Part A - Interim decisions on matters referred to an expert advisory committee: ACMS#14 (1.1-1.3)

1. Scheduling proposals referred to the March 2015 meeting of the Advisory Committee on Medicines Scheduling (ACMS #14)

1.1 Oral contraceptive pill

Scheduling proposal

The medicines scheduling delegate (the delegate) has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):

• To down-schedule oral contraceptive pills from Schedule 4 to Schedule 3. The Schedule 3 entry would be on condition that the pharmacist conducts a questionnaire about family history of heart problems, hypertension and stroke and that either an in-house blood pressure test is conducted or results from a recent blood pressure test is provided to ensure suitability of the substances. Finally the proposal recommends that the supply of the substances be limited to 3 to 6 months.

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

Substance summary

The applicant provided the following information on the substance:

Oral contraceptives are divided into two main types, progestin only and combined. Progestin-only contain synthetic progestogens (progestin), including norethindrone, ethynodiol diacetate, levenorgestrol, desogestrol and lynestronol. Combined pills contain a mixture of synthetic oestrogens and progestins, including those listed above in addition to ethinyl oestradiol and mestranol. Combined pills work by suppressing the release of gonadotropins from the pituitary gland, including follicle stimulating hormone (FSH) and luteinizing hormone (LH).

The reduction in these hormones inhibits both follicular development and ovulation, which is the primary mechanism of action of the medication. This also sees a decrease in the water content of cervical mucus, increasing its viscosity and inhibiting sperm movement. Other impacts include a thinning of endometrial lining. Uses of the contraceptive pill, aside from the obvious contraceptive effects include clearer skin, reduced risk of ovarian cancer and reduced severity of periods. Toxicity is rare but side effects can be seen on those with underlying conditions, including heart conditions, high blood pressure and those with a history of stroke. Hormonal imbalances can also cause mood swings and depression.

Scheduling status

A number of contraceptive substances are listed in Schedule 4 with the exception of LEVONORGESTREL for emergency post-coital contraception, which is included in Schedule 3.

Cyproterone, gestodene, desogestrel, drospirenone, ethinyloestradiol, levonorgestrel, mestranol and mifepristone are all listed in Schedule 4.

Scheduling history

Oestradiol

National Health and Medical Research Council Poisons Schedule (Standing) Committee - August 1979

Elanco Product Company proposed the scheduling of its product Compudose - a silicone rubber implant containing the natural hormone oestradiol-17 beta designed to improve growth rate and feed efficiency in beef cattle by controlled release over 200 to 400 days. Outcome: New Entry: OESTRADIOL-17 beta in silicone rubber controlled release implants for use in cattle.

National Health and Medical Research Council Poisons Schedule (Standing) Committee - March 1980

Committee noted that the Standing Committee and Agriculture had established a working party to review the use of hormones in cattle production.

National Drugs and Poisons Schedule Committee - May 1996

The Committee considered correspondence from Elanco Animal Health in response to advice of the rescheduling of several oral veterinary products from Schedule 6 to Schedule 5. In view of the possibility that rescheduling may affect monitoring by other agencies it was agreed the proposal should be foreshadowed in the outcomes gazette from the meeting and comment sought on the implications of the proposal. The Committee further considered that Schedule 5 may be appropriate for some of these ear implant products. However, it was agreed that the issue required further attention in view of the current scheduling concerns in regard to testosterone, the toxicity of the products and the complexity of the drafting of appropriate schedule entries.

Desogestrel

National Health and Medical Research Council Poisons Schedule (Standing) Committee - February 1993

The Committee noted that ADEC had recommended approval for registration of desogestrel (Marvelon tablets-Organon) for use with ethinyloestradiol 30 mg, as a combined oral contraceptive preparation for the inhibition of ovulation. Decision: the Committee recommended Schedule 4. Recommendation: Schedule 4 - New Entry, DESOGESTREL.

Ethinyloestradiol - No scheduling history available.

Norethisterone - No scheduling history available.

Levonorgestrel

National Health and Medical Research Council Poisons Schedule (Standing) Committee - November 1998

The Committee noted that in some states weight lifters were abusing sex hormones and anabolic steroids used for humans and/or animals. It was recommended that all such products available on the Australian market, either for humans or animals, be placed in Schedule 4 with an individual entry. The Committee recommended that various hormones listed in the National Therapeutic Goods Register be given individual entries in Schedule 4 - including levonorgestrel.

