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Scheduling delegate's interim decisions and invitation for further comment: ACMS, February 2015

4 February 2015

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Interim decisions on matters referred to an expert advisory committee: ACMS February 2015: (1.7-1.12)

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

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.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

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 it, such product would become available outside pharmacies. The question is 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 of the submissions did not support the proposal and that 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. The 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 with 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 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.
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 proposed implementation date is 1 June 2015.

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:

  • 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. Members noted some reports of abuse of benzydamine but 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. Members noted that 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.
Scheduling proposal
Schedule 2 - Amended entry

BENZYDAMINE in preparations for topical use, except:

  1. in preparations for dermal use;
  2. in divided oral preparations containing 3 mg or less of benzydamine; or
  3. in undivided 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 in preparations for topical use, except:

  1. when included in Schedule 2;
  2. in preparations for dermal use;
  3. in divided oral preparations containing 3 mg or less of benzydamine; or
  4. in undivided 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.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

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.

The delegate considered the following in regards to making a final decision:

  • advice and recommendations from the ACMS;
  • public submissions received on the interim decision;
  • scheduling factors for Schedule 3; and
  • section 52E of the Therapeutic Goods Act 1989.

The delegate decided that the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 include (a) risk and benefits, (b) purposes, dosage and formulation and (c) the toxicity of a substance.

The final decision that the current scheduling of pantoprazole remains appropriate included the following reasons:

  • the information presented does not support the down scheduling of pantoprazole.
  • pharmacist intervention may be required to ensure the quality use of the medicine and to ensure appropriate referral to a medical practitioner occurs if symptoms persist.

There are still concerns regarding the potential for chronic use in patients expecting immediate relief as well as unresolved concerns raised by ACMS regarding chronic use.

Pre-meeting public submissions

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.

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; 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.
  • The proposed labelling and provision of Consumer Medicine Information would help ensure appropriate use of the product.
  • Pantoprazole may be more effective in treatment of gastro-oesophageal reflux disease than ranitidine which is currently available as an unscheduled medicine in a 7 day pack and as a Schedule 2 medicine in a 14 day pack.
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.
Delegate's interim decision

The delegate's interim decision is 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.
  • Implement the changes on 1 June 2015.

The proposed implementation date is 1 June 2015.

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; 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.
Scheduling proposal
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.

1.9 Cyclizine

Scheduling proposal

To amend the Schedule 3 entry for cyclizine for oral use to include a pack size limit of 10 tablets.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

Substance summary

Cyclizine, a piperazine derivative, is a sedating antihistamine with antimuscarinic activity, although the sedative effects are not marked.

It is used as an antiemetic in the management of nausea and vomiting including motion sickness, postoperative nausea and vomiting, after radiotherapy, and in drug-induced nausea and vomiting. It is included as an antiemetic with some opioids, and in combination preparations for the treatment of migraine attacks. Cyclizine is also used for the symptomatic treatment of vertigo caused by Ménière's disease and other vestibular disturbances.

In the management of nausea and vomiting, cyclizine hydrochloride is given in a usual oral dose of 50 mg up to three times daily, although up to 200 mg may be given in 24 hours if necessary. For the prevention of motion sickness, the first dose should be given about 30 minutes before travelling.

Cyclizine is absorbed from the gastrointestinal tract and has an onset of action within 2 hours. The duration of action is reported to be about 4 hours. Cyclizine is metabolised in the liver to the relatively inactive metabolite, norcyclizine. Both cyclizine and norcyclizine have plasma elimination half-lives of 20 hours. Less than 1% of the total oral dose is eliminated in the urine in 24 hours.

Cyclizine tablets have been abused either alone or with opioids for their euphoric effects. They have been taken orally or used to make injections. It has been suggested that cyclizine dependence may occur when it is used with opioids in the treatment of chronic pain. Abuse of cyclizine has been reported in cancer patients receiving it by injection to control chemotherapy- or disease-related nausea (The Martindale 2014, viewed 29/08/2014).

Scheduling status

Cyclizine is currently listed in Schedule 3 and Schedule 4.

Schedule 3

CYCLIZINE in preparations for oral use.

Schedule 4

CYCLIZINE except when included in Schedule 3.

Scheduling history

The Poisons Schedule Sub-Committee Meeting in March 1966 considered the proposal that various preparations containing less than 2% antihistamines be exempt from Schedule 4 and included in Schedule 3. The committee re-affirmed its opinion that all antihistamines should be in Schedule 4 and noted its concern that motion sickness preparations are included in Schedule 3.

