Complaint to TGA: Homeopathic Products (Pretorius, Bioglan, Healthy Care)

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This is a high priority complaint to test the TGA's will to act on recalcitrant sponsors of complementary medicines.

The CRP has upheld more than 15 complaints about homeopathic medicines from 2003 to 2017. In December 2017, the CRP referred the following complaints to the TGA:

• 2017/12/004 Pretorius Homoeopathic Melatonin 6X • 2017/12/007 Healthy Care Melatonin Homeopathic and • 2017/12/008 Bioglan Melatonin Homeopathic Tablets and Spray.

To-date, Pretorius have removed the offending insomnia claims, but many other advertisers of this product have not. No action appears to have been taken about the Healthy Care and Bioglan complaints (appended).

In 2003, the Expert committee report: Complementary Medicines in the Australian Health System recommended (2.1.8) that,

“Homoeopathic medicines and related remedies that make therapeutic claims should be regulated to ensure they meet appropriate standards of safety, quality and efficacy”.

They also noted that,

“It is evident that a number of substances currently not permitted in Listed medicines are being presented on the market as homoeopathic preparations. It is also possible that some of these products are being formulated with little or no regard to homoeopathic principles or practice. The current definition of ‘homoeopathic preparation’ should be amended to make it clear that only ingredients consistent with homoeopathic principles and practice are considered homoeopathic preparations.

A homoeopathic medicine should be adequately described to ensure that it is clearly differentiated from those medicines not consistent with the homoeopathic or a related paradigm. Any misrepresentation of homoeopathic medicines as other medicines needs to be addressed as a priority”.

In 2008, a TGA Consultation on the “Regulation of homoeopathic and anthroposophic medicines in Australia” also made many suggestions about improving the regulation of these products, none of which were implemented.

In 2015, following a thorough review of the evidence, the NHMRC released a statement that concluded that there was no good quality evidence to support the claim that homeopathy is effective in treating health conditions.

In 2017, the TGA held another consultation, “Options for the future regulation of 'low risk' products”, which included homeopathic products, without any reference to the previous consultation and submissions. This consultation document failed to document many long-standing concerns about the supply and promotion of homeopathic products and, in my opinion, it failed to provide a viable solution to the well documented problems of previous reviews.

At this consultation, I (and others) advocated that all products making therapeutic claims by invoking the homeopathic tradition should be regulated as listed products with the addition of a mandatory

Complaint to TGA: Homeopathic Products (Pretorius, Bioglan, Healthy Care)

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disclaimer / warning on their ARTG Public Summary documents, product packaging, labelling and promotion like that recently suggested by the U.S. FTC,1 for example,

Warning: This product’s traditional claims are based only on theories of homeopathy from the 1700s that are not accepted by most modern medical experts. There is no scientific evidence that this product works.

In June 2018, the TGA reported on the outcome of this consultation and noted that,

“The Government is yet to determine what would be an appropriate level of regulation for aromatherapy and homoeopathic products. Further consultation with affected stakeholders may be required”.

In short, unlike other regulators, the TGA has procrastinated for 15 years about improving the regulation of these products. I’ve appended a relevant U.S. lawsuit. Meanwhile, in Australia, misleading and deceptive advertising continues.

I now attach screen shots of misleading and deceptive advertisements for Pretorius, Healthy Care and Bioglan Melatonin products taken today (12/07/2018) that continue to make claims that I previously alleged breach s.4(1)(b), 4(2)(a), 4(2)(c), 4(2)(d) of the Therapeutic Goods Advertising Code 2015.

In addition to concerns previously documented in the appended complaints, Bioglan also states:

“Rather than providing a milligram dosage of melatonin into the body, this homeopathic product enhances your body’s own melatonin production”.

I am unaware of any evidence that substantiates this claim.

https://naturalhealthorganics.com.au/pretorius-melatonin-6x-90-tablets.html

1 https://www.ftc.gov/news-events/press-releases/2016/11/ftc-issues-enforcement-policy-statement-regarding-marketing

Complaint to TGA: Homeopathic Products (Pretorius, Bioglan, Healthy Care)

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http://healthycare.com.au/our-products/sleep-well/item/hc-melatonin-homoeopathic-90-tablets?category_id=74

http://bioglan.com.au/products/vitamins/melatonin-90s/

http://bioglan.com.au/products/vitamins/melatonin-90s/

Complaint to TGA: Homeopathic Products (Pretorius, Bioglan, Healthy Care)

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http://bioglan.com.au/products/vitamins/melatonin-90s/

Complaint to TGA: Homeopathic Products (Pretorius, Bioglan, Healthy Care)

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http://bioglan.com.au/products/vitamins/melatonin-90s/

Complaint to TGA: Homeopathic Products (Pretorius, Bioglan, Healthy Care)

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http://bioglan.com.au/products/vitamins/melatonin-spray-50ml/

http://www.bioglan.com.au/products/vitamins/melatonin-spray-50ml/

Complaint to TGA: Homeopathic Products (Pretorius, Bioglan, Healthy Care)

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http://bioglan.com.au/products/vitamins/melatonin-spray-50ml/

Complaint to TGA: Homeopathic Products (Pretorius, Bioglan, Healthy Care)

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I submit that these complaints are "high priority" because the sponsor (&/or other advertisers) are recalcitrant, this class of products have had numerous upheld complaints and the sponsor (&/or others) continue to make claims that I allege breach the Therapeutic Goods Advertising Code 2017. This clearly impacts on the consumers ability to appropriately use these goods.

Similar claims can be found at:

• https://greatearth.com/pretorius-melatonin-90-tablets.html • https://vitaminking.com.au/melatonin-6x-by-pretorius • https://naturalcity.com.au/prod-pretorius-melatonin-5mg-6x-90tabs-homeopathic-21716.aspx • https://yourchemistshop.com.au/bioglan-melatonin-3mg-homeopathic-melatoni-6x-tab-90-

2.html/ • https://chemistwarehouse.com.au/Shop-Online/PS-1826/Melatonin • https://priceline.com.au/bioglan-melatonin-90-tablets • http://epharmacy.com.au/product.asp?id=31051&pname=Bioglan+Melatonin+90+Tablets+%28

Homeopathic+Formula%29 • https://chemistwarehouse.com.au/buy/74367/Healthy-Care-Melatonin-Homeopathic-90-

Tablets • http://mychemist.com.au/product.asp?id=74367&pname=Healthy+Care+Melatonin+Homeopat

hic+90+Tablets • https://westfield.com.au/products/chemist-warehouse/healthy-care-melatonin-homeopathic-

90-tablets/7d1b5df0-c995-4b19-8db3-19449f0c9918 • https://chemistwarehouse.com.au/buy/75282/Bioglan-Melatonin-Spray-50ml • https://priceline.com.au/bioglan-melatonin-sleep-spray-50-ml • https://goodpricepharmacy.com.au/bioglan-melatonin-spray-50ml • Etc.

Finally, I note that the recently enacted Therapeutic Goods Information (Outcomes of Advertising Complaints Investigations) Specification 2018 states that,

“The following specified kinds of therapeutic goods information may be released by the Secretary to the public under subsection 61(5C) of the Act….”.

Regardless, I insist on an immediate response to me as to the priority allocated to this complaint, the measures taken by the TGA to achieve compliance and the final outcome.

Sincerely, --- Dr Ken Harvey MBBS, FRCPA, AM Associate Professor Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine

Monash University Alfred Campus 553 St Kilda Rd Melbourne VIC 3004 Mobile: +61 419181910 Email: kenneth.harvey@monash.edu WWW: www.medreach.com.au 12 July 2018

TGACRP Complaint: Pretorius – Homeopathic Melatonin 6X

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Publications: • http://www.pretoriusvitamins.com.au/supplements/melatonin-90s • http://myhealthwarehouse.com.au/pretorius-melatonin-6x-90-tablets.html • https://www.vitaminking.com.au/melatonin-6x-by-pretorius • https://www.naturalhealthorganics.com.au/pretorius-melatonin-6x-90-tablets.html

Date/Edition: 5/12/2017

Product: Pretorius Homeopathic Melatonin 6X Sponsor: Key-Sun Laboratories Pty Ltd. 16 Jubilee Ave, Warriewood NSW 2102

Details of Complaint:

I allege that this product is not in accord with definition of a homeopathic preparation as outlined in Part 1(2) (Interpretation) of the Therapeutic Goods Regulations 1990 (Compilation no. 77):1

“homoeopathic preparation means a preparation:

(a) formulated for use on the principle that it is capable of producing in a healthy person symptoms similar to those which it is administered to alleviate; and (b) prepared according to the practices of homoeopathic pharmacy using the methods of:

(i) serial dilution and succussion of a mother tincture in water, ethanol, aqueous ethanol or glycerol; or (ii) serial trituration in lactose”.

Melatonin, produces sleep (product information attached), not insomnia; it is therefore not a homeopathic preparation in accord with the homeopathy “Law of Similars” (like cures like).2 Coffee, not melatonin, is traditionally used in homeopathic preparations to treat insomnia.3

In addition, the use of melatonin is not in accord the TGA evidence guidelines on traditional evidence. 4 These state:

“Traditional indications are based on evidence of a history of medicinal use of the ingredients or medicines that exceeds three generations (75 years) of use.”

Melatonin was first discovered in 1958 by dermatology professor Aaron B. Lerner and colleagues at Yale University and thus cannot be used for a “traditional indication”. 5

Accordingly, I allege that the following claims are in breach of s.4(1)(b), 4(2)(a), 4(2)(c), 4(2)(d) of the Code because they are not in accord with “traditional” indications, I could find no good scientific evidence to support them, and they exploit the lack of knowledge of consumers about homeopathic principles:

On the pack:

• Homoeopathic Melatonin 6X • Each 400mg homeopathic tablet contains Melatonin 6X • Premium potency • Insomnia

1 https://www.legislation.gov.au/Details/F2017C00528 2 https://medical-dictionary.thefreedictionary.com/like+cures+like 3 https://homeopathica.com/homeopathic-medicine-for-insomnia/ 4 https://www.tga.gov.au/publication/evidence-guidelines 5 https://www.ncbi.nlm.nih.gov/pubmed/19069840

TGACRP Complaint: Pretorius – Homeopathic Melatonin 6X

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In the advertisements:

• Homoeopathic melatonin to promote general wellbeing and to relieve the symptoms of sleeplessness

• This is a homoeopathic preparation of the naturally occurring hormone Melatonin. All of the following claims are based only on evidence of traditional use in homeopathy

• Melatonin is a naturally produced hormone, secreted by the pineal gland. It is produced during darkness to promote and regulate sleep patterns

• Pretorius Melatonin helps to relieve symptoms which are associated with sleep deprivation and may include restlessness, irritability and tiredness.

• Homoeopathic Melatonin is useful to help counteract the effects of jetlag and shift work.

I also allege that these advertisements breach s.6(3)(c) and 6(3)(d) as they do not include the words “ALWAYS READ THE LABEL”, “USE ONLY AS DIRECTED” and “IF SYMPTOMS PERSIST SEE YOUR DOCTOR/HEALTHCARE PROFESSIONAL".

The advertisements:

http://www.pretoriusvitamins.com.au/supplements/melatonin-90s

TGACRP Complaint: Pretorius – Homeopathic Melatonin 6X

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http://www.pretoriusvitamins.com.au/supplements/melatonin-90s

http://myhealthwarehouse.com.au/pretorius-melatonin-6x-90-tablets.html

TGACRP Complaint: Pretorius – Homeopathic Melatonin 6X

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Research:

Melatonin (N-acetyl-5-methoxytryptamine) was first purified and characterized from the bovine pineal gland extract by Aron Lerner and co-workers in 1958. Since then, a plethora of information has piled up on its biosynthesis, metabolism, time-bound periodicity, physiological and pathophysiological functions, as well as its interactions with other endocrine or neuro-endocrine organs and tissues in the body.6

To determine whether the claims made by Key-Sun Laboratories Pty Ltd could be supported with evidence, systematic reviews and clinical trials were searched using the Cochrane Review Library and Ovid MEDline databases. No studies were found that investigated the efficacy of melatonin at homeopathic dilutions. Whilst studies have been conducted on melatonin, there is no evidence regarding the dosage of 6X, that is, 1 part in 1,000,000 which is a significant dilution.

This is not the only Pretorius product that does not fulfil the Therapeutic Goods Regulations 1990 definition of a homoeopathic product.7,8 In addition, there are those from other companies, for example:9

I ask the Panel to refer this problem to the Code Council for consideration in their forthcoming revision of the Therapeutic Goods Advertising Code. So-called homoeopathic products that do not

6 https://www.ncbi.nlm.nih.gov/pubmed/19069840 7 http://www.pretoriusvitamins.com.au/supplements/same-90s 8 http://www.pretoriusvitamins.com.au/supplements/dhea-90s 9 http://www.biomedica.com.au/ Biomedica homoeoceuticals

TGACRP Complaint: Pretorius – Homeopathic Melatonin 6X

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fulfil the Therapeutic Goods Regulations 1990 definition of a homoeopathic product should not be allowed to advertise.