National Drugs and Poisons Schedule Committee - March 2003

A proposal was put forward to the Committee to consider releasing NDPSC decisions and outcomes of considerations as 'resolutions' within a week of the meeting. The Committee agreed, given the considerable interest on the scheduling consideration of levonorgestrel at this meeting, to publicly release a document immediately containing the details of the decision and a brief statement outlining the reasons. This document was to be provided to members for information.

National Drugs and Poisons Schedule Committee - October 2003

The Committee considered post-meeting submissions in relation to the June 2003 initial decision to reschedule levonorgestrel in a two-tablet pack, of 0.75 mg per tablet, for emergency post-coital contraception from Schedule 4 to Schedule 3 of the SUSDP. The Committee confirmed the view taken at the June 2003 Meeting that an Appendix H listing for levonorgestrel was not warranted due to insufficient information available to support an informed decision about advertising. Overall the Committee reiterated that levonorgestrel EC in a dose of 2 x 0.75 mg tablets clearly conforms to the criteria for a Schedule 3 medicine both in terms of the characteristics of the drug and the indications for use.

National Drugs and Poisons Schedule Committee - June 2004

The Committee considered the implementation of scheduling amendments subject to post-meeting submissions. It was proposed that S4 to S3 rescheduling be a two part decision-making process where confirmation is contingent on the Committee being satisfied with the pharmacy educational material. It was also proposed that the first decision be a qualified decision based upon the sponsor's pharmacists' educational/training plan and subject to seeing the final educational material.

National Drugs and Poisons Schedule Committee - October 2004

Prochlorperazine - supply with Levonorgestrel: The Committee considered the need to make provision for the availability of medicines for the treatment of nausea associated with emergency contraception (EC) and, in particular, in association with the supply of levonorgestrel EC. The Committee agreed that if professional bodies or pharmaceutical companies regarded nausea/vomiting associated with the use of levonorgestrel EC as a significant problem, then they could raise the associated scheduling issues with the Committee. To date, no concerns had been raised.

Levonorgestrel - request for advice: The Committee considered correspondence from the Minister for Health and Ageing, the Hon Tony Abbott MP, seeking advice on whether pharmacists are appropriately supplying Postinor-2 as a "Pharmacist Only Medicine". The Committee was of a view that Postinor-2 was generally being supplied in accordance with information and considerations set out in the PSA protocol.

National Drugs and Poisons Schedule Committee - February 2005

The Committee considered comments from Schering Pty Limited, the distributor of Postinor-2 (levonorgestrel), in response to the issues raised at the June 2004 NDPSC meeting relating to the website created by the distributor. The Committee reaffirmed its view that the distributor had met its obligation and commitments made in its scheduling application with regard to the appropriate supply of Postinor-2 as an S3 medicine. It was further noted that the distributor had satisfactorily addressed the issues raised by the jurisdictions in relation to the Pharmacist-Only section of the Postinor-2 website.

National Drugs and Poisons Schedule Committee - February 2006

The Committee considered a proposal to amend the Schedule 3 entry for levonorgestrel to accommodate a single 1.5 mg tablet. The Committee agreed to amend the Schedule 3 entry for levonorgestrel for emergency post-coital contraception without specifying a particular dose regime.

National Drugs and Poisons Schedule Committee - June 2006

Unharmonised Medicines in the AusNZ Scheduling Database: The Committee considered the recommendations of the June 2006 TTHWP meeting. The Committee endorsed the TTHWP recommendations and agreed that substances for consideration of the NDPSC should be included on the agenda and pre-meeting gazette notice of the October 2006 NDPSC meeting. Similarly, the Committee agreed that recommendations to New Zealand should be referred to the MCC consideration at its next meeting.

Cyproterone acetate

National Health and Medical Research Council Poisons Schedule (Standing) Committee - May 1987

The Committee noted that general marketing approval had been granted for cyproterone acetate for treatment of moderate to severe androgenisation in females (including hirsutism), reduction of excessive sex drive in males with deviations and idiopathic precocious puberty. A Schedule 4 entry for cyproterone was recommended.

Gestodene

National Drugs and Poisons Schedule Committee - April 1994

The Committee noted that ADEC had recommended approval for the registration of gestodene for the prevention of pregnancy, subject to certain conditions being met. The Committee recommended a Schedule 4 entry.