The committee recommended that the entry for antihistamines in Schedule 3 be amended to read:

  • Antihistamines, all tertiary nitrogenous organic cases which possess pharmacological properties characteristic of antihistamine compounds in preparations labelled and packed for the treatment of motion sickness in packs of 10 does or less except meclizine, cyclizine and chlorcyclizine.

The committee recommended that the entry for antihistamines in Schedule 4 be amended to read:

  • Antihistamines, all tertiary nitrogenous organic cases which possess pharmacological properties characteristic of antihistamine compounds in preparations labelled and packed for the treatment of motion sickness in packs of 10 does or less. This exemption does not apply to meclizine, cyclizine and chlorcyclizine.

The National Drugs and Poisons Schedule Committee (NDPSC) Meeting in February 2006 noted that travel sickness products containing a sedating antihistamine in S2 could be sold in premises licensed by the jurisdictions. It was noted that cyclizine for the treatment of travel sickness was reclassified from Pharmacy Only to Restricted Medicines in New Zealand as part of the rescheduling of single-active preparations containing sedating antihistamines and on the basis of its abuse potential.

There were no products containing cyclizine registered on the ARTG at the time and all cyclizine preparations were Prescription Only medicines in Australia. At the October 2005 NDPSC meeting it was agreed that it was appropriate to refer the scheduling of cyclizine to the February 2006 Trans-Tasman Harmonisation Working Party (TTHWP) meeting for initial consideration of harmonisation. The committee supported the option to retain all sedating antihistamines for travel sickness in S2 except for cyclizine and to reschedule it to S3 while retaining the primary entry in S4 to harmonise with New Zealand. The committee agreed that sedating antihistamines in small packs for use in the treatment or prevention of travel sickness remain in S2 except for cyclizine in oral preparations which the committee had agreed to include in S3 to harmonise with New Zealand.

Pre-meeting public submissions

No public submissions were received.

ACMS advice to the delegate

The ACMS recommended that the Schedule 3 entry for cyclizine be amended to specify divided preparations with a pack size limit of six dosage units.

The ACMS recommended an implementation date of 1 June 2015.

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; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • A maximum pack size of six dosage units is proposed for cyclizine in Schedule 3, due to the potential for abuse (and the recommended dosage and short-term duration of use). A six tablet pack is sufficient for the agreed dose for cyclizine HCl 50 mg tablets and the short term treatment of motion sickness. Inclusion of a pack size limit is consistent with requirements for pack size limits in the SUSMP for other OTC antihistamines for use for motion sickness, and in ARGOM for other OTC antihistamine products with abuse potential (Schedule 3 antihistamines indicated for use in insomnia). All these products are intended for short term use only.
  • There are currently no registered Schedule 3 cyclizine preparations. The only cyclizine product currently on the ARTG is a Schedule 4 injection (for prevention of nausea and vomiting, post-operatively).
  • Potential for adverse effects as a result of accumulation of cyclizine on repeated dosing (due to long half-life).
  • Cyclizine in oral preparations is currently Schedule 3 (rather than Schedule 2, as for other antihistamines with antiemetic indications) due to its abuse potential. No history of abuse is noted in Australia (no oral cyclizine products are registered), but there have been reports of abuse of OTC cyclizine products by opiate users in New Zealand (tablets are dissolved in water and injected, usually with methadone), and reports of abuse of cyclizine by methadone users in the UK.
  • The Schedule 3 entry should specify divided dose cyclizine preparations (for oral use). This would result in oral liquids being rescheduled to Schedule 4 – this is appropriate, as liquid cyclizine preparations present a greater risk of abuse than solid dose preparations, it would not affect any current products, and TGA has not considered any oral cyclizine product for use in children under 12 years.
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 factors9;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is to amend the Schedule 3 entry for cyclizine be amended to specify divided preparations with a pack size limit of six dosage units.

The proposed implementation date is 1 June 2015.

