public submissions on scheduling matters referred to the

MELATONIN - ORAL

For Melatonin products with a sublingual route of administration, please use the Melatonin-sublingual monograph.

This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications (PLAs) and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredient.

Notes Text in parentheses is additional optional information which can be included on the PLA and

product label at the applicant’s discretion. The solidus (/) indicates that the terms and/or the statements are synonymous. Either term or

statement may be selected by the applicant.

Date May 13, 2013

Proper name(s)

N-[2-(5-Methoxy-1H-indol-3-yl)ethyl]acetamide (Martindale 2012; Merck 2012) N-Acetyl-5-methoxytryptamine (Martindale 2012; Merck 2012)

Common name(s)

Melatonin (Merck 2012; Buscemi et al. 2004)

Source material(s)

Melatonin (Merck 2012)

Route(s) of administration

oral (Buscemi et al. 2004)

Dosage form(s)

The acceptable pharmaceutical dosage forms include, but are not limited to capsules, chewables (e.g. gummies, tablets), liquids, powders, strips or tablets.

This monograph is not intended to include foods or food-like dosage forms such as barchewing gums or beverages.

s,

SanteHealth Sante Canada Canada

Melatonin – oral of 13

Use(s) or Purpose(s) Statement(s) to the effect of

Helps to increase the total sleep time (aspect of sleep quality) in people suffering from sleep restriction or altered sleep schedule (e.g. shift-work, jet lag) (Zhdanova et al. 2001; Shamir et al. 2000; Skene et al. 1999; Brusco et al. 1999; Sanders et al. 1999; Dolberg et al. 1998; Garfinkel et al. 1995; Haimov et al. 1995; Sack et al. 1991).

Helps to prevent and/or reduce the effects of jet lag (e.g. daytime fatigue, sleep disturbance) for people travelling by plane easterly across two or more time zones (Brown et al. 2009; Herxheimer and Petrie 2009; Suhner et al. 1998a; Petrie et al. 1993; Claustrat et al. 1992; Petrie et al. 1989).

Helps to reduce the time it takes to fall asleep (sleep onset latency aspect of sleep quality) in people with delayed sleep phase disorder (van Geijlswijk et al. 2010).

Helps to re-set the body’s sleep-wake cycle (aspect of the circadian rhythm) (van Geijlswijk et al. 2010; Kunz et al. 2004; Sack et al. 2000).

Dose(s) Statement(s) to the effect of

Subpopulation(s)

adults (≥ 19 years) (IOM 2004)

Quantity(ies)

All uses except jet lag: 0.1-10 mg, per day (Brzezinski et al. 2005; IOM 2004; Andrade et al. 2001; Kayumov et al. 2001; Koda-Kimble 2001; Smits et al. 2001; Zhdanova et al. 2001; Citera et al. 2000; Shamir et al. 2000; Brusco et al. 1999; Jean-Louis et al. 1999; Matsumoto 1999; Dolberg et al. 1998; Lewy et al. 1998; Attenburrow et al. 1996; Garfinkel 1995; Haimov et al. 1995; Tzischinsky and Lavie 1994; Dollins et al. 1993; Dahlitz et al. 1991; James et al. 1987)

Jet lag: 0.5-10 mg, per day (Brown et al. 2009; Herxheimer and Petrie 2009; Suhner et al. 1998a)

Directions for use

All uses: Do not drive or use machinery for 5 hours after taking melatonin (Avery et al. 1998; Suhner et al. 1998b).

All uses except jet lag: Take once a day, at or before bedtime (Murray et al. 2006; Kayumov et al. 2001; Zhdanoya et al.


2001).

Jet lag: Take once a day at bedtime after darkness has fallen, while travelling, and at destination until adaptation to the new daily pattern (Brown et al. 2009; Herxheimer and Petrie 2009).

See Appendix 1 for examples of dosage preparations, frequencies of use and directions for use, according to cited references. The purpose of Appendix 1 is to provide guidance to industry.

Duration of use Statement(s) to the effect of

All uses except jet lag: For use beyond 4 weeks, consult a health care practitioner (Buscemi et al. 2004; IOM 2004).

Jet lag: For occasional short-term use (Herxheimer and Petrie 2009).

Risk information Statement(s) to the effect of

Caution(s) and warning(s)

All uses except jet lag: If symptoms persist for more than 4 weeks (chronic insomnia), consult your health care practitioner (Buscemi et al. 2004; IOM 2004; Dipiro et al. 2002).

All uses: Consumption with alcohol, other medications or natural health products with sedative

properties is not recommended (Herxheimer and Petrie 2009; Holliman and Chyka 1997).

