11th September 2014

The Secretary Communications and Secretariat

Therapeutic Goods Administration PO Box 100 WODEN ACT 2606

Dear Sir,

Re: Public Submission - under Reg. 42ZCZK of the Therapeutic Goods Regulations 1990. ACMS meeting, November 2014.

refers to the pre-November 2014 Schedu ling meeting notice .• would like comment on the proposed amendment to the schedu ling of pantoprazole .

• has no objection to the application to create a new Schedule 2 entry for pantoprazole when supplied in oral preparations containing 20mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days of supply.

All PPis have a similar mode of action, are well tolerated with similar safety and efficacy profi les.

This fact has been acknow ledged in the delegate's reasons for scheduling, most recently for the dow n scheduling of esomeprazole, but also previous meetings of the NDPSC. If this proposa l is

deemed to be in the best interest of public hea lth, and given the similar safety and efficacy profi les for PPis, it wou ld be appropriate for the panel to consider the scheduling proposal for PPis (omeprazole, esomeprazole, rabeprazole, lansoprazole and pantoprazole).

The Secretary

Communications and Secretariat

Therapeutic Goods Administration

PO Box 100

WODEN ACT 2606

Dear Sir,

11 September 2014

Re: Public Submission - under Regulation 42ZCZK of the Therapeutic Goods Regulations 1990

for the November 2014 meeting of the Advisory Committee on Medicines Scheduling (ASMS)

refers to the pre-November 2014 Scheduling meeting notice .•

XXX would like comment on the proposed amendment to the scheduling of paracetamol

in combination with Phenylephrine (PE).

A similar submission has also made to the Medicines Classification Committee (MCC) in New

Zea land by AFT Pharmaceutica ls. The detai ls of the proposa l are made public in New Zealand

through the Medsafe website (http://www.medsafe.govt.nz/profs/class/agen52 Paracetamol­

and-Phenylephrine.pdf) .• is taking the position that the information provided to the MCC in

New Zea land is consistent with the information provided as part of the application to amend

Part 4 of the Poisons standard.

-.strongly opposes this rescheduling application, as it is believed that the proposal is not in

the best interest of public health and question the robustness of the pharmacologica l and

medical rationale.

Under section 52E of the Therapeutic Goods Act 1989, in exercising a power under subsection

52D(2), the Secretary must take the following matters into account (where relevant):

a) the risks and benefits of the use of a substance;

b) the purposes for which a substance is to be used and the extent of use of a substance;

c) the toxicity of a substance;

d) the dosage, formulation, labell ing, packaging and presentation of a substance;

e ) the potential for abuse of a substance;

f) any other matters that the Secretary considers necessary to protect public health.

The proposed combination has already been demonstrated to appropriately meet Section 52E of

Therapeutic Goods Act 1989 by the National Drugs and Poisons Schedule Committee (NDPSC) in

previous decisions.

History of availability and scheduling of Phenylephrine in Australia PE is a well-established active ingredient, and has been available as Schedule 2 as well as general

sale medicine for cough, cold/ flu and sinus relief preparations both as a single ingredient, as

well as in combination products for many years. In fact at the October 2005 NDPSC meeting,

the committee agreed to amend the current Schedule 2 entry for PE to increase the exemption

for oral use to include preparations containing 50mg or less per recommended daily dose. This

decision was made on the grounds of the safety profile of oral PE and on the basis of

harmonisation with New Zealand.

At the June 2007 NDPSC meeting, the committee agreed to down-schedule from Schedule 2 to

exempt from Scheduling, Paracetamol (500mg or 1000mg) and PE (5mg or 10mg) combinations

based on the sound safety profile of these substances. Furthermore, it was noted that there

was sufficient Australian market experience to support this down scheduling. The committee

discussed that the two unscheduled substances should lead to the combination product also

being unscheduled given there was many years’ experience in the marketplace with this

combination as a Schedule 2 medicine.

The safety and efficacy of the proposed combination has already been assessed and approved

by the Therapeutic Goods Administration (TGA) and deemed appropriate at the current levels.

The indications associated with this combination include, but not limited to ‘Cold and Flu relief,’

that are common illnesses and easily recognised by consumers. They are self-limiting, with

symptoms generally present for three to four days for colds and six to eight days for flu. They

are illnesses which are suitable for self-diagnosis and self-treatment by the consumer, and they

are not associated with protracted use. Therefore given the short-term usage of these products,

we further question the need to lower the dose of phenylephrine.

The Proposed Changes The application request consideration for the following proposal:

Proposal to include the following in Schedule 3:

500 mg of paracetamol when combined with more than 2.5 mg phenylephrine

per tablet or capsule or caplet

Individually wrapped powders or sachets of granules containing paracetamol

1000 mg and more than 5 mg phenylephrine per dose

Proposal to include in the following in Schedule 2:

500 mg of paracetamol when combined with 2.5 mg phenylephrine or less per

tablet or capsule or caplet in packs containing more than 20 tablets or capsules

or caplets per pack

Individually wrapped powders or sachets of granules containing paracetamol

1000 mg and 5 mg phenylephrine or less per dose in packs containing more than

10 such powders or sachets

Proposal to exempt from scheduling the following:

500 mg of paracetamol when combined with 2.5 mg phenylephrine or less per

tablet or capsule or caplet in packs containing 20 or less tablets or capsules or

caplets per pack

Individually wrapped powders or sachets of granules containing paracetamol

1000 mg and 5 mg phenylephrine or less per dose in packs containing 10 or less

such powders or sachets.

Risk & Benefits - Proposed Changes In March 2014, a letter to the editor of the New England Journal of Medicine was published (1).

The author, Hartley Atkinson, Founder and Managing Director of AFT Pharmaceuticals reported

that administration of phenylephrine hydrochloride 10mg in combination with paracetamol

1000mg (two tablets) effectively doubles the bioavailability of PE and quadruples the maximum

plasma concentration, allegedly giving a dose equivalent to 20mg of PE.

Unfortunately details of the studies (including the number of individuals involved in the study)

conducted by AFT are not provided in the letter to the editor, making a critical analysis

impossible, but it is our understanding, based on the information available in the Australian and

New Zealand Clinical trials registry (www.anzctr.org.au) that the sample sizes are small ranging

from n = 6 to n = 30 in a limited number of trials conducted at a single centre in Jordan.

In the submission to the MCC in New Zealand, and presumably also to the ACMS in Australia,

there is a suggestion that the alleged doubling of bioavailability of PE could potentially increase

the risk of cardiovascular side effects in susceptible individuals, such as those who are

overweight/obese and/or the elderly and also those individuals who have undiagnosed or

asymptomatic cardiovascular disease(s) that may be exacerbated by an increase of blood

pressure.

The applicant speculates that there is a potential increased risk to consumers with

cardiovascular conditions when taking a combination of paracetamol and PE at the current

levels. However consumers are clearly advised through appropriate mandatory label warnings

that if they have heart conditions or hypertension to consult their doctor or pharmacist before

using the medication. The required warning statements as per the Medicines Advisory

Statements Specification 2014 (MASS) Schedule 2 include:

See your doctor or pharmacist before taking this medicine if you have high blood

pressure or heart problems or are taking antidepressant medication.

This product may cause sleeplessness

The applicant contends that moving these products to Schedule 3 will potentially reduce the risk

to consumers who may have undiagnosed hypertension or underlying, asymptomatic

cardiovascular disease. According to the Scheduling Policy Framework, Schedule 3 medicines

are substances for which mandatory professional advice is required in order to ensure safe use.

Pharmacists will not be in a position to diagnose individuals that have underlying asymptomatic

cardiovascular conditions. The pharmacists questioning of consumers will be based on the

warning statements that are present on the label and in the pharmacy texts such as the

Australian Pharmaceutical Formulary, MIMS or the Australian Medicines Handbook. Pre-

diagnosis of cardiovascular disease or hypertension are not typically conducted by pharmacists

prior to recommending particular products.

