1.2. Interim decision in relation to zolmitriptan

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

1.2. Interim decision in relation to zolmitriptan

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 zolmitriptan 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 Poisons Standard with respect to zolmitriptan was considered. The application proposed to amend the current Schedule 4 entry and to create new Schedule 3, Appendix H and Appendix M entries for zolmitriptan.

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 (5HT₁ 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 zolmitriptan 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)^[21] Sweden (2008), and Germany (2006).^[22]
• Increasing the access to zolmitriptan 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 zolmitriptan for people suffering acute, episodic migraine.

Current scheduling status

Zolmitriptan 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 November 1997, the NDPSC #15 noted that the Australian Drug Evaluation Committee (ADEC) at its 193rd meeting, had recommended that zolmitriptan be approved for registration for the treatment of migraine, with or without aura. The NDPSC decided to include a new entry in the Poisons Standard for zolmitriptan in Schedule 4 (Prescription Only).

In June 2006, October 2006 and February 2007, the NDPSC considered proposals to reschedule sumatriptan (another triptan) 50 mg in packs of two from Schedule 4 to Schedule 3 for the treatment of migraine attacks. The Committee decided Schedule 4 remained appropriate for sumatriptan, noting this was not harmonised with New Zealand.

In October 2009, the NDPSC considered the scheduling of zolmitriptan following New Zealand's Medicines Classification Committee (MCC) reclassification of zolmitriptan 5 mg nasal spray to a restricted medicine in New Zealand (equivalent to Australia's Schedule 3 Pharmacist Only Medicine). The NDPSC decided the scheduling of zolmitriptan in Schedule 4 remained appropriate, noting this was not harmonised with New Zealand.

Australian regulations

• According to the TGA Ingredient Database,^[23] zolmitriptan 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
  • Not available as an Equivalent Ingredient in any application.
• There are nine (9) medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[24] that contain zolmitriptan as an active ingredient. These include nine (9) prescription medicines.
• Zolmitriptan 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.^[25]
• The Prescribing medicines in pregnancy database^[26] classifies zolmitriptan as:

  Drug name	Category	Classification Level 1	Classification Level 2	Classification Level 3
  Zolmitriptan	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)^[27] does not require warning statements pertaining to zolmitriptan to be included on the labelling as zolmitriptan is a Prescription Only Medicine and RAMSL is not applicable.
• The Database of Adverse Event Notifications (DAEN)^[28] contains 20 reports of adverse events for products containing zolmitriptan as an active ingredient, with 13 reports where zolmitriptan was the single suspected medicine. There were no reports of deaths associated with zolmitriptan use.
• There are no products containing zolmitriptan listed on the Public Chemical Registration Information System Search (PUBCRIS).^[29]

International regulations

• In Canada, zolmitriptan (or its salts) is currently scheduled as a prescription drug and can be seen on Canada's Prescription Drug List for human use and veterinary use (with the effective date of 20 December 2013).^[30]
• In the United States (U.S.) zolmitriptan is approved by the Food and Drug Administration (FDA) as a human prescription drug and are available in oral tablet dosage forms.^[31] Zolmitriptan was first approved by the FDA in 1997.^[32]
• In Europe, zolmitriptan is nationally authorised in several countries^[33] as a migraine relief medication. In the United Kingdom (U.K), Zolmitriptan is available as a prescription medicine.^[34]
• The European Chemicals Agency (ECHA)^[35] hazard classification and labelling for zolmitriptan is as follows: 'Warning! According to the classification provided by companies to ECHA in CLP notifications this substance is harmful if swallowed, may cause damage to organs, causes serious eye irritation, causes skin irritation and may cause respiratory irritation.'
• In May 2009, New Zealand's Medicines Classification Committee considered zolmitriptan nasal spray at the 41st Meeting. The Committee's recommendation was to reclassify 5 mg zolmitriptan (single prefilled nasal spray) from prescription medicine to restricted medicine when sold in packs approved by the Minister or the Director-General for distribution as a restricted medicine. This recommendation was also to align with the over the counter (OTC) classification of sumatriptan (another triptan).^[36] Zolmitriptan as a nasal spray became pharmacist-only medicine in New Zealand in February 2010.^[37]
• In New Zealand, zolmitriptan, in the Medsafe Classification Database, is currently classified as a prescription medicine except when specified in as a restricted medicine (equivalent to Schedule 3) as follows:^[38]
  • Zolmitriptan in a pre-filled nasal spray device containing not more than 5 milligrams of zolmitriptan, for the acute relief of migraine attacks with or without aura in patients who have a stable, well-established pattern of symptoms and when sold in a pack of not more than 2 devices approved by the Minister or the Director-General for distribution as a restricted medicine.

Summary of pre-meeting public submissions

In response to the notice published under regulation 42ZCZK advising of the proposed amendment, four (4) submissions were received. Three (3) 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:

• Zolmitriptan has been on the Australian market for many years and is a safe and effective substance. The adverse effect profile of zolmitriptan is well described and the lack of overt risk of harm from zolmitriptan use is supported by toxicological information and guidance publicly available online through the US National Library of Medicine Toxnet database (on toxicological data for related sumatriptan)^[39] and the New Zealand National Poisons Centre TOXINZ database^[40]. TOXINZ notes that "No toxic dose for zolmitriptan has been established. The highest single dose used in clinical trials was 50 mg in healthy subjects producing sedation in some cases".
• It would be appropriate for consumers to access zolmitriptan under the Schedule 3 Appendix M criteria. The Appendix M criteria will ensure that consumers who have previously been diagnosed and treated with a triptan will be able to purchase from a pharmacy without prescription if they have been previously been diagnosed by a medical practitioner and trialled the substance.
• 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 or zolmitriptan to an appropriate selection of people would minimise delays in treatment and improve health outcomes.
• Down-scheduling will provide safe and timely access to zolmitriptan for people suffering acute, episodic migraine.

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

• The XXX 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 believes that zolmitriptan 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. In many overseas countries, triptans have been safely and effectively rescheduled to non-prescription status for use in patients who have well established and stable pattern of symptoms of migraine attacks. However, they have concerns over the apparent lack of preparatory work on an appropriate pharmacist training package and without discussions with the applicant are unable to comment on the suitability of an Appendix H entry for zolmitriptan.

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 (see table below noting it is for sumatriptan exposures):

  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 Known 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 zolmitriptan be amended and new Schedule 3 entry be created in the Poisons Standard. The Committee advised that the Delegate consider the appropriateness of Appendix H.

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	Benefits Zolmitriptan provides effective treatment for acute episodic migraine Requires accurate diagnosis, exclusion of contraindications and interactions and proper follow up 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 zolmitriptan, 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 headaches
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	2.5-5 mg of zolmitriptan tablets for acute attacks May repeat dose if symptoms recur. Dose is not to be repeated if the first dose is ineffective Maximum daily dose of 10 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 zolmitriptan 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 zolmitriptan;
• 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 provisions 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 3 and 4.

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

Zolmitriptan 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 zolmitriptan to Schedule 3 would improve timely access for patients with a confirmed diagnosis of migraine, thereby improving patient outcomes.

I find that zolmitriptan 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 zolmitriptan 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 zolmitriptan is used inappropriately. The use of zolmitriptan 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 zolmitriptan and other drugs. However, on balance, I consider the risk profile of zolmitriptan 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, 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 zolmitriptan to be provided by a pharmacist through inclusion in Appendix M may be relevant. However, I find that on balance, zolmitriptan 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 zolmitriptan in Appendix M.

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