1.1. Interim decision in relation to sumatriptan

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

1.1. Interim decision in relation to sumatriptan

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 sumatriptan as follows:

Proposed date of effect of the proposed amendment

1 February 2021

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 amend the current Schedule 4 entry for sumatriptan and to create new Schedule 3, Appendix H and Appendix M entries for sumatriptan was considered.

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

The Applicant's main points provided in support of the proposed amendments were as follows:

• A fundamental requirement for the efficacy of triptans (5HT-1 agonists) in the acute treatment of migraine is to administer within one hour of the onset of migraine headache.
• The current restrictions in accessing these medications via prescription only, and the time delay in seeking a GP appointment, attending and then obtaining the required prescription (in addition to economic and physical access barriers) prevents these patients from achieving proper therapeutic benefit.
• Delay in treatment increases the risk of more severe and prolonged headache pain, increases risk of inappropriate simple analgesic use and risk of medication overuse headache, increases risk of progression to chronic migraine, and increases the economic and productivity costs to Australia.
• Pharmacists have appropriate skill and knowledge to appropriately assess the migraine symptoms and history of patients/consumers. They already support people experiencing migraine with advice and the provision of simple analgesics, however also being able to provide sumatriptan to an appropriate selection of people would minimise delays in treatment and improve health outcomes.
• The assessment and management of migraine, including treatment with triptans, is within the professional scope of practice - as is recognised through undergraduate education, post-registration professional development and practice, and the medication scheduling of triptans in comparable countries such as New Zealand, the United Kingdom (2006),^[1] Sweden (2008), and Germany (2006).^[2]
• Increasing the access to sumatriptan for acute migraine through rescheduling to Schedule 3 does not eliminate the availability through prescription from a person's general practitioner. Nor will it lead to the frequently decried 'fragmentation of care', with the obligations described in the proposed Appendix M statement.
• Down-scheduling will provide safe and timely access to sumatriptan for people suffering acute, episodic migraine.

Current scheduling status

Sumatriptan is currently listed in Schedule 4 of the Poisons Standard as follows:

Other triptans are listed in Schedule 4 of the Poisons Standard as follows:

Scheduling history

In August 1992, sumatriptan was first considered by the Drugs & Poisons Schedule Standing Committee (DPSSC) at the 66th meeting. The Committee noted that the 157th Australian Drug Evaluation Committee (ADEC) meeting recommended approval for the registration of sumatriptan for the acute relief of migraine. The Committee decided to include sumatriptan in Schedule 4 (Prescription Only). Sumatriptan tablets (XXXXXXX) were first marketed in Australia in 1992.

In June 2005, the NDPSC considered a proposal to include 2 tablets x 50 mg or less of sumatriptan from Schedule 4 (Prescription Only) to Schedule 3 (Pharmacist Only). The Committee decided that the scheduling of sumatriptan in Schedule 4 remained appropriate at that time. The Committee's action item was to refer sumatriptan to the following meeting if post-meeting comments were received.

In June 2006, the NDPSC considered a proposal to include oral preparations of 50 mg sumatriptan in packs of 2 tablets for the treatment of migraine attacks in Schedule 3 and Appendix H of the Poisons Standard. The Committee decided to defer a decision on the rescheduling of sumatriptan until advice had been sought from the XXXXXXXXXXXXXXXXXXXXXXXXXXXX.

In October 2006, the NDPSC considered a proposal to include oral preparations containing 50 mg or less of sumatriptan in packs containing 2 dosage units or less for the treatment of migraine attacks in Schedule 3 and Appendix H of the Poisons Standard. The Committee decided to defer a decision on the rescheduling and Appendix H listing of sumatriptan pending review of emerging safety data from the Adverse Drug Reactions Advisory Committee (ADRAC) regarding serotonin syndrome.

In February 2007, the NDPSC considered a proposal to include oral preparations containing 50 mg or less of sumatriptan in packs containing 2 dosage units or less for the treatment of migraine attacks in Schedule 3 and Appendix H of the Poisons Standard. The Committee decided that Schedule 4 remained appropriate given concerns, at the time, for the lack of a real public health need for increased access through down-scheduling and given the 'emergency supply' provisions already in place. The Committee noted that the scheduling of sumatriptan was not harmonised with New Zealand and that this was appropriate at the time.