If you have one of the following conditions, consult a health care practitioner prior to use: asthma (Sutherland et al. 2003; Sutherland et al. 2002) cardiovascular disease (IOM 2004; Scheer et al. 2004; Cagnacci et al. 2001b; GAO 2001; Lusardi et al. 2000; Arangino et al. 1999) chronic kidney disease (IOM 2004) depression (der Marderosian and Beuttlers 2009; IOM 2004; GAO 2001; Carman et al. 1976) diabetes or hypoglycaemia (Peschke and Mühlbauer 2010; Cagnacci et al. 2001a; GAO 2001). hormonal disorder (IOM 2004; Cagnacci et al. 2001b; GAO 2011). immune system disease (der Marderosian and Beutters 2009; Carrillo-Vico et al. 2005; IOM 2004; Calvo et al. 2002; GAO 2001; Maestroni 1993) liver disease (IOM 2004) migraines (IOM 2004) seizure disorders (Herxheimer and Petrie 2009; IOM 2004; Sheldon 1998)


If you are taking one of the following medications, consult a health care practitioner prior to use:

anticoagulant (Herxheimer and Petrie 2009; Wirtz et al. 2008) anticonvulsant (IOM 2004) blood pressure medications (Herxheimer and Petrie 2009; Scheer et al. 2004; Lusardi et al. 2000) immunosuppressive medications (Lissoni et al. 1999; Maestroni 1993) sedative, hypnotic or psychotropic medications (IOM 2004; Holliman and Chyka 1997) steroids (GAO 2001)

Contraindication(s)

If you are pregnant or breastfeeding, do not use this product (IOM 2004).

Known adverse reaction(s)

Mild gastrointestinal symptoms (nausea, vomiting, or cramping) have been known to occur in which case, discontinue use (Herxheimer and Petrie 2009).

Rare allergic reactions have been known to occur in which case, discontinue use (Herxheimer and Petrie 2009).

Non-medicinal ingredients

Must be chosen from the current NHPD Natural Health Products Ingredients Database (NHPID) and must meet the limitations outlined in the database.

Storage conditions Statement(s) to the effect of

No statement required.

Specifications

The finished product specifications must be established in accordance with the requirements described in the NHPD Quality of Natural Health Products Guide.

The medicinal ingredient must comply with the requirements outlined in the Natural Health

Products Ingredients Database (NHPID). In addition, the medicinal ingredient may comply with the specifications outlined in the Melatonin monograph of the British Pharmacopoeia.

References cited


Andrade C, Srihari BS, Reddy KP, Chandramma L. Melatonin in medically ill patients with insomnia: a double blind placebo-controlled study. Journal of Clinical Psychiatry 2001;62(1):41-45.

Arangino S, Cagnacci A, Angiolucci M, Vacca AMB, Longu G, Volpe A, Melis GB. Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men. American Journal of Cardiology 1999; 83(9):1417-1419.

Attenburrow ME, Cowen PJ, Sharpley AL. Low dose melatonin improves sleep in healthy middle-aged subjects. Psychopharmacology (Berlin) 1996;126(2):179-81.

Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Annals of Medicine 1998;30(1):122-30.

Brown GM, Pandi-Perumal SR, Trakht I, Cardinali DP. Melatonin and its relevance to jet lag. Travel Medicine and Infectious Disease 2009;7:69-81.

Brusco LI, Fainstein I, Marquez M, Cardinali DP. Effect of melatonin in selected populations of sleep-disturbed patients. Biological Signals and Receptors 1999;8(1-2):126-31.

Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-Shushan A, Ford I. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Medicine Reviews 2005;9:41-50.

Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T. Melatonin for treatment of sleep disorders. Evidence Report/Technology Assessment No. 108. AHRQ Publication No. 05-E002-2. Rockville (MD): U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality. November, 2004.

Cagnacci A, Arangino S, Renzi A, Paoletti AM, Melis GB, Cagnacci P, Volpe A. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clinical Endocrinology (Oxford) 2001a;54(3):339-46.

Cagnacci A, Arangino S, Angiolucci M, Melis GB, Facchinetti F, Malmusi S, Volpe A. Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy. Clinical Endocrinology 2001b;54:261-266.

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Carman JS, Post RM, Buswell R, Goodwin FK. Negative effects of melatonin on depression. American Journal of Psychiatry 1976;133(10):1181-1186.

Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine 2005;27:189-200.

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Cardinalli DP. The effect of melatonin in patients with fibromyalgia: a pilot study. Clinical Rheumatology 2000;19(1):9-13.

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edition. St. Louis (MO): Facts and Comparisons®, a Wolters Kluwer Company.

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GAO 2001: United States General Accounting Office. Report to Chairman, Special Committee on Agin, U.S. Senate. Health Products for Seniors: “Anti-Aging” Products Pose Potential for Physical and Economic Harm. September 2001. GAO-01-1129. [Consulted 2012 December 08] Available from: http://www.gao.gov/new.items/d011129.pdf

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Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy of elderly insomniacs. Sleep 1995;18(7):598-603.

