Consumer medicine information

Belsomra

Suvorexant

BRAND INFORMATION

Brand name

Belsomra

Active ingredient

Suvorexant

Schedule

SUMMARY CMI

BELSOMRA^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking BELSOMRA?

BELSOMRA contains the active ingredient Suvorexant. BELSOMRA is used to help you to go to sleep and stay asleep by temporarily blocking wakefulness, enabling sleep to occur.
For more information, see Section 1. Why am I taking BELSOMRA? in the full CMI.

2. What should I know before I take BELSOMRA?

Do not take if you have ever had an allergic reaction to BELSOMRA or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.
For more information, see Section 2. What should I know before I take BELSOMRA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BELSOMRA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take BELSOMRA?

The recommended dose for:

Non-elderly adults (younger than 65 years) is one 20 mg tablet.
Elderly adults (65 years or older) is one 15mg tablet.

BELSOMRA may be taken with or without food. Swallow the tablet whole with a full glass of water.

More instructions can be found in Section 4. How do I take BELSOMRA? in the full CMI.

5. What should I know while taking BELSOMRA?

Things you should do	Call your doctor if your insomnia (sleep problem) worsens or is not better within 7 to 10 days of taking BELSOMRA. This may mean that there is another condition causing your sleep problem. If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking BELSOMRA.
Things you should not do	Do not take BELSOMRA if you take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take BELSOMRA with your other medicines.
Driving or using machines	Be careful driving, operating machinery or other activities that require complete alertness until you know how BELSOMRA affects you. As with other medicines used to treat insomnia, BELSOMRA may cause drowsiness in some people the day after taking it.
Drinking alcohol	Do not take BELSOMRA if you drank alcohol that evening or before bed. Alcohol can increase your chances of getting serious side effects with BELSOMRA.
Looking after your medicine	Follow the instructions in the carton on how to take care of your medicine properly

For more information, see Section 5. What should I know while taking BELSOMRA? in the full CMI.

6. Are there any side effects?

Like all medicines, BELSOMRA can cause side effects, although not everybody gets them. Your doctor will discuss these with you and will explain the risks and benefits of using BELSOMRA. When you take BELSOMRA, you can have some serious side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

BELSOMRA^®

Active ingredient: Suvorexant

Consumer Medicine Information (CMI)

This leaflet provides important information about taking BELSOMRA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking BELSOMRA.

Where to find information in this leaflet:

1. Why am I taking BELSOMRA?
2. What should I know before I take BELSOMRA?
3. What if I am taking other medicines?
4. How do I take BELSOMRA?
5. What should I know while taking BELSOMRA?
6. Are there any side effects?
7. Product details

1. Why am I taking BELSOMRA?

BELSOMRA contains the active ingredient Suvorexant.
BELSOMRA is a medicine called Orexin Receptor Antagonist. BELSOMRA is used to treat a sleep problem called insomnia, which includes problems falling asleep and/or staying asleep.

BELSOMRA is used to help you to go to sleep and stay asleep by temporarily blocking wakefulness, enabling sleep to occur.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

There is no experience with BELSOMRA in children or adolescents under 18 years of age.

Do not give BELSOMRA to a child or adolescent.

2. What should I know before I take BELSOMRA?

Warnings

Do not take BELSOMRA if:

you fall asleep often at unexpected times (narcolepsy).
you are allergic to suvorexant, or any of the ingredients listed at the end of this leaflet.
The packaging is torn or shows signs of tampering.
The expiry date on the pack has passed.
If you take this medicine after the expiry date has passed, it may not work.

Always check the ingredients to make sure you can take this medicine.

Check with your doctor if you:

have a history of a sudden onset of muscle weakness (cataplexy)
have a history of falling asleep often at unexpected times (narcolepsy) or daytime sleepiness
have a history of depression, mental illness, or suicidal thoughts
have a history of drug or alcohol abuse or addiction. BELSOMRA may be abused or misused.
have liver disease
have a lung disease or breathing problems
take any medicines for any other condition
are pregnant or plan to become pregnant.
are breast-feeding.
have allergies to any other medicines, foods, preservatives or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Sleep Walking

After taking BELSOMRA, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing, such as sleep-walking, eating, talking, or driving a car. The next morning, you may not remember that you did anything during the night.

You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with BELSOMRA.

Tell your doctor immediately if you find out that you have done any unusual activities after taking BELSOMRA.

You should contact your doctor if you experience abnormal thoughts and behaviours such as worsening of depression, and suicidal thoughts or actions.

Pregnancy

It is not known if BELSOMRA can harm your unborn baby.

Your doctor will discuss with you the risks and benefits involved.

Check with your doctor if you are pregnant or intend to become pregnant.

Breastfeeding

It is not known if BELSOMRA passes into your breast milk.

Your doctor will discuss with you the risks and benefits involved.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Medicines can interact with each other, sometimes causing serious side effects.

BELSOMRA should not be taken with some medicines because it strongly affects the level of either BELSOMRA or the other medicine in the blood.

Medicines that should not be taken with BELSOMRA include but are not limited to clarithromycin, erythromycin, fluconazole, itraconazole, diltiazem, verapamil, and certain medicines to treat HIV.

Do not take BELSOMRA with other medicines that can make you sleepy.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect BELSOMRA.

