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Scheduling delegate's final decisions: ACMS, March 2015

ACMS Meeting - 18 November 2014

18 March 2015

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Part A - Final decisions on matters referred to an expert advisory committee: 1.5-1.8

1. Scheduling proposals referred to the November 2014 meeting of the Advisory Committee on Medicines Scheduling (ACMS# 13)

1.5 Naproxen Schedule 2

Scheduling proposal

The medicines scheduling delegate considered a proposal to amend the Schedule 2 naproxen entry to exclude naproxen in a dosage form of 200 mg or less of naproxen per dosage unit in packs of 12 or less dosage units with a maximum recommended daily dose of not more than 600 mg of naproxen, and when not labelled for the treatment of children 12 years of age or less.

Substance summary

The chemical name of naproxen is (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid. Its molecular formula is C14H14O3 and molecular weight is 230.3 g/mole. It is an odourless, white to off-white crystalline substance which is lipid soluble, practically insoluble in water at low pH and freely soluble in water at high pH.

Naproxen, a propionic acid derivative related to the arylacetic acid class of medicines is a non-steroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory and antipyretic properties. It is unrelated to salicylates and the corticosteroid hormones. Its indications include treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis; symptomatic treatment of primary dysmenorrhoea, and relief of acute and/or chronic pain states in which there is an inflammatory component and as an analgesic in acute migraine attack.

Both the naproxen base and the salt are rapidly and completely absorbed from the gastrointestinal tract, both circulating as the naproxen anion and the difference between them is that peak plasma levels of naproxen occur earlier following oral administration of naproxen sodium than naproxen. When administered as a sodium salt, naproxen sodium promptly dissolves in the gastric juice upon entering the stomach and immediately precipitates into fine particles of naproxen. The subsequent pharmacokinetics of the two formulations are identical. Steady state concentrations are achieved after four to five doses.

Poisoning with NSAIDs is not uncommon but rarely severe. In mild to moderate poisoning, gastrointestinal effects (e.g. dyspepsia, ulceration, bleeding) are most commonly reported. Renal dysfunction, most often in elderly patients, may occur. Mild central nervous system (CNS) effects include altered cognition, drowsiness, headache, and mood changes, especially in the elderly population. Severe poisoning is rare but can include CNS depression, hallucinations, seizures, renal failure, gastrointestinal bleeding, and metabolic acidosis.

Scheduling status

Naproxen is currently scheduled in Schedule 4, Schedule 3 and in Schedule 2 and listed in Appendix F with warning statements 101 and 104.

Schedule 4

NAPROXEN except when included in Schedule 3 or Schedule 2.

Schedule 3

NAPROXEN in modified release dosage form of 600 mg or less per dosage unit in packs of 16 or less dosage units when labelled not for the treatment of children under 12 years of age.

Schedule 2

NAPROXEN in divided preparations containing 250 mg or less of naproxen per dosage unit in packs of 30 or less dosage units.

Appendix F, Part 3
Poison Warning statements Safety direction
NAPROXEN

101 Don't use [this product/name of the product]:

  • If you have a stomach ulcer
  • In the last 3 months of pregnancy [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.]
  • If you are allergic to (name of substance) or anti-inflammatory medicines.

104 Unless a doctor has told you to, don't use [this product/name of the product]:

  • For more than a few days at a time
  • With other medicines containing (name of substance) or other anti-inflammatory medicines
  • If you have asthma
  • If you are pregnant [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea].
Scheduling history

Naproxen first appeared in the Poisons Standard in June 1982 under Schedule 4, however, corresponding minutes cannot be located.

In February 1983, the Poisons Scheduling Committee (PSC) considered an application to reschedule naproxen from Schedule 4 to Schedule 3 when supplied in packs of 12 tablets for the treatment of the symptoms of dysmenorrhea. The committee noted the same decision was made in 1979 for a similar substance and the committee agreed that the toxicity, pharmacology and efficacy of naproxen indicated that it could be listed in Schedule 3.

The Department of Health Services, Tasmania requested the PSC to reconsider the Schedule 3 entry for naproxen in February 1985, after reports of massive internal bleeding occurred after ingesting the substance. The committee asked the secretary to contact the company and request sales information on both S3 and S4 products. It was noted in the November 1985 meeting that the company provided statistics to show there was not much evidence of this side effect and decided that the Schedule 3 entry should not be altered.

In November 1987, the committee noted that the Australian Drug Evaluation Committee (ADEC) would not support a Schedule 2 entry for naproxen.

A request for a Schedule 2 entry for naproxen sodium when labelled for the treatment of spasmodic dysmenorrhoea in packs of 12 or less was noted by the Drugs and Poisons Scheduling Committee (DPSC) in August of 1988. It was rejected as the submission had pages missing.

