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Scheduling delegate's final decisions: ACCS/ACMS, November 2013

Scheduling medicines and poisons

8 November 2013

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Part A - Final decisions on matters referred to an expert advisory committee (ACCS-ACMS)

3. Scheduling proposals referred to the July 2013 joint meeting of the Advisory Committee on Chemicals Scheduling and Advisory Committee on Medicines Scheduling (ACCS-ACMS#6)

3.1 Hydroquinone and monobenzone

Scheduling proposal

The Chemicals and Medicines Scheduling Delegate (the Delegates) considered a considered a proposal to exempt from scheduling for gel nail preparation and dental bonding materials containing hydroquinone and monobenzone in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP).

The delegates' reasons for referring this proposal to the Advisory Committee on Chemicals Scheduling (ACCS) and Advisory Committee on Medicines Scheduling (ACMS) include:

  • This is a re-scheduling request with a long history of concern by former scheduling committees about the safety of products containing hydroquinone and its more potent methyl ether (Monobenzone) in therapeutic and cosmetic products, especially when used for skin whitening. The current re-scheduling application warrants consideration by a joint meeting of the ACCS and ACMS.

The delegates sought the following specific advice from the ACCS and ACMS:

  • Does the ACCS/ACMS agree that the risks associated with the use of hydroquinone and/or its methyl ethers as ingredients of nail hardening preparations are sufficiently slight that exemption of such products from the current Schedule 4 and Schedule 2 entries is warranted?
  • If so, what wording is recommended to achieve this outcome in the current Schedule 4 and Schedule 2 entries?
  • Noting that exemption from scheduling for nail hardening products would NOT exempt from the Warning Statements for hydroquinone in Appendix F, but would exempt First Aid labelling requirements included in Appendix E, does the ACCS/ACMS recommend any changes to Appendix E or F entries?
  • The NDPSC last reviewed toxicity concerns about hydroquinone in 2008 and 2009, introducing amendments that clarified the basis for exemptions for hair products containing less than 0.3 per cent, and reinforcing scheduling arrangements for external therapeutic and cosmetic products containing up to 2 per cent in Schedule 2, with all other therapeutic/cosmetic uses in Schedule 4. Has any new information become available since 2009 (e.g. the final USFDA rule) to support any change to current scheduling of hydroquinone?
  • To what extent can the information on hydroquinone be used to support scheduling of its methyl ether (MEHQ)?
  • Is there a need to clarify the Schedule 4 entries for monobenzone and hydroquinone? Monobenzone is the benzoyl ether of hydroquinone, and it was first included in Schedule 4 in 1969, with the current entry confirmed in 1987. The monobenzene entry currently lists monobenzone and other alkyl ethers of hydroquinone, even though monobenzone is NOT an alkyl ether. The hydroquinone Schedule 4 entry excludes alkyl ethers except where otherwise listed (e.g. in the monobenzone entry), so the submission is correct in stating that any concentration of the methyl ether (MEHQ) in a cosmetic preparation would be caught up in the Schedule 4 monobenzone listing. If specific exemptions are allowed from Schedule 4 for nail hardening preparations, does the monobenzone entry require parallel adjustment? Note that there are currently no First Aid or Warning Statements prescribed for monobenzone in Appendices E and F.
Substance details

Hydroquinone (incl. its methyl ethers (MEHQ)) is a reducing agent that oxidizes to form quinone in air. It is used in nail polish products to inhibit premature polymerisation of methylacrylate-based liquid of a two component polymer system. It is also used in topical drugs as depigmenting agents for the skin and in hair preparations as lightening agent.

Monobenzone is the monobenzyl ether of hydroquinone, not an alkyl ether, although it is scheduled as 'monobenzone and other alkyl ethers of hydroquinone' in Schedule 4. Due to its chemical nature, it is used in a similar manner with hydroquinone (above).

In June 2002, Scientific Committee on Cosmetic Products and Non-food Products Intended for Consumers (SCCNFP) considered MEHQ in artificial nail system and noted that little toxicological data (no data on genotoxicity/mutagenicity) was provided for either hydroquinone or hydroquinone methyl ether. Assumptions are made but are not corroborated with data. The analytical data for the residual hydroquinone and hydroquinone methyl ether in the finished nail is inadequate.

The SCCNFP concluded that, due to the very low exposure to the consumer, the risk is minimal.

In 2006, based on data regarding potential carcinogenicity and reports of ochronosis, the USFDA proposed to reclassify these skin bleaching products (specifically containing hydroquinone) as drugs and make them available by prescription only.

The applicant has not provided toxicity data.

Scheduling status

Hydroquinone is listed in Schedules 2, 4 and 6 and Appendices E and F.

Monobenzone is listed in Schedule 4.