The following questions must be asked:

Does the co-administration of phenylephrine hydrochloride (HCL) and paracetamol at

10mg per dose result in clinically significant AEs suggestive of excess or unsafe

phenylephrine dosing? and

Does the co-administration of phenylephrine hydrochloride (HCL) and paracetamol

actually result in a clinically more superior symptomatic relief of nasal congestion

compared to phenylephrine hydrochloride taken on its own?

Martindale thirty-fifth edition, recognises 20mg of PE as a safe oral dose, - ‘Phenylephrine

hydrochloride may be given by mouth in doses up to 20mg every four hours’. In the submission

to the MCC (and presumably to the ACMS), the applicant’s rationale for restricting supply of the

paracetamol 500mg plus phenylephrine 5 mg (2 tablets) to Schedule 3 is based on theoretical

safety concerns regarding the use of the currently registered Schedule 2 and general sale

products by consumers.

It is incorrectly stated that Paracetamol & PE combinations have only been available in New

Zealand and the rest of the world since 2006 when PE was substituted for Pseudoephedrine.

This combination has had extensive use within the community and in the United Kingdom since

as early as 1997. In the 17 years of market experience globally, there has been no evidence or

any safety issues relating to cardiovascu lar disease or hypertension that could justify the up­

scheduling of these medicines to Schedu le 3.

There is also no evidence to our knowledge to suggest that consumers taking this combination

at the currently approved levels are getting superior symptomatic relief from the PE than if they

took a dose of single ingredient PEat the same level. Further, there is no evidence to suggest

that the "potentiation effects of paracetamol" negatively impacts the safety profile of PE due to -a dose response . • markets a very wide range of products indicated for cough/ cold and flu

containing this combination (approximately 120 million dosage units per annum) and company

Adverse Events data over the last 5 years, does not indicate there are any Adverse Events

relating to cardiovascular disease or hypertension.

In the absence of signa ls that suggest that the combination of paracetamol and PE represents a

safety concern in the community, any theoretical or predicted issues shou ld be addressed in an

appropriately designed and powered clinical study with the appropriate endpoints.

The patients at risk, as highlighted in the Atkinson letter to the editor (1), already have warnings

statements included on labelling as required by MASS 2014. What is not clear in the letter is

whether the apparent increase in bioavailabi lity of PE when combined with paracetamol results

in an increased therapeutic benefit of the PE, w hich is a fundamental consideration before any

up-scheduling decisions are made. If the therapeutic benefit of a lower dose of phenylephrine

(Smg per dose) as proposed, is less than what consumers are currently accustomed to, or not

tru ly equivalent to 10mg of phenylephrine per dose as claimed, there may be a temptation for a

consumer to ignore the dosage instructions and consume more than the recommended dose.

The consequence of this scenario wi ll be paracetamol overdose, w hich can have significant

clinical outcomes.

Considering the product usage is for short term symptomatic relief, any effect on blood pressure

will be short lived and of limited clinical significance for the vast majority of people w ho use this

product. Therefore the risk of consumers not getting the relief they expect from their

combination product at the lower level of PE outweighs the theoretical r isk to those individuals

that are overweight/ obese and/ or the elderly, and also those individuals w ho have undiagnosed

or asymptomatic cardiovascu lar disease(s) that may be exacerbated by an increase of blood

pressure, for all the points highlighted above.

In fact the submission to the MCC states that the doubling of PE plasma levels is expected to

have minimal safety implications to young healthy consumers. It is important to note that there

are many OTC medicines that cannot be taken by consumers with certain health issues, and for

these groups of individuals, mandatory warning labels are required as included in MASS 2014.

Dosage, formulation, labelling, packaging and presentation of the substances -All. products that contain the combination of paracetamol and phenylephrine have the

following mandatory statements which address the theoretica l concern raised in the re­

scheduling application:

Ask your doctor before use if you:

• Have high blood pressure

• Are taking anti-depressants

• Have heart problems

• Are pregnant

Burden on the Public Health System Burden on the pharmacist

The current scheduling of products containing paracetamol and PE means that cold and flu

preparations containing these actives are avai lable without the need for consultation from a

healthcare professional. According to the Scheduling Policy Framework, Schedule 3 medicines

are substances for which mandatory professional advice is required. Self-l imit ing cold and flu

symptoms treated with short term OTC substances with a history of safe use does not f it within

this framework and would resu lt in an unnecessary burden on pharmacists.

Likely increase in demand for Pseudoephedrine

If a consumer is forced to consult a pharmacist for medication to relieve the symptoms of a cold

and f lu, the consumer may request for a formulation containing pseudoephedrine as opposed to

PE. There are studies that have demonstrated that pseudoephedrine is superior to PE at

improving the symptoms of nasal congestion (2).

The concern with this outcome is that as consumer demand increases, more pseudoephedrine

products wi ll be in pharmacy and the supply chain. It could be specu lated that there will be an

increase in criminal activit y, including the i llegal conversation of pseudoephedrine to

methamphetamines. If this were to eventuate, it wou ld not be in the best interest of public

health. In fact, quite opposite- it would more than likely be to the detriment of the Australian

public health system. -In Conclusion,. strongly opposes the proposal to amend the scheduling of paracetamol

plus PE combinations for the follow ing reasons:

1. The combination of paracetamol and phenylephrine has had extensive use as Schedu le 2

and as general sale medicines, with over 4 million units sold annua lly (equates to over

120 million dosage units) with no significant adverse events relating to cardiovascular

disease or hypertension. The rationale for restricting supply to Schedule 3 is based on a

theoretical safety concern which has not been reflected in company or public adverse

events databases.

2. The absence of safety signals indicates that the combination of paracetamol and PE

represents no safety concern. Any theoretical or predicted issues should be addressed

in appropriately designed and powered clinical studies

3. The risk of paracetamol overdose outweighs the risk to those consumers with

hypertension or cardiac conditions, especially given mandatory warning labels are

already included on packaging for the “at risk” populations.

4. Paracetamol and PE combination products are used for short-term, symptomatic cold

and flu symptoms relief, therefore effects on blood pressure will be short lived and of

limited clinical significance for the vast majority of people who use the product.

5. Up-scheduling this combination to Schedule 3 will not be in the best interest of public

health and will increase the workload burden on pharmacists given the sound safety

profile of this combination and the years of extensive use of these medicines with no

significant Adverse Events data reported to date.

6. Should this combination be up-scheduled to as proposed, there is likely to be an

increased demand on the supply of pseudoephedrine. Pseudoephedrine was up-

scheduled to reduce supply and limit the amount of pseudoephedrine available for

illegal conversation to methamphetamines. With the increased demand on

pseudoephedrine, there will be more pseudoephedrine in the supply chain and greater

potential for criminal activity.

1. Atkinson, H. C., I. Stanescu, and B. J. Anderson. 2014. Increased phenylephrine plasma levels with administration of acetaminophen. N Engl J Med 370:1171-2.

2. Horak, F., P. Zieglmayer, R. Zieglmayer, P. Lemell, R. Yao, H. Staudinger, and M. Danzig. 2009. A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber. Ann Allergy Asthma Immunol 102:116-20.