Australian regulations

• According to the TGA Ingredient Database,^[3] sumatriptan is:
  • Available for use as an Active Ingredient in: Biologicals, Export Only, Prescription Medicines;
  • Available for use as an Excipient Ingredient in: Biologicals, Devices, Prescription Medicines; and
  • Available for use as an Equivalent Ingredient in: Export Only, Prescription Medicines.
• There are 45 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[4] that contain sumatriptan as an active ingredient. These include 40 prescription medicines and 5 export only medicines.
• Sumatriptan 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.^[5]
• The Prescribing medicines in pregnancy database^[6] classifies sumatriptan as:

  Drug name	Category	Classification Level 1	Classification Level 2	Classification Level 3
  Sumatriptan	B3	Cardiovascular System	Antimigraine preparations	-
  Category B3 - 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 have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.

• The Medicines Advisory Statement Specification 2019 (RASML No. 5 - Schedule 1)^[7] does not require warning statements pertaining to sumatriptan to be included on the labelling as sumatriptan is a Prescription Only Medicine and RAMSL is not applicable.
• The Database of Adverse Event Notifications (DAEN)^[8] contains 682 reports of adverse events for products containing sumatriptan as an active ingredient, with 616 reports where sumatriptan was the single suspected medicine. There were four (4) reports of deaths associated with sumatriptan use.
• There are no products containing sumatriptan listed on the Public Chemical Registration Information System Search (PUBCRIS).^[9]

International regulations

• In the United States (U.S.) sumatriptan is approved by the Food and Drug Administration (FDA) as a human prescription drug. In the U.S., sumatriptan products are available in tablet, injection, subcutaneous injection and nasal spray/powder dosage forms.^[10] Sumatriptan (as sumatriptan succinate) was the first triptan approved by the FDA in 1992.^[11]
• In Canada, sumatriptan has been used in therapeutics since the 1990's. In the Index of Published Newsletters Government of Canada, sumatriptan (or its salts) can be seen in January 1995; 5(1) and August 1993; 3(1) Canadian Adverse Reaction Newsletter.^[12] Sumatriptan is currently scheduled as a prescription drug in Canada and can be seen on Canada's Prescription Drug List for human use and veterinary use, with the effective date of 19 December 2013.^[13]
• In the United Kingdom (U.K.), certain sumatriptan products (50 mg tablets) are available without prescription, while other products in different dosage forms (e.g. nasal spray or injections) are available as prescription medicines.^[14] In March 2005, sumatriptan was considered for reclassification to Pharmacy medicine by the Committee on Safety of Medicines (UK).^[15] Sumatriptan has been available without prescription in the United Kingdom since April 2006. Sumatriptan is an active ingredient in several nationally authorised products in Europe.^[16]
• The European Chemicals Agency (ECHA)^[17] hazard classification and labelling for sumatriptan is as follows: 'Danger! According to the classification provided by companies to ECHA in CLP notifications this substance causes serious eye damage, is suspected of damaging fertility or the unborn child and is harmful to aquatic life with long lasting effects.'
• In New Zealand, sumatriptan in the Medsafe Classification Database is currently classified as a prescription medicine except when specified as a restricted medicine as follows:^[18]
  • for oral use in medicines for the acute relief of migraine attacks with or without aura in patients who have a stable, well-established pattern of symptoms when in tablets containing 50 milligrams or less per tablet and when sold in a pack containing not more than 2 tablets that has received the consent of the Minister or the Director-General to its sale as a restricted medicine.
• In June 2005, the New Zealand Medicines Classification Committee (NZ MCC) 'felt that there was need for an alternative over-the-counter treatment for migraine. It was noted that sumatriptan was [at the time] under review in Australia for reclassification'. In June 2006, the NZ MCC considered the safety profile of sumatriptan (50 mg tablets) as investigated by the UK Medicines and Healthcare Products Regulatory Agency (MHRA). The Committee recommended at their 35th Meeting, the reclassification of sumatriptan from a prescription medicine to a restricted medicine (OTC).

Summary of pre-meeting public submissions

In response to the notice published under regulation 42ZCZK advising of the proposed amendment, five (5) submissions were received. Four (4) submissions supported the amendment, two (2) of these with caveats. One (1) submission opposed the amendment.