The request was resubmitted and discussed at the August 1989 committee meeting. The committee supported the Schedule 2 proposal on the grounds that it did not present an apparent public health hazard.

In November 1989, the committee considered a rescheduling application from Schedule 4 to Schedule 3 for naproxen. During this review, the committee noted strong anecdotal evidence of gastrointestinal bleeding caused by NSAIDs that had not been reported and which was at least partly dose-related. It also noted that there was little evidence to state that naproxen was more effective than aspirin or paracetamol; therefore there was no therapeutic gap to be filled by the substance. The members were not satisfied that the case for Schedule 3 was convincing and considered the application lacked evidence. The committee did not support the proposal.

In February 1991, Western Australian Health informed the committee that they would only accept the Schedule 2 entry for naproxen when labelled with an appropriate warning statement. The committee preferred the statement 'Warning – This medication may be dangerous when used in large amounts or for a long time'.

In November 1998, the NDPSC considered a proposal to amend the Schedule 2 entry to include packs of 10 tablets, each containing 220mg of naproxen for short term pain management. Public submissions supported a Schedule 3 entry to address concerns over inappropriate use. ADEC stated that product information and labels should provide warning statements and indicate short term use only. The members stated that incidence of gastrointestinal issues associated with naproxen was not greater than with ibuprofen and aspirin. The committee decided that a Schedule 3 entry for the indicated use was more appropriate along with Appendix F warning statement 71. The Schedule 2 entry was amended to allow preparations containing 250 mg or less per dosage unit in packs of 20 or less dosage units.

In November 1999, the committee agreed to reschedule the Schedule 3 entry to Schedule 2 after considering the safety data was similar to that of other NSAIDs already listed in Schedule 2. The NZ member advised that their committee had made a similar decision on the same grounds. The Appendix F warning was to be linked to the Schedule 2 entry.

In February 2000, the committee received comments regarding the perceived inadequacy of labelling for naproxen. The committee decided to await the outcome of a review of product labelling being conducted by the TGA before making decisions regarding changes to labelling.

In August 2001, the committee considered a proposal to exempt naproxen when in 250 mg or less per dosage unit, in packs of 24 or less dosage units, for the short-term analgesic therapy of dysmenorrhoea. While the committee noted a number of key points justifying the proposal, a number of public submissions did not support it on the grounds of maintaining access to professional advice. The evaluation report did not support the proposal due to a lack of evidence regarding safety and the need to be able to access advice and counselling. A Committee member raised concerns on potential misuse of the product, as it may be used routinely for headache rather than dysmenorrhoea. Another concern was that if a product was granted an unscheduled status based on one indication (i.e. for dysmenorrhoea), while the same product remained in S2 for all other indications, and the trade name remained unchanged as proposed, then it would be likely that consumers would use the product routinely for general pain relief. The committee decided that the Schedule 2 entry remained appropriate.

In June 2003, a review of non-prescription analgesics was carried out, mainly in regards to proposed warning statements for inclusion in Appendix F. Outcomes of the review were provided, but the committee felt that further consultation with industry was required. The committee agreed to transitional arrangements in October 2003, supporting the outcome of the review. Warning statements 101 and 104 were to come into effect 1 May 2005.

In October 2004, the committee reviewed the warning statements for NSAIDs. Concerns were raised regarding warning statement 101 not warning against use in patients with a history of stomach ulcers and 104 did not warn against use in elderly patients. The committee discussed the advice sought from the Medicines Evaluation Committee (MEC) and comments received from the Gastroenterological Society regarding whether all non-prescription diclofenac should carry the same warning statements as the other NSAIDs, e.g. ibuprofen, aspirin, naproxen and mefenamic acid for consistency. The committee decided it was preferable for the MEC to consider the comments from the Gastroenterological Society and for the MEC to make the necessary labelling changes.

In June 2007, the NDPSC considered a proposal to apply a maximum daily dose restriction to the Schedule 2 entry for Naproxen. This issue arose when it was noted that naproxen didn’t have a maximum daily dose restriction when considering entries for similar substances which did have restrictions. It was felt that this inconsistency needed to be addressed. Public submissions supported the proposal, so that NSAIDs entries could be consistent and provided suggested cut off limits. The Committee discussed this and felt that the regulator would have assessed this data in allowing the current maximum daily doses to be set as part of their registered indications. It was felt that that there was no requirement for the Committee to pursue consistency for consistency's sake and therefore did not support the proposal.

It was noted in June 2008 that the scheduling entry for naproxen was essentially harmonised between Australia and New Zealand.