Reference 1 Atkinson, H. C., I. Stanescu, and B. J. Anderson. 2014. Increased phenylephrine plasma levels with administration of acetaminophen. N Engl J Med 370:1171-2.

correspondence

n engl j med 370;12 nejm.org march 20, 2014 1171

ularly in settings where liver transplantation is not available. As stated in our review, since the evidence base for care is very limited, the use of most therapies is based on opinion. Although the use of lactulose may be beneficial in some pa-tients with cirrhosis and low-grade encephalopa-thy, its role in critically ill patients with acute liver failure is not established. Its use may be deleterious because patients with acute liver fail-ure frequently have ileus that may be worsened, particularly if oral fluid intake is inadequate. There are no clinical data to suggest a prolonga-tion of survival, and we and others do not recom-mend the use of lactulose for the great majority of patients.1

Dhaliwal and Singh bring up autoimmune hepatitis and specific infections as causes of acute liver failure; space considerations prevent-ed us from an exhaustive discussion of all of these in our review. Severe liver involvement may be seen in some systemic infections, and in such cases the early administration of targeted anti-microbial medication is central to effective man-agement. Autoimmune processes may be impor-tant in the pathogenesis of liver injury in acute liver failure due to a number of causes, including new presentations of autoimmune hepatitis2;

however, this cause of acute liver failure is very uncommon, and clinical management may be challenging.3 Although some patients may have a response to immunosuppressive therapy, a key issue is that inappropriately prolonged therapy in an attempt to achieve medical control of dis-ease may preclude successful and definitive trans-plantation, owing to the development of treat-ment-related sepsis and other complications.4

William Bernal, M.D. Julia Wendon, M.B., Ch.B.King’s College London London, United Kingdom william.bernal@kcl.ac.uk.

Since publication of their article, the authors report no fur-ther potential conflict of interest.

1. Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med 2007;35:2498-508.2. Stravitz RT, Lefkowitch JH, Fontana RJ, et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011;53:517-26.3. Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013;38:343-64.4. Ichai P, Duclos-Vallée J-C, Guettier C, et al. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl 2007;13:996-1003.

DOI: 10.1056/NEJMc1400974

Increased Phenylephrine Plasma Levels with Administration of Acetaminophen

To the Editor: Over-the-counter combinations containing acetaminophen and phenylephrine for the treatment of the common cold and influenza are widespread after the substitution of phenyl-ephrine for pseudoephedrine. This substitution has been allowed in the United States and else-where without any additional safety or efficacy studies, since phenylephrine has been called “generally recognized as safe and effective” at oral doses of 10 mg on the assumption that the pharmacokinetic behavior of one drug is not altered by another, despite a lack of supporting data.1-3

Three randomized, open-label, crossover stud-ies in healthy volunteers were undertaken as part of the development of a new-fixed dose combi-nation containing acetaminophen, ibuprofen,

and phenylephrine. The results showed an unex-pected pharmacokinetic interaction among the three drugs: the administration of phenyleph-rine (at a dose of 10 mg) in combination with acetaminophen (1000 mg) and ibuprofen (300 mg), as compared with the administration of 10 mg of phenylephrine alone, resulted in nearly a qua-drupling in the maximal plasma concentration (3220 pg per milliliter vs. 874 pg per milliliter) and a doubling in the area under the curve (2220 pg per milliliter per hour vs. 1020 pg per milliliter per hour) (Fig. 1). Ibuprofen was subsequently shown not to contribute to this increase. Halv-ing the dose of phenylephrine that was combined with acetaminophen to 5 mg produced a plasma concentration–time curve similar to that for 10 mg of phenylephrine administered alone.

The New England Journal of Medicine Downloaded from NEJM Media Center by ERNIE MUNDELL on March 14, 2014. Embargo lifted March 19, 2014 at 5pm ET.

Copyright © 2014 Massachusetts Medical Society. All rights reserved.

T he N E W ENG L AND JOURNA L of M E DI C IN E

3000

.. 2500 & ..

1t .E 2000

1= _, E 1500 .,1>1

~ c:.a. ·c: .s:; e- 1000

1 .s:; 500 ....

~ 0

0 2 4 6

Hour

• Acetaminophen, 1000 mg; ibuprofen, 300 mg; phenylephrine, 10 mg

o Phenylephrine, 10 mg

8 10 12

Figure 1. Pharmacokine tic Interaction for Phe nylephrine, Acetaminophen, and Ibuprofen.

Shown are the mean plasma levels of phenylephrine after the single ad min· istration to healthy human volunteers of a combination of 1000 mg of aceta· minophen, 300 mg of ibuprofen, and 10 mg of phenylephrine (black circles), as compared with 10 mg of phenylephrine alone (white circles). The I bars indicate standard errors.

These findings have implications from both regulatory and safety perspectives. First, it is clear that many approvals for the addition of phenylephrine to any number of analgesic agents were based on assumptions that were incorrect for acetaminophen. Second, the plasma expo­sure of phenylephrine combined with acetamin­ophen (measured as the area under the curve) is doubled, increasing exposure beyond levels that were previously deemed to be safe and effective

and increasing the potential risk of adverse events.

Since phenylephrine is metabolized by sulfa­tion in the intestinal wall, it seems likely that acetaminophen interferes with this process and increases the level of phenylephrine with respect to bioavailability.4 If so, other drugs may also in­teract with phenylephrine, including ascorbic acid. Multiple variants of acetaminophen combined with phenylephrine are now available on world­wide markets. Is funher investigation required? Hartley C. Atkinson, M.Pharm., Ph.D. Joana Stanescu, PhiLLie., M.Sc. AFT Pharmaceuticals Takapuna, New Zealand

Brian J. Anderson, Ph.D. University of Auckland Auckland, New Zealand briana@adhb.govt.nz

Disclosure forms provided by the authors are available with the full text of this letter at NBJM.org.

1. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use: 21 CFR Parts 310, 341 and 369. Fed Regist 1994;59(162):43386-412. 2. Australian Department of Health. Registration of products containing phenylephrine in place of pseudoephedrine. Febru­ary 10, 2006 (httpif/www.tga.gov.au/industry/otc-phenylephrine -pseudoephedrine.htm). 3. A justification for changing the current wording of the GSL classification of phenylephrine to include a cut-off point for solid dose products containing 10 mg or less of phenylephrine. Wellington, New Zealand: Medsafe (hrtp://www.medsafe.govt.nZ/ downloads/MCC32Pbenylephrine.pdf). 4. Ibrahim KE, Midgley JM, Crowley JR, Williams CM. The mammalian metabolism of R-(-)-m-synephrine. ] Pbann Pbar­macol 1983;35:144-7.

DOl: lO.l056{NfJMcl313942

Speech in an Orally Intubated Patient

A video showing the patient

speaking with use cf an electrolarynx

is available at NEJM.org

1172

TO TH E ED ITOR: We repon the successful use of an electrolarynx in an orally intubated 59-year­old man who was receiving mechanical ventila­tion. The device enabled him to produce intelli­gible speech (Fig. 1). A video-assisted bilobectomy of the right lung for adenocarcinoma had been performed at another hospital, and the proce­dure was complicated by the development of a bronchopleural fistula. Because of this complica­tion, there was a need for continued mechanical ventilation. His family informed us that the pa­tient was frustrated by his inability to talk. He consented to the plan to use the electrolarynx,

and to his surprise -and ours- the device im­mediately returned the gift of speech to him, without the passage of air through the vocal cords. In response to the question "Were you able to sleep this evening?" he replied, "I slept reason­ably well." (See video, in Dutch, with English translation, available with the full text of this ar­ticle at NEJM.org.) Nurses were able to place the device after just 2 minutes of instruction, and the usefulness of the device in other intubated pa­tients has been confirmed.

The electrolarynx, which is known for its use after laryngectomy, is an oscillating device that

N ENGLJ MED 370;12 N EJM.ORG MARCH 20, 2014

The New England Jownal of Medicine Downloaded from NEJM Media Center by ERNIE MUNDELL on March 14, 2014. Embargo lifted March 19, 2014 at 5pm ET.

Copyright \C 2014 Massachusetts Medical Society. All rights reserved.

Reference 2 Horak, F., P. Zieglmayer, R. Zieglmayer, P. Lemell, R. Yao, H. Staudinger, and M. Danzig. 2009. A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber. Ann Allergy Asthma Immunol 102:116-20.

A placebo-controlled study of the nasaldecongestant effect of phenylephrine andpseudoephedrine in the Vienna ChallengeChamberFriedrich Horak, MD*†; Petra Zieglmayer, MD*; Rene Zieglmayer, DI†; and Patrick Lemell, PhD†;Ruji Yao, PhD‡; Heribert Staudinger, MD‡; and Melvyn Danzig, PhD‡

Background: Studies on the efficacy of phenylephrine in the treatment of nasal congestion have yielded inconsistent results,notwithstanding its approval for this indication.