4. How do I take BELSOMRA?

How much to take

Take BELSOMRA exactly as your doctor tells you.

For dosage in non-elderly adults (younger than 65 years) and elderly adults (65 years or older):

The recommended dose for non-elderly adults (younger than 65 years) is one 20 mg tablet.
The recommended dose for elderly adults (65 years or older) is one 15mg tablet.

These doses should not be exceeded. Higher doses worked similarly, but more side effects were reported.

The safety and effectiveness of BELSOMRA is similar in older and younger patients at the recommended doses.

How to take BELSOMRA

BELSOMRA may be taken with or without food.
Swallow the tablet whole with a full glass of water.

When to take BELSOMRA

Only take BELSOMRA 1 time each night within 30 minutes of going to bed.
Take BELSOMRA only when you have the opportunity for a full night of sleep (at least 7 hours) before you must be active again.

If you are not sure when to take it, ask your doctor or pharmacist.

How long to take BELSOMRA

Continue to take BELSOMRA for as long as your doctor tells you.

After starting BELSOMRA, your doctor will periodically reassess your need to continue treatment with BELSOMRA.

Ask your doctor or pharmacist if you are not sure how long to take the medicine.

If you forget to take BELSOMRA

If you miss a dose, do not take BELSOMRA unless you have the opportunity to get a full night of sleep (at least 7 hours) before you must be active again. You may continue with your usual dose the following night at bedtime.

If you are not sure what to do, ask your doctor.

If you take too much BELSOMRA

If you think that you have taken too much BELSOMRA, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking BELSOMRA?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking BELSOMRA.

Tell any other doctors, dentists and pharmacists who treat you that you are taking BELSOMRA.

Call your doctor straight away:

if your insomnia (sleep problem) worsens or is not better within 7 to 10 days of taking BELSOMRA. This may mean that there is another condition causing your sleep problem.
If you become pregnant while taking BELSOMRA

Things you should not do

Do not take BELSOMRA if you take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take BELSOMRA with your other medicines.
Do not give BELSOMRA to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful driving, operating machinery or other activities that require complete alertness until you know how BELSOMRA affects you.

As with other medicines used to treat insomnia, BELSOMRA may cause drowsiness in some people the day after taking it.

Drinking alcohol

Do not take BELSOMRA if you drank alcohol that evening or before bed.

Alcohol can increase your chances of getting serious side effects with BELSOMRA.

Looking after your medicine

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor tells you to stop taking BELSOMRA or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Getting rid of any unwanted medicine

If you no longer need to take this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not take this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

Tell your doctor if you notice or have any of the following and they worry you:

sleepiness
tiredness
headache
dizziness
upper respiratory tract infection
diarrhoea
dry mouth
nausea
vomiting
unusual dreams including nightmare
feeling abnormal
anxiety
making mistakes in taking your medicine.
memory loss
temporary weakness in your legs that can happen during the day or at night.
cough
awareness of heartbeat, fast or irregular heartbeat (palpitations, tachycardia)
itching

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Stop taking BELSOMRA and tell your doctor immediately if you notice any of the following:

abnormal thoughts and behaviour.
Symptoms include more outgoing or aggressive behaviour than normal, confusion, agitation, hallucinations (including vivid and disturbing perceptions)
worsening of depression and suicidal thoughts or actions.
temporary inability to move or talk (sleep paralysis) for up to several minutes while you are going to sleep or waking up.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Other side effects not listed above may also occur in some patients and as with any prescription drug, some side effects may be serious.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What BELSOMRA contains

Active ingredient (main ingredient)	Suvorexant 15 or 20 mg per tablet
Other ingredients (inactive ingredients)	Copovidone Microcrystalline cellulose Lactose monohydrate Croscarmellose sodium Magnesium stearate Ingredients in film-coating: Lactose monohydrate Hypromellose Titanium dioxide Triacetin

BELSOMRA does not contain gluten, sucrose, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What BELSOMRA looks like

BELSOMRA comes as two strengths of tablets:

15 mg tablet - A white, oval, biconvex, film coated tablet, marked with MSD logo on one side and 325 on the other (AUST R 207709).

20 mg tablet - A white, round, biconvex, film coated tablet, marked with MSD logo and 335 on one side, and plain on the other (AUST R 207712).

A box of BELSOMRA contains 10* tablets or 30 tablets. BELSOMRA tablets may also be supplied in packs of 3* tablets to start treatment.

* Not currently supplied in Australia

Who distributes BELSOMRA

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road
Macquarie Park NSW 2113 Australia

This leaflet was prepared in January 2023.

This leaflet was current at the time of printing. To check if it has been updated, please view our website, (www.msdinfo.com.au/belsomracmi), or ask your pharmacists.

(S-CCPPI-MK4305-T-082022)

RCN 000024704

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Belsomra

Active ingredient

Suvorexant

Schedule

1 Name of Medicine

Suvorexant.

2 Qualitative and Quantitative Composition

Belsomra tablets contain the active ingredient suvorexant.
Belsomra is available for oral use as film-coated tablets containing 15 or 20 mg of suvorexant.