Drospirenone

National Drugs and Poisons Schedule Committee - August 2001

The Australian Drug Evaluating Committee (ADEC) recommended that Yasmin tablets, containing drospirenone and ethinyloestradiol in a fixed combination, be approved for use as an oral contraceptive. The Committee agreed to include drospirenone in Schedule 4.

Pre-meeting public submissions

Twelve submissions were received.

Four submissions supported the proposal on the basis that the down scheduling would:

• Reduce the number of doctor visits and thereby help reduce the financial burden on the patients;
• Allow for repeat supply via pharmacy. However, the contributor considered that the initial take up of oral contraception should remain in the domain of general practice or other clinician;
• Allow pharmacists to provide these medications over the counter. However, the contributor considered that this should only be permitted for up to three to five years at a time, per client, before a prescription must be reissued by a GP or family planning clinician.
• The substances meet the scheduling factors for Schedule 3, however the substances should be prescribed by a GP in the first instance and legislation would need to be amended to allow trained pharmacists to authorise continuation of the substances under specified conditions.

Eight submissions opposed the proposal on the basis that:

• There is an increased risk of diabetes associated with the use of oral contraceptive pills;
• Doctor scripts last 12 months thereby minimising the number of doctor visits;
• No tests have been approved for oral contraceptive pills for use by women under 17.5 years;
• Currently, the systems and procedures for pharmacists to appropriately counsel, initiate and supply oral contraceptives to patients in community pharmacy settings are inadequate;
• The use of a checklist as proposed by the applicant is not considered an adequate alternative to comprehensive medical evaluations, factoring all aspects of a woman’s medical history and current health status that should occur prior to initiation of a contraceptive and during continuing use;
• Oral contraceptives may be supplied by pharmacists for cycle control (of irregular periods), which poses a health risk to women;
• Cost to Australian women and the Australian Government would be higher; and
• Oral contraceptives are not a 'one size fits all' medicine.

ACMS advice to the delegate

The ACMS recommended that the current scheduling of oestradiol, desogestrel, ethinyloestradiol, norethisterone, levonorgestrel, cyproterone, gestodene, drospirenone, mestranol, medroxyprogesterone, oestrogens and progestogens remains appropriate.

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 the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; and f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

• Risks included the potential increase in oral contraceptive pill use when alternative, safer, more effective and more appropriate contraceptive methods are available, potential exposure of females to oral contraceptives for up to 30 years, and that pharmacists are not currently trained to conduct physical examinations of patients. Risks to users depend on the stage of treatment - the first 3-12 months are highest risk, and may require titration and changes in treatment.
• Oral contraceptives have other uses (in addition to birth control). Concerns were expressed that women may falsely declare the indication for the purpose of supply, compromising monitoring.
• Use of oral contraceptives may potentially mask serious health issues. Chronic use is associated with adverse effects. The incidence and severity varies, and some may be detected by routine screening (e.g. cancer), while others require the patient to present for symptoms (migraine, thrombosis). There is a significant increase in the risk of stroke if the patient is a smoker.
• Inappropriate use of oral contraceptive pills, particularly to treat painful heavy bleeding, could increase future fertility problems and control symptoms for patients with undiagnosed endometrial hyperplasia, endometrial polyps or endometrial carcinoma.

Delegate's considerations

The delegate considered the following in regards to this proposal:

• Scheduling proposal;
• Public submissions received;
• The evaluation report (not publically available);
• ACMS advice;
• Section 52E of the Therapeutic Goods Act 1989;
• Scheduling factors¹;
• Other relevant information.

Delegate's interim decision

The delegate's interim decision is that the current scheduling of oestradiol, desogestrel, ethinyloestradiol, norethisterone, levonorgestrel, cyproterone, gestodene, drospirenone, mestranol, medroxyprogesterone, oestrogens and progestogens remains appropriate.

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 the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; and f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

• Risks included the potential increase in oral contraceptive pill use when alternative, safer, more effective and more appropriate contraceptive methods are available, potential exposure of females to oral contraceptives for up to 30 years, and that pharmacists are not currently trained to conduct physical examinations of patients. Risks to users depend on the stage of treatment - the first 3-12 months are highest risk, and may require titration and changes in treatment.
• Oral contraceptives have other uses (in addition to birth control). Concerns were expressed that women may falsely declare the indication for the purpose of supply, compromising monitoring.
• Use of oral contraceptives may potentially mask serious health issues. Chronic use is associated with adverse effects. The incidence and severity varies, and some may be detected by routine screening (e.g. cancer), while others require the patient to present for symptoms (migraine, thrombosis). There is a significant increase in the risk of stroke if the patient is a smoker.
• Inappropriate use of oral contraceptive pills, particularly to treat painful heavy bleeding, could increase future fertility problems and control symptoms for patients with undiagnosed endometrial hyperplasia, endometrial polyps or endometrial carcinoma.
• The use of a checklist as proposed by the applicant is not considered an adequate alternative to comprehensive medical evaluations, factoring all aspects of a woman's medical history and current.