Objective: To evaluate and compare the decongestant effect of a single dose of phenylephrine to placebo and pseudoephedrinein patients with seasonal allergic rhinitis.

Methods: This randomized, placebo-controlled, 3-way crossover study evaluated patient-scored nasal congestion, peak nasalinspiratory flow, and rhinomanometry at more than 6 hours in 39 grass-sensitive patients exposed to grass pollen in the ViennaChallenge Chamber. Patients were dosed with immediate-release formulations of phenylephrine, 12 mg, pseudoephedrine, 60 mg,as a control, or placebo.

Results: Phenylephrine was not significantly different from placebo in the primary end point, mean change in nasal congestionscore at more than 6 hours (P � .56), whereas pseudoephedrine was significantly more effective than both placebo (P � .01)and phenylephrine (P � .01). Phase 1 results showed a difference between phenylephrine and placebo that was 64% of thedifference between pseudoephedrine and placebo, substantially greater than the 17% difference observed for all phases.Carryover bias due to patient recall of the pseudoephedrine effect may have influenced these results. Rhinomanometry and peaknasal inspiratory flow results were consistent with these data. Neither phenylephrine nor pseudoephedrine had an effect on thenonnasal symptoms. No adverse events were reported in this study.

Conclusions: During a 6-hour observation period, a single dose of pseudoephedrine but not phenylephrine resulted insignificant improvement in measures of nasal congestion. Neither phenylephrine nor pseudoephedrine had an effect on nonnasalsymptoms.

Ann Allergy Asthma Immunol. 2009;102:116–120.

INTRODUCTIONIn several recent surveys of impact and burden of allergicrhinitis, nasal congestion was consistently ranked the mostbothersome symptom in both adult respondents and guardiansof children with allergies.1–3 In addition, nasal congestion wasthe symptom that most respondents (50% of adults and 63%of guardians of children with allergies) wanted to preventfrom occurring.3 Therapeutic options for the prevention andtreatment of nasal congestion include oral decongestants(sympathomimetic agents), such as pseudoephedrine andphenylephrine, which can be administered alone or in com-bination with antihistamines.4

Many manufacturers have changed the formulation of de-congestant products to include phenylephrine because ofsafety and tolerability concerns associated with the use ofpseudoephedrine in certain patient populations and recentlegislation, including the Combat Methamphetamine Epi-demic Act, which requires that all products containingpseudoephedrine be kept “behind the counter.”4,5 The effi-cacy of phenylephrine as a substitute for pseudoephedrine hasbeen questioned because several reports have indicated thatphenylephrine does not provide consistent relief of nasalcongestion or nasal resistance above that provided by place-bo5,6; therefore, the purpose of the current study was tocompare the decongestant effect of a single dose of phenyl-ephrine to placebo and pseudoephedrine in patients withallergic rhinitis.

Allergen challenge chambers are useful in determiningdrug effects in allergic patients exposed to pollen in a homo-geneous environment.7 The Vienna Challenge Chamber is thelongest standing allergen challenge system and has been usedto determine proof-of-concept, time course, and magnitude ofeffect and onset of action of antihistamines, nasal corticoste-roids, and similar agents.

Affiliations: * ENT University Clinic, University of Vienna, Vienna,Austria; † Allergy Center, Vienna West, Vienna, Austria; ‡ Schering-PloughResearch Institute, Kenilworth, New Jersey.

Funding Sources: This study was supported by a grant from Schering-Plough Research Institute.

Disclosures: Drs Danzig, Yao, and Staudinger are employees of Scher-ing-Plough Research Institute.

Trial Registration: clinicaltrials.gov Identifier: NCT00276016Received for publication August 19, 2008; Received in revised form

November 11, 2008; Accepted for publication November 30, 2008.

116 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

METHODS This was a single-center, randomized, placebo-controlled, 3-way crossover study of the decongestant effect of phenyl­ephrine compared with placebo and pseudoephedrine in pa­tients with at least a 2-year history of symptomatic and skin test positive seasonal allergic rhinitis to grass pollen after exposure to grass pollen in the Vienna Challenge Chamber. Patients were to be treated with 1 dose of phenylephrine, 12 mg, pseudoephedrine, 60 mg, or placebo at each treatment visit with a minimum washout period of 5 days between visits. Pseudoephedrine (Sudafed Decongestant Tablets; Pfizer Consumer Healthcare, Eastleigh, Hampshire, England) and phenylephrine (Sudafed Congestion Relief Capsules; Pfizer Consumer Healthcare) were purchased locally. Pla­cebo (blue capsules containing inactive ingredients) was sup­plied by Schering-Plough Research Institute. All 3 medica­tions came packaged in individual blisters. A third party was provided a master randomization code and prepared the med­ication for each patient for each period by placing 1 of the appropriate blisters into a prelabeled vial. The investigator and staff did not know the identities of the medications taken; the patients knew that they took either a tablet or a capsule.

The methods for the Vienna Challenge Chamber have been previously described.8 In brief, patients met the following minimum symptoms severity criteria during a 120-minute predose challenge in the Vienna Challenge Chamber: score of at least 2 (moderate) for nasal congestion; score of at least 6 for combined nasal symptoms (symptoms are rhinorrhea, nasal congestion, sneezing, and nasal itch); and score of at least 2 for combined nonnasal symptoms (symptoms are eye itching or burning, eye tearing, and itching of ears or palate).

The study drug was dispensed when the patient met these scores; patients remained in the Vienna Challenge Chamber for 7.5 hours. Patients were required to complete symptoms evaluations on a scale of 0, indicating none, to 3, indicating severe, at 15-minute intervals. Rhinomanometry, peak nasal inspiratory flow (PNIF), and collection of tissues used for determination of nasal secretion weights were performed at 30-minute intervals.

The primary efficacy variable was the subjective evalua­tion of nasal congestion expressed as an average change from baseline during the first 6.0 hours of the evaluation period. Additional efficacy end points included 2 objective measures of nasal congestion, rhinomanometry, and PNIF, which were evaluated as the average change at more than 6 hours for each of these measures. The average change at more than 6 hours also was evaluated for each of the individual nasal symptoms of rhinorrhea, sneezing, and nasal itching and nonnasal symp­toms of eye itching or burning, eye tearing, and itching of the ears or palate. Safety was evaluated by recording of adverse events and measurement of vital signs.

The study was performed in accordance with applicable statutes and regulations regarding the protection of patients ' rights and welfare and was approved by institutional review

VOLUME 102, FEBRUARY, 2009

boards at each study site. All patients provided written in­formed consent before any study procedure was performed.

The primary comparison for the primary efficacy variable, subjective evaluation of nasal congestion, was phenylephrine, 12 mg, vs placebo tested at 2-sided a = .05. Pseudoephed­rine, 60 mg, was included as a positive control and was also compared with placebo. The comparison of pseudoephedrine vs placebo was performed at unadjusted a = .05, primarily to validate the trial results. In addition, phenylephrine was com­pared with pseudoephedrine to evaluate relative efficacy. Pairwise comparisons were made using linear contrasts of the treatment means obtained from an analysis of variance model that extracts sources of variation due to treatment, patient, and phase. The primary comparison for all of the secondary end points was phenylephrine vs placebo tested at 2-sided a = .05; pseudoephedrine was also compared with placebo.

RESULTS Thirty-nine patients were randomized; 38 patients completed treatment, and 1 patient discontinued participation in the study for reasons unrelated to treatment with study drug after the first dose (pseudoephedrine). Patients were predomi­nantly white (97%) and female (59%); age ranged from 19 to 46 years (mean, 27 years). Baseline (at the time the patients qualified) nasal congestion scores were 2.20 for phenyleph­rine and placebo and 2.26 for pseudoephedrine.

