Consumer medicine information

Voquily

Melatonin

BRAND INFORMATION

Brand name

Voquily

Active ingredient

Melatonin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Voquily.

SUMMARY CMI

VOQUILY

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.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using VOQUILY?

VOQUILY contains the active ingredient melatonin. VOQUILY is used to treat adults with jet lag and sleep disorders in children with neurodevelopmental disorders.

For more information, see Section 1. Why am I using VOQUILY? in the full CMI.

2. What should I know before I use VOQUILY?

Do not use if you have ever had an allergic reaction to VOQUILY 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 use VOQUILY? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with VOQUILY 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 use VOQUILY?

  • The standard starting dose is 2 mg once daily, before bed or preferred sleep time. In some cases, your doctor may increase your dose.
  • VOQUILY should be taken on an empty stomach.

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

5. What should I know while using VOQUILY?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using VOQUILY.
  • If you become pregnant while taking VOQUILY, stop taking the medication and tell your doctor immediately.
Things you should not do
  • Do not give VOQUILY to anyone else, even if they have the same condition as you.
  • Do not take more than the recommended dose unless your doctor tells you to.
  • Do not drink alcohol while taking VOQUILY
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how VOQUILY affects you.
    VOQUILY causes drowsiness, which may continue into the daytime.
Looking after your medicine
  • Store below 25°C
  • Store VOQUILY in original packaging to protect from light.
  • Discard oral solution 2 months after opening.

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

6. Are there any side effects?

The most common side effects are sleepiness, headache, dizziness, nausea, stomach cramps and hyperactivity. Tell your doctor or pharmacist immediately, if you notice any of the following side effects: signs of an allergic reaction, seizures, tightness in chest, fast or irregular heartbeat, suicide attempt or suicidal thoughts.

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.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

VOQUILY

Active ingredient(s): melatonin

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using VOQUILY?

VOQUILY contains the active ingredient melatonin. Melatonin is naturally occurring hormone produced in the body. It is one of the main hormones that helps you to sleep.

VOQUILY is used for the treatment of a number of conditions.

  • Jet lag in adults 18 years and older.
  • Sleep Disorders in children and adolescents aged 6 to 18 years with neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD)

2. What should I know before I use VOQUILY?

Warnings

Do not use VOQUILY if:

  • you are allergic to melatonin, or any of the ingredients listed at the end of this leaflet.

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

Check with your doctor if you:

  • have or had the following medical conditions:
    - an autoimmune disease
    - a seizure disorder such as epilepsy
    - problems with your liver
    - problems with your kidneys
  • take any medicines for any other condition.

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?

Pregnancy and breastfeeding

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

Melatonin is not recommended if you or your child are pregnant. Melatonin crosses the placenta and there is insufficient information on the risk this may pose to the unborn child.

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

Melatonin is not recommended if you or your child are breastfeeding. Melatonin passes into human milk, and the risk to the breast-fed child cannot be excluded.

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.

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

These include:

  • hypnotics (such as benzodiazepines, zolpidem and zopiclone)
  • fluvoxamine, thioridazine and imipramine (used to treat depression or psychiatric conditions)
  • oestrogens (contraceptives or hormone replacement therapies)
  • cimetidine (used to treat reflux and stomach ulcers)
  • psoralens (used to treat skin conditions such as psoriasis)
  • antibiotics such as ciprofloxacin, moxifloxacin and norfloxacin (known as quinolones) and rifampicin
  • carbamazepine (used to treat epilepsy).
  • warfarin (anticoagulant)
  • alcohol

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

4. How do I use VOQUILY?

How much to take

Adults

  • For the treatment of jet lag:
    - The standard starting dose is 2 mg once daily.
    - Your doctor may increase your dose up to 5 mg once daily.

Children and adolescents

  • The standard starting dose is 2 mg once daily.
  • Your doctor may increase your dose up to 5 mg once daily.

When to take VOQUILY

Adults

  • For the treatment of jet lag:
    - Take the required dose at the preferred local sleep time of your travel destination.
    - Only use VOQUILY for a short period of time (no more than 5 days in a row).
    - Avoid taking VOQUILY before 8pm or after 4am.
    This may make the medicine less effective.

