1.6. Interim decision in relation to hyoscine butylbromide

1. Interim decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #28, November 2019)

1.6. Interim decision in relation to hyoscine butylbromide

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision to amend the current Poisons Standard in relation to hyoscine butylbromide as follows:

Proposed date of effect of the proposed amendment

1 June 2020

Reasons for the interim decision (including findings on material questions of fact)

In this section: Applicant's scheduling proposal and reasons for the proposal | Current scheduling status | Scheduling history | Australian regulations | International regulations | Summary of pre-meeting public submissions | Summary of ACMS advice/recommendations to the Delegate | Delegate's considerations | Reasons for the interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to reschedule oral liquid dose form of hyoscine butylbromide from Schedule 4 to Schedule2 in the Poisons Standard by removing the word 'divided' was considered.

The Applicant's proposed amendments to the Poisons Standard were:

The Applicant's main points provided in support of the proposed amendment are as follows:

• The oral tablet dose form of this medicine containing either 10 mg or 20 mg of hyoscine butylbromide per tablet in preparations containing 200 mg or less is currently scheduled as a Schedule 2 (Pharmacy only) medicine in Australia. This application seeks to amend the Poisons Standard to classify the (undivided) oral liquid dose form for preparations containing 20 mg or less per dose unit in a pack containing 200 mg or less hyoscine butylbromide from a 'Prescription only' (Schedule 4) to a 'Pharmacy only' (Schedule 2) medicine. This will result in the harmonisation of the scheduling of the oral tablet and liquid dose forms when supplied in packs containing equivalent amounts of hyoscine butylbromide per dose unit and in the entire pack.
• Abdominal cramping and pain is not life-threatening, but it has a significant impact on the patient's quality of life and subsequent socioeconomic consequences (Lovell et al., 2012).^[108] Abdominal pain is one of most common reasons for people seeking medical care and hyoscine butylbromide has been proven to be safe and effective when used for relief from pain and discomfort of stomach cramps and spasm. The down-scheduling of the oral liquid dose will provide a significant benefit for paediatric and elderly patients, or other patient groups with dysphagia and difficulty swallowing the tablets (the currently available oral dose form, and classified under Schedule 2).
• The rescheduling of the oral liquid dose form of hyoscine butylbromide at the suggested strength in the respective pack size will not impose any safety risks to the Australian population as the total amount of active pharmaceutical ingredient being sold per pack is the same as in the oral tablet packs; and, control over the medicine is maintained as the pharmacist can refer the individual to their doctor to establish clinical need if they present symptoms that are potentially due to another underlying disorder or illness.

Current scheduling status

The related substance hyoscine is currently listed in Schedule 4 and Schedule 2 and Appendix G of the Poisons Standard as follows:

Scheduling history

Hyoscine

In May 1956, hyoscine (and its derivatives) was included in the Poisons Standard in Schedule 1 (then requiring a license to dispense and purchase - Schedule 1 is now no longer is use) in preparations more than 0.25% and in Schedule 2 at less than 0.25%. In the February 1975, as part of a scheduling overhaul, the Schedule 1 entry for hyoscine was moved to Schedule 3. In November 1985, transdermal applicators of 2 mg or less of hyoscine were permitted in Schedule 2 for motion sickness.

In August 1992, a new Appendix G (dilute preparations) in Part 5 of the Poisons Standard was created and hyoscine was included in this amendment at 10 micrograms.

Hyoscine butylbromide

Hyoscine butylbromide was first included in Schedule 4 of the Poisons Standard in February 1967.

In November 1969, hyoscine butylbromide was exempt from the scheduling entries of hyoscine (and hyoscyamine) as part of editorial amendments for scheduling irregularities.

In November 1988, the Schedule 4 entry for hyoscine butylbromide was deleted and a new Schedule entry for hyoscine was included, which captured hyoscine butylbromide. No reason for this decision was minuted.

In November 1993, the Drugs and Poisons Schedule Standing Committee (DPSSC) rejected an application to reschedule hyoscine butylbromide from Schedule 4 to Schedule 3 on the basis that it had received advice from a professional body that there was no place for hyoscine butylbromide in the treatment of irritable bowel syndrome.

In April 1994, the DPSSC considered information relating to the rescheduling of hyoscine butylbromide from Schedule 4 to Schedule 3 and agreed to finalise an ongoing review of solanaceous alkaloids (including hyoscine butylbromide) and to also conduct a review of the scheduling of them.