Phenylephrine was not significantly different from placebo in decreasing nasal congestion scores at any evaluation time. The average first 6-hour postbaseline decrease nasal conges­tion score was 7.1% for phenylephrine treatment compared with 2.2% for placebo treatment (P = .56). Comparatively, pseudoephedrine, with an average 6-hour mean percentage decrease from baseline in nasal congestion score of 21.7%, was significantly more effective than either placebo (P < .01) or phenylephrine (P = .01). The difference between phenyl­ephrine and placebo in the average change from baseline during the first 4 hours after dosing (0.19 to 0.16 point) was similar to the difference in the average change from baseline during the first 6 hours after dosing (0.18 to 0.12 point). The time course for nasal congestion is shown in Figure 1. The first time point where pseudoephedrine was statistically dif­ferent from placebo in nasal congestion was at 30 minutes; because phenylephrine did not differentiate from placebo, we could not determine its onset of action.

No significant phase effect (P = .72) was found in the analysis of the primary end point. In addition, no significant sequence effect (P = .89) was found. When data from the first phase of a crossover are evaluated, however, the results can be similar to what could be expected in a parallel-group design. For phase 1 data in this study, the difference between phenylephrine and placebo (0.31 to 0.10 point) was 64% of the difference between pseudoephedrine and placebo (0.43 to 0.10 point), which is greater than the 17% phenylephrine to pseudoephedrine ratio noted when all phases were consid­ered.

117

The results of rhinomanometry (Fig 2) and PNIF (Fig 3), 2objective measures of nasal decongestant effects, were con-sistent with the results of the primary measurement. Phenyl-ephrine had no significant effect on nasal airflow comparedwith placebo as evidenced from the rhinomanometry results(P � .12), whereas pseudoephedrine was significantly moreeffective than placebo (P � .03, sum of right and left nostrils,average 6 hours after dosing). When averaged for the first 6hours of the evaluation period, PNIF showed no significanteffect on nasal airflow for phenylephrine (P � .94) vs pla-cebo and a borderline significant improvement for pseudo-

ephedrine (P � .07) vs placebo. However, the pseudoephed-rine group showed significant improvement during the first 4hours after dosing, in line with the expected duration ofaction of a 60-mg dose of pseudoephedrine. At the hour 4measurement, the pseudoephedrine group had improved sig-nificantly (P � .01) vs placebo, whereas the phenylephrinegroup had not separated from placebo (P � .87).

For the other individual nasal symptom scores averagedduring the first 6 hours, pseudoephedrine was significantlybetter than placebo for rhinorrhea (P � .04) and sneezing(P � .01), whereas phenylephrine was similar to or worse

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Figure 2. Mean change in rhinomanometry measurements (sum of right and left nostrils) at each 30-minute interval after drug administration. Baseline valueswere 366.1 (phenylephrine [PE]), 406.2 (pseudoephedrine [PSE]), and 400.9 (placebo [PL]) at 150 Pa (cm3/s).

118 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

than placebo for each (data not shown). Neither phenyleph-rine nor pseudoephedrine had a significant improvementcompared with placebo on nasal itching or the nonnasalsymptoms (eye itching or burning, eye tearing, itching of earsor palate) (data not shown). A greater decongestant effect wasfound compared with placebo in female patients than in malepatients taking pseudoephedrine; this differential treatmentresponse was not seen for phenylephrine.

No adverse events were reported in this single-dose study,and no treatment differences were observed in vital signs.These results indicated that the single doses of phenylephrine,12 mg, and pseudoephedrine, 60 mg, were safe and welltolerated, although the study was not powered to find statis-tically significant differences in safety.

DISCUSSIONIn this study, statistical significance (P � .56) was not ob-served for the primary efficacy variable, the average changefrom baseline during a 6-hour evaluation period in nasalcongestion, in patients with seasonal allergic rhinitis treatedwith a single dose of phenylephrine, 12 mg, vs patientstreated with placebo. Comparatively, treatment with a singledose of pseudoephedrine, 60 mg, showed significant im-provement in nasal congestion compared with placebo (P �.01) and phenylephrine (P � .01). Phenylephrine showed17% of the decongestant activity demonstrated by pseudo-ephedrine over placebo.

When results were evaluated by phase of the crossover, thephase 1 difference between phenylephrine and placebo was64% of the difference between pseudoephedrine and placebo.This result is similar to what would be expected in a parallel-group design. In this crossover-design study, patients mayhave recalled the effect of pseudoephedrine when pseudo-

ephedrine was taken before other treatments and influencedtheir symptom evaluation. The 3 sequences that had phenyl-ephrine taken before pseudoephedrine in any phase hadgreater changes in the mean decongestant effects comparedwith placebo of phenylephrine, whereas the other 2 sequencesthat had phenylephrine taken after pseudoephedrine in anyphase had raw mean decongestant effects that were consid-erably lower when compared with placebo of phenylephrine.This finding suggests that bias may have been introducedbecause of patient recall of the pseudoephedrine effect in aprevious phase.

Changes in patients’ symptom scores for nasal congestionand objective measures of nasal airflow as a result of theadministration of a therapeutic agent do not always occur inparallel9 because, unlike other symptoms of allergic rhinitis,the discomfort felt by patients with nasal congestion does notalways correlate with the aspects of the symptom that aphysician can evaluate, such as nasal patency.10,11 To reducethe possibility that the current study would underestimate theefficacy of phenylephrine in the relief of nasal congestion, 2objective measures were also used. Both PNIF and rhinoma-nometry were consistent with the subjective measure of effi-cacy in this study with no demonstrated improvement ineither measure after the administration of phenylephrine,whereas a significant improvement in rhinomanometry andan increase in PNIF were seen with pseudoephedrine treat-ment.

As noted, pseudoephedrine provided a significant improve-ment over placebo for rhinorrhea and sneezing but not nasalitching or the nonnasal symptoms. Similar reductions in otherrhinitis symptoms after treatment with pseudoephedrine havebeen noted,12 although it is generally thought that the oraldecongestants have no effect on other symptoms because

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Figure 3. Mean change in peak nasal inspiratory flow (PNIF) scores at each 30-minute interval after drug administration. Baseline values were 104.6(phenylephrine [PE]), 108.7 (pseudoephedrine [PSE]), and 107.0 (placebo [PL]) L/min.

VOLUME 102, FEBRUARY, 2009 119

there is no direct effect of decongestants on allergic media­tors.4 It has been suggested that the relief of symptoms other than nasal congestion by decongestant agents may reflect a "halo effect" because a reduction in nasal congestion may lead to an overall improvement in the patient's sense of well-being and reduced perception of the severity of other rhinitis symptoms. 12

Although patients were exposed for 7.5 hours after dosing, the primary end point was the average for the ftrst 6 hours. This approach was in keeping with the dosing regimens of the short-acting form of phenylephrine (every 6 hours) and pseudoephedrine (every 4 to 6 hours) that were used in this study. Although the dosing regimen for these decongestants is similar, the half-life of phenylephrine is shorter than that of pseudoephedrine, 10·13 so it may be possible that a significant effect of phenylephrine occurred during the initial response to the treatment. To determine if phenylephrine treatment re­sulted in significant improvements in either the subjective or objective measures of nasal congestion, the 4-hour time point was also examined, showing similar results. This finding suggests that it is unlikely that the lack of efficacy with phenylephrine was a result of using the short-acting formu­lation.