In addition, for consumers to make an informed choice about these medicines we submit that a claim based on “traditional use” should always have a disclaimer along the lines of what the US Federal Trade Commission uses for homeopathic products.10 For example,

“This product’s traditional claims are based on alternative health practices that are not accepted by most modern medical experts. There is no good scientific evidence that this product works. In addition, a tradition of use does not guarantee safety”.

Previous complaints:

The Panel has upheld at least 10 previous complaints about homeopathic products.11

Conclusion:

I allege that this product is not in accord with definition of a homeopathic preparation as outlined in Part 1(2) (Interpretation) of the Therapeutic Goods Regulations 1990 (Compilation no. 77):12

“homoeopathic preparation means a preparation:

(a) formulated for use on the principle that it is capable of producing in a healthy person symptoms similar to those which it is administered to alleviate; and (b) prepared according to the practices of homoeopathic pharmacy using the methods of:

(i) serial dilution and succussion of a mother tincture in water, ethanol, aqueous ethanol or glycerol; or (ii) serial trituration in lactose”.

Melatonin, produces sleep (product information attached), not insomnia; it is therefore not a homeopathic preparation in accord with the homeopathy “Law of Similars” (like cures like).13 Coffee, not melatonin, is traditionally used in homeopathic preparations to treat insomnia.14

In addition, the use of melatonin is not in accord the TGA evidence guidelines on traditional evidence. 15 These state:

“Traditional indications are based on evidence of a history of medicinal use of the ingredients or medicines that exceeds three generations (75 years) of use.”

Melatonin was first discovered in 1958 by dermatology professor Aaron B. Lerner and colleagues at Yale University and thus cannot be used for a “traditional indication”. 16

Accordingly, I allege that the following claims are in breach of s.4(1)(b), 4(2)(a), 4(2)(c), 4(2)(d) of the Code because they are not in accord with “traditional” indications, I could find no good scientific evidence to support them, and they exploit the lack of knowledge of consumers about homeopathic principles:

On the pack:

• Homoeopathic Melatonin 6X

10 https://www.ftc.gov/system/files/documents/federal_register_notices/2016/12/homeopathic_drugs_frn_12-13-2016.pdf 11 http://www.tgacrp.com.au/complaint-register/?_search=homeopath 12 https://www.legislation.gov.au/Details/F2017C00528 13 https://medical-dictionary.thefreedictionary.com/like+cures+like 14 https://homeopathica.com/homeopathic-medicine-for-insomnia/ 15 https://www.tga.gov.au/publication/evidence-guidelines 16 https://www.ncbi.nlm.nih.gov/pubmed/19069840

TGACRP Complaint: Pretorius – Homeopathic Melatonin 6X

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• Each 400mg homeopathic tablet contains Melatonin 6X • Premium potency • Insomnia

In the advertisements:

• Homoeopathic melatonin to promote general wellbeing and to relieve the symptoms of sleeplessness

• This is a homoeopathic preparation of the naturally occurring hormone Melatonin. All of the following claims are based only on evidence of traditional use in homeopathy

• Melatonin is a naturally produced hormone, secreted by the pineal gland. It is produced during darkness to promote and regulate sleep patterns

• Pretorius Melatonin helps to relieve symptoms which are associated with sleep deprivation and may include restlessness, irritability and tiredness.

• Homoeopathic Melatonin is useful to help counteract the effects of jetlag and shift work.

I also allege that these advertisements breach s.6(3)(c) and 6(3)(d) as they do not include the words “ALWAYS READ THE LABEL” , “USE ONLY AS DIRECTED” and “ IF SYMPTOMS PERSIST SEE YOUR DOCTOR/HEALTHCARE PROFESSIONAL."

Dr Ken Harvey AM Associate Professor

Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine

Monash University The Alfred Centre

99 Commercial Road Melbourne VIC 3004

Mobile: +61 419181910

Email: kenneth.harvey@monash.edu www.medreach.com.au

5/12/2017

Acknowledgment:

The research for this complaint was performed by a 2017 SPHPM Summer Vacation Scholarship student.17

17 https://www.monash.edu/medicine/sphpm/teaching/summer-vacation-program

Circadin_PI_20160609 1/13

Product Information

Circadin® Prolonged Release Tablets

Name of the medicine Melatonin Chemical name: N-[2-(5-Methoxyindol-3-yl)ethyl]acetamide. Structural formula:

Molecular formula: C13H16N2O2 Molecular weight: 232.27 CAS number: 73-31-4 pKa: 12.3 – 12.7

Description The active ingredient in Circadin prolonged release tablets is a melatonin NOT of plant or animal origin. Circadin prolonged release tablets also contain the excipients: Ammonio methacrylate copolymer, calcium hydrogen phosphate, lactose, colloidal anhydrous silica, purified talc and magnesium stearate. Melatonin is a slightly off-white, odourless crystalline powder. Melatonin is very slightly soluble in water and in dilute hydrochloric acid.

Pharmacology Pharmacotherapeutic group: Melatonin Receptor Agonists, ATC code: N05CH01

Pharmacological actions:

Melatonin is a naturally occurring hormone produced by the pineal gland and is structurally related to serotonin. Physiologically, melatonin secretion increases soon after the onset of darkness, peaks at 2-4 am and diminishes during the second half of the night. Melatonin is associated with the control of circadian rhythms and

Circadin_PI_20160609 2/13

entrainment to the light-dark cycle. It is also associated with a hypnotic effect and increased propensity for sleep. Mechanism of action The activity of melatonin at the MT1 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. Rationale for use Because of the role of melatonin in sleep and circadian rhythm regulation, and the age related decrease in endogenous melatonin production, melatonin may effectively improve sleep quality particularly in patients who are over 55 with primary insomnia.

Pharmacokinetics: The absolute bioavailability of melatonin from CIRCADIN has not been assessed. Other oral formulations of melatonin have an absolute bioavailability in the region of 15% but this is highly variable with high first-pass metabolism. The relative bioavailability of melatonin from CIRCADIN is comparable to that of an oral melatonin solution.

Data from other formulations of melatonin indicate that the absorption of orally ingested melatonin is complete in adults and may be decreased by up to 50% in the elderly. The kinetics of melatonin is linear over the range of 2-8 mg as obtained from published results using a formulation other than CIRCADIN. Bioavailability as assessed from other oral formulations of melatonin is in the order of 15%. There is a significant first pass effect with an estimated first pass metabolism of 85% as assess from other oral formulations of melatonin. Tmax occurs after 2.6 hours in a fed state. The rate of melatonin absorption following Circadin 2 mg oral administration is affected by food. The presence of food delayed the absorption of the melatonin resulting in a later Tmax (Tmax= 2.6 h versus Tmax= 1.6 h). Cmax and AUC levels were not affected by food. Distribution The in vitro plasma protein binding of melatonin is approximately 60%. Melatonin is mainly bound to albumin, alpha1-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 Experimental data suggest that isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of the cytochrome P450 system are involved in melatonin metabolism. The principal metabolite is 6-sulphatoxy-melatonin (6-S-MT), which is inactive. The site of biotransformation is the liver. The excretion of the metabolite is completed within 12 hours after ingestion.

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Excretion Terminal half life (t½) is 3.5-4 hours. Elimination is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymeltonin and 2% is excreted as melatonin (unchanged drug). Gender A 3-4-fold increase in Cmax is apparent for women compared to men. A five-fold variability in Cmax between different members of the same sex has also been observed. However, no pharmacodynamic differences between males and females were found despite differences in blood levels. 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 pg/ml in adults (18-45) versus 1200 pg/ml in the elderly (55-65); AUC levels around 3,000 pg*h/mL in adults versus 6000 pg*h/mL in the elderly. Renal impairment Melatonin did not accumulate after repeated dosing with CIRCADIN. This finding is compatible with the short half-life of melatonin in humans. The levels assessed in the blood of patients at 23:00 (2 hours after administration) following 1 and 3 weeks of daily administration were 411.4 ± 56.5 and 432.00 ± 83.2 pg/ml respectively, and are similar to those found in healthy volunteers following a single dose of Circadin 2 mg. Hepatic impairment The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in higher endogenous melatonin levels. Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin compared with controls.

Clinical trials Three Phase 3 studies and a sleep laboratory study were considered pivotal. These studies enrolled patients with primary insomnia who were aged at least 55 years. Patients suffering from severe neurological, psychiatric or neurosurgical diseases or taking CNS medications including benzodiazepines or other hypnotic agents were excluded. The primary assessment tool was the Leeds Sleep Evaluation Questionnaire (LSEQ), comprising 10 self-rated 100 mm-line analogue questions concerning aspects of sleep and early morning behaviour. The LSEQ measures ease of getting to sleep (GTS), quality of sleep (QOS), ease of waking from sleep (AFS) and behaviour following wakefulness (BFW). The primary outcome variable in the pivotal clinical trials was QOS, or a combination on QOS and BFW, where a patient had to show a clinically relevant improvement on both QOS and BFW. Time to onset of sleep and duration of sleep were measured objectively only in a polysomnography study. Efficacy of Circadin in combination with other hypnotic agents has not been assessed.

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In a polysomnographic (PSG) study (N=40; 20 Circadin, 20 placebo) with a run-in of 2 weeks (single-blind with placebo treatment), followed by a treatment period of 3 weeks (double-blind, placebo-controlled, parallel group design) and a 3-week withdrawal period, time to onset of sleep was shortened significantly by 9 minutes compared to placebo. A statistically significant difference favouring Circadin was seen for total duration of time awake prior to sleep onset (approx change from 10 to 11 minutes for Circadin and from 21 to 20 minutes for placebo). There were no modifications of sleep architecture and no effect on REM sleep duration by Circadin. Modifications in diurnal functioning did not occur with Circadin 2 mg. Circadin did not prolong the duration of sleep significantly compared to placebo. In the outpatient studies patients who failed to meet the inclusion criteria at the end of the run-in period due to the instability of their disorder (16% of the total population) were not included in the efficacy analysis. In an outpatient study (Neurim VII: N=170; 82 Circadin, 88 placebo) with two week run in baseline period with placebo, a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks and two week withdrawal period with placebo, the primary efficacy endpoint was Quality of Sleep (QOS). The rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 47% in the Circadin group as compared to 27% in the placebo group. There was a mean difference of approximately 6 mm in quality of sleep and approximately 9 mm in morning alertness, both favouring Circadin compared to placebo. Sleep variables gradually returned to baseline with no rebound, no increase in adverse events and no increase in withdrawal symptoms. In a second outpatient study (N=334; 169 Circadin, 165 placebo) with two week run in baseline period with placebo and a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks, the rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 26% in the Circadin group as compared to 15% in the placebo group. Circadin shortened patients’ reported time to onset of sleep by 24.3 minutes vs 12.9 minutes with placebo. In addition, patients’ self-reported quality of sleep, number of awakenings and morning alertness significantly improved with Circadin compared to placebo. Quality of life was improved significantly with Circadin 2 mg compared to placebo. A third study involved more than 600 patients over 55, over 400 of whom were on Circadin treatment for up to 6 months. Patients given Circadin demonstrated a difference from placebo in mean change from baseline in subjective sleep latency, assessed using a sleep diary, of -7.8 minutes after 3 weeks (p=0.014). Small differences in sleep latency were generally maintained over 13 weeks of placebo-controlled treatment. The percentage of patients showing both remission of insomnia (PSQI of <6) and a clinically relevant improvement of 10% in quality of life scores (WHO-5 index) increased from 16.7% (cf. 10.6% placebo, p=0.044) at week 3 to 25.8% at week 13 (cf. 15.7% placebo, p=0.006). This study also examined the effect of Circadin on sleep latency in younger subjects with primary insomnia and low excretion of melatonin. Clinically significant effects on sleep latency were not demonstrated in these patients.

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Long term safety: The safety profile both during 3 weeks and during the 26 week periods was comparable to placebo with no withdrawal and rebound effects. In an open study where 96 subjects completed 12 months treatment with Circadin no tolerance, rebound or withdrawal effects were reported.

Indications Monotherapy for the short term treatment of primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over.

Contraindications Circadin prolonged release tablets are contraindicated in patients with a known hypersensitivity to any ingredient of the product (see DESCRIPTION).