In August 1994, the National Drug and Poisons Schedule Committee (NDPSC) considered a large amount of information relating to the safety and efficacy of hyoscine butylbromide and were satisfied with its safety profile. However, the Committee considered that a comprehensive review still needed to be undertaken and requested that all relevant information be obtained from other sponsors of hyoscine butylbromide. This information was reviewed at the November 1994 NDPSC meeting, and it was agreed that hyoscine butylbromide should be included in Schedule 3 with dose and pack size restrictions.

In May 1998, the NDPSC considered a submission to reschedule hyoscine butylbromide to Schedule 2. However, due to concerns about mandatory pharmacist advice being required, the Committee decided that the Schedule 3 classification remained appropriate. The August 1998 NDPSC meeting reconsidered this decision with new evidence presented and felt that this new evidence addressed its concerns regarding access and use without pharmacist advice. The Committee agreed to include hyoscine butylbromide in Schedule 2.

In November 2001, in considering the scheduling of solanaceous plants and alkaloids, the NDPSC decided on a number of principles to be adopted for inclusion of preparations containing solanaceous plants and alkaloids in Schedule 2. As a consequence, the Schedule 2 entry for hyoscine was amended to specifically exclude hyoscine butylbromide.

In June 2002, the NDPSC considered an application to amend the wording of the Schedule 2 entry for hyoscine butylbromide to increase the dosage per unit from 10 mg to 20 mg or less of hyoscine butylbromide and to amend the pack size from 20 or less dosage units to 200 mg or less of hyoscine butylbromide. The Committee agreed to amend the Schedule 2 entry on the basis of a long history of safe use and there being no significant safety concerns with hyoscine butylbromide at the current Schedule 2 dose and pack size.

In February 2005, the NDPSC considered the harmonisation of the scheduling of hyoscine butylbromide with New Zealand. The New Zealand Medicines Classification Committee (MCC) expressed reservations with regards the down scheduling of hyoscine butylbromide to Schedule 2, with the need for consultation over abdominal pain. MCC members agreed that misdiagnosis was easy and there was a danger, even with a 4-day pack, that the product could be used for acute appendicitis, renal stones or gastric ulcers and that bowel problems could be masked. There were also concerns associated with cardiac arrhythmia and glaucoma and with interactions with other medicines. The Trans-Tasman Harmonisation Working Party's advice to the NDPSC was that, having regard to the established safety in use of products containing hyoscine butylbromide over an extensive period and in the interests of harmonisation, the New Zealand Ministry of Health reconsider harmonisation of scheduling with the Poisons Standard. The Committee accepted the Working Party's advice and agreed to recommend to the New Zealand Ministry of Health that the scheduling of hyoscine butylbromide be harmonised with Australia.

In October 2007, the NDPSC considered a proposal to amend the Schedule 2 entry of hyoscine butylbromide to increase the pack size restriction from 200 mg to 500 mg and remove the single active substance restriction from the Schedule 2 entry. The Committee rejected the proposal after consideration of public consultation and an expert evaluation report and that RASML should be contacted to include a warning label on all anticholinergic products including hyoscine butylbromide.

Australian regulations

• According to the TGA Database, hyoscine butylbromide is:
  • Available for use as an active ingredient in: Biologicals, Export Only, Over the Counter and Prescription Medicines;
  • Available for use as an excipient ingredient in: Biologicals, devices, Prescription Medicines; and
  • Not available as an equivalent ingredient in any application.
• There are eighteen (18) medicines as of 31 May 2018 active on the Australian Register of Therapeutic Goods (ARTG) containing hyoscine butylbromide as an active ingredient. These include six (6) prescription and twelve (12) non-prescription medicines.
• Hyoscine butylbromide is not permitted to be included in listed medicines as it is not included in the current Therapeutic Goods (Permissible Ingredients) Determination No.4 of 2019 (the Determination)^[109]. However, hyoscine and hyoscyamine are in the Determination as follows:

