full night (at least 7 hours) before being active again 

Advise patients that the effect of QUVIVIQ may be delayed if taken with or soon after a meal 

CNS-Depressant Effects and Daytime Impairment-                                                       Advise patients that QUVIVIQ can impair daytime wakefulness even when used as prescribed.

The risk of daytime impairment is increased if QUVIVIQ is taken with less than a full night of sleep remaining or if a higher than recommended dose is taken. If QUVIVIQ is taken in these circumstances, caution patients against driving and other activities requiring complete mental alertness.

Advise patients that increased drowsiness may increase the risk of falls in some patients 

Worsening of Depression/Suicidal Ideation -                                                                    Tell patients to report any worsening of depression or suicidal thoughts immediately 

Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-Like Symptoms-

Advise patients and their families that QUVIVIQ may cause sleep paralysis, which is an inability to move or speak for several minutes during sleep-wake transitions and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions.

Symptoms similar to mild cataplexy have occurred with orexin receptor antagonists 

Complex Sleep Behaviors -                                                                                            Instruct patients and their families that hypnotics may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake.

Tell patients to discontinue QUVIVIQ and notify their healthcare provider immediately if they develop any of these symptoms 

Concomitant Medications-                                                                                            Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients to avoid consuming alcohol with Quvivq

Drug Interactions-                                                                                                         . Pregnancy -Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to QUVIVIQ during pregnancy 

Tolerance, Abuse, and Dependence Tell patients not to increase the dose of QUVIVIQ on their own, and to inform you if they believe the drug “does not work”

Distributed by: Idorsia Pharmaceuticals US Inc. One Radnor Corporate Center, Suite 101 100 Matsonford Rd Radnor, PA 19087 IDRS01072022 Patent: www.idorsia.com/patents

CLINICAL PHARMACOLOGY

1. Mechanism of Action

The mechanism of action of daridorexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors.

2. Pharmacokinetics-                                                                                             Daridorexant plasma exposure is dose proportional from 25 mg to 50 mg. The daridorexant pharmacokinetic profile is similar following multiple-dose and single-dose administration with no accumulation.

Absorption-                                                                                                             Daridorexant reaches peak plasma concentrations within 1–2 hours (Tmax). Daridorexant has an absolute bioavailability of 62%.

 Effect of food In healthy subjects, a high-fat and high-calorie meal delayed the Tmax by 1.3 hours and decreased the Cmax by 16%, but did not affect the total exposure (AUC).

Distribution-                                                                                                            Daridorexant has a volume of distribution of 31 L. Daridorexant is 99.7% bound to plasma proteins. The blood to plasma ratio is 0.64. Elimination The terminal half-life of daridorexant is approximately 8 hours.

Metabolism-                                                                                                            Daridorexant undergoes extensive metabolism and is primarily metabolized by CYP3A4 (89%). Other CYP enzymes individually contribute to less than 3% of metabolic clearance of daridorexant.

Excretion-                                                                                                                      The primary route of daridorexant excretion is via feces (approximately 57%), followed by urine (approximately 28%), primarily as metabolites. Trace amounts of parent drug were found in feces and urine.

Specific Populations -                                                                                                 Age, sex, race (White, Black, Asian), body size, and mild to severe renal impairment (Cockcroft-Gault < 30 mL/min, not on dialysis) did not have a clinically significant effect on the pharmacokinetics of daridorexant.

The effect of severe hepatic impairment (Child-Pugh score = 10) on the pharmacokinetics of daridorexant has not been studied.

 USE IN SPECIFIC POPULATIONS

1 Pregnancy-                                                                                                      Pregnancy Exposure Registry- There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to QUVIVIQ during pregnancy. Pregnant women exposed to QUVIVIQ and healthcare providers are encouraged to call Idorsia Pharmaceuticals Ltd at 1-833-400-9611.

Risk Summary-                                                                                                           There are no available data on QUVIVIQ use in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.                                                                                                     All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

2.Lactation-                                                                                                                    Risk summary- There are no data on the presence of daridorexant in human milk, the effects on the breastfed infant, or the effects on milk production. Daridorexant and its metabolites were present in the milk of lactating rats.

When a drug is present in animal milk, it is likely that the drug will be present in human milk. Infants exposed to QUVIVIQ through breastmilk should be monitored for excessive sedation.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for QUVIVIQ and any potential adverse effects on the breastfed infant from QUVIVIQ or from the underlying maternal condition.

3. Pediatric Use-                                                                                                             The safety and effectiveness of QUVIVIQ have not been established in pediatric patients.

4. Geriatric Use-                                                                                                             No dose adjustment is required in patients over the age of 65 years.                               Of the total number of subjects in the clinical studies of QUVIVIQ with insomnia (N = 1854), approximately 39% (N = 727) were = 65 years and 5.9% (N = 110) were = 75 years.

The likelihood of somnolence and fatigue increased with patient age. Because QUVIVIQ can increase somnolence and drowsiness, patients, particularly the elderly, are at higher risk of falls

 5. Hepatic Impairment -                                                                                             QUVIVIQ has not been studied in patients with severe hepatic impairment (Child-Pugh score = 10). Use in this population is not recommended .

Reduce the dose of QUVIVIQ in patients with moderate hepatic impairment (Child-Pugh score 7–9)

. Moderate hepatic impairment may increase daridorexant systemic exposure to a clinically relevant extent [see Clinical Pharmacology (12.3)], which may increase the frequency or severity of adverse reactions.

6. Patients with Compromised Respiratory Function-                                       Obstructive sleep apnea The respiratory depressant effect of QUVIVIQ was evaluated after one night and after five consecutive nights of treatment in a randomized, placebo-controlled, two-period crossover study in 25 patients with mild to moderate OSA (apnea-hypopnea index [AHI] 5 to 30 events per hour) not requiring CPAP. 

Due to study limitations, including the short duration of the study, clinically meaningful respiratory effects of QUVIVIQ in OSA cannot be excluded, including for long-term treatment.

 DRUG ABUSE AND DEPENDENCE

1. Controlled Substance

Abuse Drug abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Dependence Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms upon abrupt treatment discontinuation or a significant dose reduction of a drug

There is no specific antidote to an overdosage of QUVIVIQ. In the event of an overdose, general symptomatic and supportive medical care, along with immediate gastric lavage where appropriate, should be provided and patients should be carefully monitored. Dialysis is unlikely to be effective as daridorexant is highly protein bound.

Consult a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222 or www.poison.org).