Härtter S, Nordmark A, Rose DM, Bertilsson L, Tybring G, Laine K. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. British Journal of Clinical Pharmacology 2003;56(6):679-682.

Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD001520. DOI: 10.1002/14651858.CD001520. (Assessed as up-to-date 2008 February 12). [Consulted 2010 September 22]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001520/full

Holliman BJ, Chyka PA. Problems in assessment of acute melatonin overdose. Southern Medical Journal 1997;90(4):451-453.


IOM 2004: Institute of Medicine Committee on the Framework for Evaluating the Safety of Dietary Supplements. Prototype monograph on melatonin. Dietary Supplement Ingredient Prototype Monographs, Developed as Examples for the Report Dietary Supplements: A

Framework for Evaluating Safety. Institute of Medicine and the National Research Council of the National Academies, Washington (DC): National Academies Press 2004: D1-D71.

James SP, Mendelson WB, Sack DA, Rosenthal NE, Wehr TA. The effect of melatonin on normal sleep. Neuropsychopharmacology 1987;1(1):41-4.

Jean-Louis G, von Gizycki H, Zizi F. Predictors of subjective sleepiness induced by melatonin administration. Journal of Psychosomatic Research 1999;47(4):355-8.

Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosomatic Medicine 2001;63(1):40-8.

Koda-Kimble MA, editor. Applied Therapeutics: The Clinical Use of Drugs. Baltimore (MD): Lippincott Williams and Wilkins; 2001.

Kunz D, Mahlberg R, Müller C, Tilmann A, Bes F. Melatonin in patients with reduced REM sleep duration: two randomized controlled trials. Journal of Clinical Endocrinology & Metabolism 2004;89(1):128-134.

Lewy AJ, Bauer VK, Cutler NL, Sack RL. Melatonin treatment of winter depression: a pilot study. Psychiatry Research 1998;77(1):57-61.

Lissoni P, Barni S, Mandalà M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Tancini G. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. European Journal of Cancer 1999;35(12):1688-1692.

Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. British Journal of Clinical Pharmacology 2000;49:423-427.

Maestroni GJM. The immunoneuroendocrine role of melatonin. Journal of Pineal Research 1993;14(1):1-10.

Martindale 2012: Sweetman SC, editor. Martindale: The Complete Drug Reference. [Internet]. London (GB): Pharmaceutical Press; Copyright 1933-2012. [Melatonin: last modified 2011 December 21; accessed 2012 December 03]. Available from: http://www.medicinescomplete.com

Matsumoto M. The hypnotic effects of melatonin treatment on diurnal sleep in humans. Psychiatry and Clinical Neurosciences 1999;53(2):243-5.


Merck 2012: The Merck Index Version 14.1. [Internet]. Whitehouse Station (NJ): Merck & Co., Inc. Copyright © 2006, 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. [Accessed 2012 December 03]. Available from: http://www.medicinescomplete.com

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Peschke E, Mühlbauer E. New evidence for a role of melatonin in glucose regulation. Best practice & research. Clinical endocrinology & metabolism 2010;24(5):829-841.

Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biological Psychiatry 1993;33(7): 526-30.

Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights. British Medical Journal 1989;298(6675):705-7.

Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms by melatonin in blind people. New England Journal of Medicine 2000;343 (15):1070-7.

Sack RL, Lewy AJ, Blood ML, Stevenson J, Keith LD. Melatonin administration to blind people: phase advances and entrainment. Journal of Biological Rhythms 1991;6(3):249-61.

Sanders DC, Chaturvedi AK, Hordinsky JR. Melatonin: aeromedical, toxicopharmacological, and analytical aspects. Journal of Analytical Toxicology 1999;23(3):159-67.

Scheer FAJL, Van Montfrans GA, van Someren EJW, Mairuhu G, Buijs RM. Daily nightime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension 2004;43:192-197.

Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, Zisapel N. Melatonin improves sleep quality of patients with chronic schizophrenia. Journal of Clinical Psychiatry 2000;61(5):373-7.

Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998;351:1254.

Skene DJ, Lockley SW, Arendt J. Melatonin in circadian sleep disorders in the blind. Biological Signals and Receptors 1999;8(1-2):90-5.

Smits MG, Nagtegaal EE, van der Heijden J, Coenen AM, Kerkhof GA. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. Journal of Child Neurology 2001;16(2):86-92.

Suhner A, Schlagenhauf P, Johnson R, Tschopp A, Steffen R. Comparative study to determine


the optimal melatonin dosage form for the alleviation of jet lag. Chronobiology International 1998a;15(6):655-6.

Suhner A, Schlagenhauf P, Tschopp A, Hauri-Bionda R, Friedrich-Koch A, Steffen R. Impact of melatonin on driving performance. Journal of Travel Medicine 1998b;5(1):7-13.

Sutherland ER, Martin RJ, Ellison MC, Kraft M. Immunomodulatory effects of melatonin in asthma. American Journal of respiratory and critical care medicine 2002;166:1055-1061.