A modified release dosage form of naproxen was referred to the Advisory Committee on Medicines Scheduling in March 2014, with the medicines delegate seeking their expert opinion. Considering their advice, the evaluation report and public submissions received, the delegate decided that modified release naproxen should be listed in Schedule 3 as the advice of a pharmacist would be warranted in the first stage of a new product being introduced to the market and that the advice of the pharmacist would enhance the quality use of this medicine such that inappropriate use of naproxen ER for more transient pain does not occur, where there are many more appropriate shorter acting alternatives.

Pre-meeting public submissions

Five public submissions were received. One supported the proposal with appropriate wording that is consistent with other OTC medicines such as paracetamol and ibuprofen. The others opposed any amendment to the S2 entry for naproxen due to potential risks if the substance is accessible to consumers outside registered pharmacy premises.

ACMS advice to the delegate

The ACMS recommended that the current scheduling of naproxen remains appropriate.

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 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 reasons for the recommendation comprised the following:

  • Risks: GI disorders, allergic reactions, renal toxicities & cardio vascular adverse events are some of the common risks. Potential for inappropriate use & overuse of the product, especially if advice from a pharmacist is not available if the product was to be exempt from scheduling.
  • GI risk with naproxen is greater than with ibuprofen.
  • It has analgesic, anti-inflammatory & anti-pyretic properties. It is used for the relief of a number of common conditions where pain and or inflammation are a component.
  • Poisoning with NSAIDs is known especially in high doses. Common adverse effects include dyspepsia, ulceration, GI bleeding, headaches, confusion & drowsiness. There are no new adverse events associated with this proposed product.
  • The TGA would be responsible for the registered product label. It is to be labelled not for the treatment of children 12 years of age or less. Labelling will be in accordance with mandatory Medicines Advisory Statements Specifications 7, including the Required Advisory Statements for Medicine Labelling (RASML) (101 & 104).
  • Low potential for abuse.
Delegate's interim decision

The interim decision is that the current scheduling of naproxen remains appropriate.

Reasons for the decision are:

  • Risks: GI disorders, allergic reactions, renal toxicities & cardio vascular adverse events are some of the common risks. Potential for inappropriate & overuse of the product, especially if advice from a pharmacist is not available if the product was to be exempt from scheduling. GI risk with naproxen is greater than with ibuprofen;
  • It has analgesic, anti-inflammatory & anti-pyretic properties. It is used for the relief of a number of common conditions where pain and or inflammation are a component;
  • Poisoning with NSAIDs is known especially in high doses. Common adverse effects include dyspepsia, ulceration, GI bleeding, headaches, confusion & drowsiness. There are no new adverse events associated with this proposed product;
  • The TGA would be responsible for the registered product label. It is to be labelled not for the treatment of children 12 years of age or less. Labelling will be in accordance with mandatory Medicines Advisory Statements Specifications 7, including the Required Advisory Statements for Medicine Labelling (RASML) (101 & 104);
  • Low potential for abuse; and
  • In view of increased risk versus other NSAIDS which are excluded.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACMS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors5;
  • Other relevant information.
Public submissions on the interim decision

One submission was received which did not support the delegate's interim decision as the risks associated with the use of naproxen are no greater than other analgesics such as aspirin, ibuprofen or paracetamol.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and confirms 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.

1.6 Naproxen Appendix H

Scheduling proposal

The medicines scheduling delegate considered a proposal to include naproxen in Appendix H.

Substance summary

The chemical name of naproxen is (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid. Its molecular formula is C14H14O3 and molecular weight is 230.3 g/mole. It is an odourless, white to off-white crystalline substance which is lipid soluble, practically insoluble in water at low pH and freely soluble in water at high pH.

Naproxen, a propionic acid derivative related to the arylacetic acid class of medicines is a non-steroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory and antipyretic properties. It is unrelated to salicylates and the corticosteroid hormones. Its indications include treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis; symptomatic treatment of primary dysmenorrhoea, and relief of acute and/or chronic pain states in which there is an inflammatory component and as an analgesic in acute migraine attack.

Both the naproxen base and the salt are rapidly and completely absorbed from the gastrointestinal tract, both circulating as the naproxen anion and the difference between them is that peak plasma levels of naproxen occur earlier following oral administration of naproxen sodium than naproxen. When administered as a sodium salt, naproxen sodium promptly dissolves in the gastric juice upon entering the stomach and immediately precipitates into fine particles of naproxen. The subsequent pharmacokinetics of the two formulations are identical. Steady state concentrations are achieved after four to five doses.

Scheduling status

Naproxen is currently scheduled in Schedule 4, Schedule 3 and in Schedule 2 and listed in Appendix F with warning statements 101 and 104.

Schedule 4

NAPROXEN except when included in Schedule 3 or Schedule 2.