Precautions 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 body surface area. Use in pregnancy: Category B3. No significant effects on embryofetal development were observed in rats given oral melatonin during the period of organogenesis at doses over 900-fold the recommended clinical dose, based on body surface area. No clinical data on exposed pregnancies are available. In view of the lack of clinical data, use in pregnant women and by women intended to become pregnant is not recommended. Use in lactation: Maternal transfer of exogenous melatonin to the fetus via the placenta or milk has been demonstrated in several animal species including rats, hamsters, goats, monkeys and cows. A slight reduction in post-natal growth, viability and development was found in rats given oral melatonin during gestation through weaning at doses over 900-fold the recommended clinical dose, based on body surface area; the no-effect dose was over 250-fold the clinical dose. 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. Paediatric use: Circadin is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

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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 of melatonin in the elderly. 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. Drowsiness: Circadin may cause drowsiness. Therefore the product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety. Effects on ability to drive and operate machinery: Circadin has negligible influence on the ability to drive and use machines. Nevertheless, patients should avoid engaging in hazardous activities (such as driving or operating machinery) after taking Circadin. Autoimmune diseases: No clinical data exist concerning the use of Circadin in individuals with autoimmune diseases. Therefore Circadin is not recommended for use in patients with autoimmune diseases. Excipients: The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interactions with other medicines:

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

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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 - Coadministration of CIRCADIN with cimetidine resulted in a 1.7 fold increase in exposure to melatonin with no change in the exposure to cimetidine. Caution should be exercised in patients on cimetidine, a CYP2D inhibitor which increases plasma melatonin levels by inhibiting its metabolism. Cigarette smoking - Cigarette smoking may decrease melatonin levels due to induction of CYP1A2. 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. 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 Circadin or vice versa has not been studied. Pharmacodynamic interactions

Alcohol - Alcohol should not be taken with Circadin, because it reduces the effectiveness of Circadin on sleep. The prolonged release characteristics of Circadin may be altered by alcohol, resulting in immediate release of melatonin. Hypnotics - Circadin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone.

Circadin_PI_20160609 8/13

In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between Circadin and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone. Thioridazine and imipramine - Circadin 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, Circadin co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy-headedness” compared to thioridazine alone. Effect on laboratory tests: No information is available on the effect of melatonin on laboratory tests.

Adverse Effects In clinical trials (in which a total of 1931 patients were taking Circadin and 1642 patients were taking placebo), 48.8% of patients receiving Circadin reported an adverse reaction compared with 37.8% taking placebo. Comparing the rate of patients with adverse reactions per 100 patient weeks, the rate was higher for placebo than Circadin (5.743 - placebo vs. 3.013 - Circadin). The most common adverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by MedDRA definition, in both the Circadin and placebo treated groups. In the Circadin group, there were 72 cases (2.9% of the safety population) of adverse events leading to discontinuation of the patient. In the placebo group there were 62 cases (4.0% of the safety population) of adverse events leading to discontinuation of the patient. Overall Adverse Experience for adverse events occurring with a frequency ≥ 1% Body System/Adverse Experience Circadin %

(N=1931) Placebo % (N=1642)

Gastrointestinal disorders Abdominal Pain 1.1 0.7 Abdominal Pain Upper 1.0 1.2 Constipation 1.2 0.9 Diarrhoea 3.1 1.8 Nausea 1.8 1.7 Vomiting 1.5 0.9 General Disorders and administration site conditions Asthenia 1.9 1.2 Infections and infestations Influenza 1.5 0.9 Lower respiratory tract infection 1.9 1.2 Nasopharyngitis 4.0 3.0 Pharyngitis 1.9 1.2 Upper respiratory tract infection 2.9 1.2 Urinary tract infection 2.1 0.7 Musculoskeletal and connective tissue disorder Arthralgia 3.5 1.8 Back Pain 3.8 1.5

Circadin_PI_20160609 9/13

Muscle cramp 1.1 0.6 Neck pain 1.1 0.6 Pain in extremity 1.6 1.1 Nervous system disorders Dizziness 1.6 1.2 Headache 5.7 6.2 Migraine 1.1 1.2 Psychiatric disoprders Anxiety 1.0 1.2 Respiratory, thoracic and mediastinal disorders Cough 2.2 1.3 Pharyngolaryngeal pain 1.5 0.9 Rhinitis 1.1 0.9

The adverse reactions in the table below were reported in clinical trials and were defined as possibly, probably or definitely related to treatment. A total of 9.5% of subjects receiving Circadin reported an adverse reaction compared with 7.4% of subjects taking placebo. Only those adverse events occurring in subjects at an equivalent or greater rate than placebo have been included. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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).

Circadin_PI_20160609 10/13

Adverse events related to treatment occurring with a frequency < 1% System Organ

Class Uncommon Rare Not known

Infections and Infestations

Herpes zoster

Blood and Lymphatic System Disorders

Leukopenia, Thrombocytopenia

Cardiac Disorders Angina Pectoris, Palpitations

Immune System Disorders

Hypersensitivity reaction

Metabolism and Nutrition Disorders

Hypertriglyceridaemia, Hypocalcaemia, Hyponatraemia

Psychiatric Disorders

Irritability, Nervousness, Restlessness, Insomnia, Abnormal dreams, Anxiety, Nightmares

Mood altered, Aggression, Agitation, Crying, Stress Symptoms, Disorientation, Early morning awakening, Libido increased, Depressed mood, Depression

Nervous System Disorders

Migraine, Lethargy Psychomotor hyperactivity, Dizziness, Somnolence, Headache

Syncope, Memory impairment, Disturbance in attention, Dreamy state, Restless Legs Syndrome, Poor quality sleep, Paresthesia

Eye Disorders Visual acuity reduced, Vision blurred, Lacrimation increased

Ear and Labyrinth Disorders

Vertigo positional, Vertigo

Vascular Disorders Hypertension Hot flush Gastrointestinal Disorders

Abdominal pain, Abdominal pain upper, Dyspepsia, Mouth Ulceration, Dry mouth, Nausea

Gastro-oesophageal Reflux Disease, Gastrointestinal disorder, oral Mucosal Blistering, Tongue Ulceration, Gastrointestinal upset, Vomiting, Bowel sounds abnormal, Flatulence, Salivary hypersecretion, Halitosis, Abdominal

Circadin_PI_20160609 11/13

Discomfort, Gastric disorder, Gastritis

Hepatobiliary Disorders

Hyperbilirubinaemia

Skin and Subcutaneous Tissue Disorders

Dermatitis, Night Sweats, Pruritus, Rash, Pruritus Generalised, Dry Skin

Eczema, Erythema, Hand Dermatitis, Psoriasis, Rash Generalised, Rash pruritic, , Nail disorder

Angioedema, Oedema of mouth, Tongue oedema

Musculoskeletal and Connective Tissue Disorders

Pain in extremity Arthritis, Muscle spasms, Neck pain, Night cramps

Reproductive System and Breast Disorders

Menopausal symptoms

Priapism, Prostatitis Galactorrhoea

General Disorders and Administration Site Conditions

Asthenia, Chest Pain Fatigue, Pain, Thirst

Renal and Urinary Disorders

Glycosuria, Proteinuria

Polyuria, Hematuria, Nocturia

Investigations Liver Function Test Abnormal, Weight increased

Hepatic enzyme increased, Blood Electrolytes Abnormal, Laboratory Test Abnormal

Post-Marketing Data Psychiatric Disorders: Nightmares

Dosage and Administration Oral use. Tablets should be swallowed whole. The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food. This dosage may be continued for up to thirteen weeks.

Paediatric use

Circadin is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy. Renal insufficiency The effect of any stage of renal insufficiency on melatonin pharmacokinetics has not been studied. Caution should be used when melatonin is administered to such patients. Hepatic impairment There is no experience of the use of Circadin in patients with liver impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, Circadin is not recommended for use in patients with hepatic impairment.

Circadin_PI_20160609 12/13

Overdosage In general, the main therapy for all overdoses is supportive and symptomatic care. Symptoms No case of overdose has been reported. Circadin has been administered at 5 mg daily doses in clinical trials over 12 months without significantly changing the nature of the adverse reactions reported. Administration of daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions have been reported in the literature. If overdose occurs, drowsiness is to be expected. Treatment Clearance of the active substance is expected within 12 hours after ingestion. No special treatment is required For further advice on management of overdose please contact the Poisons Information Centre (Tel: 13 11 26 for Australia and Tel: 0800 764 766 for New Zealand).

Presentation and storage conditions

Presentation Circadin 2 mg prolonged release tablets: White to off-white, round, biconvex tablets in blister packs of 21, 30 or 7 (sample pack) tablets. AUST R 153959.

Storage conditions Store below 25ºC. Protect from light

Name and address of the sponsor Sponsor: RAD Data Australia Pty Ltd PKF Melbourne Level 12, 440 Collins Street Melbourne, VIC, 3000 Distributor: Aspen Pharma Pty Ltd 34-36 Chandos Street St Leonards NSW 2065

Circadin_PI_20160609 13/13

Poisons Schedule of the medicine Schedule 4. Prescription Only Medicine

Date of first inclusion in the Australian Register of Therapeutic Goods (the ARTG): 25 November 2009

Date of most recent amendment 9 June 2016 CIRCADIN is a registered trademark of Neurim Pharmaceuticals

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 1 of 11

Publications: • http://www.bioglan.com.au/products/vitamins/melatonin-90s/ • http://www.bioglan.com.au/products/vitamins/melatonin-spray-50ml/ • http://health365.com.au/shop/bioglan-melatonin • http://health365.com.au/shop/bioglan-melatonin-spray-50ml • http://www.chemistwarehouse.com.au/buy/31051/Bioglan-Melatonin-90-Tablets-

Homeopathic-Formula • https://superpharmacyplus.com.au/bioglan-melatonin-homeopathic-sleep-formula-90-

tablets/ • http://www.epharmacy.com.au/product.asp?id=31051 • Etc.

Date/Edition: 8/12/2017

Product: Bioglan Melatonin Homeopathic tablets & spray 6X Sponsor: Natural Bio Pty Limited, PO Box 384, MONA VALE, NSW, 1660, now part of Pharm-a-care Laboratories Pty Ltd, 18 Jubilee Ave, Warriewood NSW 2102 (ABN 99003468219). N.B. The domain name: health365.com.au is registered to Pharm-a-care Laboratories Pty. Limited

Details of Complaint:

I allege that Pharmacare Laboratories Pty Ltd has breached s.4(1)(b), 4(2)(a), 4(2)(c), 4(2)(d) of the Therapeutic Goods Advertising Code 2015 by claiming that their $20-$22 Bioglan homeopathic melatonin products have the same therapeutic effect as the $33 prescription product (Circadin).1 The company is exploiting the lack of knowledge of consumers about homeopathic principles. As a result, consumers are being deluded into purchasing a $20-$22 product that contains no active ingredient.

In addition, I allege that these products are not in accord with definition of a homeopathic preparation as outlined in Part 1(2) (Interpretation) of the Therapeutic Goods Regulations 1990 (Compilation no. 77):2

“homoeopathic preparation means a preparation:

(a) formulated for use on the principle that it is capable of producing in a healthy person symptoms similar to those which it is administered to alleviate; and (b) prepared according to the practices of homoeopathic pharmacy using the methods of:

(i) serial dilution and succussion of a mother tincture in water, ethanol, aqueous ethanol or glycerol; or (ii) serial trituration in lactose”.

Melatonin, produces sleep (product information attached), not insomnia; it is therefore not a homeopathic preparation in accord with the homeopathy “Law of Similars” (like cures like).3 Coffee, not melatonin, is traditionally used in homeopathic preparations to treat insomnia.4

In addition, this use of melatonin is not in accord the TGA evidence guidelines on traditional evidence. 5 These state:

“Traditional indications are based on evidence of a history of medicinal use of the ingredients or medicines that exceeds three generations (75 years) of use.”

1 http://www.chemistwarehouse.com.au/buy/65201/Circadin-2mg-Tablets-30 2 https://www.legislation.gov.au/Details/F2017C00528 3 https://medical-dictionary.thefreedictionary.com/like+cures+like 4 https://homeopathica.com/homeopathic-medicine-for-insomnia/ 5 https://www.tga.gov.au/publication/evidence-guidelines

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 2 of 11

Melatonin was first discovered in 1958 by dermatology professor Aaron B. Lerner and colleagues at Yale University and thus cannot be used for a “traditional indication”. 6

Accordingly, I allege that the following claims are in breach of s.4(1)(b), 4(2)(a), 4(2)(c), 4(2)(d) of the Therapeutic Goods Advertising Code 2015 because they are not in accord with “traditional” indications; I could find no good scientific evidence to support them, and they exploit the lack of knowledge of consumers about homeopathic principles:

On the packs (screen shots appended):

• Melatonin (90s) • Homeopathic Sleep Formula • Sleep & Mood • Helps

o Relieve insomnia o Relieve mild tension and anxiety o Each tablet contains Melatonin 6X

• Melatonin • Homeopathic Sleep Spray • Sleep & Mood • Fast acting • Helps relieve insomnia • Contains Melatonin 6X

In the advertisements (screen shots appended):

• Bioglan Melatonin is a homeopathic solution to help relieve insomnia and nervous tension as well as provide stamina and endurance when taken in the morning. 90 tablets.

• WHAT IS BIOGLAN MELATONIN FOR? • Bioglan Melatonin helps:

o Relieve nervous tension, stress and mild anxiety o Relieve insomnia (sleeplessness) when taken before bedtime o Provide stamina and endurance when taken in the morning.