Sutherland ER, Ellison MC, Kraft M, Martin RJ. Elevated serum melatonin is associated with the nocturnal worsening of asthma. Journal of Allergy and Clinical Immunology 2003;112(3):513-517.

Tzischinsky O, Lavie P. Melatonin possesses time-dependent hypnotic effects. Sleep 1994;17(7):638-45.

van Geijlswijk IM, Korzilius HP, Smits MG. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep 2010;33(12):1605-1614.

Wirtz PH, Spillmann M, Bärtschi C, Ehlert U, von Känel R. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. Journal of Pineal Research 2008;44:127-133.

Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonin treatment for age-related insomnia. Journal of Clinical Endocrinology and Metabolism 2001;86(10):4727-30.

References reviewed

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Appendix 1: Examples of dosage preparations, frequencies of use and directions for use

All uses except jet lag:

0.1-10 mg, per day (Brzezinski et al. 2005; IOM 2004; Andrade et al. 2001; Kayumov et al. 2001; Koda-Kimble 2001; Smits et al. 2001; Zhdanova et al. 2001; Citera et al. 2000; Shamir et al. 2000; Brusco et al. 1999; Jean-Louis et al. 1999; Matsumoto 1999; Dolberg et al. 1998; Lewy et al. 1998; Attenburrow et al. 1996; Garfinkel 1995; Haimov et al. 1995; Tzischinsky and Lavie 1994; Dollins et al. 1993; Dahlitz et al. 1991; James et al. 1987)

Direction for use

All uses: Take once a day at or before bedtime (Murray et al. 2006; Kayumov et al. 2001;

Zhdanova et al. 2001). Do not drive or use machinery for 5 hours after taking melatonin (Avery et al. 1998;

Suhner et al. 1998b).

Jet lag:

0.5-10 mg, per day (Brown et al. 2009; Herxheimer and Petrie 2009; Suhner et al. 1998a)

Direction for use

Take once a day at bedtime after darkness has fallen, while travelling and at the destination until adaptation to the new daily pattern (Herxheimer and Petrie 2009).

Do not drive or use machinery for 5 hours after taking melatonin (Avery et al. 1998; Suhner et al. 1998b).

Consumer Medicine Information

CIRCADIN®

Melatonin

Prolonged Release Tablet

Consumer Medicine Information (CMI)

What is in this leaflet purpose. to your doctor. Ask your doctor or pharmacist

Before you start to take it This leaflet contains answers to if you have any questions about some common questions about why it has been prescribed for Tell your doctor if: CIRCADIN. you. 1. you have any allergies to any

It is particularly important that other medicines or any otherThis medicine is only available substances, such as foods,you read the sections "When to with a doctor’s prescription preservatives ortake it" and "How to take it" . dyes.

before you take this medicine. 2. you are pregnant or plan toThe leaflet does not contain all CIRCADIN is not addictive. become pregnantthe information that is known 3. you are breast-feeding orabout CIRCADIN. Before you take

planning to breast-feedCIRCADIN It does not take the place of 4. you have, or have had the

talking to your doctor or When you must not take it following medical conditions:pharmacist. suffer from liver

Do not take CIRCADIN if you are All medicines have risks and problems

allergic to it or any of the benefits. Your doctor has ingredients listed at the end of this suffer from kidneyweighed the risks of you taking leaflet. problemsCIRCADIN against the benefits

If you suffer from anthey expect it will have for you. Symptoms of an allergic reaction

autoimmune diseasemay include shortness of breath, If you have any concerns about

wheezing or difficulty breathing, have a rare hereditarytaking this medicine, ask your

swelling of the face, lips, tongue problem of galactosedoctor or pharmacist.

or other parts of the body, or rash, intolerance, the LAPP

Keep this leaflet with the itching or hives on the skin. lactase deficiency or

medicine. glucose-galactoseDo not take CIRCADIN if you

malabsorptionYou may need to read it again. have been drinking alcohol or

intend to drink alcohol or believe Do not give CIRCADIN to a child What CIRCADIN is used that you may have alcohol, in your or adolescent. There is no

for blood stream. experience with its use in children or adolescents under 18 years

Do not take CIRCADIN if you are CIRCADIN is used to improve old. pregnant or breast-feeding. sleep quality and morning CIRCADIN has not been studied If you have not told your doctor alertness in patients over 55 in pregnant or breast-feeding about any of the above, so years of age with poor quality of women. before you use CIRCADIN. sleep.

Do not take it after the expiry Taking other medicines The active substance of date printed on the pack. CIRCADIN, melatonin (not of Tell your doctor if you are taking

If you take it after the expiry date plant or animal origin), belongs to any other medicines, including has passed, it may not work as a group of naturally occurring any that you buy without a well. The expiry date refers to the hormones produced in the body. prescription from your pharmacy, last day of the month. supermarket or health food shop.