Children and adolescents

  • For treatment of sleep disorders with neurodevelopmental disorders:
    - Take the required dose 30 minutes to 1 hour before bed.
    - Continue using VOQUILY only as long as the doctor recommends.

How to take the VOQUILY capsules

VOQUILY should be taken on an empty stomach, at least 1 hour before and at least 1 hours after a meal. The capsules should be swallowed whole with a glass of water or juice.

How to take the VOQUILY oral solution

VOQUILY should be taken on an empty stomach at least 1 hour before and at least 1 hour after a meal.

The oral solution pack contains a 10 mL oral syringe (with markings for each 0.5 mL) and a press-in bottle adapter.

  1. Open the bottle and at first use, insert the press-in bottle adapter. The adapter remains in the bottle.
  2. Insert the syringe into the adapter, invert the bottle and draw out the required dose.
  3. Return bottle to upright position and remove the filled syringe.
  4. Empty the syringe into the patient's mouth.
  5. Replace the cap on the bottle and rinse the syringe.

If you forget to use VOQUILY

VOQUILY should be used regularly at the same time each day. If you forget to take a dose, it could be taken before going to sleep that night, but after this time, no other dose should be taken before the next evening. Do not take a double dose to make up for the dose you missed.

If you have trouble remembering to take VOQUILY, ask your pharmacist for some hints.

If you use too much VOQUILY

If you think that you have used too much VOQUILY, 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 using VOQUILY?

Things you should do

Call your doctor straight away if you:

  • Become pregnant while taking VOQUILY.

Remind any doctor, dentist or pharmacist you visit that you are using VOQUILY.

Things you should not do

  • Do not give VOQUILY to anyone else, even if they have the same condition as you.
  • Do not take more than the recommended dose unless your doctor tells you to.
  • Do not use this medicine to treat any other complaints unless your doctor tells you to.

Driving or using machines

VOQUILY may cause drowsiness and may decrease alertness for several hours after intake. Therefore, this medicine should not be taken prior to driving or using machines.

VOQUILY makes you sleepy, and it could make you sleepy in the daytime as well.

Drinking alcohol

Tell your doctor or pharmacist if you drink alcohol.

Alcohol may cause drowsiness, so should not be taken together with VOQUILY.

Smoking

Tell your doctor if you smoke

Smoking may affect how well this medicine works.

Looking after your medicine

  • Store below 25°C
  • Store VOQUILY in original packaging to protect from light.

Follow the instructions on 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

Discard the oral solution 2 months after opening.

Getting rid of any unwanted medicine

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

Do not use 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 effectsWhat to do
Body as a whole:
  • Generally feeling unwell
  • Feeling of weakness
  • Pain
  • Thirst
  • Fatigue
  • Changes in weight
  • Decreased appetite
  • Cough
Brain and nerves:
  • Irritability
  • Nervousness
  • Abnormal dreams or nightmares
  • Anxiety
  • Difficultly sleeping
  • Sleepiness
  • Headache or migraine
  • Dizziness
  • Hyperactivity
  • Lethargy
  • Fainting
  • Disorientation
  • Confusion
  • Memory problems
  • Aggression
  • Depression
  • Restlessness
  • Tremor
  • Lightheadedness
  • Changes to libido (sex drive)
  • Pins and needles
Heart and vascular system:
  • Bleeding or bruising more easily than normal
  • Hot flushes
Speak to your doctor if you have any of these less serious side effects and they worry you.
Eyes, ears and mouth:
  • Blurred vision or vision impairment
  • Watery eyes
  • Vertigo (spinning sensation)
  • Dry mouth
  • Excessive saliva productions
  • Bad breath
Gut and digestion:
  • Nausea
  • Vomiting
  • Stomach pain
  • Diarrhoea
  • Constipation
  • Indigestion
  • Flatulence (wind)
Urinary:
  • Wetting the bed
  • Excessing urination
  • Persistent urge to urinate
  • Pain and burning with urination
Muscles and bone:
  • Muscle spasms
  • Muscle pain
  • Muscle weakness
  • Joint swelling and/or joint pain
Skin and nails:
  • Dry skin
  • Rash
  • Itchy skin
  • Excessive sweating
  • Night sweats
  • Nail problems
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Immune system:
  • Allergic reaction such as shortness of breath, wheezing or difficulty breathing, swelling of the face lips, tongue or other parts of the body, hives, itching or skin rash
Infections:
  • Frequent infections such as fever, chills, sore throat
  • Painful, blistering rash (shingles)
Heart and vascular system:
  • Chest pain, or a feeling or tightness in the chest
  • Fast or irregular heartbeat
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.
Side effects affecting different parts of the body:
  • Persistent gut pain, nausea or vomiting (more than 1 week)
  • Blood in your stool or urine
  • Vomit containing what looks like coffee-grounds.
  • Persistent painful erection
  • Mouth ulcers, swelling of the tongue, swelling of the mouth
  • Seizure
  • Visual disturbances
  • Suicide attempt or ideation
  • Milky discharge from nipple
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.