• WHO IS BIOGLAN MELATONIN FOR? • Bioglan Melatonin may be of benefit to:

o Those experiencing insomnia and having trouble sleeping. o People that travel a lot. o Those that are prone to developing jet lag after a long flight. o People undergoing a difficult period in life.

• WHEN SHOULD I TAKE BIOGLAN MELATONIN? o Take daily for best results.

• WHY SHOULD I TAKE BIOGLAN MELATONIN? o Helps regulate sleep o May help with feelings of anxiety o May alleviate jet lag

• Bioglan Melatonin Sleep Spray is a fast-acting spray that helps relieve insomnia. The homoeopathic spray solution is ideal for sleep as it is rapidly absorbed into the bloodstream, to start working quickly.

• WHAT IS BIOGLAN MELATONIN SPRAY FOR? o Bioglan Melatonin Spray is a fast-acting formula that helps: o Relieve stress, nervous tensions & mild anxiety.

6 https://www.ncbi.nlm.nih.gov/pubmed/19069840

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 3 of 11

o Relieve insomnia (sleeplessness) when taken before bedtime o Establish sleep patterns to overcome jetlag

• WHO IS BIOGLAN MELATONIN SPRAY FOR? o Bioglan Melatonin Spray may be of benefit to: o Those experiencing insomnia and having trouble sleeping. o People that travel a lot. o Those that are prone to developing jet lag after a long flight. o People undergoing a difficult period in life. o Women especially during their menstrual cycles.

• WHEN SHOULD I TAKE BIOGLAN MELATONIN SPRAY? o To aid sleep 3-5 sprays in the mouth or under the tongue half an hour before bedtime or as

directed by your healthcare professional. • WHY SHOULD I TAKE BIOGLAN MELATONIN SPRAY?

o Helps regulate sleep o May help with feelings of anxiety o May alleviate jet lag o May help regulate hormone release in women o Helps maintain the regularity of menstruation in women

I also allege that the advertisements breach s.6(3)(c) and 6(3)(d) of the Code as the directions (below) do not include the words “ALWAYS READ THE LABEL”, “USE ONLY AS DIRECTED” and “IF SYMPTOMS PERSIST SEE YOUR DOCTOR/HEALTHCARE PROFESSIONAL."

The advertisements:

http://health365.com.au/shop/bioglan-melatonin

http://health365.com.au/shop/bioglan-melatonin-spray-50ml

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 4 of 11

http://www.bioglan.com.au/products/vitamins/melatonin-90s/

SKU: 542284 Availability: In stock http://health365.com.au

$22.25

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 5 of 11

http://www.bioglan.com.au/products/vitamins/melatonin-spray-50ml/

SKU: 542491 Availability: In stock http://health365.com.au

$22.05

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 6 of 11

Research:

Melatonin (N-acetyl-5-methoxytryptamine) is a naturally occurring hormone produced by the pineal gland structurally related to serotonin. It was first purified and characterized from the bovine pineal gland extract by Aron Lerner and co-workers in 1958. 7 Physiologically, melatonin secretion increases soon after the onset of darkness, peaks at 2-4 am and diminishes during the second half of the night. Melatonin is associated with the control of circadian rhythms and entrainment to the light-dark cycle. It is also associated with a hypnotic effect and increased propensity for sleep.

Melatonin prolonged-release tablets are a prescription product, registered by the TGA for short-term treatment (up to 3 weeks) of primary insomnia characterised by poor quality of sleep in people aged ≥ 55 years. They are not PBS listed. In clinical trials, people aged ≥ 55 years who received prolonged-release melatonin gained modest improvements in quality of sleep and morning alertness over those seen with placebo. Clinically meaningful improvements in both outcomes occurred in one-third of patients. N.B. Non-drug therapies are first line for treating primary insomnia.8

To determine whether the claims made by Pharmacare Laboratories Pty Ltd could be supported with evidence, systematic reviews and clinical trials were searched using the Cochrane Review Library and Ovid MEDline databases. No studies were found that investigated the efficacy of melatonin at the homeopathic dilution of 6X, that is, 1 part in 1,000,000. Regardless, at this dilution no therapeutic effect could be expected.

This is not the only product marketed to Australian consumers that incorporates prescription pharmaceuticals to mislead consumers and does not fulfil the Therapeutic Goods Regulations 1990 definition of a homoeopathic product. See below, also:9, 10,11,12 In addition, given the TGA’s apparent acceptance of over 1000 “traditional” indications on its current list of “permitted indications”,13 I would expect that more sponsors will be attracted to formulating homoeopathic and other “traditional” products. This attraction needs to be stopped.

7 https://www.ncbi.nlm.nih.gov/pubmed/19069840 8 https://www.nps.org.au/radar/articles/melatonin-prolonged-release-tablets-circadin-for-primary-insomnia-in-older-people 9 http://www.biomedica.com.au/ Biomedica homoeoceuticals 10 http://www.pretoriusvitamins.com.au/supplements/same-90s 11 http://www.pretoriusvitamins.com.au/supplements/dhea-90s 12 http://www.pretoriusvitamins.com.au/supplements/melatonin-90s 13 https://www.tga.gov.au/draft-list-permitted-indications

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 7 of 11

Previous complaints:

The Panel has upheld at least 15 previous complaints about hom(o)eopathic products.14

Regulatory inaction by the Therapeutic Goods Administration (TGA)

Homoeopathic preparations are exempt from regulation (being entered in the ARTG) if they are more dilute than a one-thousand-fold dilution of a mother tincture (4X and above); are not required to be sterile, do not include ingredients of human or animal origin and do not refer to serious diseases or conditions. Preparations that meet these conditions are also exempt from requiring the manufacturer to hold a GMP licence.

Regardless, there have been long-standing concerns by consumers and health professionals about the regulation of these products by the TGA and the claims they make.

For example, other homeopathic products, such as homeopathic melatonin (the subject of this complaint) do not fit the homeopathic tradition, yet misleading and deceptive claims continue to be promoted, despite upheld TGACRP complaints.

There is also concern that the promotion of homeopathic Baby & Child Cold & Flu remedies can cause unsuspecting parents to forego more evidence based medicines, such as ibuprofen, that could better address their child’s symptoms.15

In addition, most consumers do not understand homeopathic principles; are not aware that these principles lack scientific validity,16 and are confused by Latin terminology, such as Natrum Muriaticum (instead of salt), which obscure the names of the ingredients and exploits the lack of knowledge of consumer, as does the use of decimal (X) and centesimal (C) dilutions.

In 2003, the Expert Committee on Complementary Medicines in the Health System recommended that homoeopathic medicines that make therapeutic claims should be regulated to ensure they meet appropriate standards of safety, quality and efficacy.17 No action was taken.

In 2008, the TGA held a consultation on the regulation of homoeopathic and anthroposophic medicines in Australia.18 Numerous submissions were received but no action eventuated.

14 http://www.tgacrp.com.au/complaint-register/?_search=homeopath 15 https://theconversation.com/kids-smarts-dumb-ads-consumers-complain-of-misleading-claims-9989 16 https://www.nhmrc.gov.au/media/releases/2015/nhmrc-releases-statement-and-advice-homeopathy 17 http://www.tga.gov.au/archive/committees-eccmhs.htm 18 https://www.tga.gov.au/regulation-homoeopathic-and-anthroposophic-medicines-australia

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 8 of 11

In 2017, the TGA sought comments on proposed options for future regulation of 'low risk products' including homoeopathic products. The consultation paper made no reference to previous recommendations or consultations. It suggested four options for reform:

• maintain the status quo (does not address long-standing problems), • serious therapeutic claims must be supported by scientific evidence (impossible for

homeopathic products), • exempt from listing in the ARTG and/or GMP (likely to produce a greater range of products

and increase the potential for dangerous products)19 or • declare homeopathic products not to be therapeutic goods (this would handball the

problems to the ACCC and effectively mean no regulation at all as the ACCC only has the resources to act in the most egregious cases).20

In short, the latest TGA consultation document failed to acknowledge many long-standing concerns about the supply and promotion of homeopathic products and, in my opinion, it fails to provide a viable solution to the longstanding problems.

I (and others) have long advocated that all products making therapeutic claims by invoking the homeopathic tradition should be regulated as listed products with the addition of a mandatory disclaimer / warning on their ARTG Public Summary documents, product packaging, labelling and promotion like that recently suggested by the U.S. FTC, for example,

Warning: This product’s traditional claims are based only on theories of homeopathy from the 1700s that are not accepted by most modern medical experts. There is no scientific evidence that this product works.21

Finally, the Therapeutic Goods Act and the Therapeutic Goods Advertising Code needs to be updated to address the longstanding problems documented above. Public and non-registered health professional education by the TGA is also required.

Conclusion:

I allege that Pharmacare Laboratories Pty Ltd has breached s.4(1)(b), 4(2)(a), 4(2)(c), 4(2)(d) of the Therapeutic Goods Advertising Code 2015 by claiming that their $20-$22 Bioglan homeopathic melatonin products have the same therapeutic effect as the $33 prescription product (Circadin).22 The company is exploiting the lack of knowledge of consumers about homeopathic principles. As a result, consumers are being deluded into purchasing a $20 product that contains no active ingredient.

I also allege that these products are not formulated in accord with definition of a homeopathic preparation as outlined in Part 1(2) (Interpretation) of the Therapeutic Goods Regulations 1990 (Compilation no. 77):23

“homoeopathic preparation means a preparation:

(a) formulated for use on the principle that it is capable of producing in a healthy person symptoms similar to those which it is administered to alleviate; and (b) prepared according to the practices of homoeopathic pharmacy using the methods of:

19 http://www.smh.com.au/national/hylands-homeopathic-baby-tablets-recalled-in-australia-over-safety-fears-20170429-gvvfgx.html 20 https://www.accc.gov.au/media-release/court-imposes-penalty-for-false-or-misleading-claims-by-homeopathy-plus-and-ms-frances-sheffield 21 https://www.ftc.gov/news-events/press-releases/2016/11/ftc-issues-enforcement-policy-statement-regarding-marketing 22 http://www.chemistwarehouse.com.au/buy/65201/Circadin-2mg-Tablets-30 23 https://www.legislation.gov.au/Details/F2017C00528

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 9 of 11

(i) serial dilution and succussion of a mother tincture in water, ethanol, aqueous ethanol or glycerol; or (ii) serial trituration in lactose”.

Melatonin, produces sleep (product information attached), not insomnia; it is therefore not a homeopathic preparation in accord with the homeopathy “Law of Similars” (like cures like).24 Coffee, not melatonin, is traditionally used in homeopathic preparations to treat insomnia.25

In addition, this use of melatonin is not in accord the TGA evidence guidelines on traditional evidence. 26 These state:

“Traditional indications are based on evidence of a history of medicinal use of the ingredients or medicines that exceeds three generations (75 years) of use.”

Melatonin was first discovered in 1958 by dermatology professor Aaron B. Lerner and colleagues at Yale University and thus cannot be used for a “traditional indication”. 27

Accordingly, I allege that the following claims are in breach of s.4(1)(b), 4(2)(a), 4(2)(c), 4(2)(d) of the Therapeutic Goods Advertising Code 2015 because they are not in accord with “traditional” indications; I could find no good scientific evidence to support them, and they exploit the lack of knowledge of consumers about homeopathic principles:

On the packs (screen shots appended):

• Melatonin (90s) • Homeopathic Sleep Formula • Sleep & Mood • Helps • Relieve insomnia • Relieve mild tension and anxiety • Each tablet contains Melatonin 6X

• Melatonin • Homeopathic Sleep Spray • Sleep & Mood • Fast acting • Helps relieve insomnia • Contains Melatonin 6X

In the advertisements (screen shots appended):

• Bioglan Melatonin is a homeopathic solution to help relieve insomnia and nervous tension as well as provide stamina and endurance when taken in the morning. 90 tablets.

• WHAT IS BIOGLAN MELATONIN FOR? o Bioglan Melatonin helps: o Relieve nervous tension, stress and mild anxiety o Relieve insomnia (sleeplessness) when taken before bedtime o Provide stamina and endurance when taken in the morning.

• WHO IS BIOGLAN MELATONIN FOR? o Bioglan Melatonin may be of benefit to: o Those experiencing insomnia and having trouble sleeping.

24 https://medical-dictionary.thefreedictionary.com/like+cures+like 25 https://homeopathica.com/homeopathic-medicine-for-insomnia/ 26 https://www.tga.gov.au/publication/evidence-guidelines 27 https://www.ncbi.nlm.nih.gov/pubmed/19069840

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 10 of 11

o People that travel a lot. o Those that are prone to developing jet lag after a long flight. o People undergoing a difficult period in life.

• WHEN SHOULD I TAKE BIOGLAN MELATONIN? o Take daily for best results.