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; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • Availability of OTC motion sickness products is appropriate however the risks of abuse or adverse events require restrictions on availability and pack size as OTC products.
  • A maximum pack size of 6 dosage units is proposed for cyclizine in S3, due to the potential for abuse (and the recommended short-term duration use of up to 1 table three times a day for 48 hours). A 6 tablet pack is more than sufficient for the agreed dose for cyclizine 50 mg tablets.
  • Inclusion of a pack size limit is consistent with requirements for pack size limits in the SUSMP for other OTC antihistamines for use for motion sickness, and in ARGOM for other OTC antihistamine products with abuse potential (S3 antihistamines indicated for use in insomnia). All these products are intended for short term use only.
  • Availability of OTC motion sickness products is appropriate.
  • There currently are no registered S3 cyclizine preparations.
  • The only cyclizine product on the ARTG is a S4 injection (for prevention of nausea & vomiting, post-operatively)
  • Potential for adverse effects as a result of accumulation of cyclizine on repeated dosing (due to long half-life).
  • A maximum pack size of 6 dosage units is proposed for cyclizine in S3, due to the potential for abuse (and the recommended short-term duration use of up to 1 table three times a day for 48 hours). A 6 tablet pack is more than sufficient for the agreed dose for cyclizine 50 mg tablets.
  • Inclusion of a pack size limit is consistent with requirements for pack size limits in the SUSMP for other OTC antihistamines for use for motion sickness, and in ARGOM for other OTC antihistamine products with abuse potential (S3 antihistamines indicated for use in insomnia). All these products are intended for short term use only.
  • Cyclizine in oral preparations is currently S3 (rather than S2, as for other antihistamines with antiemetic indications) due to its abuse potential.
  • No history of abuse is noted in Australia (no oral cyclizine products are registered), but there have been reports of abuse of OTC cyclizine products by opiate users in New Zealand (tablets are dissolved in water and injected, usually with methadone); also reports of abuse of cyclizine by methadone users in the UK.
  • The S3 entry should specify divided dose cyclizine preparations (for oral use). This would result in oral liquids being rescheduled to S4 - this would not affect any current products, and TGA has not considered any cyclizine product for use in children under 12 years.
Scheduling proposal
Schedule 3 - Amended entry

CYCLIZINE in divided preparations for oral use in primary packs containing 6 dosage units or less.

1.10 Pomalidomide

Scheduling proposal

To list pomalidomide in Appendix D Item 4, Appendix L, Part 2; and Appendix F, Part 3.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

Substance summary

Pomalidomide is a derivative of thalidomide that has immunomodulatory and antiangiogenic properties. It is used with dexamethasone or as monotherapy for the treatment of multiple myeloma in patients who have been treated with at least 2 other therapies including lenalidomide and bortezomib, and whose disease has progressed within 60 days of completing the last therapy. A usual oral dose of pomalidomide is 4 mg once daily taken on an empty stomach, for 21 days of a 28-day cycle.

Maximum serum concentrations of pomalidomide occur 2 to 3 hours after an oral dose. Plasma protein binding ranges from 12 to 44%. Pomalidomide is distributed into the semen. It is mainly metabolised in the liver by the cytochrome P450 isoenzymes CYP1A2 and CYP3A4, with CYP2C19 and CYP2D6 playing a minor role. Pomalidomide is excreted via the kidneys with a plasma half-life of about 9.5 hours in healthy adults and 7.5 hours in those with multiple myeloma. About 73% of a dose was eliminated in the urine and 15% in the faeces, mainly as metabolites with a small portion as unchanged drug.

Because of its potential teratogenicity, pomalidomide use is restricted in women of child-bearing potential and similar precautions to thalidomide are required.

Pomalidomide is associated with haematological toxicity, particularly neutropenia, anaemia, and thrombocytopenia. Full blood counts should be monitored weekly for the first 8 weeks of treatment and then monthly thereafter; dose adjustments may be required. Venous thromboembolism has occurred during pomalidomide treatment, and prophylactic measures should be considered in those at increased risk.

Neuropathy, including peripheral neuropathy, has been reported with pomalidomide. Dizziness, confusion, anxiety, insomnia, and headache have occurred.

Other common adverse effects include fatigue, pyrexia, chills, gastrointestinal disorders, anorexia, changes in body weight, muscle spasm or weakness, arthralgia, pain including bone and muscle pain, dyspnoea, cough, epistaxis, hyperhidrosis, rash, dry skin, pruritus, electrolyte disturbances, hyperglycaemia, increases in blood creatinine, and renal failure. Vertigo, increases in bilirubin and hepatic enzymes, and interstitial lung disease have also occurred (Martindale 2014, viewed on 29 August 2014).

The mechanism of action of pomalidomide includes a variety of immunomodulatory effects such as induction of immune responses, enhancement of activity of immune cells, alteration and modulation of the induction of pro- and anti-inflammatory cytokines, and inhibition of inflammation. These compounds also have tumoricidal and anti-angiogenic activities that contribute to their anti-tumour activities.