Both pseudoephedrine and phenylephrine have been de­scribed as safe and effective drugs.14 A recent letter ques­tioned the effectiveness of phenylephrine as a nasal decon­gestant when given orally.6 Our study was clinically complete when this letter appeared online in May 2006. Within the limitations of the first phase data from this small chamber study, it appears that phenylephrine may have activity, al­though the magnitude and the duration of effect may not be optimized by the current existing doses and formulations. However, because no difference between phenylephrine and placebo for any of the primary subjective or objective mea­sures of nasal congestion was found at any time point, this would suggest that there is little, if any, appreciable effect of phenylephrine compared with placebo in the relief of nasal congestion. The results of the current study are similar to the results of a recent meta-analysis that examined the efficacy and safety of phenylephrine in relieving nasal congestion that occurred because of a variety of causes (eg, "head cold," chronic sinusitis, allergies).5 In that study, the decongestive effects of phenylephrine also were not consistently any better than placebo.5

The following conclusions can be drawn from this study. First, in this crossover design, patients with seasonal allergic rhinitis treated with a single dose of 12 mg of phenylephrine were not significantly different from placebo-treated patients in reduction of their nasal congestion scores from baseline; pseudoephedrine at a dose of 60 mg was superior to placebo. It is possible that recall bias in the crossover design may have

120

influenced this result. Second, treatment with a single dose of phenylephrine, 12 mg, and pseudoephedrine, 60 mg, in male and female patients with seasonal allergic rhinitis, ages 19 to 46 years, was safe and well tolerated.

ACKNOWLEDGMENTS We thank Sandria De Sapio and Karin Gansch for study monitoring; Lucy Shneyer, MS, for statistical oversight; and Craig Ostroff, PharmD, for logistical and regulatory support.

REFERENCES I. Allergies in AmericaTM: a landmark survey of nasal allergy sufferers:

pediatric. http://www.myallergiesinamerica.com. Accessed October 21 , 2008.

2. Allergies in America™: a landmark survey of nasal allergy sufferers: adult. http://www.myallergiesinamerica.com. Accessed October 21 , 2008.

3. Shedden A. Impact of nasal congestion on quality of life and work productivity in allergic rhinitis: findings from a large online survey. Treat Respir Med. 2005;4:439- 446.

4. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63(suppl 86): 8-160.

5. Hatton RC, Winterstein AG, McKelvey RP, Shuster J, Hendeles L. Efficacy and safety of oral phenylephrine: systematic review and meta­analysis. Ann Pharmacother. 2007;41:381- 390.

6. Hendeles L, Hatton RC. Oral phenylephrine: an ineffective replacement for pseudoephedrine? J Allergy Clin lmmwwl. 2006; 118:279- 280.

7. Day JH, Horak F, Briscoe MP, et al. The role of allergen challenge chambers in the evaluation of anti-allergic medication: an international consensus paper. Clin Exp Allergy Rev . 2006;6:31- 59.

8. Horak F, Zieglmayer UP, Zieglmayer R, et al. Azelastine nasal spray and desloratadine tablets in pollen-induced seasonal allergic rhinitis: a phar­macodynamic study of onset of action and efficacy. Curr Med Res Opin. 2006;22: 151-157.

9. Nathan RA. The pathophysiology, clinical impact, and management of nasal congestion in allergic rhinitis. Clin Tiler. 2008;30:573-586.

10. Davis SS, Eccles R. Nasal congestion: mechanisms, measurement and medications: core information for the clinician. Clin Otolaryngol Allied Sci. 2004;29:659- 666.

II. Nathan RA, Eccles R, Howarth PH, Steinsvag SK, Togias A. Objective monitoring of nasal patency and nasal physiology in rhinitis. J Allergy Clin lmmunol. 2005;115:S442-459.

12. Greiner AN, Meltzer EO. Pharmacologic rationale for treating allergic and nonallergic rhinitis. J Allergy Clin Jmm11110l. 2006; 118:985- 998.

13. Eccles R. Substitution of phenylephrine for pseudoephedrine as a nasal decongestant: an illogical way to control methamphetamine abuse. Br J Clin Pharmacal. 2007;63: 10-14.

14. Food and Drug Administration establishment of a monograph for OTC cold, cough, allergy, bronchodilator and antiasthmatic drug products. Fed Regist. 1976;41:38399- 38400.

Requests for reprints should be addressed to: Melvyn R. Danzig, PhD 2015 Galloping Hill Rd Kenilworth, NJ 07033 E-mail: Melvyn.danzig@spcorp.com

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

The SecretaryCommunications and SecretariatTherapeutic Goods AdministrationPO Box 100WODEN ACT 2606

Dear Sir/Madam

Proposed Amendment to the Poisons StandardParacetamol in Combination with Caffeine

I refer to the proposal to exempt paracetamol from the Schedules whencompounded with caffeine, in a powder or granule product containing 1,000 mgor less of paracetamol and in tablets or capsules containing 500 mg or less ofparacetamol when paracetamol is the only therapeutic active constituent andwhen supplied in primary packs of not more than 20 tablets/caplets or10 sachets of powders/granules.

I am old enough to remember when APC (aspirin, phenacetin and caffeine)powders and tablets were widely available from pharmacies, grocery shops andother outlets. I remember also the campaign by academics, members of thehealth professions and ultimately the media to have analgesic productscontaining caffeine placed in Schedule 4. That occurred in NSW on 1 July 1979,and in other States and Territories around the same time.

The reason for having combination products containing an analgesic and caffeineclassified as a prescription only medicine was the high risk of overdosage of theanalgesic component when users took an excess of the product because theywished to experience the stimulant effect of the caffeine. Research had shownthat many of the patients admitted to hospital for acute kidney damage hadconsumed excessive quantities of caffeine-containing analgesics, particularly APCpowders and tablets.

I am concerned that, if the proposal is approved, we will see a rise in liverdamage due to excessive consumption of the product. Research shows thatcaffeine has little, if any, analgesic effect and would make no real contribution tothe analgesic activity of the product. In fact, the proponent is claiming thatparacetamol will be the only therapeutically active constituent, thus suggestingthat caffeine has no therapeutic activity.

If the proponent does not believe that caffeine has any therapeutic activity, Iwonder why the proposal was made in the first place. I would strongly suggestthat the proposal be not approved.

Yours sincerely

Chemicals Scheduling Secretariat GPO Box 9848 CANBERRA ACT 2601

Email : chemicals.scheduling@health.gov.au

Dear Sir/Madam

Public Comment Submission to the November 2014 joint meeting of the Advisory Committee on Chemicals Scheduling (ACCS)

and the Advisory Committee on Medicines Scheduling (ACMS)

We refer to the notice published on 25 September 2014 inviting public submissions, with respect to certain substances, addressing a matter raised in s.52E of the Therapeutic Goods Act 1989.

- wishes to provide information on: • 1-butanol; • 1-propanol; • 2-cyclohexylphenol; • Lemongrass oil; and • Soluble oxalates;

for consideration at the November 2014 joint meeting of the ACCS and ACMS.

Please see the attached submission for details.

- is an interested party and stakeholder with regard to the nominated substances and would appreciate being advised of the Committees' considerations and the Delegate's interim decision, with the opportunity for further submission, if appropriate.

We look forward to further advice from the ACCS, ACMS and the Delegate. Should the Committees or the Delegate re~nal information from- at this stage please do not hesitate to contact me on-

Yours faithfully

[ lmsigned for electronic submission]

23 October 2014

Page 2 of 7

ACCS/ACMS joint-meeting: November 2014

1-butanol

had previously questioned the need to schedule 1-butanol based solely on ocular irritancy

that is common to most solvents. While we now understand that the concern is raised with the aerosol or spray formats of products containing, we are still unsure whether scheduling of this solvent is necessary. Hydrocarbon aerosol propellants such as butane are also eye irritants (although it appears milder than 1-butanol), especially when they are in their liquid form (liquefied butane can cause burns or frostbites to the eyes). However, it is well known that aerosols are meant to be sprayed away from the eyes, which could explain the reason for the low level of incidents involving propellant eye irritancy. We also note that trigger nozzle sprays are designed in such a way so that the nozzle is aimed away from person using the spray. While we understand that aerosols and sprays can still be aimed at others, we believe this is moving into deliberate misuse scenario. NICNAS IMAP report on 1-butanol notes that 1-butanol is classified as irritating to eyes between 5-10%, and irritant causing irreversible eye damage at concentrations greater than or equal to 10%. It also notes that internationally, 1-butanol is used between 1-10% in domestic products. Given that 1-butanol classified as reversible eye irritant in concentrations < 10%, which is known to be the use concentration based on the US domestic products data, we do not believe that scheduling of 1-butanol is necessary. However, if some controls are deemed necessary, we believe products containing up to 10% should be exempt from scheduling. Further other controls such as safety, warning and first aid statements should be considered for higher concentrations rather than inclusion in schedules i.e. reverse scheduling. Any scheduling controls should also be restricted to products in aerosol or spray formats.