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

• A Schedule 3 entry with inclusion in Appendix M to ensure that the patient has had a formal diagnosis by a medical practitioner would be an appropriate change to scheduling. This would bring Australia into harmonisation with New Zealand where this substance has been available without prescription for some time without adverse consequences.
• The maximum quantity to be available under Schedule 3 will be 2 tablets of 50 mg, which will be sufficient for one episode of a migraine. This is the same as the quantity and strength available in New Zealand which has been available since at least 2007.
• The proposed Appendix M in which the pharmacist will verify the diagnosis of migraine by checking the patient's My Health Record for the prescription and dispensing of sumatriptan will adequately address the issue of migraine diagnosis by a pharmacist. If the patient does not have a My Health Record or has no previous prescription and dispensing of sumatriptan, they can attend a general practitioner for further investigation of their condition.
• The possibility of sumatriptan and serotonergic antidepressants causing serotonin syndrome is low and this submission argues that it can be managed by the pharmacist by completing Migraine Questionnaire and verifying other medicines a patient is using by consulting the patient's My Health Record.
• The use of the My Health Record to verify previous diagnosis of migraine and dispensing of sumatriptan is analogous to the Continued Dispensing^[19] option where a pharmacist can supply a PBS maximum quantity of a statin or oral contraceptive pill if the patient has previously been dispensed these medicines.
• Community pharmacies quite regularly have migraineurs who find themselves without a supply of sumatriptan. Pharmacists can provide these patients with such Schedule 3 preparations as metoclopramide + paracetamol (XXXXXXXX) or prochlorperazine (XXXXXX) but not sumatriptan. Further, the already available products under Schedule 3 for symptomatic treatment of migraine headaches largely aim to relieve nausea or vomiting associated with the headache, with paracetamol possibly only offering some relief against the headache itself. Having 50 mg x 2 tablets sumatriptan available as a Schedule 3 medicine would improve accessibility to this substance especially in after-hours situations or rural and remote areas where access to a GP is not possible.

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

• XXXXX supports increased access to zolmitriptan and sumatriptan for patients experiencing migraines. However, there should be safeguards to ensure that access to this medication does not delay more urgent care. For example, symptoms similar to those of a migraine may actually be the result of a brain tumour. There needs to be increased pharmacist education around how to accurately and confidently diagnose a migraine. Further, the new Schedule entries should specify a certain number of times a patient can purchase this medication until it is recommended to consult a medical practitioner.
• Overall, XXX believe sumatriptan can be included in Schedule 3 with additional controls. The proposed Appendix M controls are appropriate in mitigating the risks associated with the provision of this triptan without a prescription. However, there is an apparent lack of preparatory work on an appropriate pharmacist training package. Without discussions with the Applicant, we are unable to comment on whether advertising of sumatriptan is appropriate.

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

• NSW PIC regularly receive calls regarding exposures to triptan medications, and although not large in numbers, these calls are very likely to be symptomatic and require medical treatment. Over 60% of exposures to sumatriptan were symptomatic and 62 of the 92 exposures (67%) required medical treatment:

  Sumatriptan exposures 06.01.14 to 15.10.19 Count of Exposure type and symptoms of those exposures
  	Accidental	Adverse reaction	Deliberate-self poisoning	Intentional: other	Therapeutic error	Grand total
  Asymptomatic	10		6	2	10	28
  Not know if related	1	7	1			9
  Related symptomatic	5	13	21	1	8	48
  Symptoms unknown			3		1	4
  Unrelated symptomatic				1	2	3
  Grand total	16	20	31	4	21	92

• The ability of triptans to interact with other medications and existing medical conditions is likely to contribute to this increased incidence of symptomatic adverse reactions and poisoning exposures.
• Wider availability as a Schedule 3 product will see an increased use of triptans in the community and growth in these numbers of adverse reactions and poisoning exposures. The very real possibility exists that these exposures will increase disproportionally to usage as community awareness grows and patients begin self-prescribing.
• Current regulations which allow for emergency supply to patients who have a clear history of dispensing are sufficient to ensure those patients in need are able to safely access their regular medication in times of need without increasing risk to the community.

Summary of ACMS advice/recommendations to the Delegate

The Committee recommended that the current Schedule 4 entry for sumatriptan be amended and new Schedule 3 and Appendix H entries be created in the Poisons Standard as follows:

The Committee also recommended an implementation date of 1 February 2021.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) the 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 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 reasons for the advice included:

52E(1) Considerations	Reasons
a - the risks and benefits of the use of a substance	Benefits Sumatriptan provides effective treatment for acute episodic migraine Safe when used as directed Down scheduling would improve patient access, reduce treatment delay and improve patient quality of life Risks There are possible vascular side effects associated with sumatriptan, including rare cases of vasospasm related symptoms causing peripheral vascular ischemia, colonic ischemia. There is a risk of delayed diagnosis and treatment of depressive and anxiety disorders associated with migraine, contraindications, drug interactions, adverse effects such as dyspnoea, inaccurate/inappropriate assessment by pharmacist. Increased pharmacist knowledge and development of migraine questionnaire by pharmacist professional bodies will help to mitigate the above risks. Misuse by adolescents as efficacy of oral triptans has not been established in people aged 12-17 years. However, this risk will remain the same as prescribed by a medical practitioner.
b - the purposes for which a substance is to be used and the extent of use of a substance	Acute episodic migraine treatment Cluster headache
c - the toxicity of a substance	Contraindications: severe or uncontrolled hypertension ischemic heart disease coronary vasospasm cerebrovascular disease peripheral vascular disease basilar or hemiplegic migraine pregnant or at risk for pregnancy MAOI use used another triptan or ergotamine/dihydroergotamine in the previous 24hrs Drug interaction between triptans and selective serotonin reuptake inhibitors (SSRI)/selective norepinephrine reuptake inhibitor (SNRI), which can lead to serotonin syndrome. However, risk is low and recommendation is to monitor. Viewing patient medication history via My Health Record and the use of a 'Migraine Questionnaire' will help to mitigate this. Adverse effects: Cardiovascular effects mild and transient chest symptoms not associated with electrocardiogram (ECG) changes or enzymatic evidence of myocardial ischemia
d - the dosage, formulation, labelling, packaging and presentation of a substance	50-100 mg of sumatriptan tablets for acute attacks of migraine May repeat dose if symptoms recur. Dose is not to be repeated if the first dose is ineffective Maximum daily dose of 300 mg/24 hours
e - the potential for abuse of a substance	Overuse of triptans may be associated with medication overuse headache.
f - any other matters that the Secretary considers necessary to protect public health	Other Schedule 3 substances indicated for migraine are not in Appendix H Committee advised that Appendix M was not required as sumatriptan meets the scheduling factors for a Schedule 3 medicine.

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 sumatriptan;

• Advisory Committee on Medicines Scheduling's (ACMS# 28) advice;
• The public submission 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 provisions of section 52E of the Therapeutic Goods Act 1989 are: (a) the 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 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 3 and 4.

I have made an interim decision to amend the Poisons Standard by creating a new Schedule 3 entry for sumatriptan and I have set out my reasons below.

Sumatriptan is indicated for administration with migraine symptom onset and time critical access is crucial for management of the condition. I am of the view that the down-scheduling of sumatriptan to Schedule 3 would improve timely access for patients with a confirmed diagnosis of migraine, thereby improving patient outcomes.

I find that sumatriptan meets the Schedule 3 Scheduling Factors in that it is not expected to produce dependency at either the established therapeutic dose or at supratherapeutic doses. Where risk of misuse, abuse or illicit use is identified, the risk can be minimised through pharmacist-consumer consultation. I consider that sumatriptan is substantially safe with pharmacist advice, to ensure quality use under a Schedule 3 classification.

I have considered that there is the potential for harm and adverse effects if sumatriptan is used inappropriately. The use of sumatriptan at established therapeutic dosage levels may mask the symptoms or delay diagnosis of more serious conditions. Further, there is the potential for drug interactions between sumatriptan and other drugs. However, on balance, I consider the risk profile of sumatriptan is well defined and the adverse effects, interactions and contraindications are known, identifiable and manageable by a pharmacist and by the pack size limitation. I am of the view that risk reduction can be further mitigated by pharmacist counselling and if necessary verification of diagnosis by a medical practitioner.

I acknowledge that emergency supply provisions could be an option for timely migraine management. However, I am of the opinion that these provisions are more commonly used for conditions where other over the counter medications are not available. Whilst I find that a consumer is able to identify the ailments or symptoms of acute episodic migraine, I am of the view that the diagnosis, medical management or monitoring of this medical condition should be undertaken by a pharmacist before this substance is dispensed.

In making my decision, I have considered a recommendation that the pack size should be restricted, with the inclusion of appropriate warning and cautionary statements (such as possible contraindications and risk of serotonin toxicity with overuse) on product labelling. For this reason, I have made the decision that the Schedule 3 entry will be appropriate to mitigate the risk concerning overuse.

I have decided on an implementation date of 1 February 2021 to allow the opportunity for sponsors to adhere to regulatory change. In particular, this implementation date will provide sponsors the opportunity to align labelling requirements, Required Advisory Statements for Medicine Labels (RASML) statements to be developed and allow for the development of education and training material to be provided to pharmacists.

As part of the review of the Scheduling Policy Framework (SPF), it was agreed 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,^[20] I am satisfied that there are no foreseeable potential impacts on public health that would preclude advertising sumatriptan directly to consumers and have decided that it should be included in Appendix H.

I have considered that additional controls over access and training to enable sumatriptan to be provided by a pharmacist through inclusion in Appendix M may be relevant.However, I find that on balance, sumatriptan meets the Scheduling Factors for a Schedule 3 medicine in the SPF and the access controls in place for a Schedule 3 medicine are appropriate and sufficient to mitigate the risk of misuse. Therefore, I have made the decision not to include sumatriptan in Appendix M.

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