Schedule 3

NAPROXEN in modified release dosage form of 600 mg or less per dosage unit in packs of 16 or less dosage units when labelled not for the treatment of children under 12 years of age.

Schedule 2

NAPROXEN in divided preparations containing 250 mg or less of naproxen per dosage unit in packs of 30 or less dosage units.

Appendix F, Part 3
Poison Warning statements Safety direction
NAPROXEN

101 Don't use [this product/name of the product]:

  • If you have a stomach ulcer
  • In the last 3 months of pregnancy [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.]
  • If you are allergic to (name of substance) or anti-inflammatory medicines.

104 Unless a doctor has told you to, don't use [this product/name of the product]:

  • For more than a few days at a time
  • With other medicines containing (name of substance) or other anti-inflammatory medicines
  • If you have asthma
  • If you are pregnant [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea].
Scheduling history

Naproxen first appeared in the Poisons Standard in June 1982 under Schedule 4, however, corresponding minutes cannot be located.

In February 1983, the Poisons Scheduling Committee (PSC) considered an application to reschedule naproxen from Schedule 4 to Schedule 3 when supplied in packs of 12 tablets for the treatment of the symptoms of dysmenorrhea. The committee noted the same decision was made in 1979 for a similar substance and the committee agreed that the toxicity, pharmacology and efficacy of naproxen indicated that it could be listed in Schedule 3.

The Department of Health Services, Tasmania requested the PSC to reconsider the Schedule 3 entry for naproxen in February 1985, after reports of massive internal bleeding occurred after ingesting the substance. The committee asked the secretary to contact the company and request sales information on both S3 and S4 products. It was noted in the November 1985 meeting that the company provided statistics to show there was not much evidence of this side effect and decided that the Schedule 3 entry should not be altered.

In November 1987, the committee noted that the Australian Drug Evaluation Committee (ADEC) would not support a Schedule 2 entry for naproxen.

A request for a Schedule 2 entry for naproxen sodium when labelled for the treatment of spasmodic dysmenorrhoea in packs of 12 or less was noted by the Drugs and Poisons Scheduling Committee (DPSC) in August of 1988. It was rejected as the submission had pages missing.

The request was resubmitted and discussed at the August 1989 committee meeting. The committee supported the Schedule 2 proposal on the grounds that it did not present an apparent public health hazard.

In November 1989, the committee considered a rescheduling application from Schedule 4 to Schedule 3 for naproxen. During this review, the committee noted strong anecdotal evidence of gastrointestinal bleeding caused by NSAIDs that had not been reported and which was at least partly dose-related. It also noted that there was little evidence to state that naproxen was more effective than aspirin or paracetamol; therefore there was no therapeutic gap to be filled by the substance. The members were not satisfied that the case for Schedule 3 was convincing and the application lacked evidence. The committee did not support the proposal.

In February 1991, Western Australian Health informed the committee that they would only accept the Schedule 2 entry for naproxen when labelled with an appropriate warning statement. The committee preferred the statement 'Warning - This medication may be dangerous when used in large amounts or for a long time'.

In November 1998, the NDPSC considered a proposal to amend the Schedule 2 entry to include packs of 10 tablets, each containing 220mg of naproxen for short term pain management. Public submissions supported a Schedule 3 entry to address concerns over inappropriate use. ADEC stated that product information and labels should provide warning statements and indicate short term use only. The members stated that incidence of gastrointestinal issues associated with naproxen was not greater than with ibuprofen and aspirin. The committee decided that a Schedule 3 entry for the indicated use was more appropriate along with Appendix F warning statement 71. The Schedule 2 entry was amended to allow preparations containing 250 mg or less per dosage unit in packs of 20 or less dosage units.

In November 1999, the committee agreed to reschedule the Schedule 3 entry to Schedule 2 after considering the safety data was similar to that of other NSAIDs already listed in Schedule 2. The NZ member advised that their committee had made a similar decision on the same grounds. The Appendix F warning was to be linked to the Schedule 2 entry.

In February 2000, the committee received comments regarding the perceived inadequacy of labelling for naproxen. The committee decided to await the outcome of a review of product labelling being conducted by the TGA before making decisions regarding changes to labelling.

In August 2001, the committee considered a proposal to exempt naproxen when in 250 mg or less per dosage unit, in packs of 24 or less dosage units, for the short-term analgesic therapy of dysmenorrhoea. While the committee noted a number of key points justifying the proposal, a number of public submissions did not support it on the grounds of maintaining access to professional advice. The evaluation report did not support the proposal due to a lack of evidence regarding safety and the need to be able to access advice and counselling. A Committee member raised concerns on potential misuse of the product, as it may be used routinely for headache rather than dysmenorrhoea. Another concern was that if a product was granted an unscheduled status based on one indication (i.e. for dysmenorrhoea), while the same product remained in S2 for all other indications, and the trade name remained unchanged as proposed, then it would be likely that consumers would use the product routinely for general pain relief. The committee decided that the Schedule 2 entry remained appropriate.