  Item	Ingredient name	Purpose	Specific requirements
  2634	HYOSCYAMUS LEAF DRY	A, H	Alkaloids calculated as hyoscyamine and hyoscine are mandatory components of Hyoscamus leaf dry. The concentration of alkaloids calculated as hyoscyamine in the medicine must be no more than 300 micrograms/Kg or 300 micrograms/L or 0.00003%. The concentration of hyoscine in the medicine must be no more than 300 micrograms/kg or 300 micrograms/L or 0.00003%.
  2635	HYOSCYAMUS LEAF POWDER	A, H	Alkaloids calculated as hyoscyamine and hyoscine are mandatory components of Hyoscamus leaf powder. The concentration of alkaloids calculated as hyoscyamine in the medicine must be no more than 300 micrograms/Kg or 300 micrograms/L or 0.00003%. The concentration of hyoscine in the medicine must be no more than 300 micrograms/kg or 300 micrograms/L or 0.00003%.
  2636	HYOSCYAMUS NIGER	A, H	Alkaloids calculated as hyoscyamine and hyoscine are mandatory components of Hyoscyamus niger. The concentration of hyoscyamine in the medicine must be no more than 3 micrograms/kg or 3 micrograms/L or 0.3%. The concentration of hyoscine in the medicine must be no more than 300 micrograms/kg or 300 micrograms/L or 0.00003%.
  A = active ingredient for a medicine has the same meaning as in the Regulations H = homoeopathic preparation ingredient meaning an ingredient that is a constituent of a homoeopathic preparation

• The Prescribing medicines in pregnancy database^[110] classifies hyoscine-N-butylbromide as:

  Drug name	Category	Classification Level 1	Classification Level 2	Classification Level 3
  Hyoscine-N-butylbromide	B2	Alimentary System	Antispasmodics	-
  Hyoscine-N-butylbromide	B2	Cholinergic and Anticholinergic Agents	-	-
  Category B2 - Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage.

• The Medicines Advisory Statement Specification 2019 (RASML No. 5 - Schedule 1)^[111] does not specifically list hyoscine butylbromide. However, hyoscine, hyoscyamine and Hyoscyamus niger require the following warning statements to be included on the labelling:

  Column 1 Substance(s)	Column 2 Conditions	Column 3 Required statements(s)
  Hyoscine	In preparations for oral use, EXCEPT where indicated exclusively for the treatment of motion/travel sickness	If the condition persists after two days of treatment, seek medical advice as soon as possible.
  Hyoscyamine	In preparations for oral use, EXCEPT where indicated exclusively for the treatment of motion/travel sickness	If the condition persists after two days of treatment, seek medical advice as soon as possible. Do not use during pregnancy or breastfeeding unless advised by your doctor or pharmacist
  Hyoscyamus niger	In preparations for oral use, EXCEPT where indicated exclusively for the treatment of motion/travel sickness	If the condition persists after two days of treatment, seek medical advice as soon as possible.

• The Database of Adverse Event Notifications (DAEN)^[112] contains 205 reports of adverse events for products containing hyoscine butylbromide as an active ingredient, with 102 reports where hyoscine butylbromide was the single suspected medicine. There was one (1) report of death associated with hyoscine butylbromide use.
• As of 31 May 2019, there is one (1) hyoscine butylbromide active constituent approval (XXXXX) and one product (XXXXX) containing hyoscine butylbromide listed on the Public Chemical Registration Information System Search (PUBCRIS).

International regulations

Hyoscine butylbromide preparations are currently available in 41 countries worldwide.^[113] Hyoscine butylbromide was first registered in Germany in 1951 and became commercially available in 1952. Since then, it has become a widely available medication worldwide, both as a prescription drug and an OTC medicine in several countries.^[114] Hyoscine butylbromide is currently registered as an OTC product in Belgium, Germany, Italy, Luxembourg, the Netherlands, Spain, Switzerland, the United Kingdom (UK), Argentina, Colombia, Mexico, Venezuela, Japan and South Korea.^[115]

• Hyoscine butylbromide is on the World Health Organisation's Model List of Essential Medicines^[116] in Section 2.3 Medicines for other common symptoms in palliative care (Injection: 20 mg/mL).
• The European Chemicals Agency (ECHA)^[117] hazard classification and labelling for hyoscine butylbromide is as follows: 'Danger....this substance is harmful if swallowed, is harmful if inhaled and causes serious eye damage.'
• Hyoscine butylbromide is not available in the United States.
• Injectable hyoscine butylbromide is included on Health Canada's Prescription Drug List for both human and veterinary use with the qualifier, 'when recommended for parenteral use'. Hyoscine butylbromide non-injectable is also available as an 'ethical' medicine for human use,^[118] i.e. a drug that does not require a prescription, but is generally prescribed by a medical practitioner.^[119]
• In the UK, hyoscine butylbromide, as XXXXXXXXXXXX, is included in the 'General sales List (GSL)' and is available off the shelf in a variety of shops including newsagents, convenience stores, petrol stations etc.(i.e. no pharmacy training is required to sell). Hyoscine butylbromide, as XXXXXXXXXXXXX only available as a Pharmacist medicine.^[120]

Summary of pre-meeting public submissions

In response to the notice published under regulation 42ZCZK advising of the proposed amendment, three (3) submissions were received. One (1) submission supported the amendment and two (2) submissions opposed the amendment.