Hydroquinone salts or derivatives which are not alkyl ethers of hydroquinone are likely to be captured under the current hydroquinone entries through Paragraph 1(2)(c) of the SUSMP which indicates that "every salt, active principle or derivative of the substance, including esters and ethers, and every salt of such an active principle or derivative" will be captured by a schedule entry unless the contrary intention appears.

Scheduling history

Hydroquinone was first included in Schedule 4 in 1969 by the Poisons Schedule Sub-Committee (PSSC). This listing was due to concerns raised about the promotion and free availability of skin lightening creams which were being targeted to the PNG and Indigenous Australian populations.

In February 1971, the PSSC agreed to amend the Schedule 4 entry for hydroquinone to allow an exemption from scheduling for preparations of hydroquinone containing ≤ 2 per cent.

In May 1986, the Drugs and Poisons Schedule Committee (DPSC) considered deleting the ≤ 2 per cent exemption i.e. all human use hydroquinone and monobenzone becoming Schedule 4. The DPSC considered the overall Adverse Drug Reactions Advisory Committee (ADRAC) profile for hydroquinone and monobenzone and recommended that these Substances warranted a Schedule 4 listing; however, this recommendation was not implemented.

In May 1987, the DPSC agreed to foreshadow creation of a new Schedule 2 entry for hydroquinone for human therapeutic or cosmetic use at ≤ 2 per cent (with an Appendix F Warning Statement). This was confirmed at the July 1987 meeting.

In June 2008, the NDPSC, following a request from the Over the Counter (OTC) Medicines Section of the TGA, gave consideration as to whether hydroquinone was appropriately scheduled. The NDPSC noted concerns about possible carcinogenicity of hydroquinone with prolonged usage.

In October 2008, the NDPSC foreshadowed consideration of the rescheduling of hydroquinone and possible up-scheduling hydroquinone in preparations for human external use (excluding hair dyes) to Schedule 3.

Hair preparations

In July 1987, the DPSC agreed to a general exemption from scheduling for ≤ 1 per cent hydroquinone in hair preparations.

In October 2008, the NDPSC noted that the European Union (EU) cut-offs for hydroquinone as an unapproved cosmetic ingredient (≤ 0.3 per cent in hair dyes) were more restrictive than the SUSMP controls (allowing ≤ 1 per cent).

In February 2009, the NDPSC considered a proposal to amend the exemption for use in hair dyes from 1 per cent to 0.3 per cent, in line with the European Union (EU) cut-offs. The NDPSC decided to amend the exemption for hair preparations containing hydroquinone from 1 per cent to 0.3 per cent or less.

Salts and derivatives

In May 1987, the DPSC noted that monobenzone was actually more potent than hydroquinone and agreed to foreshadow that it should be in Schedule 4, together with other derivatives of hydroquinone for human therapeutic or cosmetic use, with no exceptions (whereas hydroquinone had a Schedule 2 entry). The NDPSC also noted that the other ether derivatives of hydroquinone were more potent than hydroquinone and had a similar side effect level to monobenzone.

In July 1987, the DPSC amended the foreshadowed monobenzone entry by specifying capture of 'other alkyl ethers of hydroquinone for human therapeutic use or cosmetic use' rather than all derivatives. [No reason was recorded]. This remains the wording in the current monobenzone entry.

In February and June 2009, the NDPSC considered the scheduling of hydroquinone for therapeutic and cosmetic use. Both meetings supported deferring a decision on the scheduling of hydroquinone in skin bleaching products (for external therapeutic use) until the USFDA report was available.

Public pre-meeting submission

One public submission was received. The submission supported the proposal as the use as a polymerisation inhibitor in nail polish posed minimal risk to human health once the substances are exposed to UV/LED light. The redacted public submissions are available at Public submissions on scheduling matters referred to ACCS #8, ACMS #9 and the joint ACCS-ACMS #6 (July 2013).

ACCS & ACMS advice to delegates

The joint Committee recommended that the Schedules 2 and 4 hydroquinone and Schedule 4 monobenzone entries be amended to exclude cosmetic nail preparations containing 0.02 per cent or less from scheduling.

The joint Committee recommends an implementation date of 1 February 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included; (a) the risks and benefits of the use of a substance, (b) the purpose, (c) the toxicity of a substance, (d) the dosage, formulation, labelling, packaging and presentation of a substance and (e) the potential for abuse.

  • Risk is very low in cosmetic nail preparations because of the low concentration of hydroquinone and transient exposure.
  • Benefits associated with proper use of cosmetic nail preparations.
  • The purpose of the use of product is very specific.
  • Toxicity is low in the product at that concentration and deactivation on exposure to light mitigates toxicity.
  • No additional labelling is required.
  • Minimal potential risk.
Delegates' interim decision

The Delegates accept the advice of the Joint ACCS/ACMS meeting, that cosmetic nail preparations containing 0.02% or less of hydroquinone, methylhydroquinone or monobenzone should be exempted from the current entries in Schedules 2 and 4.