List of excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Belsomra (suvorexant) 15 mg is a white, oval, biconvex, film coated tablet, marked with Merck logo on one side and 325 on the other side.
Belsomra (suvorexant) 20 mg is a white, round, biconvex, film coated tablet, marked with Merck logo and 335 on one side, and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Belsomra is indicated for the treatment of insomnia, characterised by difficulties with sleep onset and/or sleep maintenance.
Following initiation of treatment, continuation should be re-evaluated after 3 months (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.8 Adverse Effects (Undesirable Effects) for clinical trial durations).

4.2 Dose and Method of Administration

Belsomra may be taken with or without food.
Belsomra should be taken no more than once per night and within 30 minutes of going to bed, with at least 7 hours remaining before the planned time of awakening.

For dosage in nonelderly adults (< 65 years) and elderly adults (≥ 65 years).

The recommended dose is 20 mg for nonelderly adults and 15 mg for elderly adults.
This dose should not be exceeded. Higher doses (30 mg and 40 mg) were found to have similar efficacy to lower doses (15 mg and 20 mg) but significantly more adverse effects were reported at the higher doses (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.8 Adverse Effects (Undesirable Effects)).

For use with strong or moderate CYP3A inhibitors.

Belsomra is not recommended for patients taking concomitant strong or moderate CYP3A inhibitors as the exposure to suvorexant is increased.

Patients with hepatic impairment.

Suvorexant pharmacokinetics were similar in patients with moderate hepatic impairment and healthy subjects. Belsomra has not been studied in patients with severe hepatic impairment and is not recommended for these patients (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment; Section 5.2 Pharmacokinetic Properties).

Patients with renal impairment.

Suvorexant pharmacokinetics were similar in patients with severe renal impairment and healthy subjects (see Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Belsomra is contraindicated in patients with known hypersensitivity to suvorexant or any of its inactive ingredients.
Belsomra is contraindicated in patients with narcolepsy.

4.4 Special Warnings and Precautions for Use

CNS depressant effects.

Belsomra is a central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed. Prescribers should monitor for somnolence and CNS depressant effects, but impairment can occur in the absence of symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal testing of daytime wakefulness and/or psychomotor performance). CNS depressant effects may persist in some patients for up to several days after discontinuing Belsomra.
Belsomra can impair driving skills and may increase the risk of falling asleep while driving. Discontinue in patients who drive if daytime somnolence develops. In a study of healthy adults, driving ability was impaired in some individuals taking 20 mg Belsomra (see Section 4.8 Adverse Effects (Undesirable Effects), Studies pertinent to safety concerns for hypnotic medicines). Although pharmacodynamic tolerance or adaptation to some adverse depressant effects of Belsomra may develop with daily use, patients using the 20 mg dose of Belsomra should be cautioned against next day driving and other activities requiring full mental alertness.
Coadministration with other CNS depressants (e.g. benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Patients should be advised not to consume alcohol in combination with Belsomra because of additive effects (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The use of Belsomra with other drugs to treat insomnia is not recommended (see Section 4.2 Dose and Method of Administration).
The risk of next day impairment, including impaired driving, is increased if Belsomra is taken with less than a full night of sleep remaining, if a higher than the recommended dose is taken, if coadministered with other CNS depressants, or if coadministered with other drugs that increase blood levels of Belsomra. Patients should be cautioned against driving and other activities requiring complete mental alertness if Belsomra is taken in these circumstances.

Need to evaluate for co-morbid diagnoses.

The effect of Belsomra has been assessed in patients with primary insomnia in clinical trials. Since sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. Worsening of insomnia or the emergence of new cognitive or behavioural abnormalities may be the result of an unrecognised underlying psychiatric or physical disorder other than insomnia. Such findings have emerged during the course of treatment with hypnotic medicines. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.

Abnormal thinking and behavioural changes.

A variety of cognitive and behavioural changes have been reported to occur in association with the use of hypnotics such as Belsomra. Complex behaviours such as "sleep driving" (i.e. driving while not fully awake after ingestion of an hypnotic) and other complex behaviours (e.g. sleep walking, preparing and eating food), with amnesia for the event, have been reported in association with the use of hypnotics. These events can occur in hypnotic naïve as well as in hypnotic experienced persons. The use of alcohol and other CNS depressants may increase the risk of such behaviours.
Discontinuation of Belsomra should be strongly considered for patients who report any complex sleep behaviour due to the risks to patient and others (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, CNS active agents).

Worsening of depression/ suicidal ideation.

In clinical studies, a dose dependent increase in suicidal ideation was observed in patients taking Belsomra as assessed by questionnaire. Immediately evaluate patients with suicidal ideation or any new behavioural sign or symptom.
In primarily depressed patients treated with sedative hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time.
The emergence of any new behavioural sign or symptom of concern requires careful and immediate evaluation.

Patients with compromised respiratory function.

Belsomra has not been studied in patients with severe Obstructive Sleep Apnoea (OSA) or severe Chronic Obstructive Pulmonary Disease (COPD). Caution is advised if Belsomra is prescribed to patients with compromised respiratory function. (See Section 4.8 Adverse Effects (Undesirable Effects), Studies pertinent to safety concerns for hypnotic medicines.)

Sleep paralysis, hypnagogic/ hypnopompic hallucinations, cataplexy-like symptoms.

Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/ hypnopompic hallucinations, including vivid and disturbing perceptions by the patient, can occur with the use of Belsomra. Prescribers should explain the nature of these events to patients when prescribing Belsomra.
Symptoms similar to mild cataplexy can occur, with risk increasing with the dose of Belsomra. Such symptoms can include periods of leg weakness lasting from seconds to a few minutes, can occur both at night and during the day, and may not be associated with an identified triggering event (e.g. laughter or surprise).

Abuse.

Abuse of Belsomra poses an increased risk of somnolence, daytime sleepiness, impaired reaction time and impaired driving skills. Patients at risk for abuse may include those with prolonged use of Belsomra, those with a history of drug abuse, and those who use Belsomra in combination with alcohol or other abused drugs.

For use with strong and moderate CYP3A inhibitors.

Concomitant use of Belsomra with strong or moderate CYP3A inhibitors is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of other medicines on Belsomra).

Use in hepatic impairment.

Belsomra has not been studied in patients with severe hepatic impairment and is not recommended for these patients (see Section 4.2 Dose and Method of Administration, Patients with hepatic impairment).

Use in the elderly.

Of the total number of patients treated with Belsomra (N = 1784) in phase 3 clinical safety and efficacy studies, 829 patients were 65 years and over, while 159 patients were 75 years and over. No clinically meaningful differences in safety or effectiveness were observed between these patients and younger patients at the recommended doses. However, greater sensitivity of some older individuals cannot be ruled out (see Section 4.2 Dose and Method of Administration, For dosage in nonelderly adults (< 65 years) and elderly adults (≥ 65 years); Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Safety and effectiveness of Belsomra in paediatric patients have not been established. Therefore, Belsomra should not be used in children.

Effect on laboratory tests.

In the pooled data from the three placebo controlled studies in patients with insomnia, no clinically meaningful differences were observed between patients receiving Belsomra and those receiving placebo in routine serum chemistry, haematology, or urinalysis parameters.

4.5 Interactions with Other Medicines and Other Forms of Interactions

CNS active agents.

When Belsomra was coadministered with alcohol, additive psychomotor impairment was demonstrated. There was no alteration in the pharmacokinetics of either medicine (see Section 4.4 Special Warnings and Precautions for Use, Abnormal thinking and behavioural changes, CNS depressant effects; Section 5.2 Pharmacokinetic Properties).
When Belsomra was coadministered with paroxetine, no clinically significant pharmacokinetic or pharmacodynamic interaction was demonstrated (see Section 4.4 Special Warnings and Precautions for Use, Abnormal thinking and behavioural changes, CNS depressant effects; Section 5.2 Pharmacokinetic Properties).

Effects of other medicines on Belsomra.

Metabolism by CYP3A is the major elimination pathway for suvorexant.

CYP3A inhibitors.

Concomitant administration of Belsomra with ketoconazole (a strong CYP3A inhibitor) substantially increased Belsomra exposure (2.79-fold change in AUC). Concomitant use of Belsomra with strong inhibitors of CYP3A (e.g. ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) is not recommended (see Section 4.4 Special Warnings and Precautions for Use, For use with strong and moderate CYP3A inhibitors; Section 5.2 Pharmacokinetic Properties).
Concomitant administration of suvorexant with diltiazem (a moderate CYP3A inhibitor) also increased suvorexant exposure (2.05-fold change in AUC).
Concomitant administration of Belsomra with moderate CYP3A inhibitors (e.g. amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil) is not recommended.

CYP3A inducers.

Suvorexant exposure can be substantially decreased when coadministered with strong CYP3A inducers (e.g. rifampin, carbamazepine and phenytoin). The efficacy of Belsomra may be reduced (see Section 5.2 Pharmacokinetic Properties).

Effects of suvorexant on other medicines.

Suvorexant is a weak inhibitor of CYP3A and the intestinal P-glycoprotein (P-gp) transporter following consecutive, multiple dose administration.

Midazolam.

Concomitant administration of Belsomra with midazolam (a sensitive CYP3A substrate) slightly increased midazolam exposure. For most medicines metabolised by CYP3A, Belsomra is not expected to increase plasma concentrations to a clinically significant degree (see Section 5.2 Pharmacokinetic Properties).

Digoxin.

Concomitant administration of Belsomra with digoxin slightly increased digoxin levels due to inhibition of intestinal P-gp. Digoxin concentrations should be monitored as clinically indicated when coadministering Belsomra with digoxin (see Section 5.2 Pharmacokinetic Properties).

Other concomitant therapy.

No clinically significant pharmacokinetic interactions were observed following coadministration of Belsomra with warfarin or oral contraceptives (see Section 5.2 Pharmacokinetic Properties).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In male and female rats treated orally prior to and during mating and early gestation, decreases were observed in corpora lutea, implantations, and resultant live fetuses. There were no effects in males. At the no-effect dose for females and males, estimated exposures were approximately 25 and 43 times the clinical exposure at the MRHD (20 mg), respectively.
(Category B3)
No clinical studies have been conducted in pregnant women. Belsomra should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Suvorexant crosses the placenta in rats and rabbits. Teratogenicity was not observed in pregnant rats or rabbits treated orally during the period of organogenesis. In rats, developmental toxicity was limited to a decrease in fetal body weights at maternotoxic doses. In rabbits, there was no evidence of developmental toxicity. The maternal exposure in rats and rabbits at the no-effect dose was 25 times and 39 times the clinical exposure at the MRHD (20 mg), respectively.
Following oral administration to rats throughout gestation and lactation, effects in the offspring were limited to a transient decrease in bodyweight; estimated maternal exposure at the no-effect dose was 25 times the clinical exposure at the MRHD (20 mg).
It is not known whether suvorexant is excreted into human milk; however, suvorexant is excreted into the milk of lactating rats. Because many medicines are excreted into human milk, caution should be exercised when administered to a nursing woman.