• WHY SHOULD I TAKE BIOGLAN MELATONIN? o Helps regulate sleep o May help with feelings of anxiety o May alleviate jet lag

• Bioglan Melatonin Sleep Spray is a fast-acting spray that helps relieve insomnia. The homoeopathic spray solution is ideal for sleep as it is rapidly absorbed into the bloodstream, to start working quickly.

• WHAT IS BIOGLAN MELATONIN SPRAY FOR? o Bioglan Melatonin Spray is a fast-acting formula that helps: o Relieve stress, nervous tensions & mild anxiety. o Relieve insomnia (sleeplessness) when taken before bedtime o Establish sleep patterns to overcome jetlag

• WHO IS BIOGLAN MELATONIN SPRAY FOR? o Bioglan Melatonin Spray may be of benefit to: o Those experiencing insomnia and having trouble sleeping. o People that travel a lot. o Those that are prone to developing jet lag after a long flight. o People undergoing a difficult period in life. o Women especially during their menstrual cycles.

• WHEN SHOULD I TAKE BIOGLAN MELATONIN SPRAY? o To aid sleep 3-5 sprays in the mouth or under the tongue half an hour before bedtime or as

directed by your healthcare professional. • WHY SHOULD I TAKE BIOGLAN MELATONIN SPRAY?

o Helps regulate sleep o May help with feelings of anxiety o May alleviate jet lag o May help regulate hormone release in women o Helps maintain the regularity of menstruation in women

I also allege that the advertisements breach s.6(3)(c) and 6(3)(d) of the Code as the directions (below) do not include the words “ALWAYS READ THE LABEL”, “USE ONLY AS DIRECTED” and “IF SYMPTOMS PERSIST SEE YOUR DOCTOR/HEALTHCARE PROFESSIONAL."

I also ask the Panel to refer the increasing problem of manufacturers of homoeopathic products incorporating prescription pharmaceuticals in their products to the Therapeutic Goods Advertising Code Council for consideration in their forthcoming revision of the Therapeutic Goods Advertising Code. In my opinion, so-called homoeopathic products that do not fulfil the Therapeutic Goods Regulations 1990 definition of a homoeopathic product should not be allowed to advertise.

In addition, for consumers to make an informed choice about these medicines I (and others) have long argued that a claim based on “traditional use” should always have a disclaimer along the lines of what the US Federal Trade Commission uses for homeopathic products.28 For example,

28 https://www.ftc.gov/system/files/documents/federal_register_notices/2016/12/homeopathic_drugs_frn_12-13-2016.pdf

TGACRP Complaint: Bioglan –Melatonin Homeopathic

Page 11 of 11

“This product’s traditional claims are based on alternative health practices that are not accepted by most modern medical experts. There is no good scientific evidence that this product works”.

I should be grateful if the Panel could also put this suggestion to the Code Council.

Dr Ken Harvey AM

Associate Professor Department of Epidemiology and Preventive Medicine

School of Public Health and Preventive Medicine

Monash University The Alfred Centre

99 Commercial Road Melbourne VIC 3004

Mobile: +61 419181910

Email: kenneth.harvey@monash.edu www.medreach.com.au

8/12/2017

Acknowledgment:

The research for this complaint was performed by a 2017 SPHPM Summer Vacation Scholarship student.29

29 https://www.monash.edu/medicine/sphpm/teaching/summer-vacation-program

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Product Information

Circadin® Prolonged Release Tablets

Name of the medicine Melatonin Chemical name: N-[2-(5-Methoxyindol-3-yl)ethyl]acetamide. Structural formula:

Molecular formula: C13H16N2O2 Molecular weight: 232.27 CAS number: 73-31-4 pKa: 12.3 – 12.7

Description The active ingredient in Circadin prolonged release tablets is a melatonin NOT of plant or animal origin. Circadin prolonged release tablets also contain the excipients: Ammonio methacrylate copolymer, calcium hydrogen phosphate, lactose, colloidal anhydrous silica, purified talc and magnesium stearate. Melatonin is a slightly off-white, odourless crystalline powder. Melatonin is very slightly soluble in water and in dilute hydrochloric acid.

Pharmacology Pharmacotherapeutic group: Melatonin Receptor Agonists, ATC code: N05CH01

Pharmacological actions:

Melatonin is a naturally occurring hormone produced by the pineal gland and is structurally related to serotonin. Physiologically, melatonin secretion increases soon after the onset of darkness, peaks at 2-4 am and diminishes during the second half of the night. Melatonin is associated with the control of circadian rhythms and

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entrainment to the light-dark cycle. It is also associated with a hypnotic effect and increased propensity for sleep. Mechanism of action The activity of melatonin at the MT1 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. Rationale for use Because of the role of melatonin in sleep and circadian rhythm regulation, and the age related decrease in endogenous melatonin production, melatonin may effectively improve sleep quality particularly in patients who are over 55 with primary insomnia.

Pharmacokinetics: The absolute bioavailability of melatonin from CIRCADIN has not been assessed. Other oral formulations of melatonin have an absolute bioavailability in the region of 15% but this is highly variable with high first-pass metabolism. The relative bioavailability of melatonin from CIRCADIN is comparable to that of an oral melatonin solution.

Data from other formulations of melatonin indicate that the absorption of orally ingested melatonin is complete in adults and may be decreased by up to 50% in the elderly. The kinetics of melatonin is linear over the range of 2-8 mg as obtained from published results using a formulation other than CIRCADIN. Bioavailability as assessed from other oral formulations of melatonin is in the order of 15%. There is a significant first pass effect with an estimated first pass metabolism of 85% as assess from other oral formulations of melatonin. Tmax occurs after 2.6 hours in a fed state. The rate of melatonin absorption following Circadin 2 mg oral administration is affected by food. The presence of food delayed the absorption of the melatonin resulting in a later Tmax (Tmax= 2.6 h versus Tmax= 1.6 h). Cmax and AUC levels were not affected by food. Distribution The in vitro plasma protein binding of melatonin is approximately 60%. Melatonin is mainly bound to albumin, alpha1-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 Experimental data suggest that isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of the cytochrome P450 system are involved in melatonin metabolism. The principal metabolite is 6-sulphatoxy-melatonin (6-S-MT), which is inactive. The site of biotransformation is the liver. The excretion of the metabolite is completed within 12 hours after ingestion.

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Excretion Terminal half life (t½) is 3.5-4 hours. Elimination is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymeltonin and 2% is excreted as melatonin (unchanged drug). Gender A 3-4-fold increase in Cmax is apparent for women compared to men. A five-fold variability in Cmax between different members of the same sex has also been observed. However, no pharmacodynamic differences between males and females were found despite differences in blood levels. 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 pg/ml in adults (18-45) versus 1200 pg/ml in the elderly (55-65); AUC levels around 3,000 pg*h/mL in adults versus 6000 pg*h/mL in the elderly. Renal impairment Melatonin did not accumulate after repeated dosing with CIRCADIN. This finding is compatible with the short half-life of melatonin in humans. The levels assessed in the blood of patients at 23:00 (2 hours after administration) following 1 and 3 weeks of daily administration were 411.4 ± 56.5 and 432.00 ± 83.2 pg/ml respectively, and are similar to those found in healthy volunteers following a single dose of Circadin 2 mg. Hepatic impairment The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in higher endogenous melatonin levels. Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin compared with controls.

Clinical trials Three Phase 3 studies and a sleep laboratory study were considered pivotal. These studies enrolled patients with primary insomnia who were aged at least 55 years. Patients suffering from severe neurological, psychiatric or neurosurgical diseases or taking CNS medications including benzodiazepines or other hypnotic agents were excluded. The primary assessment tool was the Leeds Sleep Evaluation Questionnaire (LSEQ), comprising 10 self-rated 100 mm-line analogue questions concerning aspects of sleep and early morning behaviour. The LSEQ measures ease of getting to sleep (GTS), quality of sleep (QOS), ease of waking from sleep (AFS) and behaviour following wakefulness (BFW). The primary outcome variable in the pivotal clinical trials was QOS, or a combination on QOS and BFW, where a patient had to show a clinically relevant improvement on both QOS and BFW. Time to onset of sleep and duration of sleep were measured objectively only in a polysomnography study. Efficacy of Circadin in combination with other hypnotic agents has not been assessed.

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In a polysomnographic (PSG) study (N=40; 20 Circadin, 20 placebo) with a run-in of 2 weeks (single-blind with placebo treatment), followed by a treatment period of 3 weeks (double-blind, placebo-controlled, parallel group design) and a 3-week withdrawal period, time to onset of sleep was shortened significantly by 9 minutes compared to placebo. A statistically significant difference favouring Circadin was seen for total duration of time awake prior to sleep onset (approx change from 10 to 11 minutes for Circadin and from 21 to 20 minutes for placebo). There were no modifications of sleep architecture and no effect on REM sleep duration by Circadin. Modifications in diurnal functioning did not occur with Circadin 2 mg. Circadin did not prolong the duration of sleep significantly compared to placebo. In the outpatient studies patients who failed to meet the inclusion criteria at the end of the run-in period due to the instability of their disorder (16% of the total population) were not included in the efficacy analysis. In an outpatient study (Neurim VII: N=170; 82 Circadin, 88 placebo) with two week run in baseline period with placebo, a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks and two week withdrawal period with placebo, the primary efficacy endpoint was Quality of Sleep (QOS). The rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 47% in the Circadin group as compared to 27% in the placebo group. There was a mean difference of approximately 6 mm in quality of sleep and approximately 9 mm in morning alertness, both favouring Circadin compared to placebo. Sleep variables gradually returned to baseline with no rebound, no increase in adverse events and no increase in withdrawal symptoms. In a second outpatient study (N=334; 169 Circadin, 165 placebo) with two week run in baseline period with placebo and a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks, the rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 26% in the Circadin group as compared to 15% in the placebo group. Circadin shortened patients’ reported time to onset of sleep by 24.3 minutes vs 12.9 minutes with placebo. In addition, patients’ self-reported quality of sleep, number of awakenings and morning alertness significantly improved with Circadin compared to placebo. Quality of life was improved significantly with Circadin 2 mg compared to placebo. A third study involved more than 600 patients over 55, over 400 of whom were on Circadin treatment for up to 6 months. Patients given Circadin demonstrated a difference from placebo in mean change from baseline in subjective sleep latency, assessed using a sleep diary, of -7.8 minutes after 3 weeks (p=0.014). Small differences in sleep latency were generally maintained over 13 weeks of placebo-controlled treatment. The percentage of patients showing both remission of insomnia (PSQI of <6) and a clinically relevant improvement of 10% in quality of life scores (WHO-5 index) increased from 16.7% (cf. 10.6% placebo, p=0.044) at week 3 to 25.8% at week 13 (cf. 15.7% placebo, p=0.006). This study also examined the effect of Circadin on sleep latency in younger subjects with primary insomnia and low excretion of melatonin. Clinically significant effects on sleep latency were not demonstrated in these patients.

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Long term safety: The safety profile both during 3 weeks and during the 26 week periods was comparable to placebo with no withdrawal and rebound effects. In an open study where 96 subjects completed 12 months treatment with Circadin no tolerance, rebound or withdrawal effects were reported.

Indications Monotherapy for the short term treatment of primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over.

Contraindications Circadin prolonged release tablets are contraindicated in patients with a known hypersensitivity to any ingredient of the product (see DESCRIPTION).

Precautions 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 body surface area. Use in pregnancy: Category B3. No significant effects on embryofetal development were observed in rats given oral melatonin during the period of organogenesis at doses over 900-fold the recommended clinical dose, based on body surface area. No clinical data on exposed pregnancies are available. In view of the lack of clinical data, use in pregnant women and by women intended to become pregnant is not recommended. Use in lactation: Maternal transfer of exogenous melatonin to the fetus via the placenta or milk has been demonstrated in several animal species including rats, hamsters, goats, monkeys and cows. A slight reduction in post-natal growth, viability and development was found in rats given oral melatonin during gestation through weaning at doses over 900-fold the recommended clinical dose, based on body surface area; the no-effect dose was over 250-fold the clinical dose. 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. Paediatric use: Circadin is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

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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 of melatonin in the elderly. 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. Drowsiness: Circadin may cause drowsiness. Therefore the product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety. Effects on ability to drive and operate machinery: Circadin has negligible influence on the ability to drive and use machines. Nevertheless, patients should avoid engaging in hazardous activities (such as driving or operating machinery) after taking Circadin. Autoimmune diseases: No clinical data exist concerning the use of Circadin in individuals with autoimmune diseases. Therefore Circadin is not recommended for use in patients with autoimmune diseases. Excipients: The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interactions with other medicines:

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

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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 - Coadministration of CIRCADIN with cimetidine resulted in a 1.7 fold increase in exposure to melatonin with no change in the exposure to cimetidine. Caution should be exercised in patients on cimetidine, a CYP2D inhibitor which increases plasma melatonin levels by inhibiting its metabolism. Cigarette smoking - Cigarette smoking may decrease melatonin levels due to induction of CYP1A2. 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. 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 Circadin or vice versa has not been studied. Pharmacodynamic interactions

Alcohol - Alcohol should not be taken with Circadin, because it reduces the effectiveness of Circadin on sleep. The prolonged release characteristics of Circadin may be altered by alcohol, resulting in immediate release of melatonin. Hypnotics - Circadin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone.