Melatonin works by controlling Some medicines may affect the Do not take it if the packaging the circadian rhythms and way other medicines work. is torn or shows signs of increasing the propensity to tampering. sleep. Some medicines and CIRCADIN

may interfere with each other. If you are not sure whether you Your doctor, however, may

These include:

should start taking CIRCADIN talk prescribe CIRCADIN for another


hypnotics and tranquilisers They may differ from the and pharmacist that you are

(e.g. benzodiazepine), information contained in this taking CIRCADIN.

leaflet. fluvoxamine, thioridazine Tell any other doctors, dentists and imipramine (used to If you do not understand the and pharmacists who treat you treat depression or instructions on the box, ask that you are taking this medicine. psychiatric problems), your doctor or pharmacist for

If you become pregnant while help.

oestrogen (contraceptives orWhen to take it

taking CIRCADIN, stop taking the hormone replacement tablets and tell your doctor therapy),

After food, 1-2 hours before you immediately. cimetidine and psoralens go to bed.

(used to treat skin problemsThings you must not do

e.g. psoriasis) How long to take it Do not give CIRCADIN to

It is important that you continue anyone else, even if they have alcohol

taking CIRCADIN for as long as the same condition as you. caffeine

your doctor prescribes. Do not take more than the The effect of adding CIRCADIN CIRCADIN may be continued for recommended dose unless to other medicines used to treat up to thirteen weeks. your doctor tells you to. insomnia has not been examined. It is not known if If you forget to take it Do not use this medicine to CIRCADIN will increase or treat any other complaints If you forget to take your tablet, decrease the effects of other unless your doctor tells you to. take another as soon as you treatments for insomnia.

remember, before going to bed or Do not drink alcohol before or Your doctor or pharmacist has wait until it is time for your next after taking this medicine more information on medicines to dose. be careful with or avoid while Things to be careful of

Do not take a double dose to taking CIRCADIN. CIRCADIN rarely causes make up for a forgotten dose.

drowsiness, nevertheless it is not If you are not sure what to do, recommended to drive or operate

How to take CIRCADIN talk to your doctor or machinery for 8 hours after you

How much to take pharmacist. take it. Circadin does not impair

morning alertness, but if you If you have trouble remembering Take CIRCADIN only when suffer from drowsiness during the to take your CIRCADIN, ask your prescribed by your doctor. day you should consult your pharmacist for some hints. The standard dose of CIRCADIN doctor. is one tablet once a day. If you take too much (overdose)

There is no evidence that taking Immediately telephone your more than the recommended doctor or Poisons Information Side Effects dose will increase the effect of Centre (In Australia 13 11 26 CIRCADIN. Tell your doctor or pharmacist and in New Zealand 0800

as soon as possible if you do POISON [0800 764 766]), or go not feel well while you are

How to take it to your nearest accident and

taking CIRCADIN. emergency centre, if you think

Swallow your tablet whole with a that you or anyone else may CIRCADIN has been shown to full glass of water. have taken too much improve the sleep of most people

CIRCADIN. Do this even if there aged over 55 years, but it may Do not crush, chew or divide are no signs of discomfort or have unwanted side effects in a your tablet. poisoning. few people. All medicines can

Each CIRCADIN tablet has been have side effects. Sometimes

specially designed to release the they are serious, but most of the

right dose of medicine while you While you are using time they are not. You may need

sleep. If you crush, chew or divide the tablet they will not work CIRCADIN medical treatment if you get some

of the side effects. properly

Things you must do Ask your doctor or pharmacist to Follow all directions given to

If you are about to be started on answer any questions you may you by your doctor carefully. any new medicine tell your doctor have.

Tell your doctor if you notice quality sleep, ‘pins and needles’ Keep CIRCADIN away from any of the following and they feeling (paresthesia) reduced sunlight.worry you. visual acuity (visual impairment),

Keep the medicine in a cool dry blurred vision, watery eyes,

These are considered to be place where the temperature dizziness when standing or sitting,

uncommon side effects (i.e., stays below 25°C. vertigo, hot flushes, gastro-

likely to occur in fewer than 1 in oesophageal reflux, Do not store it or any other

100 patients): gastrointestinal disorder, blistering medicine in the bathroom, near

Irritability, nervousness, in the mouth, tongue ulceration, a sink, or on a window-sill. restlessness insomnia, abnormal gastrointestinal upset, vomiting,

