Daridorexant PI

Question 1

What is the indication for use of QUVIVIQ?

Answer 1

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

(Section 1)

Question 2

What is the recommended dosage of QUVIVIQ?

Answer 2

The recommended dose range is 25 to 50 mg of QUVIVIQ taken orally no more than once per night within 30 minutes of going to bed and with at least 7 h remaining prior to planned awakening
(Section 2.1)

25 mg tablet - light purple triangle
50 mg tablet - light orange triangle
(Section 3)

Question 3

Should QUVIVIQ be taken with food?

Answer 3

QUVIVIQ can be taken with food, but time to sleep onset may be delayed due to decreased absorption.

(Section 2.1, Section 12.3)

Question 4

Can QUVIVIQ be used concomitantly with STRONG CYP3A4 inhibitors?

Answer 4

Concomitant use of moderate or strong CYP3A4 inhibitors increases exposure to QUVIVIQ, which may increase the risk of adverse reactions. (Section 7.1)

Use of QUVIVIQ with strong CYP3A4 inhibitors is not recommended. (Section 2.2)

Question 5

Can QUVIVIQ be used concomitantly with MODERATE CYP3A4 inhibitors?

Answer 5

Concomitant use of moderate or strong CYP3A4 inhibitors increases exposure to QUVIVIQ, which may increase the risk of adverse reactions. (Section 7.1)

Yes. The recommended dose is 25 mg no more than once per night. (Section 2.2)

Question 6

Can QUVIVIQ be used with moderate to strong CYP3A4 INDUCERS?

Answer 6

Concomitant use of QUVIVIQ with a moderate or strong inducer of CYP3A4 decreases exposure to QUVIVIQ, which may reduce the efficacy of QUVIVIQ. (Section 7.1)

QUVIVIQ should not be used with moderate to strong CYP3A4 inducers. (Section 2.2)

Question 7

Can QUVIVIQ be used in patients with MODERATE hepatic impairment?

Answer 7

Yes. The maximum recommended dosage is 25 mg no more than once per night in patients with Child-Pugh scores 7-9.(Section 2.3)

Moderate hepatic impairment may increase QUVIVIQ systemic exposure and result in increased frequency or severity of ADRs. (Section 8.6)

Question 8

Can QUVIVIQ be used in patients with severe hepatic impairment?

Answer 8

No. QUVIVIQ is not recommended for use in in patients with severe hepatic impairment (Child-Pugh score >10)

(Section 2.3, Section 8.6)

Question 9

What are the contraindications for QUVIVIQ?

Answer 9

QUVIVIQ is contraindicated in patients with NARCOLEPSY

Section 4

Question 10

What are the CNS depressant effects of QUVIVIQ?

Answer 10

Patients should be advised that CNS depressive effects may be present up to several days after discontinuation

Patients shoud be advised that next-day somnolence can occur

Driving ability was impaired in some subjects taking 50 mg. Risk of impairment is increased if less than a full night’s sleep is achieved, or if higher than the recommended dose is taken.

Co-administration with other CNS depressants increase the risk of daytime impairment. Dose adjustments may be required if administered with another CNS depressant b/c of potentially additive effects

(Section 5.1)

Question 11

Can QUVIVIQ be used with alcohol?

Answer 11

No. Patients should not consume alcohol while taking QUVIVIQ b/c of additive effects on psychomotor performance.

(Section 5.1, Section 7.1)

Question 12

Does QUVIVIQ increase the risk of falling?

Answer 12

Yes. Because QUVIVIQ can cause drowsiness, patients (particularly the elderly) are at a higher risk for falls

(Section 5.1)

Question 13

Does taking QUVIVIQ worsen depression or suicidal ideation

Answer 13

As with other hypnotics, QUVIVIQ should be administered with caution in patients exhibiting depression. Monitoring of suicide risk and protective measures may be required.

(Section 5.2)

Question 14

Are sleep paralysis or Hypnagogic/Hypnopompic hallucinations associated with taking QUVIVIQ?

Answer 14

Yes, these experiences may occur with QUVIVIQ use.

Section 5.3

Question 15

Are cataplexy-like symptoms associated with the use of QUVIVIQ?

Answer 15

Symptoms similar to cataplexy have been reported with orexin receptor antagonists. These symptoms can occur either at night or during the day and may not be associated with a triggering event.

(Section 5.3)

Question 16

Are complex sleep behaviors associated with QUVIVIQ use?

Answer 16

Complex sleep behaviors have been reported to occur with use of hypnotics, including orexin receptor antagonists.

These events can occur in hypnotic-naive and hypnotic-experienced persons, with the first use or after subsequent use of the hypnotic, and/or with or without concomitant use of alcohol or other CNS depressants.

Discontinue use of QUVIVIQ immediately if a patient experiences complex sleep behaviors.