Your doctor can only detect some side effects with a medical test. Attend any medical appointments needed to monitor these side effects.

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

Other side effects not listed here may occur in some people.

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 VOQUILY contains

Active ingredient
(main ingredient)		Melatonin
Other ingredients
(inactive ingredients)

Capsules:

  • Microcrystalline cellulose
  • Povidone
  • Maltodextrin
  • Magnesium stearate
  • Purified water
  • Titanium dioxide
  • Indigo carmine (FD&C Blue No. 2) (2 mg and 5 mg only)
  • Gelatin
Other ingredients
(inactive ingredients

Oral Solution

  • Propylene glycol
  • Sorbitol
  • Sucralose
  • Strawberry flavour
  • Hydrochloric acid
  • Purified water
Potential allergens

Capsules:

  • Gelatin – may contain residual sulfites.

Oral Solution

  • Sucralose
  • Sorbitol – 200mg/mL.
    Products containing sorbitol may have a laxative effects or cause diarrhoea.

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

What VOQUILY looks like

Capsules

2 mg: Opaque hard gelatin capsules with a white body and light blue cap. (AUST R 388309).

3 mg: Opaque hard gelatin capsules with a white body and white cap. (AUST R 388310).

5 mg: Opaque hard gelatin capsules with a light blue body and light blue cap. (AUST R 388311)

Oral Solution

A clear, colourless to yellowish solution with a strawberry scent. (AUST R 388312)

Who distributes VOQUILY

Link Medical Products Pty Ltd
5 Apollo Street
Warriewood
NSW, 2102
Australia

This leaflet was prepared in September 2023.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Voquily

Active ingredient

Melatonin

Schedule

S4

 

1 Name of Medicine

Melatonin.

2 Qualitative and Quantitative Composition

Voquily capsules contain 2 mg, 3 mg or 5 mg of melatonin.
Voquily oral solution contains 1 mg/mL of melatonin.

Excipients with known effect.

Capsules.

Gelatin - may contain traces of sulfites.

Oral solution.

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

3 Pharmaceutical Form

Capsules.

2 mg: opaque hard gelatin capsules with a white body and light blue cap.
3 mg: opaque hard gelatin capsules with a white body and white cap.
5 mg: opaque hard gelatin capsules with a light blue body and light blue cap.

Oral solution.

A clear, colourless to yellowish solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Adult.

Short-term treatment of jet lag in adults aged 18 and over.

Paediatric.

Sleep disorders in children and adolescents aged 6 to 18 with neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), where sleep hygiene measures have been insufficient.

4.2 Dose and Method of Administration

Dosage.

Adults.

Jet lag.

The recommended dose is 2 mg once daily taken at the preferred local sleep time. The dose may be increased to up to a maximum of 5 mg if the standard dose does not adequately alleviate symptoms. The lowest effective dose should be used.
Voquily should be taken for the shortest period of time, with a maximum duration of 5 days.
Due to the potential for incorrectly timed intake of melatonin to have no effect, or an adverse effect, on re-synchronisation following jet lag, Voquily should not be taken before 8 pm or after 4 am destination time.
Paediatrics.

