1.7. Interim decision in relation to Lidocaine

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

1.7. Interim decision in relation to Lidocaine

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 lidocaine 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 amend the Schedule 2 entry for lidocaine in the Poisons Standard 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:

• Lidocaine 0.6% throat sprays can appropriately be classified as 'exempted from scheduling' as set out in the Scheduling Handbook.
• Lidocaine 0.6% throat sprays can be supplied with reasonable safety and without any access to health professional advice on the same basis that lidocaine throat lozenges are currently available at higher doses without access to health professional advice.
• The proposed amendment meets and exceeds all of the factors for Schedule 2.
• There are legitimate reasons for people to prefer the use of a low-dose spray in preference to a lozenge in relieving the pain of a sore throat.
• Changing the classification of lidocaine 0.6% throat sprays to unscheduled will allow people to choose between those dose forms without having to visit a pharmacy.

Current scheduling status

Lidocaine is currently listed in Schedules 2, 4 and 5 of the Poisons Standard as follows:

There are other local anaesthetics listed in the Poisons Standard as follows:

Scheduling history

The TGA is currently harmonising medicine ingredient names and are updating some medicine ingredient names used in Australia to align with names used internationally. Lidocaine was previously scheduled under the name lignocaine. As a result, the two names are used interchangeably in the scheduling history.

In November 1987, the Drugs and Poisons Schedule Committee (DPSC) recommended that a new Schedule 4 entry for lignocaine be created given that the proposed use of a cream product (2.5% lignocaine and 2.5% prilocaine) requires medical supervision and approval. The Committee also noted that the similar substance, prilocaine was already listed in Schedule 4. There is no information available on when lignocaine was first entered into Schedule 2 of the Poisons Standard.

In August 1994, the National Drugs and Poisons Schedule Committee (NDPSC) considered a request to review the clarity of the definition of 'topical use' and 'internal use' as they apply to local anaesthetic substances. Lignocaine preparations could be classified as both for topical use, as they produce a localised effect, and as internal use, as most can only be administered orally. The Applicant raised concern that while these products should be classified as Schedule 2 ('LIGNOCAINE preparations for topical use, other than eye drops, containing 10% or less of local anaesthetic substance'), they may also be considered as Schedule 4 (entry wording not found in historical documents) as lignocaine products are used on areas of the body to which the definition topical and internal use apply. The Committee noted that the definition for internal use does not preclude topical use. It is this anomaly that the Committee agreed required further consideration pending advice from the states and territories.

In February 1998, the NDPSC considered a submission for the rescheduling of dermal preparations containing one (1) per cent or less of lignocaine in packs of 30 g or less from Schedule 2 to unscheduled. Noting that 14 out of 15 products containing ≤1% of lignocaine present on the Australian Register of Therapeutic Goods (ARTG) had 'grandfathered' status, for which indications for use were not included on the ARTG and considering the adverse reaction profile of lignocaine, the Committee decided that based on the use pattern at that time, lignocaine should remain a scheduled substance. This decision was affirmed in May 1998 following the Committee's reconsideration of the Applicant's comments, and subsequent examination of public comments.

In February 2001, the NDPSC decided to amend the Schedule 2 and Schedule 4 entries for lignocaine so that the entries were expressed in terms of total local anaesthetic substances. The Committee also considered and agreed to a recommendation from the Trans-Tasman Harmonisation Working Party that two (2) per cent lignocaine or less in dermal preparations should be exempted from scheduling.

In February 2002, the NDPSC reviewed all the local anaesthetic substance entries in the Poisons Standard to ensure that all cut-offs are defined in terms of the total local anaesthetic substance content for consistency. The rationale was to ensure that the cut-offs were consistent and defined in terms of the 'total local anaesthetic substance' content. Following examination of entries for local anaesthetic substances, the Committee noted that the entries appeared to have the appropriate cut-off definition and that no further action was required.