(Section 5.4)

Question 17

Can I use QUVIVIQ in my patients with compromised respiratory function?

Answer 17

QUVIVIQ has not been studied in patients with moderate OSA requiring CPAP, or severe OSA (> 30 AHI) (Section 5.5)
The respiratroy depressant effect of QUVIVIQ was evaluated after 1 night and 5 consecutive nights of treatment in a RPC in 25 patients with mild-to-moderate OSA (AHI 5-30/h) not requiring CPAP.
Daily dosing of 50 mg did not show an increase in respiratory depression.
Study limitations (small number, short duration) prohibit long-term clinically meaningful effects from being excluded
(Section 8.7)

QUVIVIQ has not been studied in patients with severe COPD. (Section 5.5)
The respiratory depressant effect o QUVIVIQ in patients with moderate COPD (FEV1/FVC <70%; 40%

Question 18

Describe, in general, the SAFETY trial design for the QUVIVIQ phase 3 program.

Answer 18

Safety of QUVIVIQ was assessed in 3 placebo-controlled trials:
Study 1 (301) - examined 50 mg and 25 mg QUVIVIQ against placebo
Study 2 (302) - examined 25 mg and 10 mg QUVIVIQ against placebo
Study 3 - 9 month extension study

A total of 1232 patients (approx. 40% >65 years old) received either 50 mg (308), 25 mg (618), or 10 mg (306)

A total of 576 patients were treated for at least 6 months and 331 for at least 12 months.

The 10 mg dose is not an approved dose.

(Section 6.1)

Question 19

What were the most common adverse reactions to taking QUVIVIQ?

Answer 19

The ADRs that occurred in at least 2% of QUVIVIQ-treated patients and more frequently than placebo are Headache, Somnolence/Fatigue, Dizziness and Nausea.

(Section 6.1)

Question 20

Are there other ADRs to be concerned about?

Answer 20

Other ADRs that occurred in < 2% of QUVIVIQ-treated patients, but still more frequently than placebo are:

Sleep paralysis - 0.5% for 50 mg, 0.3% for 25 mg, 0 for placebo

Hypnagogic/Hypnopompic hallucinations - 0 for 50 mg, 0.6% for 25 mg, 0 placebo

Question 21

Can QUVIVIQ be taken by pregnant women?

Answer 21

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.

Animal studies suggest no maternal, fetal or developmental toxicity in rats administered between 8 and 10 times the maximum recommended human dose (MRHD) of 50 mg.

(Section 8.1)

Question 22

Is QUVIVIQ present in breast milk?

Answer 22

There is no data on the presence of QUVIVIQ 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.

Infants exposed to QUVIVIQ through breast milk should be monitored for excessive sedation

(Section 8.2)

Question 23

Can QUVIVIQ be used by pediatric patients?

Answer 23

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

(Section 8.4)

Question 24

Are their special considerations for the use of QUVIVIQ in elderly patients?

Answer 24

No dose adjustment is required in patients over the age of 65

Of the total number of subjects in our clinical studies (1854), 39% were > 65 (727) and 5.9% were > 75

The likelihood of somnolence and fatigue increased with age. The elderly are at a higher risk of falls.

(Section 8.5)

Question 25

Is there a potential for abuse of QUVIVIQ?

Answer 25

The abuse potential of QUVIVIQ was evaluated in preclinical models, recreational sedative drug users and insomnia subjects.

Human abuse potential was evaluated in 63 recreational sedative drug users.

A single dose of either 50mg, 100mg or 150 mg QUVIVIQ, 30 mg zolpidem, 150 mg suvorexant, or placebo and a subjective rating of ‘drug liking’ was evaluated

50 mg QUVIVIQ showed significantly lower ‘drug liking’ ratings compared to Zolpidem and suvorexant, but higher than placebo.

100 mg and 150 mg QUVIVIQ showed similar ‘drug liking’ ratings as Zolpidem or suvorexant

Phase 3 studies showed no reports indicative of abuse liability.

(Section 9.2)

Question 26

Does chronic use of QUVIVIQ result in physical dependence?

Answer 26

In trials evaluating physical dependence, chronic administration of QUVIVIQ did not produce withdrawal signs or symptoms upon discontinuation

(Section 9.3)

Question 27

Does QUVIVIQ affect cardiac ECG readings?

Answer 27

At doses 4x the maximum recommended dose, QUVIVIQ does not prolong the QTc interval to any clinically relevant extent.

(Section 12.2)

Question 28

What are the effects of overdosing QUVIVIQ

Answer 28

There is limited experience with QUVIVIQ overdose

Healthy subjects administered a single dose up to 200 mg (4xd maximum recommended dose) showed the following adverse reactions: somnolence, muscle weakness, cataplexy-like symptoms, sleep paralysis, disturbance in attention, fatigue, headache, and constipation.

Consult a certified poison control center for more information.

(Section 10)