The multiple pharmacological properties of pomalidomide suggest a potential therapeutic benefit in patients with multiple myeloma (MM). While it is structurally similar to both thalidomide and lenalidomide and shares a number of potentially therapeutic pharmacological properties, pomalidomide has a distinctly different activity and potency profile. It exhibits greater potency than thalidomide with regard to immune modulation, anti-inflammatory and anti-proliferative activity, and has greater potency than lenalidomide at anti-proliferative effects in MM cell lines, augmentation of CD4+ and CD8+ T cell proliferation, Th1 cytokine production and natural killer T cell activation. These differences allow the administration of pomalidomide at lower relative doses compared with thalidomide or lenalidomide.

In vitro and in vivo studies suggest that pomalidomide plus dexamethasone may be effective in MM resistant to lenalidomide/dexamethasone therapy. The mechanism underlying the synergistic responses is not fully understood.

Scheduling status

Pomalidomide is not currently scheduled in Australia or New Zealand. However, in 2013 pomalidomide was approved by the US Food and Drug Administration and the European Commission; and by Health Canada in 2014. In Canada the substance in contraindicated in pregnant women and women at risk of becoming pregnant and breast feeding women, while in the US only has the former contradiction. In the European Union, pomalidomide is contraindicated in females who are pregnant, and if used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be appraised of the potential hazard to the foetus.

Scheduling history

Pomalidomide has not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

No public submissions were received.

ACMS advice to the delegate

The ACMS recommended that pomalidomide be included in Appendix D item 4; Appendix L, Part 2 with warning statements 7, 62 and 76; and Appendix F, part 3 with warning statements 7, 62 and 76 with an implementation date of 1 June 2015.

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; and c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • Known teratogen, Pregnancy Category X, similar pharmacological and toxicological profile to thalidomide therefore requires equivalent warning statements.
  • Requires specialist oversight.
  • Known teratogen, Pregnancy Category X.
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 factors10;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is to include pomalidomide in:

  • Appendix D item 4;
  • Appendix L, Part 2 with warning statements 7, 62 and 76; and
  • Appendix F, part 3 with warning statements 7, 62 and 76.

The proposed implementation date is 1 June 2015.

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; and c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • it is a known teratogen,
  • it is Pregnancy Category X,
  • it has similar pharmacological and toxicological profile to thalidomide therefore requires equivalent warning statements, and
  • it requires specialist oversight.
Scheduling proposal
Appendix D - New entry

Poisons available only from or on the order of a specialist physician and for which the prescriber must, where the patient is a woman of child bearing age:

  1. Ensure that the possibility of pregnancy has been excluded prior to commencement of treatment; and
  2. Advises the patient to avoid becoming pregnant during or for a period of 1 month after completion of treatment.

POMALIDOMIDE

Appendix L, Part 2 - New entry

ADDITIONAL LABELLING REQUIREMENTS FOR CERTAIN HUMAN MEDICINES

Column 1
Substance
Column 2
Warning Statement
Pomalidomide 7, 62, and 76
Appendix F, Part 3 - New entry

POISONS (other than agricultural and veterinary chemicals) TO BE LABELLED WITH WARNING STATEMENTS OR SAFETY DIRECTIONS

POISONS WARNING STATEMENTS SAFETY DIRECTIONS
Pomalidomide 7, 62, and 76

1.11 Enzalutamide

Scheduling proposal

To list enzalutamide in Appendix D, Appendix L and Appendix F, Part 3.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

Substance summary

Enzalutamide is a non-steroidal androgen receptor antagonist that blocks several steps in the androgen receptor signalling pathway binding to the androgen receptor, nuclear translocation of the activated receptor, and association of the translocated receptor with nuclear DNA. It is used in the treatment of metastatic castration-resistant prostate cancer in patients who have previously been treated with docetaxel. Enzalutamide itself is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19.

Scheduling status

Enzalutamide is not specifically scheduled.

Scheduling history

Enzalutamide has not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

No public submissions were submitted.

ACMS advice to the delegate

The ACMS recommended that enzalutamide be included in Appendix L, Part 2 with warning statements 7, 67 and 87, in Appendix F, Part 3 also with warning states 7, 67 and 87 and in Appendix D, Item 6.

The ACMS recommended an implementation date of 1 June 2015.