In October 2008, the NDPSC considered a proposal to broaden the Schedule 2 exemption for lidocaine for dermal use (at 2% or less) to also include use on gums. The application was based around a teething gel containing 2% choline salicylate combined with 0.5% lignocaine. The Committee decided to retain the current Schedule 2 entry based on concerns around the potential for over-use and possible adverse effects in infants and young children.

Australian regulations

Lidocaine is an approved active ingredient in both veterinary and human medicines, with a long history of use.

• According to the TGA Ingredient Database,^[126] lidocaine (lignocaine) and is:
  • Available for use as an Active Ingredient in: Biologicals, Export Only, Over the Counter, Prescription Medicines;
  • Available for use as an Excipient Ingredient in: Biologicals, Devices, Prescription Medicines; and
  • Available for use as an Equivalent Ingredient in: Prescription Medicines.
• There are 188 products containing lidocaine, lidocaine hydrochloride and lidocaine hydrochloride monohydrate for therapeutic use currently active on the Australian Register of Therapeutic Goods (ARTG).^[127] Of these 188 products, 38 are prescription medicines and 94 are non-prescription medicines. The formulation types include spray (aerosol), ointment, gel, lozenges, dermal patches, medicated dressings, cream, pellets, lotion, liquid, jelly and injectables.
• There are 18 lozenge/throat spray products listed on the Australian Register of Therapeutic Goods^[128] (ARTG) as of January 2019. These products contain up to 30 mg lidocaine per lozenge and all of these products are unscheduled. XXXXXXXXXXXXXXXXXXX at 0.78 mg lidocaine per spray remains the only spray product on the ARTG and this product is currently in Schedule 2.
• Lidocaine is not permitted to be used in listed medicines as it is not included in the current Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2019.^[129]
• The Prescribing medicines in pregnancy database^[130] classifies lidocaine as:

  Drug name	Category	Classification Level 1	Classification Level 2	Classification Level 3
  Lidocaine	A	Cardiovascular System	Antiarrhythmics	-
  Lidocaine	A	Drugs Used in Anaesthesia	Local anaesthetics	-
  Lignocaine (lidocaine)	A	Cardiovascular System	Antiarrhythmics	-
  Lignocaine (lidocaine)	A	Drugs Used in Anaesthesia	Local anaesthetics	-
  Category A - Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.

• The Medicines Advisory Statement Specification 2019 (RASML No. 5 - Schedule 1)^[131] requires the following warning statements pertaining to lidocaine to be included on the labelling:

  Substance	Conditions	Required statements
  Lidocaine (Lignocaine) (Entry 1 of 3)	In dermal preparations containing MORE THAN 2 per cent of total local anaesthetic substances	Do not apply to large areas of the body, except on the advice of a healthcare practitioner. If skin irritation occurs, discontinue use and seek advice from your doctor or pharmacist.
  Lidocaine (Lignocaine) (Entry 2 of 3)	In dermal preparations containing 2 per cent OR LESS of total local anaesthetic substances	If skin irritation occurs, discontinue use and seek advice from your doctor or pharmacist.
  Lidocaine (Lignocaine) (Entry 3 of 3)	In lozenges	Do not take hot food or drink if the mouth feels numb after taking this product as it may burn the mouth. Do not give to children under 6 years of age, unless recommended by a doctor, pharmacist or dentist.

• The Database of Adverse Event Notifications (DAEN)^[132] contains 906 reports of adverse events for products containing lidocaine as an active ingredient, with 511 reports where lidocaine was the single suspected medicine. There were 16 reports of deaths associated with lidocaine use.
• There are seventy five (75) products containing lidocaine listed on the Public Chemical Registration Information System Search (PUBCRIS).^[133] Twenty-three products contain lidocaine as an active constituent.