Neurodevelopmental disorders.

The recommended starting dose is 2 mg once daily taken 30 minutes to 1 hour before bedtime. If an inadequate response has been observed, the daily dose should be increased to a maximum of 5 mg per day.
The patient should be monitored at regular intervals (at least every 6 months) to check that Voquily is still the most appropriate treatment. After at least 3 months of treatment, the physician should evaluate the treatment effect and consider stopping treatment if no clinically relevant treatment effect is seen. If a lower treatment effect is seen after titration to a higher dose, the prescriber should first consider a down-titration to a lower dose before deciding on a complete discontinuation of treatment.

Method of administration.

Food can enhance the increase in plasma melatonin concentration (see Section 5.2). Intake of melatonin with carbohydrate-rich meals may impair blood glucose control for several hours (see Section 4.4). It is recommended that Voquily is administered on an empty stomach and food is not consumed 1 h before and 1 h after intake of Voquily.

Capsules.

Voquily capsules should be swallowed whole with fluid.

Oral solution.

A 10 mL graduated oral syringe with 0.5 mL graduations and a press-in bottle adapter are provided with the product.
1. Open the bottle and at first use, insert the press-in bottle adapter. The adapter will remain in the bottle.
2. Insert the syringe into the adapter, invert the bottle and draw out the required dose.
3. Return bottle to upright position and remove the filled syringe.
4. Empty the syringe into the patient's mouth.
5. Replace the cap on the bottle and rinse the syringe.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed, see Section 6.1.

4.4 Special Warnings and Precautions for Use

Drowsiness.

Melatonin may cause daytime drowsiness. Therefore, Voquily should be used with caution if the effects of drowsiness are likely to be associated with a risk to patient safety.

Autoimmune diseases.

There is no data concerning the use of melatonin in patients with autoimmune diseases. Therefore, Voquily is not recommended in patients with autoimmune diseases.

Seizure risk.

Melatonin may increase seizure frequency in patients experiencing seizures (e.g. epileptic patients). Patients suffering from seizures must be informed about this possibility before using melatonin 1 mg/mL oral solution. Melatonin may promote or increase the incidence of seizures in children and adolescents with multiple neurological defects.

Sorbitol and propylene glycol.

Voquily oral solution, contains 140 mg sorbitol and 150 mg propylene glycol in each mL.
This medicinal product contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

Use in hepatic impairment.

Limited data indicates that daytime endogenous blood melatonin concentration is markedly elevated in patients with hepatic impairment due to reduced clearance. Therefore, Voquily is not recommended for patients with hepatic impairment.

Use in renal impairment.

Limited data is available for the use of melatonin in patient with renal impairment. Therefore, Voquily is not recommended for patients with renal impairment.

Use in the elderly.

Melatonin metabolism is known to decline with age. Across a range of doses, higher AUC and Cmax levels have been reported in older subjects compared to younger subjects, reflecting the lower metabolism in the elderly. Also, see Section 5.2 Pharmacokinetic Properties, Elderly.

Paediatric use (under 6 years of age).

Efficacy and safety of Voquily in children under 6 years of age has not been established.

Effects on laboratory tests.

No information is available on the effect of melatonin on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Melatonin is metabolised primarily through the CYP1A1 and CYP1A2 enzymes. As a result, drugs that affect CYP enzymes which are involved in melatonin's metabolism could potentially affect melatonin's exposure with or without potential clinical consequences. However, there is a limited data available in terms of melatonin's potential for pharmacokinetic interactions.

Hepatic enzymes.

Melatonin has been observed to induce CYP3A in vitro at supra-therapeutic concentrations. The clinical relevance of the finding is unknown. If induction occurs, plasma concentrations of concomitantly administered drugs can be reduced.
Melatonin does not appear to induce CYP1A enzymes in vitro at supra-therapeutic concentrations. Therefore, interactions between melatonin and other active substances as a consequence of melatonin's effect on CYP1A enzymes are not likely to be significant.
Melatonin's metabolism is mainly mediated by CYP1A enzymes. Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP1A enzymes is possible:

Quinolones.