4.7 Effects on Ability to Drive and Use Machines

See Section 4.4 Special Warnings and Precautions for Use, CNS depressant effects, Abnormal thinking and behavioural changes, Abuse; Section 4.8 Adverse Effects (Undesirable Effects).

4.8 Adverse Effects (Undesirable Effects)

Clinical studies experience in adults.

In three phase 3 clinical studies, 1784 patients were exposed to Belsomra, including 160 patients for at least one year. The pooled safety data described below reflects the adverse event profile during the first 3 months of treatment.
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a medicine cannot be directly compared to rates in the clinical trials of another medicine and may not reflect the rates observed in practice.

Adverse events resulting in discontinuation of treatment.

The incidence of discontinuation due to adverse events for patients treated with the recommended doses (15 mg or 20 mg) of Belsomra, higher doses (30 mg or 40 mg) of Belsomra and placebo was 3.0%, 6.2%, and 4.9%, respectively. The most frequent adverse events leading to discontinuation in patients receiving Belsomra were somnolence (0.2% Belsomra 15 mg or 20 mg; 1.7% Belsomra 30 mg or 40 mg; 0.3% placebo) and fatigue (0.2% Belsomra 15 mg or 20 mg; 0.7% Belsomra 30 mg or 40 mg; 0.0% placebo).

Adverse events observed at an incidence of ≥ 2% and greater than placebo in controlled trials.

Table 1 shows the percentage of patients with adverse events during the first three months of treatment based on the pooled data from the three placebo controlled clinical studies.
The adverse event profile in elderly patients was generally consistent with nonelderly patients. The adverse events reported during long-term treatment up to 1 year were generally consistent with those observed during the first 3 months of treatment.

In these clinical studies, cough was reported in patients taking Belsomra (1.8% Belsomra 15 mg or 20 mg; 1.1% Belsomra 30 mg or 40 mg; 0.9% placebo). Additionally, in these clinical studies, sleep paralysis and hypnagogic/hypnopompic hallucinations have been reported in patients taking Belsomra (< 1%).

Post-marketing experience.

The following adverse reactions have been identified during postapproval use of Belsomra. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders.

Palpitations, tachycardia.

Gastrointestinal disorders.

Nausea, vomiting.

General disorders and site administration conditions.

Feeling abnormal.

Nervous system disorders.

Psychomotor hyperactivity.

Psychiatric disorders.

Anxiety, nightmare.

Skin and subcutaneous tissue disorders.

Pruritus.

Studies pertinent to safety concerns for hypnotic medicines.

Next day residual effects.

Effects of suvorexant on psychomotor performance using digit symbol substitution test (DSST).

In two phase 3 confirmatory clinical studies, next day performance was assessed using DSST on the mornings (approximately 9 hours postdose) following PSG on night 1, month 1, and month 3 of treatment. In the overall population of patients with insomnia treated with Belsomra (n = 590), no clinically meaningful next day impairment of psychomotor performance was observed compared to placebo.

Driving studies.

Two randomized, double blind, placebo and active controlled, four period crossover studies evaluated the effects of nighttime administration of Belsomra on next morning driving performance 9 hours after dosing in 24 healthy elderly (≥ 65 years old, mean age 69 years; 14 men, 10 women) and 28 nonelderly (mean age 46 years; 13 men, 15 women) subjects.
The primary outcome measure was change in mean Standard Deviation of Lane Position (SDLP), a measure of driving performance. There was no significant impairment of next day driving performance as assessed by mean SDLP after one night and 8 consecutive nights of suvorexant dosed at 15 or 30 mg in elderly, 20 or 40 mg in nonelderly subjects. However, some subjects had SDLP changes suggestive of clinically meaningful impaired driving performance following treatment with suvorexant. Across these two studies, five subjects (4 nonelderly women on suvorexant; 1 elderly woman on placebo) prematurely stopped their driving tests due to somnolence. Due to individual variation, patients should be advised not to drive, operate machinery or engage in other activities requiring full mental alertness until fully awake. (See Section 4.4 Special Warnings and Precautions for Use.)

Effects on next day memory and balance in elderly and nonelderly.