International regulations

• In the United States (U.S), lidocaine is available in general sale, over the counter (OTC) and prescription medicines. In January 2016, the US Food and Drug Administration (FDA) issued a warning that prescription oral viscous lidocaine two (2) per cent solution should not be used to treat infants and children with teething pain.
• In the United Kingdom (U.K):
  • Lidocaine is available in general sale, OTC and prescription medicines. In December 2018, it was announced that all oral lidocaine-containing products for infant teething are only to be available under the supervision of a pharmacist; and
  • During the period 01 August 2014 to 31 July 2017, patient exposure to amylmetacresol, 2,4-dichlorobenzyl alcohol and lidocaine (XXXXXXXXXXXXXXXXXXXXXXXXXXXXX) estimated as XXXXXXXX patients (XXXXXXXX patients exposed to lozenge formulations and XXXXXXX patients exposed to spray formulations). XXXXXXXXXXXXXXXXXXXXXXXXXX holds the marketing authorisation for amylmetacresol, 2,4-dichlorobenzyl alcohol and lidocaine in XX countries. During the reporting period, there has been no marketing authorisation withdrawal, revocation or suspension; no failure to obtain marketing authorisation renewal; no restrictions on distribution; no clinical trial suspension; no dosage modification, no changes in target populations or indications and no formulation changes due to safety reasons.
• In New Zealand (Medicines and Medical Devises Safety Authority (MEDSAFE)), lidocaine is available in general sale, OTC and prescription medicines. Lidocaine is classified as general sale in New Zealand in throat sprays containing two (2) per cent or less of lidocaine.
• In Canada, there is one (1) active spray formulation containing lidocaine. It is available OTC at a concentration of 100 mg/mL (ten (10) per cent).

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:

• The amendment will allow unscheduled access to lidocaine 0.6% topical aqueous spray. Lidocaine throat lozenges are currently available at higher dose limits without access to health professional advice.
• Lidocaine 0.6% throat spray offers an alternative method of delivery for people who prefer a choice of formulation without having to visit a pharmacy.

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

• The current scheduling for lidocaine remains appropriate given the potential dangers of this liquid preparation if available outside a pharmacy. As noted in the article 'Lidocaine toxicity',^[134] lidocaine is not without the potential for serious side effects. Applied either by injection, inhalation or as a topical agent to provide anaesthesia, lidocaine has a good safety margin before reaching toxic blood levels. However, since it can be applied in various forms to the same patients, care must be taken to keep track of the total dose given to minimise its systemic toxicity. Lidocaine toxicity not only is determined by the total dose (usually 4.5 mg/kg), but also by the rate of absorption, which is dependent on the blood flow of that tissue.
• There is an assumption that because lidocaine is available in lozenges that it is as safe when it is available as a liquid preparation. Consumers also assume that just because a product is available in a non-pharmacy retail outlet then the product must be safe. However, it is very much easier to overdose with a liquid preparation that it is with a slowly dissolving oral lozenge, especially when considering access by younger children.
• There is greater potential for overdose with a liquid formulation compared to a box of lozenges and it is unlikely that labelling, packaging and presentation would prevent misadventure, especially for young children.
• The use of lidocaine in throat sprays warrant additional vigilance as inadvertent misuse or overuse of topical lidocaine by the general population or use by people with methaemoglobinaemia, even at commonly accepted doses, can have significant negative outcomes. Throat sprays could also be regarded to be more susceptible to unintentional misuse or overuse because of the ease of administration of multiple doses.
• Safe and timely access to medicines is important for consumers. However, a medicine should not be deregulated on the basis that people will be able to choose between different dose forms "without having to visit a pharmacy".
• There are international reports that state that there is a demand for local anaesthetics for use in cutting illegal drugs. In an article by the BBC,^[135]'Mild anaesthetics, found in sunburn and first-aid treatments bought at any chemist, are the latest substances being sought by drug dealers'. Whilst lidocaine is available in lozenges, one would assume that in a liquid preparation if would be easier

Summary of ACMS advice/recommendations to the Delegate

The Committee recommended that the current Schedule 2 entry for lidocaine be amended in the Poisons Standard as follows:

Schedule 2 - Amend Entry

LIDOCAINE in preparations for topical use other than eye drops:

1. containing 10 per cent or less of total local anaesthetic substances, except:
   1. in dermal preparations containing 2 per cent or less of total local anaesthetic substances; or
   2. in aqueous sprays for oromucosal use containing 0.6 per cent or less of total local anaesthetic substances; or
2. in divided preparations containing 200 mg or less of total local anaesthetic substances, except in lozenges containing 30 mg or less of total local anaesthetic substances per dosage unit.