In June 2003, a review of non-prescription analgesics was carried out, mainly in regards to proposed warning statements for inclusion in Appendix F. Outcomes of the review were provided, but the committee felt that further consultation with industry was required. The committee agreed to transitional arrangements in October 2003, supporting the outcome of the review. Warning statements 101 and 104 were to come into effect 1 May 2005.

In October 2004, the committee reviewed the warning statements for NSAIDs. Concerns were raised regarding warning statement 101 not warning against use in patients with a history of stomach ulcers and 104 did not warn against use in elderly patients. The committee discussed the advice sought from the Medicines Evaluation Committee (MEC) and comments received from the Gastroenterological Society regarding whether all non-prescription diclofenac should carry the same warning statements as the other NSAIDs, e.g. ibuprofen, aspirin, naproxen and mefenamic acid for consistency. The committee decided it was preferable for the MEC to consider the comments from the Gastroenterological Society and for the MEC to make the necessary labelling changes.

In June 2007, the NDPSC considered a proposal to apply a maximum daily dose restriction to the Schedule 2 entry for Naproxen. This issue arose when it was noted that naproxen didn't have a maximum daily dose restriction when considering entries for similar substances which did have restrictions. It was felt that this inconsistency needed to be addressed. Public submissions supported the proposal, so that NSAIDs entries could be consistent and provided suggested cut off limits. The Committee discussed this and felt that the regulator would have assessed this data in allowing the current maximum daily doses to be set as part of their registered indications. It was felt that that there was no requirement for the Committee to pursue consistency for consistency's sake and therefore did not support the proposal.

It was noted in June 2008 that the scheduling entry for naproxen was essentially harmonised between Australia and New Zealand.

A modified release dosage form of naproxen was referred to the Advisory Committee on Medicines Scheduling in March 2014, with the medicines delegate seeking their expert opinion. Considering their advice, the evaluation report and public submissions received, the delegate decided that modified release naproxen should be listed in Schedule 3 as the advice of a pharmacist would be warranted in the first stage of a new product being introduced to the market and that the advice of the pharmacists would enhance the quality use of this medicine such that inappropriate use of naproxen ER for more transient pain does not occur, where there are many more appropriate shorter acting alternatives.

Pre-meeting public submissions

Four public submissions were received. Three submissions supported the proposal as it was considered it would better inform the public of products available without prescription. One requested that the pharmacy profession have input into the development of any advertisement or promotional material.

One public submission opposed the proposal as no benefit to the consumer would result from advertising.

ACMS advice to the delegate

The ACMS recommended that the current scheduling of naproxen remains appropriate.

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.

The reasons for the recommendation comprised the following:

  • The Schedule 3 entry for a sustained released product was recently resolved. There is an inadequate body of evidence to support Appendix H listing.
Delegate's interim decision

The interim decision is that the current scheduling of naproxen remains appropriate.

Reasons for the decision are:

  • Schedule 2 naproxen products can currently be advertised to consumers, and there does not appear to be any additional public health benefit in advertising modified release formulations of naproxen.
  • Concern that advertising of the Schedule 3 product might encourage consumers to ask for the modified release product when use of conventional lower dose product might be more appropriate.
  • Modified release naproxen has only recently been included in Schedule 3. No Schedule 3 naproxen products are currently registered in the Australian Register of Therapeutic Goods (ARTG), and consequently there is no experience with marketing Schedule 3 modified release naproxen products in Australia.
  • The Schedule 3 entry for a modified released product was recently resolved.
  • S3 entry is for a modified release formulation.
  • No additional benefit in advertising the S3 product as already advertising allowed for S2 product. There is an inadequate body of evidence to support Appendix H listing.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACMS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors6;
  • Other relevant information.
Public submissions on the interim decision

One submission was received which did not support the delegate's interim decision as naproxen is substantially safe for short term treatment and the potential for harm from inappropriate use is low. Advertising the availability of safe, proven and affordable medicine would increase consumer awareness of a medicine that may provide a useful long-lasting analgesic.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and confirms 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.

1.7 Benzydamine

Scheduling proposal

To exempt from scheduling benzydamine in preparations for topical use containing 3 mg or less of benzydamine in divided oral preparations and 3 mg/mL or less in undivided oral preparations in a pack of 50 mL or less.