Do not leave it in the car. dreams, anxiety, nightmares, abnormal bowel sounds,

Heat and damp can destroy some migraine, lethargy, psychomotor flatulence (wind), salivary

medicines. hyperactivity (restlessness hypersecretion (excess saliva

associated with increased production), halitosis (bad breath), Keep it where children cannot activity), dizziness, somnolence abdominal discomfort, gastric reach it. (tiredness), headache, high blood disorder, inflammation of the A locked cupboard at least one-pressure, (upper) abdominal stomach lining, eczema, erythema and-a-half metres above the pain, indigestion, mouth (skin rash), hand dermatitis,

ground is a good place to store ulceration, dry mouth, nausea, psoriasis, pruritic rash (itchy rash),

medicines. hyperbilirubinaemia (changes in nail disorder, arthritis, muscle

the composition of your blood spasms, neck pain, night cramps, Disposalwhich could cause yellowing of increased duration of erection,

inflammation of the prostate If your doctor tells you to stop the skin or eyes (jaundice), inflammation of the skin gland, tiredness, pain, thirst, taking the tablets or the tablets

(dermatitis), night sweats, pruritis passing large volumes or urine, have passed their expiry date,

presence of red blood cells in the ask your pharmacist what to do (itching), rash, dry skin, pain in extremities, menopausal urine, urination during the night, with any that are left over.

symptoms, asthenia (feeling of increased liver enzymes, Return any unused medicine to weakness), chest pain, excretion abnormal blood electrolytes and your pharmacist. of glucose in urine, excess abnormal laboratory tests.

proteins in the urine, abnormal Other side effects not listed above

liver function and weight may also occur in some patients. Product description

increase. Tell your doctor if you notice any

What CIRCADINother effects. looks like

The following events are CIRCADIN 2 mg tablets are white Do not be alarmed by this list of considered to be rare (i.e., likely to off-white round bi-convexpossible side effects. You may not to occur in fewer than 1 in 1,000 shaped tablets experience any of them patients):

CIRCADIN tablets are available in a 30 tablet pack and a 7 tablet Shingles, reduced number of sample pack. white blood cells in the blood, After using CIRCADIN

decreased number of platelets in Storage Ingredients the blood, high level of fatty

Keep your tablets in the blister molecules in the blood, severe Active ingredient

pack until it is time to take chest pain due to angina, feeling Each CIRCADIN 2 mg tablet

them. your heartbeat (palpitations). low contains 2 mg melatonin as the

If you take the tablets out of the serum calcium levels in the blood, active ingredient

low sodium levels in the blood, blister pack they may not keep Inactive ingredients:

altered mood, aggression, well. Ammonio methacrylateagitation, crying, stress copolymer type B,symptoms, disorientation, early calcium hydrogenmorning awakening, increased

phosphate,sex drive, depressed mood, lactose,depression, loss of

colloidal anhydrous silica,consciousness or fainting,

purified talcmemory impairment, disturbance magnesium stearate.in attention, dreamy state,

restless legs syndrome, poor



Australian Sponsor RAD Data Australia Pty Ltd PKF Melbourne Level 12, 440 Collins Street Melbourne, VIC, 3000

Distributed in Australia by:

Aspen Pharma Pty Ltd 34-36 Chandos Street St Leonards NSW 2065

Distributed in New Zealand by:

Pharmacy Retailing t/a Healthcare Logistics 58 Richard Pearse Drive Airport Oaks Mangere Auckland

This leaflet was prepared in May 2016

Australian Registration Number: AUST R: 153959

CIRCADIN is a registered trademark of NeurimPharmaceuticals.

Database of Adverse Event Notifications -

medicinesMedicine summary

You searched for the following 3 medicines between 01/01/1981 – 18/05/2016:

• Bioglan Melatonin (Melatonin)

• Circadin (Melatonin)

• Not specified (Melatonin)

© Commonwealth of Australia 2016.This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal useor, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do notuse the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part ofthat reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice,all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way(electronic or otherwise) without first being given specific written permission from the Commonwealth to do so.Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, TherapeuticGoods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>.

Australian Government

Department of Health Therapeutic Goods Administration

Important information The TGA uses adverse event reports to identify when a safety issue may be present. An adverse event report

does not mean that the medicine is the cause of the adverse event. If you are experiencing an adverse event,

or think you may be experiencing one, please seek advice from a health professional as soon as possible. The

TGA strongly advises people taking prescription medicines not to change their medication regime without

prior consultation with a health professional.

About the Database of Adverse Event Notifications (DAEN) - medicines • The DAEN - medicines contains information from reports of adverse events that the TGA has received in

relation to medicines including vaccines used in Australia.

• The DAEN - medicines does not contain all known safety information about a particular medicine. Please do not

make an assessment about the safety of a medicine based on the information in the DAEN - medicines.

The TGA medicine safety monitoring program More information about the DAEN - medicines and the TGA medicines safety monitoring program is available at:

• About the DAEN - medicines <http://www.tga.gov.au/safety/daen-about.htm>

• Medicines safety <http://www.tga.gov.au/safety/information-medicines.htm>

You are encouraged to report an adverse event suspected of being related to a medicine used in Australia. Reports of

adverse events in relation to medicines and vaccines can be reported using the 'blue card' reporting form, by phone

and online <http://www.tga.gov.au/safety/problem.htm>.