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; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • Some efficacy in the treatment of metastatic castration-resistant prostate cancer
  • Use in or exposure of women of child-bearing age poses a significant threat.
  • Treatment of metastatic castration-resistant prostate cancer
  • Not currently indicated for uses other than the treatment of prostate cancer
  • Teratogen
  • Does not appear to produce dependency
  • May be subject to extensions of indications or 'off-label' use in women.
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 factors11;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is to include Enzalutamide in:

  • Appendix D, Item 6;
  • Appendix F, Part 3 with warning states 7, 67 and 87; and
  • Appendix L, Part 2 with warning statements 7, 67 and 87.

The proposed implementation date is 1 June 2015.

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; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • it is a known teratogen,
  • it is Pregnancy Category X,
  • in the US it is contraindicated in women who are or may become pregnant
  • in Europe the Product Information states:
    • 4.6 Fertility, pregnancy and lactation - Women of childbearing potential. There are no human data on the use of Xtandi in pregnancy and this medicinal product is not for use in women of childbearing potential.
    • Contraception in males and females - It is not known whether enzalutamide or its metabolites are present in semen. A condom is required during and for 3 months after treatment with enzalutamide if the patient is engaged in sexual activity with a pregnant woman. If the patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for 3 months after treatment. Studies in animals have shown reproductive toxicity (see section 5.3).
    • Pregnancy - Enzalutamide is not for use in women. Enzalutamide is contraindicated in women who are or may become pregnant (see sections 4.3 and 5.3).
Scheduling proposal
Appendix D, Item 6 - New entry

Poisons available only from or on the order of a specialist physician and for which the prescriber must, where the patient is a woman of child bearing age:

  1. Ensure that the possibility of pregnancy has been excluded prior to commencement of treatment; and
  2. Advises the patient to avoid becoming pregnant during or for a period of 3 months after completion of treatment.

ENZALUTAMIDE for human use

Appendix L, Part 2 - New entry

ADDITIONAL LABELLING REQUIREMENTS FOR CERTAIN HUMAN MEDICINES

Column 1
Substance
Column 2
Warning Statement
Enzalutamide 7, 67 and 87
Appendix F, Part 3 - New entry

POISONS (other than agricultural and veterinary chemicals) TO BE LABELLED WITH WARNING STATEMENTS OR SAFETY DIRECTIONS

POISONS WARNING STATEMENTS SAFETY DIRECTIONS
Enzalutamide 7, 67 and 87

1.12 Ponatinib

Scheduling proposal

To list ponatinib in Appendix D, Item 1.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

Substance summary

Ponatinib is the active substance in an anticancer medicine. It is used to treat adults with the following types of leukaemia (cancer of the white blood cells):

  • chronic myeloid leukaemia (CML);
  • acute lymphoblastic leukaemia (ALL) in patients who are 'Philadelphia-chromosome positive' (Ph+).

Ponatinib is a BCR-ABL tyrosine kinase inhibitor that is used for the treatment of chronic, accelerated, or blast phase chronic myeloid leukaemia, or Philadelphia chromosome-positive acute lymphoblastic leukaemia, that is resistant to, or in patients who are intolerant of, prior tyrosine kinase inhibitor therapy.

Ponatinib is used in patients who do not respond to dasatinib or nilotinib (other medicines of the same class); or who cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib (a third such medicine) is not considered appropriate. It is also used in patients who have a genetic mutation called 'T315I mutation' which makes them resistant to treatment with imatinib, dasatinib or nilotinib.

Scheduling status

Ponatinib is not specifically scheduled.

Scheduling history

Ponatinib has not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

No public submissions were received.

ACMS advice to the delegate

The ACMS recommended that Ponatinib not be listed in Appendix D, Item 1.

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 f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • Benefits: Treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia.
  • Risks: Life-threatening blood clots, severe occlusion of blood vessels, cardiac failure, pancreatitis and hepatotoxicity. Possible fetotoxicity.
  • Purposes as above. Use is limited by the incidence of the diseases, adverse effects and cost.
  • Attracts a FDA "black box" warning and a "risk evaluation and mitigation strategy" in view of the above risks.
  • Oral tablets.
  • The specialised nature of this drug is such that only haematologists are likely to use it.
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 factors12;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is to not include Ponatinib in Appendix D, Item 1.

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 f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the recommendation comprised the following:

  • Ponatinib will be prescribed by specialists only due to the nature of the disease being treated as well as the toxicity profile of the drug. It was very unlikely that GPs would prescribe Ponatinib.

Footnotes

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