The main points provided in support of the proposed amendment were:

• This amendment provides for a set amount of liquid (in undivided oral doses) hyoscine butylbromide per pack to be available within Schedule 2. This aligns with the current scheduling of oral tablet formulation and enhances access without a prescription to a liquid formulation for treatment of abdominal cramping and pain.

The main points provided in opposition to the proposed amendment were:

• In New Zealand, hyoscine butylbromide in the forms and amounts equivalent to Schedule 2 in Australia are classified as Restricted. While there were not major concerns about the inherent safety of the substance, the scheduling of hyoscine butylbromide across the two countries was not harmonised in 2005 as the New Zealand regulator was concerned about "the very broad indication for abdominal pain" and felt "there should be an opportunity to refer consumers to a medical practitioner if they were suffering from abdominal pain".^[121]
• Due to its physicochemical characteristics, hyoscine butylbromide cannot readily cross the blood-brain barrier and is therefore associated with a lower frequency of central nervous system side effects. Nevertheless, there are reported cases^[122],^[123] of intentional misuse of hyoscine butylbromide (in tablet form) through crushing and smoking for its hallucinogenic effects. The Product Information for a registered product of hyoscine butylbromide also states that it may cause drowsiness.^[124] The liquid form may be considered a more convenient option by those who intentionally misuse the product.
• The TGA-approved indications for the currently marketed products that contain hyoscine butylbromide include for the treatment of spasm of the gastrointestinal tract. In severe cases, unexplained abdominal pain can persist or worsen or can occur together with symptoms like fever, nausea, vomiting, changes in bowel movements, abdominal tenderness, decreased blood pressure, fainting or blood in stool. In these cases, medical advice should immediately be sought.
• The currently marketed product containing the substance states that the tablets are not recommend for children under 6 years of age. Given that consumers will assume that a liquid presentation is especially formulated for children, the public submission notes that they do not believe that it would be appropriate for this product to be Schedule 2.
• While there is probably little potential for abuse of this substance, there may be a potential for inadvertent misuse as was seen with the infant colic drops, which were the subject of the Australian Prescriber article 'Dosing errors with XXXXXXXXXXXXX'.^[125] Given there is currently no product registered on the ARTG there is no compelling reason to down-schedule hyoscine butylbromide from Schedule 4. Therefore, the current scheduling remains appropriate.
• Oral liquid dose form of hyoscine butylbromide may be of benefit for paediatric and elderly patients, or other patient groups with dysphagia and difficulty swallowing the tablet formulation. However, these are regarded as more vulnerable population groups where the risk of adverse effects is higher and professional intervention would be beneficial to ensure patient safety and quality use of medicines.
• A preference for pharmacist oversight in the handling and provision of liquid preparations of hyoscine butylbromide is indicated. Therefore, inclusion of liquid oral preparations of hyoscine butylbromide with a recommended single dose not exceeding 20 mg of hyoscine butylbromide in a pack containing 100 mg or less of hyoscine butylbromide should be included in Schedule 3 rather than Schedule2.

Summary of ACMS advice/recommendations to the Delegate

The Committee recommended that a new Schedule 3 entry for undivided preparations of hyoscine butylbromide be created in the Poisons Standard as follows:

The Committee also recommended an implementation date of 1 June 2020.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