Other useful sources of information on Australian medicines More information about a medicine is available from the Product Information (PI)

<http://www.tga.gov.au/hp/information-medicines-pi.htm> and Consumer Medicine Information (CMI)

<http://www.tga.gov.au/consumers/information-medicines-cmi.htm> leaflet or the labelling of the medicine. Australian

Public Assessment Report for Prescription Medicines (AusPARs) <http://www.tga.gov.au/industry/pm-auspar.htm> for

some prescription medicines, are also available from the TGA website. <http://www.tga.gov.au>

Your health professional can also provide help and assistance on how to use medicines.

Information on medicines used in Australia is available from NPS MedicineWise <http://www.nps.org.au/>.

About the release of this information While reasonable care is taken to ensure that the information is an accurate record of the adverse events reported to

the TGA, the TGA does not guarantee or warrant the accuracy, reliability, completeness or currency of the information

or its usefulness in achieving any purpose.

To the fullest extent permitted by law, including but not limited to section 61A of the Therapeutic Goods Act 1989, the

TGA will not be liable for any loss, damage, cost or expense incurred in or arising by reason of any person relying on

this information.

Copyright restrictions apply to the DAEN - medicines <http://www.tga.gov.au/about/website-copyright.htm>.

Database of Adverse Event Notifications - medicines Medicine summary

Report generated 29/08/2016 7:01:55 PM Page 2 of

Results Number of reports (cases): 65(Multiple adverse events have been reported for some patients)

Number of cases with a single suspected medicine: 53(The TGA thinks there is a possibility that the medicine caused the adverse event)

Number of cases where death was a reported outcome: 0(These reports of death may or may not have been a result of taking a medicine)


MedDRA system organ classi MedDRA reaction termii Number ofcasesiii

Number ofcases witha singlesuspectedmedicineiv

Number ofcaseswheredeath wasa reportedoutcomev

Nervous system disorders Dizziness 8 8 0

Psychiatric disorders Insomnia 8 6 0

Gastrointestinal disorders Nausea 5 4 0

Psychiatric disorders Anxiety 4 2 0

Nervous system disorders Tremor 4 4 0

Injury, poisoning and proceduralcomplications

Off label use 4 4 0

Skin and subcutaneous tissuedisorders

Rash 3 1 0

Nervous system disorders Somnolence 3 3 0

Eye disorders Vision blurred 3 3 0

Psychiatric disorders Confusional state 3 2 0

Psychiatric disorders Depression 3 2 0


Night sweats 3 3 0

Nervous system disorders Paraesthesia 3 3 0

Nervous system disorders Psychomotor hyperactivity 3 3 0

Nervous system disorders Lethargy 3 2 0


Hyperhidrosis 3 3 0

Respiratory, thoracic andmediastinal disorders

Hyperventilation 2 2 0

Gastrointestinal disorders Gastrooesophageal reflux disease 2 2 0

Nervous system disorders Headache 2 0 0

General disorders andadministration site conditions

Malaise 2 2 0

Psychiatric disorders Irritability 2 1 0

Infections and infestations Herpes zoster 2 2 0

Cardiac disorders Palpitations 2 2 0

Psychiatric disorders Nightmare 2 1 0

Report generated 29/08/2016 7:01:55 PM Page 3 of

7

The TGA uses adverse event reports to identify when a safety issue may be present. An adverse event report does notmean that the medicine is the cause of the adverse event. If you are experiencing an adverse event, or think you maybe experiencing one, please seek advice from a health professional as soon as possible. The TGA strongly advisespeople taking prescription medicines not to change their medication regime without prior consultation with a healthprofessional. Please read all the important information at the beginning of this report.