Substance summary

Benzydamine lozenges and throat sprays are currently marketed for management of sore throats and other painful conditions of the mouth. If the proposal is accepted, such product would become available outside pharmacies. The question in this evaluation is whether or not the quality use of benzydamine can be achieved through labelling and packaging alone without access to advice of a pharmacist and whether wider availability of benzydamine is likely to lead to abuse or misuse.

In the management of common sore throats, the application reasonably argues that a patient can self-manage the ailment without intervention from a health professional (provided instructions are followed) as common sore throats are transient and the community has considerable experience with the condition. It also has a low abuse potential.

However, the application fails to address whether or not quality use of benzydamine can be achieved for other marketed indications, i.e. mouth ulcers, redness and inflammatory conditions of the mouth, pain following mouth and throat conditions, radiation mucositis, and pain following dental procedures. For some of these conditions, the aetiologies of the ailments are less clear and consumers would benefit from advice from a pharmacist, particularly for first time users.

Scheduling status

Benzydamine is currently listed in Schedules 2 and 4.

Schedule 4

BENZYDAIME except:

  1. when included in Schedule 2; or
  2. in preparations for dermal use.
Schedule 2

BENZYDAIME in preparations for topical use, except in preparations for dermal use.

Scheduling history

Benzydamine was first considered in November 1969 and recommended it be included in Schedule 4.

The Drugs and Poisons Scheduling Committee, in 1986, considered a proposal to down schedule benzydamine to Schedule 2 after two products - a 3% topical cream for inflamed muscles and a 0.15% oral rinse for the oral cavity - were approved for marketing. Based on the toxicity and side effect data, product labelling restricting use to 14 days for the cream and 7 days for the oral rinse and its documented safety for topical use, the committee recommended a new Schedule 2 entry for topical use containing 3 per cent or less of benzydamine.

In February 1999, the Trans-Tasman Harmonisation Working Party (TTHWP) advised that the National Drugs and Poisons Scheduling Committee (NDPSC) should amend the Schedule 2 entry to read "Benzydamine in preparations for topical use." The NDPSC noted that this amendment was to be considered later in the meeting as a part of a company submission.

That company submission was from 3M Pharmaceuticals for Difflam 5% topical gel, requesting that benzydamine in 5% preparations be moved from Schedule 4 to Schedule 2. Noting no difference in the adverse effects between the 3% and 5% product, the similar toxicity profile to other non-steroidal anti-inflammatory drug (NSAIDs) topical treatments already in Schedule 2 and the TTHWP recommendation, the NCPSC decided to amend the Schedule 2 entry to Benzydamine in preparations for topical use.

The NDPSC considered the scheduling of benzydamine for dermal use in February 2007. The committee agreed to exempt benzydamine for dermal use from scheduling given its indications for use and safety profile. It had been noted by the committee that other NSAIDs for dermal use were already exempt from scheduling and the level of adverse drug reactions with benzamine was similar to these exempt substances.

Pre-meeting public submissions

Three public submissions were received. Two submissions did not support the proposal and believe the substance should remain in a pharmacy setting so that consumers have access to health professionals who can determine the nature and cause of the condition being treated, and determine a more suitable treatment or referral to a doctor, if required. One submission stated that they may provide further comment on publication of the interim decision.

ACMS advice to the delegate

The ACMS recommended that benzydamine be exempt from Schedule 2 in preparations for topical use containing 3 mg or less of benzydamine in divided oral preparations and 3 mg/mL (0.3%) or less in undivided oral preparations in a pack containing 50 mL or less.

The ACMS recommended an implementation date of 1 June 2015.

The ACMS also recommended that the TGA should consider whether the Required Advisory Statements for Medicine Labels (RASML) should include any requirements for benzydamine.

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 purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of a substance; and e) the potential for abuse of a substance.

The reasons for the recommendation comprised the following:

  • Minimal risk of masking a condition with short-term use. Risk of substance is such that unscheduled status is acceptable and there is a potential benefit in wider access.
  • Surgery and radiation therapy are managed interventions and under clinical supervision.
  • Established safety profile of benzydamine in preparations for topical oral use.
  • Limited potential for abuse/misuse.
Delegate's interim decision

The delegate's interim decision is that benzydamine be exempt from Schedule 2 in preparations for topical use containing 3 mg or less of benzydamine in divided oral preparations and 3 mg/mL (0.3%) or less in undivided oral preparations in a pack containing 50 mL or less with an implementation date of 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: 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; and e) the potential for abuse of a substance.