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; and (e) the potential for abuse of a substance.

The reasons for the advice included:

52E(1) Considerations	Reasons
a - the risks and benefits of the use of a substance	Risks Low risk; adverse event reports of lidocaine show small numbers of adverse events. The risk of adverse events is related to the strength lidocaine in a product. Benefits The proposed scheduling is for a low strength, significantly lower than lidocaine lozenges containing 30 mg or less of total local anaesthetic substances that are currently exempt from scheduling. May be useful for people who would like to avoid lozenges for reasons such as convenience and avoidance of sugar/artificial sweeteners.
b - the purposes for which a substance is to be used and the extent of use of a substance	Lidocaine containing sprays are primarily indicated for relief of painful sore throat. However, the products are registered for additional indications such as mouth and dental ulcers, discomfort associated with tonsillitis and pharyngitis and relief of the symptoms of inflammation.
c - the toxicity of a substance	Lidocaine can result in significant toxicity when swallowed and effects are dose dependent. There have been reports of central nervous system effects, seizures and death in children and adults after ingestion of topical solutions and after use of viscous preparations in the mouth. However, spray preparations are low strength (0.6% in this case) and the amount delivered per actuation is very small (0.78 mg), which is a factor that mitigates against risk and overdose
d - the dosage, formulation, labelling, packaging and presentation of a substance	The product is a liquid spray, 20mL container with a directional nozzle. Labelling contains RASML warning statements. Product is labelled for painful sore throats and is also indicated for other conditions e.g. mouth and oral ulcers, tonsillitis and pharyngitis.
e - the potential for abuse of a substance	Low potential for abuse or misuse.
f - any other matters that the Secretary considers necessary to protect public health	Nil.

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 lidocaine;
• 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; and (e) the potential for abuse of a substance;
• 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; and (e) the potential for abuse of a substance.

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

I have made an interim decision to amend the Schedule 2 entry of lidocaine in the Poisons Standard and I have set out my reasons below.

I am of the view that lidocaine spray products containing up to 0.6 per cent lidocaine does not meet the Scheduling Factors for Schedule 2 and determine that it is able to be supplied, with reasonable safety, without any access to health professional advice. While lidocaine can result in significant toxicity when swallowed, effects are dose dependent. I have considered that spray products containing up to 0.6 per cent lidocaine have a good safety profile that is comparable to the currently available unscheduled lozenges containing up to 30 mg lidocaine.

I note that two pre-meeting public submissions did not support the scheduling proposal on the basis of concerns that a liquid formulation is more likely to cause misadventure or overdose compared to lozenges, citing the risk of methaemoglobinaemia. However, the adverse effects that have been reported following oral use have involved the administration of solutions of 2 to 4 per cent. On balance, I am persuaded by the fact that an individual taking all actuations of a product containing lidocaine in quick succession would ingest approximately 1.44 g of lidocaine base. This is well within the maximum recommended daily dose for oromucosal uses of 2.4 g lidocaine. As such, I consider the toxicity risk low in this case. Further, the risk of children swallowing the whole contents of the bottle is low due to the packaging. Packaging is a directional nozzle and the product is currently exempted from compliance with Therapeutic Goods Order No. 95 - Child-resistant packaging requirements for medicines 2017.^[136]

I also recommend the RASML entry for lozenges be updated to include 'lozenges and oromucosal sprays' to ensure that all labels for oromucosal spray preparations contain the required warning statements regarding hot food and drinks and contraindication against use in children under 6 years.

In making my decision, I acknowledge that while there are risks associated with lidocaine, I recognise that it has a long history of use. Further, given the restrictions on dosage form, route of administration, strength, packaging and warning statements, I am satisfied that there is low potential for abuse or misuse.

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