CYP1A2 inhibitors such as quinolones may give rise to increased melatonin exposure.

Carbamazepine and rifampicin.

CYP1A2 inducers such as carbamazepine and rifampicin may give rise to reduced plasma concentrations of melatonin.

Fluvoxamine.

Caution should be exercised in patients on fluvoxamine, which increases melatonin levels (17-fold higher AUC and 12-fold higher serum Cmax) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19. The combination should be avoided.

5- or 8-methoxypsoralen.

Caution should be exercised in patients on 5- or 8-methoxypsoralen (5 and 8-MOP), which increases melatonin levels by inhibiting its metabolism.

Cimetidine.

Caution should be exercised in patients on cimetidine, a CYP2D inhibitor which increases plasma melatonin levels by inhibiting its metabolism.

Oestrogens.

Caution should be exercised in patients on oestrogens (e.g. contraceptives or hormone replacement therapy), which increase melatonin levels by inhibiting its metabolism by CYP1A1 and CYP1A2.

Thioridazine and imipramine.

Melatonin has been co administered in studies with thioridazine and imipramine, active substances which affect the central nervous system. No clinically significant pharmacokinetic interactions were found in each case. However, melatonin co administration resulted in increased feelings of tranquillity and difficulty in performing tasks compared to imipramine alone, and increased feelings of "muzzy-headedness" compared to thioridazine alone.

Hypnotics.

Melatonin may enhance the sedative properties of benzodiazepines and nonbenzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In a study of jet lag therapy the combination of melatonin and zolpidem resulted in a higher incidence of morning sleepiness, nausea, and confusion, increased impairment of attention, memory and coordination as well as reduced activity during the first hour after getting up, compared to zolpidem alone. The use of melatonin in combination with these drugs is not recommended.

Warfarin.

Melatonin may increase the anticoagulation activity of warfarin. The combination of warfarin or other vitamin K antagonists with melatonin may require dose adjustment of the anticoagulant drugs and should be avoided.

Cigarette smoking.

Cigarette smoking may decrease melatonin levels due to induction of CYP1A2.

Alcohol.

Alcohol is a sedative with the ability to alter physical and mental functions. There is a potential for patients to have enhanced drowsiness when alcohol is co-administered with melatonin.

Other.

There is a large amount of data in the literature regarding the effect of adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressant medicinal products, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol, on endogenous melatonin secretion. Whether or not these active substances interfere with the dynamic or kinetic effects of melatonin or vice versa has not been studied.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No significant effects on fertility or reproductive performance were observed in rats given oral melatonin prior to mating through to early gestation at doses over 900-fold the recommended clinical dose, based on surface area.
Voquily is not recommended in women and men planning pregnancy.
(Category B3)
No clinical data on exposed pregnancies are available. In view of the lack of clinical data, use in pregnant women and by women intending to become pregnant is not recommended.
 Endogenous melatonin has been detected in human breast milk, thus exogenous melatonin is likely excreted into human milk. The effects of melatonin on the nursing infant have not been established. Therefore, breast-feeding is not recommended in women under treatment with melatonin.

4.7 Effects on Ability to Drive and Use Machines

No studies were identified which evaluated the impact of melatonin on the ability to drive or operate machinery. However, as melatonin may cause drowsiness, Voquily is not recommended prior to driving and using machines until the effects are known.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

A review of published clinical trials indicated that the most common adverse events in adults are somnolence, headache, dizziness, nausea and stomach cramps.
A review of published clinical trials indicated that the most common adverse events in children and adolescents are somnolence, headache, nausea, seizures, dizziness and hyperactivity.

Tabulated list of adverse reactions.

The adverse reactions reported in Table 1 are those generally reported for melatonin in published clinical trials and spontaneous case reports.
The adverse reactions are reported according to MedDRA system organ classification and frequencies. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be established from the available data).