The reasons for the recommendation comprised the following:

  • As stated by the external evaluator it is accepted that conditions such as sore throats, mouth ulcers and redness and inflammatory conditions of the mouth are amenable to safe self-treatment by consumers without access to a health professional.
  • Support for the requested scheduling exemption was provided by the availability for many years of unscheduled local anaesthetic preparations for relief of sore throats (e.g. benzocaine, lignocaine) without safety issues arising. Benzydamine lozenges and mouth sprays would provide a different therapeutic option for relief of uncomplicated sore throats.
  • Patients with conditions such as radiation mucositis and those who have undergone mouth or throat surgery or dental procedures would be under the care of a medical or dental professional. Surgeons and dentists may initially prescribe benzydamine mouthwash for relief of pain associated with these conditions (and a 500 mL mouthwash is on the PBS for radiation-induced mucositis and as a PBS Dental item), but consumers could subsequently use benzydamine lozenges or mouth spray for these indications.
  • Established safety profile of benzydamine in preparations for topical oral use.
  • Limited potential for abuse/misuse.
  • Similar risks apply to both divided and undivided oral benzydamine preparations for topical use, provided an appropriate pack size limit is set for undivided preparations. There have been some reports of abuse of benzydamine but it was considered that a 50 mL pack size limit for undivided oral preparations adequately addressed concerns about abuse of unscheduled benzydamine products.
  • A maximum pack size was not considered necessary for divided oral preparations. Current scheduling exemptions for lozenges containing local anaesthetic substances did not include a pack size limit.
  • Minimal risk of masking a condition with short-term use. Risk of substance is such that unscheduled status is acceptable and there is a potential benefit in wider access.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACMS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors7;
  • Other relevant information.
Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate has made a minor amendment to the schedule entry published in the interim decision. The delegate reasons for the final decision are:

  • Minimal risk of masking a condition with short-term use. Risk of substance is such that unscheduled status is acceptable and there is a potential benefit in wider access.
  • Surgery, radiation therapy are managed interventions and under clinical supervision.
  • Established safety profile.
  • Limited potential for abuse/misuse.

The implementation date of this decision will be 1 June 2015.

Schedule entry
Schedule 2 - Amended entry:

BENZYDAMINE in preparations for topical use, except:

  1. in preparations for dermal use;
  2. in divided topical oral preparations containing 3 mg or less of benzydamine; or
  3. in undivided topical oral preparations containing 0.3 per cent or less of benzydamine in a primary pack containing not more than 50 mL.
Schedule 4 - Amended entry

BENZYDAMINE except:

  1. when included in Schedule 2;
  2. in preparations for dermal use;
  3. in divided topical oral preparations containing 3 mg or less of benzydamine; or
  4. in undivided topical oral preparations containing 0.3 per cent or less of benzydamine in a primary pack containing not more than 50 mL.

1.8 Pantoprazole

Scheduling proposal

To amend Schedule 2 to create a new entry for pantoprazole when supplied in oral preparations containing 20mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days of supply.

To create two new warning statements in Appendix F, Part 1 and to apply these warning statements to the Schedule 2 pantoprazole entry under Appendix F, Part 3:

107. For short-term relief of minor and temporary ailments only; and

108. If symptoms persist beyond 7 days, recur or worsen, consult your pharmacist or doctor.

Substance summary

Pantoprazole is a Proton Pump Inhibitor (PPI). It inhibits specifically and dose proportionately H+/K+-ATPase, the enzyme which is responsible for gastric acid secretion in the parietal cells of the stomach. The substance is a substituted benzimidazole which accumulates in the acidic environment of the parietal cells after absorption. There, it is converted into the active form, a cyclic sulphonamide which binds to the H+/K+-ATPase, thus inhibiting the proton pump and long-lasting suppression of basal and stimulated gastric acid secretion. As pantoprazole acts distal to the receptor level, it can influence gastric acid secretion irrespective of the nature of the stimulus (acetylcholine, histamine, gastrin). Pantoprazole's selectivity is due to the fact that it only exerts its full effect in a strongly acidic environment (pH < 3), remaining mostly inactive at higher pH values. As a result, its complete pharmacological, and thus therapeutic effect, can only be achieved in the acid secretory parietal cells. By means of a feedback mechanism this effect is diminished at the same rate as acid secretion is inhibited. As with other PPIs and H2 receptor inhibitors, treatment with pantoprazole causes reduced acidity in the stomach and thereby an increase in gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible.

Scheduling status

Pantoprazole is currently listed in Schedule 3 and Schedule 4.

Schedule 4

PANTOPRAZOLE except when included in Schedule 3.

Schedule 3

PANTOPRAZOLE in oral preparations containing 20 mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days'.

Scheduling history

The National Drugs & Poisons Schedule Committee (NDPSC), at its February 1995 meeting, noted that ADEC, at its 173rd meeting, had recommended approval for the registration of pantoprazole for the treatment of duodenal ulcer, gastric ulcer, reflux oesophagitis and gastrointestinal lesions refractory to H2-receptor antagonists. The Committee recommended a Schedule 4 entry.