The effects of suvorexant on next day memory and balance were evaluated using word learning test and body sway test, respectively, in four placebo controlled studies following night time administration of suvorexant. Three studies showed no significant effects on memory or balance compared to placebo. In a fourth study in healthy nonelderly subjects, there was a significant decrease in word recall after the words were presented to subjects in the morning following single dose of 40 mg suvorexant; and there was a significant increase on body sway area in the morning following single dose of 20 or 40 mg suvorexant.
Middle of the night safety in elderly subjects. A double blind, randomised, placebo controlled study in healthy elderly subjects (n = 12) evaluated the effect of a single dose of Belsomra on balance, memory and psychomotor performance after being awakened during the night. Night time dosing of Belsomra 30 mg did not result in impairment of balance (measured by body sway area) or psychomotor performance (measured by choice reaction time) at 4 and 8 hours postdose as compared to placebo; a small impairment was seen at 90 minutes postdose. Memory was not impaired, as assessed by immediate and delayed word recall test at 4 hours postdose.
Rebound effects. In the combined analysis of three phase 3 studies in patients with insomnia, rebound insomnia following discontinuation of Belsomra relative to placebo and baseline was assessed in nonelderly adult patients receiving Belsomra 40 mg or 20 mg and in elderly patients receiving 30 mg or 15 mg. Objective assessments (2 studies) were based on the polysomnographic measures of sleep onset (LPS) and maintenance (WASO) performed the night after treatment discontinuation at month 3. Subjective assessments (3 studies) were based on patient reported measures of sleep onset (sTSO) and maintenance (sTST) in the 3 nights following treatment discontinuation at month 3, month 6 or month 12.
Based on the overall assessment of both doses of Belsomra evaluated in nonelderly and elderly patients, no effects were seen on measures of sleep onset. Effects were seen on some sleep maintenance measures following Belsomra discontinuation but had the characteristics of the return of insomnia symptoms and did not appear to be consistent with clinically meaningful rebound insomnia.
Abuse. In an abuse liability study conducted in recreational polydrug users (N=36), suvorexant (40, 80 and 150 mg) produced similar effects as zolpidem (15, 30 mg) on subjective ratings of "drug liking". As with other hypnotics, care should be taken when prescribing Belsomra to individuals with a history of addiction to, or abuse of, drugs or alcohol due to risk of misuse or abuse.
Dependence. In the combined analysis of three phase 3 clinical studies, when Belsomra was discontinued after chronic administration, no clinically meaningful withdrawal was observed. Thus, Belsomra does not appear to produce physical dependence.
Withdrawal effects. Potential withdrawal effects following discontinuation of Belsomra were assessed in three phase 3 clinical studies in which nonelderly adult patients received Belsomra 40 mg or 20 mg and elderly patients received 30 mg or 15 mg. No indication of withdrawal was observed in the overall study population based on assessment of patient responses to the Tyrer Withdrawal Symptom Questionnaire or assessment of withdrawal related adverse events following the discontinuation of Belsomra.
Respiratory safety.

Use in healthy subjects with normal respiratory function.

The respiratory depressant effect of suvorexant (40 and 150 mg) was evaluated after one night of treatment in a randomised, placebo controlled, double blind, crossover study in healthy nonelderly subjects (n = 12). At the doses studied, suvorexant had no respiratory depressant effect as measured by oxygen saturation (see Section 4.4 Special Warnings and Precautions for Use, Patients with compromised respiratory function).

Chronic obstructive pulmonary disease (COPD).

The respiratory depressant effect of suvorexant was evaluated after one night and after four consecutive nights of treatment in a randomised, placebo controlled, 2 period crossover study in patients (n = 25) with mild to moderate COPD. Suvorexant (40 mg in nonelderly, 30 mg in elderly) had no respiratory depressant effects in patients with mild to moderate COPD, as measured by oxygen saturation. Clinically meaningful respiratory effects of Belsomra in patients with COPD cannot be excluded. Belsomra has not been studied in patients with severe COPD (see Section 4.4 Special Warnings and Precautions for Use, Patients with compromised respiratory function).

Obstructive sleep apnoea (OSA).

The respiratory depressant effect of suvorexant was evaluated after one night and after four consecutive nights of treatment in a randomised, placebo controlled, 2 period crossover study in patients (n = 26) with mild to moderate OSA. Following once daily doses of 40 mg, the mean Apnoea/Hyponoea Index treatment difference (suvorexant - placebo) on day 4 was 2.7 (90% CI: 0.22 to 5.09). Clinically meaningful respiratory effects of Belsomra in patients with OSA cannot be excluded. Belsomra has not been studied in patients with severe obstructive sleep apnoea (see Section 4.4 Special Warnings and Precautions for Use, Patients with compromised respiratory function).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (in Australia).
There is limited premarketing clinical experience with the effects of an overdosage of Belsomra. In clinical pharmacology studies, healthy subjects were administered doses of up to 240 mg of suvorexant in the morning with dose dependent increase in frequency and duration of somnolence reported.
General symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. As in all cases of medication overdose, respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures employed. The value of dialysis in the treatment of overdosage has not been determined. As suvorexant is highly protein bound, haemodialysis is not expected to contribute to elimination of suvorexant.
As with the management of all overdosage, the possibility of ingestion of multiple medications should be considered.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Suvorexant is a highly selective reversible high affinity orexin receptor antagonist at OX1R (K_i 0.55 nanoM) and OX2R (K_i 0.35 nanoM) receptors.
The orexin neuropeptide signalling system is a central promoter of wakefulness. Orexin producing neuronal cell bodies localised specifically in the hypothalamus project to the wakefulness mediating neurons of the brain.
Blocking the binding of wake promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive. Antagonism of orexin receptors may also underlie potential adverse effects such as signs of narcolepsy/cataplexy. Genetic mutations in the orexin system in animals result in hereditary narcolepsy; loss of orexin neurons has been reported in humans with narcolepsy.
Suvorexant has no direct pharmacological activity or binding affinity (K_i > 10 microM) at gamma-aminobutyric acid (GABA), serotonin, dopamine, noradrenaline, melatonin, histamine, acetylcholine, or opiate receptors.