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In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between Circadin and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone. Thioridazine and imipramine - Circadin 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, Circadin co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy-headedness” compared to thioridazine alone. Effect on laboratory tests: No information is available on the effect of melatonin on laboratory tests.

Adverse Effects In clinical trials (in which a total of 1931 patients were taking Circadin and 1642 patients were taking placebo), 48.8% of patients receiving Circadin reported an adverse reaction compared with 37.8% taking placebo. Comparing the rate of patients with adverse reactions per 100 patient weeks, the rate was higher for placebo than Circadin (5.743 - placebo vs. 3.013 - Circadin). The most common adverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by MedDRA definition, in both the Circadin and placebo treated groups. In the Circadin group, there were 72 cases (2.9% of the safety population) of adverse events leading to discontinuation of the patient. In the placebo group there were 62 cases (4.0% of the safety population) of adverse events leading to discontinuation of the patient. Overall Adverse Experience for adverse events occurring with a frequency ≥ 1% Body System/Adverse Experience Circadin %

(N=1931) Placebo % (N=1642)

Gastrointestinal disorders Abdominal Pain 1.1 0.7 Abdominal Pain Upper 1.0 1.2 Constipation 1.2 0.9 Diarrhoea 3.1 1.8 Nausea 1.8 1.7 Vomiting 1.5 0.9 General Disorders and administration site conditions Asthenia 1.9 1.2 Infections and infestations Influenza 1.5 0.9 Lower respiratory tract infection 1.9 1.2 Nasopharyngitis 4.0 3.0 Pharyngitis 1.9 1.2 Upper respiratory tract infection 2.9 1.2 Urinary tract infection 2.1 0.7 Musculoskeletal and connective tissue disorder Arthralgia 3.5 1.8 Back Pain 3.8 1.5

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Muscle cramp 1.1 0.6 Neck pain 1.1 0.6 Pain in extremity 1.6 1.1 Nervous system disorders Dizziness 1.6 1.2 Headache 5.7 6.2 Migraine 1.1 1.2 Psychiatric disoprders Anxiety 1.0 1.2 Respiratory, thoracic and mediastinal disorders Cough 2.2 1.3 Pharyngolaryngeal pain 1.5 0.9 Rhinitis 1.1 0.9

The adverse reactions in the table below were reported in clinical trials and were defined as possibly, probably or definitely related to treatment. A total of 9.5% of subjects receiving Circadin reported an adverse reaction compared with 7.4% of subjects taking placebo. Only those adverse events occurring in subjects at an equivalent or greater rate than placebo have been included. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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).

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Adverse events related to treatment occurring with a frequency < 1% System Organ

Class Uncommon Rare Not known

Infections and Infestations

Herpes zoster

Blood and Lymphatic System Disorders

Leukopenia, Thrombocytopenia

Cardiac Disorders Angina Pectoris, Palpitations

Immune System Disorders

Hypersensitivity reaction

Metabolism and Nutrition Disorders

Hypertriglyceridaemia, Hypocalcaemia, Hyponatraemia

Psychiatric Disorders

Irritability, Nervousness, Restlessness, Insomnia, Abnormal dreams, Anxiety, Nightmares

Mood altered, Aggression, Agitation, Crying, Stress Symptoms, Disorientation, Early morning awakening, Libido increased, Depressed mood, Depression

Nervous System Disorders

Migraine, Lethargy Psychomotor hyperactivity, Dizziness, Somnolence, Headache

Syncope, Memory impairment, Disturbance in attention, Dreamy state, Restless Legs Syndrome, Poor quality sleep, Paresthesia

Eye Disorders Visual acuity reduced, Vision blurred, Lacrimation increased

Ear and Labyrinth Disorders

Vertigo positional, Vertigo

Vascular Disorders Hypertension Hot flush Gastrointestinal Disorders

Abdominal pain, Abdominal pain upper, Dyspepsia, Mouth Ulceration, Dry mouth, Nausea

Gastro-oesophageal Reflux Disease, Gastrointestinal disorder, oral Mucosal Blistering, Tongue Ulceration, Gastrointestinal upset, Vomiting, Bowel sounds abnormal, Flatulence, Salivary hypersecretion, Halitosis, Abdominal

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Discomfort, Gastric disorder, Gastritis

Hepatobiliary Disorders

Hyperbilirubinaemia

Skin and Subcutaneous Tissue Disorders

Dermatitis, Night Sweats, Pruritus, Rash, Pruritus Generalised, Dry Skin

Eczema, Erythema, Hand Dermatitis, Psoriasis, Rash Generalised, Rash pruritic, , Nail disorder

Angioedema, Oedema of mouth, Tongue oedema

Musculoskeletal and Connective Tissue Disorders

Pain in extremity Arthritis, Muscle spasms, Neck pain, Night cramps

Reproductive System and Breast Disorders

Menopausal symptoms

Priapism, Prostatitis Galactorrhoea

General Disorders and Administration Site Conditions

Asthenia, Chest Pain Fatigue, Pain, Thirst

Renal and Urinary Disorders

Glycosuria, Proteinuria

Polyuria, Hematuria, Nocturia

Investigations Liver Function Test Abnormal, Weight increased

Hepatic enzyme increased, Blood Electrolytes Abnormal, Laboratory Test Abnormal

Post-Marketing Data Psychiatric Disorders: Nightmares

Dosage and Administration Oral use. Tablets should be swallowed whole. The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food. This dosage may be continued for up to thirteen weeks.

Paediatric use

Circadin is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy. Renal insufficiency The effect of any stage of renal insufficiency on melatonin pharmacokinetics has not been studied. Caution should be used when melatonin is administered to such patients. Hepatic impairment There is no experience of the use of Circadin in patients with liver impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, Circadin is not recommended for use in patients with hepatic impairment.

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Overdosage In general, the main therapy for all overdoses is supportive and symptomatic care. Symptoms No case of overdose has been reported. Circadin has been administered at 5 mg daily doses in clinical trials over 12 months without significantly changing the nature of the adverse reactions reported. Administration of daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions have been reported in the literature. If overdose occurs, drowsiness is to be expected. Treatment Clearance of the active substance is expected within 12 hours after ingestion. No special treatment is required For further advice on management of overdose please contact the Poisons Information Centre (Tel: 13 11 26 for Australia and Tel: 0800 764 766 for New Zealand).

Presentation and storage conditions

Presentation Circadin 2 mg prolonged release tablets: White to off-white, round, biconvex tablets in blister packs of 21, 30 or 7 (sample pack) tablets. AUST R 153959.

Storage conditions Store below 25ºC. Protect from light

Name and address of the sponsor Sponsor: RAD Data Australia Pty Ltd PKF Melbourne Level 12, 440 Collins Street Melbourne, VIC, 3000 Distributor: Aspen Pharma Pty Ltd 34-36 Chandos Street St Leonards NSW 2065

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Poisons Schedule of the medicine Schedule 4. Prescription Only Medicine

Date of first inclusion in the Australian Register of Therapeutic Goods (the ARTG): 25 November 2009

Date of most recent amendment 9 June 2016 CIRCADIN is a registered trademark of Neurim Pharmaceuticals

TGACRP Complaint: Healthy Care –Melatonin Homeopathic

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Publications: • http://healthycare.com.au/our-products/item/hc-melatonin-homoeopathic-90-tablets • https://www.chemistwarehouse.com.au/Buy/74367/Healthy-Care-Melatonin-Homeopathic-

90-Tablets • http://www.epharmacy.com.au/product.asp?id=74367 • http://www.mychemist.com.au/product.asp?id=74367&pname=Healthy+Care+Melatonin+H

omeopathic+90+Tablets • Etc.

Date/Edition: 8/12/2017

Product: Healthy Care Melatonin Homeopathic 6X Sponsor: Nature's Care Manufacture Pty Limited, 5 Minna Close, BELROSE, NSW, 2085, ABN: 75 059 975 834.

Details of Complaint:

I allege that this product is not in accord with definition of a homeopathic preparation as outlined in Part 1(2) (Interpretation) of the Therapeutic Goods Regulations 1990 (Compilation no. 77):1

“homoeopathic preparation means a preparation:

(a) formulated for use on the principle that it is capable of producing in a healthy person symptoms similar to those which it is administered to alleviate; and (b) prepared according to the practices of homoeopathic pharmacy using the methods of:

(i) serial dilution and succussion of a mother tincture in water, ethanol, aqueous ethanol or glycerol; or (ii) serial trituration in lactose”.

Melatonin, produces sleep (product information attached), not insomnia; it is therefore not a homeopathic preparation in accord with the homeopathy “Law of Similars” (like cures like).2 Coffee, not melatonin, is traditionally used in homeopathic preparations to treat insomnia.3

In addition, the use of melatonin is not in accord the TGA evidence guidelines on traditional evidence. 4 These state:

“Traditional indications are based on evidence of a history of medicinal use of the ingredients or medicines that exceeds three generations (75 years) of use.”

Melatonin was first discovered in 1958 by dermatology professor Aaron B. Lerner and colleagues at Yale University and thus cannot be used for a “traditional indication”. 5

Accordingly, I allege that the following claims are in breach of s.4(1)(b), 4(2)(a), 4(2)(c), 4(2)(d) of the Therapeutic Goods Advertising Code 2015 because they are not in accord with “traditional” indications; I could find no good scientific evidence to support them, and they exploit the lack of knowledge of consumers about homeopathic principles:

On the pack in many advertisements (screen shots appended):

• Jetlag and Insomnia • Melatonin Homoeopathic 6X • Melatonin in homoeopathic preparation 6x

1 https://www.legislation.gov.au/Details/F2017C00528 2 https://medical-dictionary.thefreedictionary.com/like+cures+like 3 https://homeopathica.com/homeopathic-medicine-for-insomnia/ 4 https://www.tga.gov.au/publication/evidence-guidelines 5 https://www.ncbi.nlm.nih.gov/pubmed/19069840

TGACRP Complaint: Healthy Care –Melatonin Homeopathic

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In the Healthy Care advertisements:

• Melatonin is a naturally produced hormone, secreted by the pineal gland. It is produced during darkness to promote and regulate sleep patterns.

• Healthy Care Melatonin Homoeopathic may be beneficial in the management of stress, tension and mild anxiety. It helps maintain circadian rhythm in frequent travelling.

• Helps with sleeplessness and jetlag. • As sleep aid, take 1-3 tablets sublingual (place tablets under tongue and let dissolve) half an

hour before bed. • For stress management, take 1 tablet 3 times daily sublingual or in mouth, or as directed by your

healthcare professional. • Homoeopathic product without approved therapeutic indications.

I also allege that the Chemist Warehouse and other pharmacy advertisements breach s.6(3)(c) and 6(3)(d) as they do not include the words “ALWAYS READ THE LABEL”, “USE ONLY AS DIRECTED” and “IF SYMPTOMS PERSIST SEE YOUR DOCTOR/HEALTHCARE PROFESSIONAL."

The advertisements:

http://www.chemistwarehouse.com.au/buy/74367/Healthy-Care-Melatonin-Homeopathic-90-

Tablets, etc.

TGACRP Complaint: Healthy Care –Melatonin Homeopathic

Page 3 of 7

http://healthycare.com.au/our-products/item/hc-melatonin-homoeopathic-90-tablets

(page currently unavailable; however, captured 2 times, April 27, 2017 and May 29, 2017).

Research:

Melatonin (N-acetyl-5-methoxytryptamine) was first purified and characterized from the bovine pineal gland extract by Aron Lerner and co-workers in 1958. Since then, a plethora of information has piled up on its biosynthesis, metabolism, time-bound periodicity, physiological and pathophysiological functions, as well as its interactions with other endocrine or neuro-endocrine organs and tissues in the body.6

To determine whether the claims made by Nature's Care Manufacture Pty Limited could be supported with evidence, systematic reviews and clinical trials were searched using the Cochrane Review Library and Ovid MEDline databases. No studies were found that investigated the efficacy of melatonin at homeopathic dilutions. Whilst studies have been conducted on melatonin, there is no evidence regarding the dosage of 6X, that is, 1 part in 1,000,000 which is a significant dilution.

This is not the only product that does not fulfil the Therapeutic Goods Regulations 1990 definition of a homoeopathic product, for example:7, 8,9,10 In addition, given the TGA’s apparent acceptance of over 1000 “traditional” indications on its current list of “permitted indications”,11 I would expect that sponsors will increasing be attracted to make “traditional” rather than “scientific” claims. This attraction needs to be stopped.