52E(1) Considerations	Reasons
a - the risks and benefits of the use of a substance	Hyoscine butylbromide has a favourable benefit-risk profile and has proven to be safe and effective in treatment. It has low absorption and bioavailability after oral administration and therefore minimal side effects. It also has short elimination half-life therefore any side effects are mild and short lived. Making the agent available in a liquid form as a Schedule 3 medicine is unlikely to impact the risk-benefit profile significantly. To maximise safe use of hyoscine butylbromide, access to advice from a pharmacist should be available as per Schedule 3 medicines. There is a risk of hyoscine butylbromide masking more serious medical conditions. This risk can be minimised through pharmacist-consumer consultation.
b - the purposes for which a substance is to be used and the extent of use of a substance	Hyoscine butylbromide is used for the treatment of abdominal pain and discomfort in adults and children, irritable bowel syndrome and dysmenorrhoea.
c - the toxicity of a substance	Hyoscine butylbromide is well tolerated following oral administration due to its low oral bioavailability with no clinically significant differences between tablets and liquid. There is a low frequency of adverse events.
d - the dosage, formulation, labelling, packaging and presentation of a substance	There is a potential that consumers may assume that a liquid preparation of hyoscine butylbromide is intended for young children. There is no evidence for hyoscine butylbromide use in those less than 6 years.
e - the potential for abuse of a substance	There are minimal isolated reports of abuse of hyoscine butylbromide in prison populations.
f - any other matters that the Secretary considers necessary to protect public health	Functional gastrointestinal disorders are common in children. Australian clinicians have reported that there is parental pressure to find an immediate cure (Journal of Paediatrics and Child Health 55 (2019) 1063-1069), which in turn increases the risk of potential likelihood of inappropriate use of a liquid preparation of hyoscine butylbromide in children.

Delegate's considerations

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to hyoscine butylbromide;
• Advisory Committee on Medicines Scheduling's advice;
• The public submissions received by the first closing date;
• Section 52E of the Therapeutic Goods Act 1989, in particular (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, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• Scheduling Handbook (V 1.1, July 2019).

Reasons for the interim decision

I agree with the Committee's finding that the relevant matters of section 52E of the Therapeutic Goods Act 1989 are: (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, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the Scheduling Factors for Schedule 2 and 3.

I have made an interim decision to amend the Poisons Standard by creating new Schedule 3 and 4 entries for hyoscine butylbromide and I have set out my reasons below.

I have taken into consideration that there are currently no Australian Register of Therapeutic Goods (ARTG) listed liquid preparations for oral use of hyoscine butylbromide. However, there are liquid ampoules containing 20 mg/mL hyoscine butylbromide for intravenous and intramuscular injections (Schedule 4 prescription medicines) on the ARTG.

I note that hyoscine butylbromide has been commercially available since 1952 and it is a well-tolerated medicine with a long history of worldwide over the counter experience. Side effects are uncommon, as hyoscine butylbromide has low absorption and bioavailability, does not cross the blood brain barrier and is not associated with central nervous system adverse effects as seen with other hyoscine compounds. Further, there are no clinically significant differences between hyoscine butylbromide tablets and liquid. However, on balance, I am of the opinion that undivided preparations of hyoscine butylbromide do not meet the Scheduling Factors for inclusion in Schedule 2 as there is no evidence for the use of hyoscine butylbromide in those aged less than 6 years. If hyoscine butylbromide were to be a Schedule 2 medicine available as a liquid form for oral use, I am concerned that consumers may assume that a liquid preparation is intended for use in young children to treat conditions such as functional gastrointestinal disorders (FGIDs), which are common in children.

I consider that undivided preparations of hyoscine butylbromide better meet the Scheduling Factors for Schedule 3, as it has a favourable risk-benefit profile. The availability of access to advice from a pharmacist via a Schedule 3 listing will ensure its safe and quality use. Further, the down-scheduling of the oral liquid to Schedule 3 will provide a significant benefit to more vulnerable patient groups with dysphagia and difficulty swallowing the tablet form.

I have also made a decision to create a new Schedule 4 entry for hyoscine butylbromide and to remove the reference to hyoscine butylbromide in in the Schedule 2 entry for hyoscine. I am of the view that as hyoscine butylbromide is specifically scheduled in Schedule 2, then it is potentially not captured outside of this by the Schedule 4 entry for hyoscine. By creating a specific Schedule 4 entry for hyoscine butylbromide in addition to the Schedule 2 and 3 entries, this will help provide clarity and remove ambiguity of the scheduling of hyoscine butylbromide outside the schedule entries of hyoscine.

As part of the review of the Scheduling Policy Framework (SPF), it was decided that advertising of medicines containing Schedule 3 substances should be permitted unless there was reason not to. In order for these medicines to be lawfully advertised, they need to be included in Appendix H of the Poisons Standard. Having considered the matters set out in the Guidelines for advertisements for medicines containing Schedule 3 substances I am satisfied that there are no foreseeable potential impacts on public health that would preclude advertising hyoscine butylbromide directly to consumers and have decided that it should be included in Appendix H.

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