Clinical trials.

Two randomised, double blind, placebo controlled, parallel group, multicenter questionnaire and polysomnography (PSG) studies assessed the safety, tolerability and efficacy of Belsomra in the treatment of adult patients with primary insomnia over a 3 month period. One of these studies had an optional 3 month double blind extension period in which PSG was not performed. In both studies Belsomra was given at doses of 20 mg or 40 mg for patients aged < 65 years (mean age 46 years) and at doses of 15 mg or 30 mg for patients aged ≥ 65 years (mean age 71 years).
In PN028 and PN029, Belsomra 15 mg or 20 mg was superior to placebo for sleep latency as assessed both objectively by polysomnography (Table 2) and subjectively by patient estimated sleep latency (Table 3). Belsomra 15 mg or 20 mg was also superior to placebo for sleep maintenance as assessed both objectively by polysomnography (Tables 4 and 5), and subjectively by patient estimated total sleep time (Table 6). The effects of Belsomra at night 1 (objective) and week 1 (subjective) were generally consistent with later time points as compared to placebo. Relative to baseline, subjective measures steadily improved through month 3 (Table 6). Additional analysis of the objective sleep maintenance effect by hour on night 1 in PN028 and PN029 is shown in Table 7 and demonstrated Belsomra treatment decreased the time spent awake after the first hour during night 1. Improvement compared to placebo was evident for the primary subjective sleep endpoints at timepoints during the 3 month optional extension period.

Belsomra was also evaluated at doses of 30 mg and 40 mg in the 3 month placebo controlled studies (PN028 and PN029). The higher doses were found to have similar efficacy to lower doses but more adverse reactions were reported at the higher doses.

Evaluation of Belsomra on QTc interval.

The effects of Suvorexant on QTc interval were evaluated in a randomised, placebo, and active-controlled (moxifloxacin 400 mg) crossover study in healthy subjects (n = 53). The upper bound of the one sided 95% confidence interval for the largest placebo adjusted, baseline corrected QTc interval was below 10 ms based on analysis of suvorexant doses up to 240 mg. Thus, suvorexant does not prolong the QTc interval to any clinically relevant extent.

5.2 Pharmacokinetic Properties

Suvorexant exposure increases in a less than strictly dose proportional manner over the range of 10-80 mg due to decreased absorption. Suvorexant pharmacokinetics are similar in healthy subjects and patients with insomnia.

Absorption.

Suvorexant peak concentrations occur at a median t_max of 2.0 hours (range 0.5 to 6.0) under fasted conditions. The mean absolute bioavailability of 20 mg is 62% (5^th-95^th percentile: 55% to 69%).
Ingestion of suvorexant with a high-fat meal resulted in no meaningful change in AUC or C_max and with a delay in t_max by approximately 1.5 hours. Suvorexant may be taken with or without food.

Distribution.

The mean volume of distribution of suvorexant is approximately 49 litres. Suvorexant is extensively bound (> 99%) to human plasma proteins and does not preferentially distribute into red blood cells. Suvorexant binds to both human serum albumin and α1-acid glycoprotein.

Metabolism.

Suvorexant is mainly eliminated by metabolism, primarily by CYP3A with a minor contribution from CYP2C19. The major circulating entities are suvorexant and a hydroxy-suvorexant metabolite. This metabolite is not expected to be pharmacologically active.

Excretion.

The primary route of elimination is through the faeces, with approximately 66% of radiolabeled dose recovered in the faeces compared to 23% in the urine. Suvorexant is eliminated primarily in the form of metabolites, with < 1% of the dose recovered in faeces and urine as suvorexant.
The systemic pharmacokinetics of suvorexant are linear with accumulation predictable from single-dose data. Steady-state is achieved by 3 days following once-daily dosing and is consistent with a mean t_1/2of approximately 12 hours (95% CI: 12.0 to 13.1).

Special populations.

Gender, age, body mass index (BMI), and race were included as factors assessed in the population pharmacokinetic model to evaluate suvorexant pharmacokinetics in healthy subjects and to predict exposures in the patient population. Age and race are not predicted to have any clinically meaningful changes on suvorexant pharmacokinetics.
Suvorexant exposure is higher in females than in males. In females, the AUC and C_max are increased by 17% and 9%, respectively, following administration of Belsomra 40 mg. The average concentration of suvorexant 9 hours after dosing is 5% higher for females across the dose range studied (10-40 mg).
Apparent oral clearance of suvorexant is inversely related to body mass index. In obese patients, the AUC and C_max are increased by 31% and 17%, respectively. The average concentration of suvorexant approximately 9 hours after a 20 mg dose is 15% higher in obese patients (BMI > 30 kg/m²) relative to those with a normal BMI (BMI ≤ 25 kg/m²).
In obese females, the AUC and C_max are increased by 46% and 25%, respectively, compared to nonobese females.
The effects of renal and hepatic impairment on the pharmacokinetics of suvorexant were evaluated in specific pharmacokinetic studies.
Suvorexant exposure after a single dose was similar in patients with moderate hepatic impairment (Child-Pugh category 7 to 9) and healthy matched control subjects; however, the suvorexant apparent terminal half-life was increased from approximately 15 hours (range 10-22 hours) in healthy subjects to approximately 19 hours (range 11-49 hours) in patients with moderate hepatic impairment. Belsomra was not studied in patients with severe hepatic impairment and is not recommended in these patients (see Section 4.2 Dose and Method of Administration, Patients with hepatic impairment).
Suvorexant exposure (expressed as total and unbound concentrations) was similar between patients with severe renal impairment (urinary creatinine clearance ≤ 30 mL/min/1.73 m²: CKD stage 4 or 5) and healthy matched control subjects (see Section 4.2 Dose and Method of Administration, Patients with renal impairment).