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

Ingestion of daily doses of up to 300 mg of melatonin did not cause clinically significant adverse reactions.
Drowsiness, headache, dizziness, and nausea are the most commonly reported signs and symptoms of high doses with oral melatonin. Flushes, abdominal cramps, diarrhoea, headache, and scotoma lucidum have been reported after ingestion of extremely high melatonin doses (3000 - 6600 mg) for several weeks.
In cases of overdose, general supportive measures should be employed. Gastric lavage and administration of activated charcoal can be considered.
Clearance of the active substance is expected within 12 hours of ingestion.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: melatonin receptor agonists, ATC code: N05CH01.
Melatonin is a hormone and antioxidant. Melatonin secreted by the pineal gland is involved in the synchronisation of circadian rhythms to the diurnal light-dark cycle. Physiologically, melatonin secretion increases shortly after the onset of darkness, peaks at 2-4 and diminishes during the second half of the night. Peak melatonin secretion is almost diametrically opposite peak daylight intensity, with daylight being the primary stimulus for maintaining the circadian rhythmicity of melatonin secretion.
Melatonin has a hypnotic/sedative effect and increases propensity for sleep. Melatonin administered earlier or later than the nocturnal peak in melatonin secretion can, respectively, advance or delay the circadian rhythmicity of melatonin secretion.

Mechanism of action.

The activity of melatonin at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties via their distinct actions on the circadian clock. The MT1 receptors are thought to inhibit neuronal firing, while the MT2 receptors have been implicated in the phase-shifting response.

Clinical trials.

Adults.

Jet lag.

Clinical evidence to support the use of Voquily for the short-term treatment of jet lag in adults aged 18 and over is derived from 19 published reports. Table 2 summarises the patient populations, dosage regimens, efficacy data for the pivotal studies.
Paediatrics.

Neurodevelopmental disorders.

Clinical evidence to support the use of Voquily for the treatment of sleep disorders in children and adolescents aged 6 to 18 with neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), where sleep hygiene measures have been insufficient, is derived from 24 published reports. Table 3 summarises the patient populations, dosage regimens, efficacy data for the pivotal studies.

5.2 Pharmacokinetic Properties

Melatonin is a small, amphiphilic molecule (molecular weight 232 g/mol) active in its parent form. Melatonin is synthesised in the human body from tryptophan via serotonin. Small quantities are obtained via diet. Data summarised below are from studies that generally involved healthy men and women, primarily young and middle-aged adults.

Absorption.

Orally administered melatonin is almost completely absorbed. Oral bioavailability is ~ 15%, owing to first-pass metabolism of ~ 85%. Plasma Tmax is ~ 50 minutes. A 3 mg dose of immediate-release melatonin raises plasma melatonin Cmax to ~ 3400 picogram/mL, which is ~ 60 times the nocturnal (endogenous) plasma melatonin Cmax, though both endogenous- and exogenous Cmax show considerable inter-individual variation.
Data on the effect of intake of food at or around the time of intake of melatonin on its pharmacokinetics are limited, though suggest that concomitant food intake may increase bioavailability almost 2-fold. Food appears to have a limited effect on Tmax for immediate-release melatonin. This is not expected to affect the efficacy or safety of Voquily.
Plasma melatonin Cmax and AUC increase in a directly proportional, linear manner for oral doses of immediate-release melatonin in the range 1 - 6 mg whereas Tmax and plasma t½ remain constant.

Distribution.

The in vitro plasma protein binding of melatonin is approximately 60%. Melatonin is mainly bound to albumin, alpha-1-acid glycoprotein and high-density lipoprotein. The binding to the other serum proteins is insignificant. The melatonin binding was constant over the range of the studied concentrations in serum. Literature data indicates that melatonin is distributed in all body fluids and is accessible at all tissues.

Metabolism.