1.2 Hydrocortisone/Aciclovir

Scheduling proposal

The medicines scheduling delegate (the delegate) has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):

• To amend the Schedule 3 entry for hydrocortisone 1 per cent (1%w/w) when compounded with aciclovir 5% w/w or less in primary packs of not more than 2 g for dermal use in adults and adolescents (12 years of age and older); and
• To include aciclovir in Appendix H.

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

Substance summary

The applicant has provided the following information regarding the substance:

• Aciclovir is a synthetic nucleoside analogue active, which is an antiviral agent highly active in vitro against HSV-1 and HSV-2.
• Hydrocortisone is the main glucocorticoid secreted by the adrenal cortex. Pharmacologically, it is a mild corticosteroid that exerts a range of immunomodulatory effects; when applied topically, it reduces skin inflammation.

Scheduling status

Hydrocortisone compounded with aciclovir is not specifically scheduled.

ACICLOVIR is currently listed in Schedule 4.

Schedule 4

ACICLOVIR except in preparations containing 5 per cent or less of aciclovir for the treatment of herpes labialis in packs containing 10 g or less.

HYDROCORTISONE and HYDROCORTISONE ACETATE is currently listed in Schedules 4, 3 and 2.

Schedule 4

HYDROCORTISONE:

1. For human use except when included in Schedule 2 or 3; or
2. For the treatment of animals.

Schedule 3

HYDROCORTISONE and HYDROCORTISONE ACETATE, but excluding other salts and derivatives, in preparations for human therapeutic use containing 1 per cent or less of hydrocortisone:

1. for dermal use, in packs containing 30 g or less of such preparations, containing no other therapeutically active constituent other than an antifungal substance; or
2. for rectal use when combined with a local anaesthetic substance but no other therapeutically active constituent except unscheduled astringents:
   1. in undivided preparations, in packs of 35 g or less; or
   2. in packs containing 12 or less suppositories,
   3. except when included in Schedule 2.

Schedule 2

HYDROCORTISONE and HYDROCORTISONE ACETATE, but excluding other salts and derivatives, in preparations for human therapeutic use containing 0.5 per cent or less of hydrocortisone:

1. for dermal use, in packs containing 30 g or less of such preparations, containing no other therapeutically active constituent other than an antifungal substance; or
2. for rectal use when combined with a local anaesthetic substance but no other therapeutically active constituent except unscheduled astringents:
   1. in undivided preparations, in packs of 35 g or less; or
   2. in packs containing 12 or less suppositories.

HYDROCORTISONE is also included under the entry Hydrocortisone in Appendix H and in Appendix F with the following statements.

Appendix F

Scheduling history

Hydrocortisone

National Health and Medical Research Poisons (Standing) Committee May 1981

The Committee confirmed that the scheduling of hydrocortisone remained appropriate, i.e. in Schedule 4. The PSC confirmed this position again in February 1982.

National Health and Medical Research Poisons (Standing) Committee: August 1985

The Committee decided to reschedule hydrocortisone to Schedule 3 for 0.5% or less of hydrocortisone when present as the only therapeutically active substance.

National Health and Medical Research Poisons (Standing) Committee: November 1988

The Committee decided not to reschedule 1% or less of hydrocortisone to Schedule 3 on the basis of advice from the then Australian Drug Evaluation Committee that the product in question was pharmacologically more active than other brands of 1% hydrocortisone cream in causing vasoconstriction.

National Drugs and Poisons Schedule Committee: May 1995

The Committee considered an application to reschedule rectal preparations containing hydrocortisone and cinchocaine from Schedule 4 to Schedule 3. In-principle support was given to the scheduling proposal, pending further advice. A decision was subsequently made out–of-session to reschedule hydrocortisone and cinchocaine topical preparations for rectal use, from Schedule 4 to Schedule 3.