6 https://www.ncbi.nlm.nih.gov/pubmed/19069840 7 http://www.biomedica.com.au/ Biomedica homoeoceuticals 8 http://www.pretoriusvitamins.com.au/supplements/same-90s 9 http://www.pretoriusvitamins.com.au/supplements/dhea-90s 10 http://www.pretoriusvitamins.com.au/supplements/melatonin-90s 11 https://www.tga.gov.au/draft-list-permitted-indications

TGACRP Complaint: Healthy Care –Melatonin Homeopathic

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Accordingly, I ask the TGACRP to refer this problem to the Code Council for consideration in their forthcoming revision of the Therapeutic Goods Advertising Code. So-called homoeopathic products that do not fulfil the Therapeutic Goods Regulations 1990 definition of a homoeopathic product should not be allowed to advertise.

In addition, for consumers to make an informed choice about these medicines I (and others) have submitted that a claim based on “traditional use” should always have a disclaimer along the lines of what the US Federal Trade Commission uses for homeopathic products.12 For example,

“This product’s traditional claims are based on alternative health practices that are not accepted by most modern medical experts. There is no good scientific evidence that this product works”.

Previous complaints:

The Panel has upheld at least 10 previous complaints about homeopathic products.13

Regulatory inaction by the Therapeutic Goods Administration (TGA)

Homoeopathic preparations are exempt from regulation (being entered in the ARTG) if they are more dilute than a one-thousand-fold dilution of a mother tincture (4X and above); are not required

12 https://www.ftc.gov/system/files/documents/federal_register_notices/2016/12/homeopathic_drugs_frn_12-13-2016.pdf 13 http://www.tgacrp.com.au/complaint-register/?_search=homeopath

TGACRP Complaint: Healthy Care –Melatonin Homeopathic

Page 5 of 7

to be sterile, do not include ingredients of human or animal origin and do not make reference to serious diseases or conditions. Preparations that meet these conditions are also exempt from requiring the manufacturer to hold a GMP licence.

Regardless, there have been long-standing concerns by consumers and health professionals about the regulation of these products and the claims they make.

For example, certain homeopathic products, such as homeopathic melatonin (the subject of this complaint) do not fit the homeopathic tradition, yet misleading and deceptive claims continue to be promoted, despite upheld TGACRP complaints.

There is also concern that the promotion of homeopathic Baby & Child Cold & Flu remedies can cause unsuspecting parents to forego more evidence based medicines, such as ibuprofen, that could better address their child’s symptoms.14

In addition, most consumers do not understand homeopathic principles; are not aware that these principles lack scientific validity,15 and are confused by Latin terminology, such as Natrum Muriaticum (instead of salt), which obscure the names of the ingredients and exploits the lack of knowledge of consumer, as does the use of decimal (X) and centesimal (C) dilutions.

In 2003, the Expert Committee on Complementary Medicines in the Health System recommended that homoeopathic medicines that make therapeutic claims should be regulated to ensure they meet appropriate standards of safety, quality and efficacy.16 No action was taken.

In 2008, the TGA held a consultation on the regulation of homoeopathic and anthroposophic medicines in Australia.17 Numerous submissions were received but no action eventuated.

In 2017, the TGA sought comments on proposed options for future regulation of 'low risk products' including homoeopathic products. The consultation paper made no reference to previous recommendations or consultations. It suggested four options for reform:

• maintain the status quo (does not address long-standing problems), • serious therapeutic claims must be supported by scientific evidence (impossible for

homeopathic products), • exempt from listing in the ARTG and/or GMP (likely to produce a greater range of products

and increase the potential for dangerous products)18 or • declare homeopathic products not to be therapeutic goods (this would handball the

problems to the ACCC and effectively mean no regulation at all as the ACCC only has the resources to act in the most egregious cases).19

In short, the latest TGA consultation document failed to acknowledge many long-standing concerns about the supply and promotion of homeopathic products and, in my opinion, it fails to provide a viable solution to the longstanding problems.

I (and others) advocate that all products making therapeutic claims by invoking the homeopathic tradition should be regulated as listed products with the addition of a mandatory disclaimer / warning on their ARTG Public Summary documents, product packaging, labelling and promotion like that recently suggested by the U.S. FTC, for example,

14 https://theconversation.com/kids-smarts-dumb-ads-consumers-complain-of-misleading-claims-9989 15 https://www.nhmrc.gov.au/media/releases/2015/nhmrc-releases-statement-and-advice-homeopathy 16 http://www.tga.gov.au/archive/committees-eccmhs.htm 17 https://www.tga.gov.au/regulation-homoeopathic-and-anthroposophic-medicines-australia 18 http://www.smh.com.au/national/hylands-homeopathic-baby-tablets-recalled-in-australia-over-safety-fears-20170429-gvvfgx.html 19 https://www.accc.gov.au/media-release/court-imposes-penalty-for-false-or-misleading-claims-by-homeopathy-plus-and-ms-frances-sheffield

TGACRP Complaint: Healthy Care –Melatonin Homeopathic

Page 6 of 7

Warning: This product’s traditional claims are based only on theories of homeopathy from the 1700s that are not accepted by most modern medical experts. There is no scientific evidence that this product works.20

Finally, the Therapeutic Goods Act and the Therapeutic Goods Advertising Code needs to be updated to address the longstanding problems documented above. Public and non-registered health professional education by the TGA is also required.

Conclusion:

I allege that this product is not in accord with definition of a homeopathic preparation as outlined in Part 1(2) (Interpretation) of the Therapeutic Goods Regulations 1990 (Compilation no. 77):21

“homoeopathic preparation means a preparation:

(a) formulated for use on the principle that it is capable of producing in a healthy person symptoms similar to those which it is administered to alleviate; and (b) prepared according to the practices of homoeopathic pharmacy using the methods of:

(i) serial dilution and succussion of a mother tincture in water, ethanol, aqueous ethanol or glycerol; or (ii) serial trituration in lactose”.

Melatonin, produces sleep (product information attached), not insomnia; it is therefore not a homeopathic preparation in accord with the homeopathy “Law of Similars” (like cures like).22 Coffee, not melatonin, is traditionally used in homeopathic preparations to treat insomnia.23

In addition, the use of melatonin is not in accord the TGA evidence guidelines on traditional evidence. 24 These state:

“Traditional indications are based on evidence of a history of medicinal use of the ingredients or medicines that exceeds three generations (75 years) of use.”

Melatonin was first discovered in 1958 by dermatology professor Aaron B. Lerner and colleagues at Yale University and thus cannot be used for a “traditional indication”. 25

Accordingly, I allege that the following claims are in breach of s.4(1)(b), 4(2)(a), 4(2)(c), 4(2)(d) of the Therapeutic Goods Advertising Code 2015 because they are not in accord with “traditional” indications; I could find no good scientific evidence to support them, and they exploit the lack of knowledge of consumers about homeopathic principles:

On the pack in many advertisements (screen shots appended):

• Jetlag and Insomnia • Melatonin Homoeopathic 6X • Melatonin in homoeopathic preparation 6x

In the Healthy Care advertisements:

• Melatonin is a naturally produced hormone, secreted by the pineal gland. It is produced during darkness to promote and regulate sleep patterns.

20 https://www.ftc.gov/news-events/press-releases/2016/11/ftc-issues-enforcement-policy-statement-regarding-marketing 21 https://www.legislation.gov.au/Details/F2017C00528 22 https://medical-dictionary.thefreedictionary.com/like+cures+like 23 https://homeopathica.com/homeopathic-medicine-for-insomnia/ 24 https://www.tga.gov.au/publication/evidence-guidelines 25 https://www.ncbi.nlm.nih.gov/pubmed/19069840

TGACRP Complaint: Healthy Care –Melatonin Homeopathic

Page 7 of 7

• Healthy Care Melatonin Homoeopathic may be beneficial in the management of stress, tension and mild anxiety. It helps maintain circadian rhythm in frequent travelling.

• Helps with sleeplessness and jetlag. • As sleep aid, take 1-3 tablets sublingual (place tablets under tongue and let dissolve) half an

hour before bed. • For stress management, take 1 tablet 3 times daily sublingual or in mouth, or as directed by your

healthcare professional. • Homoeopathic product without approved therapeutic indications.

I also allege that the Chemist Warehouse and other pharmacy advertisements breach s.6(3)(c) and 6(3)(d) as they do not include the words “ALWAYS READ THE LABEL”, “USE ONLY AS DIRECTED” and “IF SYMPTOMS PERSIST SEE YOUR DOCTOR/HEALTHCARE PROFESSIONAL."

Dr Ken Harvey AM Associate Professor

Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine

Monash University The Alfred Centre

99 Commercial Road Melbourne VIC 3004

Mobile: +61 419181910

Email: kenneth.harvey@monash.edu www.medreach.com.au

8/12/2017

Acknowledgment:

The research for this complaint was performed by a 2017 SPHPM Summer Vacation Scholarship student.26

26 https://www.monash.edu/medicine/sphpm/teaching/summer-vacation-program

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Product Information

Circadin® Prolonged Release Tablets

Name of the medicine Melatonin Chemical name: N-[2-(5-Methoxyindol-3-yl)ethyl]acetamide. Structural formula:

Molecular formula: C13H16N2O2 Molecular weight: 232.27 CAS number: 73-31-4 pKa: 12.3 – 12.7

Description The active ingredient in Circadin prolonged release tablets is a melatonin NOT of plant or animal origin. Circadin prolonged release tablets also contain the excipients: Ammonio methacrylate copolymer, calcium hydrogen phosphate, lactose, colloidal anhydrous silica, purified talc and magnesium stearate. Melatonin is a slightly off-white, odourless crystalline powder. Melatonin is very slightly soluble in water and in dilute hydrochloric acid.

Pharmacology Pharmacotherapeutic group: Melatonin Receptor Agonists, ATC code: N05CH01

Pharmacological actions:

Melatonin is a naturally occurring hormone produced by the pineal gland and is structurally related to serotonin. Physiologically, melatonin secretion increases soon after the onset of darkness, peaks at 2-4 am and diminishes during the second half of the night. Melatonin is associated with the control of circadian rhythms and

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entrainment to the light-dark cycle. It is also associated with a hypnotic effect and increased propensity for sleep. Mechanism of action The activity of melatonin at the MT1 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. Rationale for use Because of the role of melatonin in sleep and circadian rhythm regulation, and the age related decrease in endogenous melatonin production, melatonin may effectively improve sleep quality particularly in patients who are over 55 with primary insomnia.

Pharmacokinetics: The absolute bioavailability of melatonin from CIRCADIN has not been assessed. Other oral formulations of melatonin have an absolute bioavailability in the region of 15% but this is highly variable with high first-pass metabolism. The relative bioavailability of melatonin from CIRCADIN is comparable to that of an oral melatonin solution.

Data from other formulations of melatonin indicate that the absorption of orally ingested melatonin is complete in adults and may be decreased by up to 50% in the elderly. The kinetics of melatonin is linear over the range of 2-8 mg as obtained from published results using a formulation other than CIRCADIN. Bioavailability as assessed from other oral formulations of melatonin is in the order of 15%. There is a significant first pass effect with an estimated first pass metabolism of 85% as assess from other oral formulations of melatonin. Tmax occurs after 2.6 hours in a fed state. The rate of melatonin absorption following Circadin 2 mg oral administration is affected by food. The presence of food delayed the absorption of the melatonin resulting in a later Tmax (Tmax= 2.6 h versus Tmax= 1.6 h). Cmax and AUC levels were not affected by food. Distribution The in vitro plasma protein binding of melatonin is approximately 60%. Melatonin is mainly bound to albumin, alpha1-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 Experimental data suggest that isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of the cytochrome P450 system are involved in melatonin metabolism. The principal metabolite is 6-sulphatoxy-melatonin (6-S-MT), which is inactive. The site of biotransformation is the liver. The excretion of the metabolite is completed within 12 hours after ingestion.

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Excretion Terminal half life (t½) is 3.5-4 hours. Elimination is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymeltonin and 2% is excreted as melatonin (unchanged drug). Gender A 3-4-fold increase in Cmax is apparent for women compared to men. A five-fold variability in Cmax between different members of the same sex has also been observed. However, no pharmacodynamic differences between males and females were found despite differences in blood levels. 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 pg/ml in adults (18-45) versus 1200 pg/ml in the elderly (55-65); AUC levels around 3,000 pg*h/mL in adults versus 6000 pg*h/mL in the elderly. Renal impairment Melatonin did not accumulate after repeated dosing with CIRCADIN. This finding is compatible with the short half-life of melatonin in humans. The levels assessed in the blood of patients at 23:00 (2 hours after administration) following 1 and 3 weeks of daily administration were 411.4 ± 56.5 and 432.00 ± 83.2 pg/ml respectively, and are similar to those found in healthy volunteers following a single dose of Circadin 2 mg. Hepatic impairment The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in higher endogenous melatonin levels. Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin compared with controls.