The proposed amendments to the current schedule entries recommended by the Committees are accepted.

The delegates considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 includes: (a) the risks and benefits, (b) purpose, (c) toxicity of a Substance.

  • Risk is very low in cosmetic nail preparations because of the low concentration of these polymerisation agents and the transient nature of their potential exposure.
  • This specific scheduling exemption relates only to use of these materials at low concentration in light-activated cosmetic nail preparations.
  • Toxicity at such a low concentration in the products is expected to be minimal and the concentration of the materials, and hence the toxicity, is expected to be further mitigated by deactivation on exposure to light.

It is noted that hydroquinone and methylhydroquinone may also be used in light-activated dental bonding materials. However a specific schedule exemption in Schedules 2 & 4 for such use is not required because of the general exemption for medical/veterinary adhesives, glues and cements in Appendix A.

Submissions on interim decision

One valid submission was supporting the interim decision. The submission asks for the implementation date to be brought forward to allow to benefit businesses who wish to sell these products. The redacted public submissions are available at Public submissions on scheduling matters.

Delegates' consideration

The delegate considered the following in regards to this proposal:

  • scheduling application (not publically available);
  • ACCS & ACMS advice;
  • section 52E of the Therapeutic Goods Act 1989;
  • scheduling factors20; and
  • other relevant information.
Delegate's final decision

The delegate has reviewed the public submissions and other evidence and has confirmed the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The ACCORD proposal to bring forward the implementation date of 1 Feb 2014 is not accepted. The date of publication of the SUSMP Amendment is the formal trigger for the States/Territories to amend their Poisons lists, and this publication date cannot be brought forward. The issue of monitoring compliance with Poisons legislation rests with the States and Territories.

Schedule entry
Schedule 2 - Amendment

HYDROQUINONE (excluding monobenzone and alkyl ethers of hydroquinone included in Schedule 4) in preparations for human external therapeutic or cosmetic use containing 2 per cent or less of hydroquinone except:

  1. In hair preparations containing 0.3 per cent or less of hydroquinone; or
  2. in cosmetic nail preparations containing 0.02 per cent or less of hydroquinone.
Schedule 4 - Amendment

HYDROQUINONE (other than its alkyl ethers separately specified in this Schedule) in preparations for human therapeutic or cosmetic use except:

  1. when included in Schedule 2; or
  2. in hair preparations containing 0.3 per cent or less of hydroquinone; or
  3. in cosmetic nail preparations containing 0.02 per cent or less of hydroquinone.
Schedule 4 - Amendment

MONOBENZONE and alkyl ethers of hydroquinone for human therapeutic use or cosmetic use except in cosmetic nail preparations containing 0.02 per cent or less of monobenzone or alkyl ethers of hydroquinone.

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3.2 Pradofloxacin

Scheduling proposal

The Chemicals Scheduling Delegate and the Medicines Scheduling Delegate (the delegates) considered a proposal to include pradofloxacin in Schedule 4 or Schedule 7. This proposal also includes if a Schedule 4 listing is appropriate for pradofloxacin, whether this entry should specify 'for the treatment of animals'.

The delegates sought the following specific advice from the Advisory Committee on Chemicals Scheduling (ACCS) and the Advisory Committee on Medicines Scheduling (ACMS):

  • Does the ACCS/ACMS support listing of pradofloxacin in Schedule 4 on the basis that veterinarian supervision of treatment is required?
  • If so, should the listing in Schedule 4 be restricted to 'animal use only'?
  • Does the ACCS/ACMS agree that toxicological issues (genotoxicity and developmental toxicity) raised in the 2006 evaluation have been adequately addressed in the current evaluation report, and in the European Medicines Agency (EMA) report?
  • If not, does the ACCS/ACMS consider that a more restrictive schedule (e.g. S7) would be more appropriate for pradofloxacin?
  • Although no longer a matter for scheduling consideration, does the ACCS/ACMS have any opinion on the adequacy of the First Aid Instructions & Safety Directions, and would it advise the OCS to incorporate them into the FAISD handbook?
Substance details

Pradofloxacin, a fifth generation fluoroquinolone, is a new veterinary 8-cyano-fluoroquinolone developed for use against bacterial infections in dogs and cats involving both aerobic and anaerobic bacteria21.

The primary mode of action of the fluoroquinolones involves interaction with enzymes essential for major DNA functions such as replication, transcription and recombination. The primary targets for pradofloxacin are the bacterial DNA gyrase and topoisomerase IV enzymes.

Reversible association between pradofloxacin and DNA gyrase, or DNA topoisomerase IV in the target bacteria results in inhibition of these enzymes and rapid death of the bacterial cell. The rapidity and extent of bacterial killing are directly proportional to the drug concentration22.