Medicine related interactions.

CNS active medicines.

An additive effect on psychomotor performance was observed when a single dose of 40 mg of suvorexant was coadministered with a single dose of 0.70 g/kg alcohol. Suvorexant did not affect alcohol concentrations and alcohol did not affect suvorexant concentrations (see Section 4.4 Special Warnings and Precautions for Use, Abnormal thinking and behavioural changes, CNS depressant effects; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, CNS active agents).
An interaction study with single dose of 40 mg suvorexant and paroxetine 20 mg at steady-state levels in healthy subjects did not demonstrate a clinically significant pharmacokinetic or pharmacodynamic interaction (see Section 4.4 Special Warnings and Precautions for Use, Abnormal thinking and behavioural changes, CNS depressant effects; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, CNS active agents).

Effects of other medicines on suvorexant.

Strong CYP3A inhibitors (e.g. ketoconazole) significantly increased suvorexant exposure (2.79-fold change in AUC). Moderate CYP3A inhibitors (e.g. diltiazem) also increased suvorexant exposure (2.05-fold change in AUC). Strong CYP3A inducers (e.g. rifampin) substantially decreased suvorexant exposure (see Section 4.4 Special Warnings and Precautions for Use, For use with strong and moderate CYP3A inhibitors; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of other medicines on Belsomra).

Effects of suvorexant on other medicines.

In vitro metabolism studies indicate that suvorexant has a potential to inhibit CYP3A and intestinal P-gp. Suvorexant is unlikely to cause clinically significant inhibition of human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. In addition, no clinically meaningful inhibition of OATP1B1, BCRP and OCT2 transporters is anticipated. Chronic administration of suvorexant is unlikely to induce the metabolism of medicines metabolised by major CYP isoforms. Specific in vivo effects on the pharmacokinetics of midazolam, warfarin, digoxin and oral contraceptives are presented in Figure 1 as a change relative to the interacting medicine administered alone (test/reference) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of suvorexant on other medicines, Other concomitant therapy).

5.3 Preclinical Safety Data

Genotoxicity.

Suvorexant was negative in in vitro (bacterial reverse mutation, alkaline elution, and chromosomal aberration in Chinese Hamster Ovary cells) and in vivo (rat and mouse micronucleus) genotoxicity assays.

Carcinogenicity.

No evidence of carcinogenic potential was observed in hemizygous Tg.rasH2 mice dosed orally for 6 months; a separate kinetic study suggested that exposures achieved were up to 105 times the clinical exposure at the MRHD (20 mg).
In the 2 year carcinogenicity study in rats, there was an increased incidence of hepatic and thyroid follicular cell adenomas. These changes were secondary to hepatic enzyme induction and increased TSH production, respectively, which are mechanisms well described to be rodent specific. At the no-effect dose for tumours, exposure was 7 times the clinical exposure (plasma AUC) at the MRHD (20 mg).
In the rat carcinogenicity study, there was an increased incidence of very slight to slight retinal atrophy at exposures (plasma AUC) 11 times or greater the clinical exposure at the MRHD (20 mg); at the no-effect dose, exposure was 7 times clinical exposure. This retinal change was of the same type and severity found in untreated aged rats. The mechanism involved in this change and its clinical significance are not known.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each film coated tablet contains the following inactive ingredients: copovidone, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and magnesium stearate.
In addition, the film coating contains the following inactive ingredients: lactose monohydrate, hypromellose, titanium dioxide and triacetin.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

The expiry date can be found on the packaging. In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

Store below 25°C. Store in original container.

6.5 Nature and Contents of Container

Belsomra is available in aluminium/aluminium blister packs of 10*, and 30 film coated tablets. Belsomra is also available in starter packs of 3* tablets.
* Not currently supplied in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Suvorexant is a white to off white powder that is insoluble in water. pKa is 2.19 ± 0.02. The log of the distribution (partition) coefficient at pH 7 of suvorexant is log D (pH 7) = 3.73 ± 0.01.
Suvorexant is described chemically as: [(7R)-4-(5-chloro-2-benzoxazolyl)hexahydro-7-methyl-1H-1,4-diazepin-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone.
Its empirical formula is C₂₃H₂₃ClN₆O₂ and the molecular weight is 450.92.

Chemical structure.

CAS number.

The CAS Registry Number is 1030377-33-3.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

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