Clinical trials Three Phase 3 studies and a sleep laboratory study were considered pivotal. These studies enrolled patients with primary insomnia who were aged at least 55 years. Patients suffering from severe neurological, psychiatric or neurosurgical diseases or taking CNS medications including benzodiazepines or other hypnotic agents were excluded. The primary assessment tool was the Leeds Sleep Evaluation Questionnaire (LSEQ), comprising 10 self-rated 100 mm-line analogue questions concerning aspects of sleep and early morning behaviour. The LSEQ measures ease of getting to sleep (GTS), quality of sleep (QOS), ease of waking from sleep (AFS) and behaviour following wakefulness (BFW). The primary outcome variable in the pivotal clinical trials was QOS, or a combination on QOS and BFW, where a patient had to show a clinically relevant improvement on both QOS and BFW. Time to onset of sleep and duration of sleep were measured objectively only in a polysomnography study. Efficacy of Circadin in combination with other hypnotic agents has not been assessed.

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In a polysomnographic (PSG) study (N=40; 20 Circadin, 20 placebo) with a run-in of 2 weeks (single-blind with placebo treatment), followed by a treatment period of 3 weeks (double-blind, placebo-controlled, parallel group design) and a 3-week withdrawal period, time to onset of sleep was shortened significantly by 9 minutes compared to placebo. A statistically significant difference favouring Circadin was seen for total duration of time awake prior to sleep onset (approx change from 10 to 11 minutes for Circadin and from 21 to 20 minutes for placebo). There were no modifications of sleep architecture and no effect on REM sleep duration by Circadin. Modifications in diurnal functioning did not occur with Circadin 2 mg. Circadin did not prolong the duration of sleep significantly compared to placebo. In the outpatient studies patients who failed to meet the inclusion criteria at the end of the run-in period due to the instability of their disorder (16% of the total population) were not included in the efficacy analysis. In an outpatient study (Neurim VII: N=170; 82 Circadin, 88 placebo) with two week run in baseline period with placebo, a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks and two week withdrawal period with placebo, the primary efficacy endpoint was Quality of Sleep (QOS). The rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 47% in the Circadin group as compared to 27% in the placebo group. There was a mean difference of approximately 6 mm in quality of sleep and approximately 9 mm in morning alertness, both favouring Circadin compared to placebo. Sleep variables gradually returned to baseline with no rebound, no increase in adverse events and no increase in withdrawal symptoms. In a second outpatient study (N=334; 169 Circadin, 165 placebo) with two week run in baseline period with placebo and a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks, the rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 26% in the Circadin group as compared to 15% in the placebo group. Circadin shortened patients’ reported time to onset of sleep by 24.3 minutes vs 12.9 minutes with placebo. In addition, patients’ self-reported quality of sleep, number of awakenings and morning alertness significantly improved with Circadin compared to placebo. Quality of life was improved significantly with Circadin 2 mg compared to placebo. A third study involved more than 600 patients over 55, over 400 of whom were on Circadin treatment for up to 6 months. Patients given Circadin demonstrated a difference from placebo in mean change from baseline in subjective sleep latency, assessed using a sleep diary, of -7.8 minutes after 3 weeks (p=0.014). Small differences in sleep latency were generally maintained over 13 weeks of placebo-controlled treatment. The percentage of patients showing both remission of insomnia (PSQI of <6) and a clinically relevant improvement of 10% in quality of life scores (WHO-5 index) increased from 16.7% (cf. 10.6% placebo, p=0.044) at week 3 to 25.8% at week 13 (cf. 15.7% placebo, p=0.006). This study also examined the effect of Circadin on sleep latency in younger subjects with primary insomnia and low excretion of melatonin. Clinically significant effects on sleep latency were not demonstrated in these patients.

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Long term safety: The safety profile both during 3 weeks and during the 26 week periods was comparable to placebo with no withdrawal and rebound effects. In an open study where 96 subjects completed 12 months treatment with Circadin no tolerance, rebound or withdrawal effects were reported.

Indications Monotherapy for the short term treatment of primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over.

Contraindications Circadin prolonged release tablets are contraindicated in patients with a known hypersensitivity to any ingredient of the product (see DESCRIPTION).

Precautions 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 body surface area. Use in pregnancy: Category B3. No significant effects on embryofetal development were observed in rats given oral melatonin during the period of organogenesis at doses over 900-fold the recommended clinical dose, based on body surface area. No clinical data on exposed pregnancies are available. In view of the lack of clinical data, use in pregnant women and by women intended to become pregnant is not recommended. Use in lactation: Maternal transfer of exogenous melatonin to the fetus via the placenta or milk has been demonstrated in several animal species including rats, hamsters, goats, monkeys and cows. A slight reduction in post-natal growth, viability and development was found in rats given oral melatonin during gestation through weaning at doses over 900-fold the recommended clinical dose, based on body surface area; the no-effect dose was over 250-fold the clinical dose. 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. Paediatric use: Circadin is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

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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 of melatonin in the elderly. 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. Drowsiness: Circadin may cause drowsiness. Therefore the product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety. Effects on ability to drive and operate machinery: Circadin has negligible influence on the ability to drive and use machines. Nevertheless, patients should avoid engaging in hazardous activities (such as driving or operating machinery) after taking Circadin. Autoimmune diseases: No clinical data exist concerning the use of Circadin in individuals with autoimmune diseases. Therefore Circadin is not recommended for use in patients with autoimmune diseases. Excipients: The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interactions with other medicines:

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

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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 - Coadministration of CIRCADIN with cimetidine resulted in a 1.7 fold increase in exposure to melatonin with no change in the exposure to cimetidine. Caution should be exercised in patients on cimetidine, a CYP2D inhibitor which increases plasma melatonin levels by inhibiting its metabolism. Cigarette smoking - Cigarette smoking may decrease melatonin levels due to induction of CYP1A2. 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. 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 Circadin or vice versa has not been studied. Pharmacodynamic interactions

Alcohol - Alcohol should not be taken with Circadin, because it reduces the effectiveness of Circadin on sleep. The prolonged release characteristics of Circadin may be altered by alcohol, resulting in immediate release of melatonin. Hypnotics - Circadin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone.

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In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between Circadin and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone. Thioridazine and imipramine - Circadin 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, Circadin co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy-headedness” compared to thioridazine alone. Effect on laboratory tests: No information is available on the effect of melatonin on laboratory tests.

Adverse Effects In clinical trials (in which a total of 1931 patients were taking Circadin and 1642 patients were taking placebo), 48.8% of patients receiving Circadin reported an adverse reaction compared with 37.8% taking placebo. Comparing the rate of patients with adverse reactions per 100 patient weeks, the rate was higher for placebo than Circadin (5.743 - placebo vs. 3.013 - Circadin). The most common adverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by MedDRA definition, in both the Circadin and placebo treated groups. In the Circadin group, there were 72 cases (2.9% of the safety population) of adverse events leading to discontinuation of the patient. In the placebo group there were 62 cases (4.0% of the safety population) of adverse events leading to discontinuation of the patient. Overall Adverse Experience for adverse events occurring with a frequency ≥ 1% Body System/Adverse Experience Circadin %

(N=1931) Placebo % (N=1642)

Gastrointestinal disorders Abdominal Pain 1.1 0.7 Abdominal Pain Upper 1.0 1.2 Constipation 1.2 0.9 Diarrhoea 3.1 1.8 Nausea 1.8 1.7 Vomiting 1.5 0.9 General Disorders and administration site conditions Asthenia 1.9 1.2 Infections and infestations Influenza 1.5 0.9 Lower respiratory tract infection 1.9 1.2 Nasopharyngitis 4.0 3.0 Pharyngitis 1.9 1.2 Upper respiratory tract infection 2.9 1.2 Urinary tract infection 2.1 0.7 Musculoskeletal and connective tissue disorder Arthralgia 3.5 1.8 Back Pain 3.8 1.5

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Muscle cramp 1.1 0.6 Neck pain 1.1 0.6 Pain in extremity 1.6 1.1 Nervous system disorders Dizziness 1.6 1.2 Headache 5.7 6.2 Migraine 1.1 1.2 Psychiatric disoprders Anxiety 1.0 1.2 Respiratory, thoracic and mediastinal disorders Cough 2.2 1.3 Pharyngolaryngeal pain 1.5 0.9 Rhinitis 1.1 0.9

The adverse reactions in the table below were reported in clinical trials and were defined as possibly, probably or definitely related to treatment. A total of 9.5% of subjects receiving Circadin reported an adverse reaction compared with 7.4% of subjects taking placebo. Only those adverse events occurring in subjects at an equivalent or greater rate than placebo have been included. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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).

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Adverse events related to treatment occurring with a frequency < 1% System Organ

Class Uncommon Rare Not known

Infections and Infestations

Herpes zoster

Blood and Lymphatic System Disorders

Leukopenia, Thrombocytopenia

Cardiac Disorders Angina Pectoris, Palpitations

Immune System Disorders

Hypersensitivity reaction

Metabolism and Nutrition Disorders

Hypertriglyceridaemia, Hypocalcaemia, Hyponatraemia

Psychiatric Disorders

Irritability, Nervousness, Restlessness, Insomnia, Abnormal dreams, Anxiety, Nightmares

Mood altered, Aggression, Agitation, Crying, Stress Symptoms, Disorientation, Early morning awakening, Libido increased, Depressed mood, Depression

Nervous System Disorders

Migraine, Lethargy Psychomotor hyperactivity, Dizziness, Somnolence, Headache

Syncope, Memory impairment, Disturbance in attention, Dreamy state, Restless Legs Syndrome, Poor quality sleep, Paresthesia

Eye Disorders Visual acuity reduced, Vision blurred, Lacrimation increased

Ear and Labyrinth Disorders

Vertigo positional, Vertigo

Vascular Disorders Hypertension Hot flush Gastrointestinal Disorders

Abdominal pain, Abdominal pain upper, Dyspepsia, Mouth Ulceration, Dry mouth, Nausea

Gastro-oesophageal Reflux Disease, Gastrointestinal disorder, oral Mucosal Blistering, Tongue Ulceration, Gastrointestinal upset, Vomiting, Bowel sounds abnormal, Flatulence, Salivary hypersecretion, Halitosis, Abdominal

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Discomfort, Gastric disorder, Gastritis

Hepatobiliary Disorders

Hyperbilirubinaemia

Skin and Subcutaneous Tissue Disorders

Dermatitis, Night Sweats, Pruritus, Rash, Pruritus Generalised, Dry Skin

Eczema, Erythema, Hand Dermatitis, Psoriasis, Rash Generalised, Rash pruritic, , Nail disorder

Angioedema, Oedema of mouth, Tongue oedema

Musculoskeletal and Connective Tissue Disorders

Pain in extremity Arthritis, Muscle spasms, Neck pain, Night cramps

Reproductive System and Breast Disorders

Menopausal symptoms

Priapism, Prostatitis Galactorrhoea

General Disorders and Administration Site Conditions

Asthenia, Chest Pain Fatigue, Pain, Thirst

Renal and Urinary Disorders

Glycosuria, Proteinuria

Polyuria, Hematuria, Nocturia

Investigations Liver Function Test Abnormal, Weight increased

Hepatic enzyme increased, Blood Electrolytes Abnormal, Laboratory Test Abnormal

Post-Marketing Data Psychiatric Disorders: Nightmares

Dosage and Administration Oral use. Tablets should be swallowed whole. The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food. This dosage may be continued for up to thirteen weeks.

Paediatric use

Circadin is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy. Renal insufficiency The effect of any stage of renal insufficiency on melatonin pharmacokinetics has not been studied. Caution should be used when melatonin is administered to such patients. Hepatic impairment There is no experience of the use of Circadin in patients with liver impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, Circadin is not recommended for use in patients with hepatic impairment.

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Overdosage In general, the main therapy for all overdoses is supportive and symptomatic care. Symptoms No case of overdose has been reported. Circadin has been administered at 5 mg daily doses in clinical trials over 12 months without significantly changing the nature of the adverse reactions reported. Administration of daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions have been reported in the literature. If overdose occurs, drowsiness is to be expected. Treatment Clearance of the active substance is expected within 12 hours after ingestion. No special treatment is required For further advice on management of overdose please contact the Poisons Information Centre (Tel: 13 11 26 for Australia and Tel: 0800 764 766 for New Zealand).

Presentation and storage conditions

Presentation Circadin 2 mg prolonged release tablets: White to off-white, round, biconvex tablets in blister packs of 21, 30 or 7 (sample pack) tablets. AUST R 153959.

Storage conditions Store below 25ºC. Protect from light

Name and address of the sponsor Sponsor: RAD Data Australia Pty Ltd PKF Melbourne Level 12, 440 Collins Street Melbourne, VIC, 3000 Distributor: Aspen Pharma Pty Ltd 34-36 Chandos Street St Leonards NSW 2065

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Poisons Schedule of the medicine Schedule 4. Prescription Only Medicine

Date of first inclusion in the Australian Register of Therapeutic Goods (the ARTG): 25 November 2009

Date of most recent amendment 9 June 2016 CIRCADIN is a registered trademark of Neurim Pharmaceuticals