Musculoskeletal and connectivetissue disorders

Muscle spasms 2 2 0


Muscular weakness 2 2 0


Chest pain 2 2 0

Psychiatric disorders Abnormal dreams 2 2 0

Psychiatric disorders Aggression 2 1 0

Psychiatric disorders Disorientation 2 2 0


Drug ineffective 2 2 0

Gastrointestinal disorders Dry mouth 2 2 0

Nervous system disorders Dyskinesia 2 1 0


Dyspnoea 2 2 0


Fatigue 2 2 0

Psychiatric disorders Hallucination 2 2 0

Psychiatric disorders Suicidal ideation 2 1 0

Psychiatric disorders Suicide attempt 2 1 0

Cardiac disorders Tachycardia 2 0 0

Ear and labyrinth disorders Tinnitus 2 1 0

Gastrointestinal disorders Vomiting 2 2 0

Investigations Weight decreased 2 1 0

Investigations Weight increased 2 1 0


Onychomadesis 1 1 0

Nervous system disorders Balance disorder 1 1 0


Contusion 1 1 0


Growth retardation 1 0 0

Gastrointestinal disorders Tongue oedema 1 1 0

Hepatobiliary disorders Venoocclusive liver disease 1 0 0

Infections and infestations Sepsis syndrome 1 0 0

Endocrine disorders Precocious puberty 1 1 0

Nervous system disorders Restless legs syndrome 1 1 0

Vascular disorders Hot flush 1 1 0

Nervous system disorders Motor dysfunction 1 1 0

Report generated 29/08/2016 7:01:55 PM Page 4 of The TGA uses adverse event reports to identify when a safety issue may be present. An adverse event report does notmean that the medicine is the cause of the adverse event. If you are experiencing an adverse event, or think you maybe experiencing one, please seek advice from a health professional as soon as possible. The TGA strongly advisespeople taking prescription medicines not to change their medication regime without prior consultation with a healthprofessional. Please read all the important information at the beginning of this report.





Nervous system disorders Partial seizures 1 1 0

Metabolism and nutrition disorders Decreased appetite 1 1 0

Psychiatric disorders Parasomnia 1 1 0

Psychiatric disorders Psychotic disorder 1 1 0


Oropharyngeal pain 1 1 0

Investigations Streptococcus test positive 1 0 0

Infections and infestations Candida infection 1 1 0


Intentional product misuse 1 1 0

Investigations Liver function test increased 1 0 0

Vascular disorders Thrombophlebitis 1 0 0

Nervous system disorders Speech disorder 1 1 0

Investigations Spermatozoa morphology abnormal 1 1 0

Investigations Spermatozoa progressive motilitydecreased

1 1 0


Rash erythematous 1 0 0

Renal and urinary disorders Renal tubular necrosis 1 0 0

Investigations Respiratory rate increased 1 1 0

Psychiatric disorders Restlessness 1 1 0

Nervous system disorders Sedation 1 0 0

Nervous system disorders Seizure 1 1 0

Nervous system disorders Serotonin syndrome 1 0 0


Skin reaction 1 1 0

Psychiatric disorders Somnambulism 1 1 0

Nervous system disorders Visual field defect 1 1 0

Eye disorders Visual impairment 1 0 0

Psychiatric disorders Hallucination, auditory 1 1 0

Psychiatric disorders Hallucination, visual 1 1 0

Psychiatric disorders Hallucinations, mixed 1 1 0


Hangover 1 1 0

Gastrointestinal disorders Flatulence 1 1 0


Eczema 1 1 0

Nervous system disorders Dysarthria 1 1 0






Nervous system disorders Dysgeusia 1 1 0


Drug withdrawal syndrome 1 1 0

Eye disorders Dry eye 1 1 0

Nervous system disorders Disturbance in attention 1 0 0

Immune system disorders Drug hypersensitivity 1 1 0

Psychiatric disorders Agitation 1 1 0

Gastrointestinal disorders Abdominal discomfort 1 0 0

Gastrointestinal disorders Abdominal pain 1 0 0

Nervous system disorders Aphasia 1 1 0


Arthralgia 1 1 0

Cardiac disorders Atrial fibrillation 1 1 0

Eye disorders Chromatopsia 1 0 0

Vascular disorders Circulatory collapse 1 0 0


Cold sweat 1 1 0


Concomitant disease aggravated 1 1 0

Gastrointestinal disorders Diarrhoea 1 0 0

Gastrointestinal disorders Crohn's disease 1 1 0

Nervous system disorders Depressed level of consciousness 1 0 0


Myalgia 1 0 0

Psychiatric disorders Nervousness 1 1 0

Eye disorders Ocular hyperaemia 1 0 0


Oedema peripheral 1 1 0


Overdose 1 1 0


Pyrexia 1 0 0

Nervous system disorders Paresis 1 1 0


Pruritus 1 1 0

Reproductive system and breastdisorders

Pruritus genital 1 1 0


Joint swelling 1 1 0

Eye disorders Lacrimation increased 1 1 0


Footnotes i A description of what, in general terms, was affected by the adverse event, as described by the Medical Dictionary for

Regulatory Activities MedDRA (for example 'cardiac disorders')

ii A description of the adverse event as defined by MedDRA; these adverse events are grouped by system organ class.

You can use the MedlinePlus medical dictionary <http://www.nlm.nih.gov/medlineplus/mplusdictionary.html> to look up

terms.

iii The number of cases for which each type of adverse event was reported

iv Results show where a medicine is the only medicine suspected to be related to the adverse event

v These reports of death may or may not have been the result of taking a medicine





Nervous system disorders Migraine 1 1 0

Gastrointestinal disorders Mouth ulceration 1 1 0


Muscle rigidity 1 0 0

Nervous system disorders Hemiparesis 1 1 0

Renal and urinary disorders Glomerulonephritis 1 1 0

Nervous system disorders Hypoaesthesia 1 1 0

Vascular disorders Hypotension 1 0 0

Immune system disorders Hypersensitivity 1 1 0

Vascular disorders Hypertension 1 0 0


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