Melatonin is mainly metabolised by the liver. Experimental data suggest that the cytochrome P450 enzymes CYP1A1 and CYP1A2 are primarily responsible for melatonin metabolism, with CYP2C19 of minor importance. Melatonin is primarily metabolised to 6hydroxymelatonin (constituting ~ 80 - 90% of melatonin metabolites recovered in the urine). N-acetylserotonin appears to be the primary minor metabolite (constituting ~ 10% of melatonin metabolites recovered in the urine). Melatonin metabolism is very rapid, with plasma 6-hydroxymelatonin level rising within minutes of exogenous melatonin entering the systemic circulation. 6-hydroxymelatonin undergoes sulphate conjugation (~ 70%) and glucuronide conjugation (~ 30%) prior to excretion.

Excretion.

Plasma elimination half-life (t½) is ~ 45 minutes (normal range ~ 30 - 60 minutes) in healthy adults. The half-life, on average, is comparable or slightly shorter in children compared to adults. Dosage once daily in combination with the short half-life means minimal accumulation of melatonin during regular treatment. Melatonin metabolites are mainly eliminated by the urine, ~ 90% as sulphate and glucuronide conjugates of 6-hydroxymelatonin. Less than ~ 1% of a melatonin dose is excreted unchanged in urine.

Gender.

Limited data suggest that Cmax and AUC following ingestion of immediate-release melatonin may be higher (potentially roughly double) in women compared to men, however a large variability in the pharmacokinetics is observed. Plasma melatonin half-life does not appear to be significantly different in men and women.

Pre-pubertal children.

Limited data suggests that prepubertal children metabolise melatonin faster than adults and, display a significantly shorter t½ and AUC compared to adult patients.

Elderly.

Data from other formulations of melatonin indicate that the absorption of orally ingested melatonin may be decreased up to 50% in the elderly.
Melatonin metabolism is known to decline with age. Across a range of doses, higher AUC and Cmax levels have been reported in older subjects compared to younger subjects, reflecting the lower metabolism of melatonin in the elderly. Cmax levels around 500 picogram/mL in adults (18-45) versus 1200 picogram/mL in the elderly (55-65); AUC levels around 3,000 picogram.h/mL in adults versus 6000 picogram.h/mL in the elderly.

Hepatic impairment.

The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in higher endogenous melatonin levels.
Limited data indicates that daytime endogenous blood melatonin concentration is markedly elevated in patients with cirrhosis due to reduced clearance.

Renal impairment.

Decreased renal function is no expected to influence the elimination of melatonin as < 1% of the dose is excreted unchanged in the urine. Melatonin is primarily excreted as metabolites; plasma levels of melatonin metabolites can be expected increase in patients with more advanced renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Results from a standard battery of in vitro and in vivo assays showed no evidence of a genotoxic potential for melatonin.

Carcinogenicity.

An oral lifetime carcinogenicity study with melatonin in rats showed an increased incidence of thyroid follicular cell adenomas in males at doses around 700-fold the recommended clinical dose, based on body surface area. No neoplastic tissue histopathology was examined at lower doses and therefore the no-effect dose could not be determined. These effects were associated with liver enzyme induction in this species and are unlikely to be relevant to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsules.

Microcrystalline cellulose, povidone, maltodextrin, magnesium stearate, titanium dioxide, indigo carmine (2 mg and 5 mg only), gelatin.

Oral solution.

Propylene glycol, sorbitol solution (70 per cent) (non-crystallising), sucralose, strawberry flavour TEG 10315784 (ARTG PI No. 144274), hydrochloric acid, purified water.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Capsules.

Store below 25°C. Store in outer carton to protect from light.

Oral solution.

Store below 25°C. Use within 2 months of opening. Store in original package in order to protect from light.

6.5 Nature and Contents of Container

Capsules.

PVC/PVDC/Al blister pack with 30 capsules.
Voquily is also available as a starter pack with 10 capsules.

Oral solution.

A 150 mL type III amber glass bottle, with a HDPE child-resistant, tamper-evident screw cap, bottle adapter and 10 mL graduated dosage syringe.
Not all strengths or pack sizes may be available.

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

Chemical structure.

Chemical name: N-[2-(5-methyloxy-1H-indol-3-yl)ethyl]acetamide.
Chemical structure:
Molecular formula: C13H16N2O2.
Molecular weight: 232.27.

CAS number.

73-31-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4: Prescription Only Medicine.

Summary Table of Changes