In June 2005, the NDPSC agreed to include in Schedule 3 pantoprazole in oral preparations containing 20 mg or less of pantoprazole for the relief of heartburn and other symptoms of GORD in packs containing not more than 14 days supply. Members were convinced that the available efficacy and safety data supported an acceptable safety profile of pantoprazole 20 mg once daily for 14-day treatment consistent with S3 medicines. It was also agreed that the implementation date for this Decision would be 1 March 2006 to allow adequate time for collaboration with the pharmacy profession and the generation and provision of education materials and supply protocols for pharmacists to supply S3 pantoprazole appropriately. The Committee also agreed that the warning statements as proposed by the sponsor should be referred to the TGA's OTC Medicines Section for consideration of inclusion into the CMI and packaging for Somac Relief and the Required Advisory Statements for Medicine Labels (RASML) document. In addition, the matter relating to the wording of the indication in the proposed CMI should be referred to this Section. However, the Committee did not consider an Appendix H listing for pantoprazole as there was insufficient information available at the time to make an informed decision.

In October 2005, the NDPSC agreed to vary their pervious decision by delaying the implementation date for the rescheduling of oral pantoprazole 20mg to Schedule 3 to 1 May 2006 to allow the sponsor adequate time to develop pharmacist educational material.

Having regard to this advice, the NDPSC in February 2006, agreed to amend the implementation date for the oral pantoprazole Schedule 3 amendment to 1 May 2008 and to include this decision in the Gazette Notice and the Record of Reasons.

The NDPSC, in February 2009, reviewed the scheduling of the substance and agreed that the current scheduling of pantoprazole remained appropriate.

In February 2010, the NDPSC decided that the inclusion of pantoprazole in Appendix H was inappropriate.

In May 2012, after considering the ACMS's recommendation on the proposal to review the scheduling of the substance, the delegate made a final decision that the current scheduling of pantoprazole remains appropriate i.e. pantoprazole 20 mg, in packs containing no more than 14 tablets (equivalent to 14 day's supply) in Schedule 3.

Pre-meeting public submissions

Five public submissions were received.

Three public submissions did not support the proposal because: the 7-day pack did not provide optimal therapy and was therefore of limited benefit to consumers; the risks associated with prolonged use; and the need for consumers with gastrointestinal problems to seek professional advice to determine cause of their symptoms. The recommendations were that pantoprazole remain in S3 and that it also be listed in Appendix H.

One public submission recommended explicit labelling should pantoprazole be down scheduled to Schedule 2.

One public submission supported the proposal.

ACMS advice to the delegate

The ACMS recommended that a new entry in Schedule 2 for pantoprazole when supplied in oral preparations containing 20 mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' of supply.

The ACMS recommended an implementation date of 1 June 2015.

Delegate's interim decision

Delegate's interim decision was to:

  • Include a new entry in Schedule 2 for pantoprazole when supplied in oral preparations containing 20 mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' of supply.
  • Amend S3 and S4 entries for pantoprazole accordingly.
  • Not include two new warning statements in Appendix F, Part 1 and to apply these warning statements to the Schedule 2 pantoprazole entry under Appendix F, Part 3:
    • 107. For short-term relief of minor and temporary ailments only; and
    • 108. If symptoms persist beyond 7 days, recur or worsen, consult your pharmacist or doctor.

The proposed implementation date was 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: 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; d) the dosage, formulation, labelling, packaging and presentation of a substance; and f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • Short term use of pantoprazole for the treatment of heartburn and other symptoms of gastro-oesophageal reflux disease is likely to be safe and effective.
  • Heartburn and other symptoms of gastro-oesophageal reflux disease are common. Other agents for the same indication are available as Schedule 2 medicines or are exempt from scheduling.
  • All OTC proton pump inhibitor (PPI) medicines have similar efficacy and safety profiles. PPIs differ in this respect from many other pharmacological drug classes (such as H2-receptor antagonists or NSAIDs).
  • Availability of a pharmacist would assist patients.
  • The current RASML label warning statements for all OTC PPIs would apply to pantoprazole in Schedule 2 or Schedule 3.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACMS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors8;
  • Other relevant information.
Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Scheduling entry
Schedule 2 - New entry

PANTOPRAZOLE in oral preparations containing 20 mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days supply.

Schedule 3 - Amended entry

PANTOPRAZOLE in oral preparations containing 20 mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days supply except when included in Schedule 2.

Schedule 4 - Amended entry

PANTOPRAZOLE except when included in Schedule 2 or 3

Footnotes

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