Page 3 of 7

ACCS/ACMS joint-meeting: November 2014

1-propanol

had previously questioned the need to schedule 1-propanol based solely on ocular

irritancy that is common to most solvents. While we now understand that the concern is raised with the aerosol or spray formats of products containing, we are still unsure whether scheduling of this solvent is necessary. As noted in our submission for 1-butanol, aerosols and sprays designed to be held in such a way to spray away from the person using the spray or aerosol. Further, we note that 1-propanol appears to be milder than 1-butanol. NICNAS IMAP report on 1-propanol notes that 1-propanol is classified as irritating to eyes between 5-10%, and irritant causing irreversible eye damage at concentrations greater than or equal to 10%. However, it also notes that internationally, 1-propanol is used at up to 60% in domestic products. As far as we are aware, there has not been any concerns raised with the types of products containing 1-propanol in these concentrations.

has previously noted in our submission that 1-propanol can be used as an active ingredient in alcohol based hand rubs in both cosmetic and therapeutic preparations. The active alcohol concentration in these products range between 60 – 95%. We do not believe that any scheduling controls are required for 1-propanol. However, if some controls are deemed necessary, we believe these controls should be restricted to the aerosol or spray format products containing >10% 1-propanol. Further other controls such as safety, warning and first aid statements should be considered for higher concentrations rather than inclusion in schedules i.e. reverse scheduling.

Page 4 of 7

ACCS/ACMS joint-meeting: November 2014

1-cyclohexylphenol

welcomes the proposal to exempt certain product categories from Schedule 9. We

understand that the reason for the initial addition of cyclohexylphenols to Schedule 9 was its use as a recreational drug (“non-classical” cannabinoid). Feedback from members suggests that 1-cyclohexylphenol is an impurity present in quantities < 0.5% in certain preservatives and disinfectants. We believe this level of impurity should be exempt from scheduling as it is unlikely that they can be isolated for use as a recreational drug – the reason they exist as an impurity in the product is because they are not easily isolated. We also welcome the move to include certain uses of 1-cyclohexylphenol in Schedule 6. While we are unsure what cut-off levels would be appropriate, generally speaking, isolation substances like 1-cyclohexylphenol from complex formulated products is quite difficult. Exemption from scheduling could apply if 1-cyclohexylphenol is contained in a formulated product i.e. not a simple solution.

ACCS/ACMS joint-meeting: November 2014

Lemongrass oil

- notes that this agenda item relates to the recent decision on citral , neral and geranial.

We have received no direct feedback to date on the use of lemongrass oil from !!I However, during our consultation on citral, neral and geranial, it became apparen a --well understood that citral, neral and geranial are present in a large number of essen 1a ~ding lemongrass oil, and any decision made on citral and its isomers would also affect these essential oils.

- therefore has no objections to scheduling of lemon~n line with citral, neral and geramal, as we believe this would provide clarity for industry- that may not be aware that lemongrass oil is 90% citral.

Page 5 of7

Page 6 of 7

ACCS/ACMS joint-meeting: November 2014

Soluble oxalates

notes that the ACCS considered whether the current schedule entry for OXALIC ACID

except its derivatives and insoluble salts captures soluble oxalate salts. We note that generally, solubility of salts is not specifically mentioned when scheduling or reverse scheduling a substance. The fact that the reverse scheduling specifically mentions insoluble salts only i.e. not soluble salts, has led to the conclusion by most in industry that soluble salts are captured by the oxalic acid schedule 6 entry. If this was not the intent of the scheduling committee, then we would welcome a clarification, which could be provided by removing the word “insoluble” from the current schedule 6 entry. While we note that the intent of the use of soluble oxalates in dental care products is to form insoluble calcium oxalate crystals, products contain soluble oxalate salts, not the insoluble calcium oxalate crystals.

has previously supported exempting certain uses and concentrations of soluble oxalates. Our views have not changed since making our last submission made on 20 February 2014 to the ACCS meeting. Our comments to the March 2014 ACCS meeting are reproduced below for ease of consideration:

supports the proposed exemption from scheduling of oxalic acid in domestic cleaning preparations containing 8% or less oxalic acid. We also request that the ACCS and the Delegate consider exemption for dental products including mouthwashes containing 3% or less of soluble salts of oxalic acid. While the exemption could be limited to therapeutic dental products, if the use of up to 3% soluble salts of oxalic acid is considered acceptable in therapeutic dental products, the same should apply to non-therapeutic dental products. Further, if a company markets products to treat tooth sensitivity, the product would automatically become therapeutic. Potassium oxalate is currently in products used to treat dental sensitivity marketed in the UK, and its use for this purpose is also permitted in the United States. The oxalate ion works by combining with calcium ions in the oral cavity to form insoluble calcium oxalate crystals which block the dentinal tubules. According to the SCCS notes of guidance for the testing of cosmetic ingredients and their safety evaluation, 7th revision1, approximately 10% mouthwash is expected to be retained in the oral cavity after use (conservatively estimating). The intended dose of the mouthwash is between 10-20ml. This equates to maximum absorption of approximately 30mg of oxalate ion. Oxalic acid is a naturally occurring substance found in common foods such as coffee, spinach, carrots, lettuce and chocolate. Based on information on average quantities of oxalic acid in foods from the United States Department of Agriculture (USDA)2, more than 10 times the amount of oxalic acid retained from a mouthwash can be consumed from eating one medium sized carrot (carrots contain approximately 0.5g (500mg) oxalic acid per 100g – an average carrot weighs approximately 70g). We therefore request that the following scheduling proposal be considered:

1 http://ec.europa.eu/health/scientific committees/consumer safety/docs/sccs s 004.pdf. 2 http://www.ars.usda.gov/Services/docs htm?docid=9444

Page 7 of 7

Schedule 6 OXALIC ACID except: a) its derivatives and insoluble salts,

b) in household and domestic cleaning preparations containing 8 per cent or less oxalic acid or its soluble salts, and c) in dental care preparations including mouthwashes containing 3 per cent or less oxalic acid or its soluble salts.

16th October 2014

The Secretary Scheduling Secretariat GPO Box 9848 Canberra ACT 2601

Dear Si r or Madam,

Re: Invitation for public comment- ACCS, ACMS and joint ACCS I ACMS meetings, November 2014; ASMI Comment- Joint ACCS/ ACMS meeting

We refer to the notice inviting public comment under Regulation 42ZCZK of the Therapeutic Goods Regulations and would like to provide comment on the scheduling proposals that will be considered by the ACCS and joint ACCS/ACMS meetings in November 2014. The comments submitted below address matters raised in section 52E of the Therapeutic Goods Act 1989, and are in relation to the proposed amendments referred by the delegate for scheduling advice for consideration by the ACCS.

For ease of reference, comments are in the same order as the proposals in the consultation document.

ACCS Agenda- General comments

We have reviewed the entire agenda and to the extent possible, have commented on any specific items which are relevant to our members. Some of the proposals do not appear to be relevant to the therapeutic goods industry. However given the limited information provided, the complexity of nomenclature and the large number of possible salts and derivatives, we cannot be certain t hat no impact exists and we would appreciate the opportunity to provide further comment on any of the agenda items should possible impact be identified following the release of the Delegate's interim decisions.