Toxicity

Pradofloxacin showed low acute oral toxicity in mice and rats. It has a low acute dermal toxicity in rats and it was not a skin irritant in rabbits or a skin sensitiser in guinea pigs. Eye irritation potential in a rabbit study was adjudged to be slight. In a study in guinea pigs, an oral dose of pradofloxacin was stated to cause slight photoirritation of the skin.

The antibiotic activity of pradofloxacin was responsible for a number of adverse findings which were reversible. These include diarrhoea and altered faecal excretion, increased water intake, caecal dilation and intestinal pathology which were probably secondary to local microbiological effects on colonic microflora. Suppression of the resident microbial population and the subsequent reduced stimulation of the immune system was the likely cause of decreased leukocyte counts and thymus weight, and altered pathology in the lymph nodes.

While these effects are not considered to arise from a toxicological mechanism they are nonetheless treatment-related and unwanted.

In dogs, pradofloxacin exposure was associated with degenerative changes of the articular cartilage in multiple joints consisting of blisters or erosions, proliferative clusters of chondrocytes and inflammation of the synovial membrane. Arthropathy is a well-known property of the fluoroquinolone antibiotics and was observed after single and repeated doses in dogs. Degeneration of knee joint cartilage was also found in a single study in rats given repeat doses of pradofloxacin.

Tubular degeneration/regeneration and altered staining and swelling of renal tubular epithelial cells in rats and enlarged and pleomorphic nuclei in the tubular epithelium of the renal cortex in mice were detected at high single or multiple doses. Since 30 to 40 per cent of an oral dose of pradofloxacin was eliminated in the urine of rats, kidney tissue would be exposed to high concentrations of pradofloxacin which could account for the kidney as a target tissue for toxicity.

Chronic toxicity/carcinogenicity studies in rats revealed increased bile duct hyperplasia and periportal infiltration in the liver after 1 year of treatment. The incidence of bile duct hyperplasia was similar to controls at 2 years indicating that treatment may have hastened the onset. In rats, approximately 20 per cent of an oral dose of pradofloxacin was excreted via the bile into the faeces. The resulting prolonged exposure of the biliary system to high concentrations of drug could provide the conditions for stimulation of increased epithelial cell division. There was no evidence of neoplastic activity in rats.

Products

No data was submitted on the toxicity of the tablet formulations. The formulations are of different strengths but the concentration of ingredients in each is the same. Therefore, the acute toxicity estimates were based on the available information on the active and excipient components and their concentration in the formulation.

The applicant has proposed that the tablet formulations will be available in blister packs and the suspension formulation will be packaged in high density bottles with a child resistant closure. These measures would limit the likelihood of access by children. Similarly, the label statements required for a Schedule 4 Substance will indicate the need to keep the products out of the reach of children. In addition, a label statement indicating the products are harmful if swallowed would be appropriate.

Scheduling status

Pradofloxacin is not specifically scheduled.

Other fluoroquinolones, such as ciprofloxacin, difloxacin, enrofloxacin, marbofloxacin and orbifloxacin are listed in Schedule 4.

Scheduling history

Pradofloxacin has not been considered previously.

Public pre-meeting submissions

No public submissions were received.

ACCS & ACMS advice to delegates

The joint Committee recommended that preparations containing pradofloxacin be included in Schedule 4.

The joint Committee also recommended an implementation date of 1 February 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (b) the toxicity.

The following reason was noted:

  • Antibiotics require oversight of an appropriate prescriber.
Delegates' interim decision

The Delegates accept the advice tendered by the Joint ACCS/ACMS meeting, and propose that pradofloxacin be included in Schedule 4.

The proposed entry in Schedule 4 is:

Pradofloxacin.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 includes: (b) the purposes for which a substance is to be used and the extent of use of a Substance.

Pradofloxacin is an antibiotic and its use requires the oversight of an appropriate prescriber.

Submissions on interim decision

No submissions were received.

Delegates consideration

The delegate considered the following in regards to this proposal:

  • scheduling proposal;
  • public submissions received;
  • the evaluation report (not publicly available);
  • ACMS advice;
  • section 52E of the Therapeutic Goods Act 1989;
  • scheduling factors23;
  • other relevant information.
Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Schedule entry
Schedule 4 - New entry

Pradofloxacin.


Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (2010)
  2. Peter Silly et al, Bactericidal properties of pradofloxacin against veterinary pathogens, Veterinary Microbiology Volume 157, Issues 1-2. 25 May 2012.
  3. Annexe 1, Summary of Product Characteristics, <http://ec.europa.eu/health/documents/community-register/2012/20120910124289/anx_124289_en.pdf>
  4. Scheduling Policy Framework for Medicines and Chemicals

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