Joint ACCS/ACMS Agenda

Proposed scheduling amendments and - comment

Substance Proposal

1-Butanol Based on advice received during consultation on the interim decision from the March 2014 ACCS meeting to include 1-butanol in Schedules 5 and 6, the delegate determined that the interim decision be set aside and that further advice be sought

Comment:

on the specific range of products conta ining 1-butanol that would warrant scheduling to protect against eye damage, and whether these should include such products as aerosol or spray products and/ or arts & craft materials, where there may be a greater risk of being taken into the eye. This entry may include further considerat ion of ACCS advice that 1-butanol in cosmetics and therapeutic goods be exempted from any proposed schedule ent ry.

A search of t he TGA e-BS sit e shows that 1-Butanol is entered in the ARTG ingredient list as n-butyl alcohol BP, indicating that it may have uses in therapeutic goods, although specific uses are not defined .• understands that this ingredient may have use as a propellant in certain aerosol dosage forms for medicines and also in trace amounts as a component of printing inks used as an identifier on t ablets and capsules.

-up ports the exclusion of therapeutic goods from any proposed schedule entry. It would be inappropriate to capt ure therapeutic goods as part of any proposed Schedule 5 or Schedule 6 entry.

Substance Proposal

!-Propanol Based on advice received during consultation on the int erim decision f rom the March 2014 ACCS meeting t o include 1-propanol in Schedules 5 and 6, t he delegate determined that the interim decision be set aside and that further advice be sought on the specific range of products containing !-propanol t hat wou ld warrant scheduling to protect against eye damage, and whether these should include such products as alcohol based hand rubs, and/or arts & craft materials, where the 1-propanol concentrations are likely to be substantive ly higher t han the proposed scheduling cut-offs fo r spray product s where there is a greater risk of being t aken into the eye. This may include further consideration of ACCS advice that 1-propanol in cosmet ics and therapeutic goods be exempted from any proposed schedule entry.

Comment: A search of the TGA e-BS site shows that ! -Propanol is entered in the ARTG ingredient list as propan-1-ol BP, and is allowed in therapeutic goods in products for derm al use up to a maximum concentrat ion of 18% w/v.

-understands that it may be used in t race amounts, with similar uses as 1-butanol as a solvent for printing inks used on coated tablets as well as in propellants for aerosol dosage forms.

supports the exclusion of therapeutic goods from any proposed schedule entry for!­propanoL

Substance Proposal Soluble oxalates At the March 2014 meeting of the ACCS, an issue was raised

regarding w hether soluble oxa late sa lts used in therapeutic goods such as mouthwashes would be captured by the current

Page 2 of 4

Comment:

Schedule 6 entry OXALIC ACID except its derivatives and

insoluble salts. This issue needs to be clarified along with the need for a specific clause exempting soluble oxalates in mouthwashes.

- supports the exclusion of therapeutic goods such as mouthwashes from the Schedule 6 entry for oxalic acid I oxalates.

Potassium oxalate, a solub le oxalate sa lt, is currently used in mouthwashes for the treatment of dentinal sensitivity in a concentration of 1.4% in some overseas markets. These products are available in the UK and European markets as Class lla medical devices.

Potassium oxalate in the mouthwash, when present in the aqueous environment of saliva, dissociates into potassium cations and oxalate anions. The oxalate then combines with calcium ions in tile oral environment to form water insoluble calcium oxalate crystals which block the dentinal tubules to inhibit the movement of fluid which stimulates nerves causing the sensation of pain.

The agenda and scheduling proposal does not provide information on a proposed cut-off. However, some stakeholders, in their public comments submitted as part of the pre-meeting public consultation process, requested an exemption threshold of 3% for soluble oxalates I potassium oxalate in mouthwash1.

- believes that 3% is an appropriate threshold, based on the following reasons, as outlined in these submissions:

• The Australian regulatory environment wou ld be aligned with Europe and the US

• The population likely to use mouthwash containing potassium oxalate are adults aged 20-40; this is not a product that would be used by children

• There is a favourable safety profile, as there is a low retention of oxalate in the mouth or systemically when used as a mouthwash;

• There is low abuse potential for mouthwash used to treat dentine sensitivity

• Accidental misuse (e.g. swallowing) of a 10 ml dose of a 3% potassium oxalate mouthwash has low potential for harm as it is poorly absorbed from the gastroint estinal tract, and is unlikely to pose significant clinical risks .

• would be supportive of appropriate labelling advice for consumers, such as keeping the product out of reach of children and any other safety instructions that have been adopted by comparable regulatory bodies in overseas markets.

Conclusion

.. supports co-ordination between the various agencies to minimise the impact of scheduling changes proposed for cosmetics, personal care products, commercial and industria l products on products such as therapeutic goods, foods and veterinary products, and is supportive of the Delegate's decision to refer the above items to the joint meeting ofthe ACCSIACMS for further advice.

1 Public Submissions on the proposed amendments to the Poisons Standard. http://www. tga. gov .au/pdf/submissions/scheduling-submissions-1406. pdf

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.. requests the joint ACCS/ ACMS to carefully consider the possible impact of the above scheduling proposals on therapeutic goods, and care should be taken to ensure that any amendments are clearly and carefully drafted to exclude any impact on these products.

The ACCS should also allow sponsors adequate time to make changes to formulation s and/or labelling if needed; adequate transition times are important to industry, as is the need to allow existing stock in market to be sold through.

is a key stakeholder in scheduling matters and we are keen to provide further input as requi red. We look fo rward to the Delegate's interim decisions and greater detail on the final scheduling proposals.

Please contact me should you require any further clarification relating to this submission.

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Request for Public Comment: Scheduling Decision on AOD9604

Overview ----wish to provide comment on the proposed amendments to the ~hedule the compound AOD9604 with an individual listing in Schedule 4 of the SUSMP and further restrictions of the peptide under Appendix D of the SUSMP.

As the Committee (Anti-Obesity Drug 9604) was initially developed by the patent holder as an anti-obe , however, its applications and the majority of research undertaken was to i it in combination with other known active compoun in topical applications to provide skin condition ing benefits.

Cosmetic Ingredient Regulatory Status In 2012 the International Nomenclature Committee reviewed a request­- to assign an International Nomenclature Cosmetic Ingredient ( I~ compound AOD9604.

This name is now published in the International Cosmetic Ingredient Dictionary and Handbook and the International Buyer's Guide.

End.

Page2

The Secretary Chemicals Scheduling Secretruiat Office ofChemkal Safety (MDP 88) GPO Box 9848 CANBERRA ACT 260 I

Email: chemicals.scheduling@healtb.gov.au

D ear Secretariat

Publk comment on scheduling of 1-butanol and 1-pt·opnnol - Joint committee of the Advisory Committee on Chemicals Scheduling (ACCS) and the Advisory Committee on Medicines Scheduling (ACMS), November 2014

As a follow up to the notice published on 25 September 2014 of the Delegate's request for public comments under subsection 42ZCZK of the Therapeutic Goods Regulations 1990, with respect to chemicals 1-butanol (CAS No. 71-36-3) and !-propanol (CAS No. 71-23-28), addressing a matter raised in section 52E of the Therapeutic Goods Act 1989, I am now forwarding a public submission in support of listing these chemicals in Schedules 5 and 6.

For both chemicals, I recommendations for scheduling are based on evidence for a specific usc scenario of coarse aerosols in pump and/or spray products at concentrations of concem for severe eye irritation, where there is potential for ocular exposure.

- therefore recommends to the Committee that these short chain alcohols should be treated separately fi·om other short chain alcohols· such as 1-hexanol (CAS No. 1 Ll-27-3) and ethanol (CAS No. 64-17-5) as they are qualitatively distinct due to evidence of irreversible eye irritation with 1-butanol and 1-propanol.

-g~·ees with the percentage cut-offs discussed in the interim decision for both chemicals. However, our main concern is in aerosol product applications where ocular exposure can lead to i1Teversible eye damage, which could be controlled through appropriate scheduling of aerosol use of these chemicals as recommended in the NICNAS report.

If you require more infonnation or would li ke to discuss tllis matter fi.uther, please do not hesitate to cal