National Drugs and Poisons Schedule Committee: February 1996

The Committee confirmed that the intent of the May 1995 decision was to allow preparations containing 0.5% or less of hydrocortisone (alone or in combination with cinchocaine) to be available for rectal use (internal and externally) in both the ointment and suppository form, as Schedule 3.

National Drugs and Poisons Schedule Committee: August 1998

The Committee decided not to list hydrocortisone and cinchocaine rectal preparations in Appendix H. This decision was primarily on the grounds that the incidence of misdiagnosis of fungal infections may be increased.

National Drugs and Poisons Schedule Committee: February 1999

The Committee decided to reschedule hydrocortisone and hydrocortisone acetate for dermal use containing 0.5% or less of hydrocortisone in packs containing 30 g or less of such preparation with no other therapeutically active substance or an antifungal as the only other therapeutically active substance, to Schedule 2. The Schedule 3 entry was also amended to include a specific reference to suppositories.

National Drugs and Poisons Schedule Committee: May 1999

The Committee decided to include hydrocortisone in preparations for rectal use in Appendix H.

National Drugs and Poisons Schedule Committee: November 2001

The Committee considered the scheduling of products containing hydrocortisone and hydrocortisone acetate, with astringents as active ingredients, for rectal use. The Committee decided to amend the scheduling of hydrocortisone and hydrocortisone acetate to exempt unscheduled astringents and restore the product to Schedule 3. The NDPSC considered that the presence of aluminium acetate and zinc oxide the product, whilst therapeutically active, were there primarily for their astringent effects rather than for systemic effects.

National Drugs and Poisons Schedule Committee: June 2002

The Committee decided not to include hydrocortisone for dermal use in Appendix H. However, in response to post-meeting comment, the October 2002 they reconsidered this scheduling proposal and decided to include hydrocortisone for dermal use in Appendix H.

National Drugs and Poisons Schedule Committee: October 2005

The Committee considered an application for the rescheduling of hydrocortisone acetate (in combination with an anaesthetic) for rectal use from Schedule 3 to Schedule 2. The NDPSC decided that the scheduling of hydrocortisone remained appropriate.

National Drugs and Poisons Schedule Committee: June 2006

The Committee reconsidered an application to reschedule hydrocortisone acetate (in combination with an anaesthetic) for rectal use. The Committee decided that the current scheduling of hydrocortisone and hydrocortisone acetate remained appropriate.

National Drugs and Poisons Schedule Committee: February 2007

The Committee decided to reschedule hydrocortisone 0.5% in combination with an anaesthetic for rectal use from Schedule 3 to Schedule 2 to harmonise with New Zealand.

National Drugs and Poisons Schedule Committee: June 2007

The Committee decided to amend the Schedule 2 and 3 entries to only capture human use. This was a result of a decision to vary the February 2007 decision to capture all veterinary use in Schedule 4.

National Drugs and Poisons Schedule Committee: October 2007

The Committee decided to correct the wording of the Schedule 2 entry for hydrocortisone to specify human rectal use, in line with the decision of the June 2007 meeting.

National Drugs and Poisons Schedule Committee: June 2008

The Committee decided to include hydrocortisone in Appendix F, Part 3, with warning statements 38, 72, 73, 74 and 75 (for dermal use when included in Schedule 2 or 3), and warning statements 38 & 75 (for topical rectal use when included in Schedule 2 or 3).

Advisory Committee on Medicines Scheduling: March 2014

The Committee considered a proposal to reschedule preparations containing 1 per cent or less of hydrocortisone and hydrocortisone acetate when combined with antifungal substances for dermal use from Schedule 3 to Schedule 2. The Committee decided that the current scheduling of hydrocortisone and hydrocortisone acetate remains appropriate.

Aciclovir

National Health and Medical Research Council Poisons Schedule (Standing) Committee: August 1984

The Committee agreed that cefoperazone, ciclacillin and acyclovir should be scheduled in Schedule 4.

National Health and Medical Research Council Poisons Schedule (Standing) Committee: May 1993

The Committee considered a request from Wellcome Australia Limited to consider an application for a change of topical acyclovir scheduling from Schedule 4 to Schedule 3, for an OTC indication, without the product or indication having already been approved by the TGA. The Committee declined to consider the application for a drug product which it believed should be evaluated through the appropriate channels.

National Drugs and Poisons Schedule Committee: May 1996

The Committee considered a submission from GlaxoWellcome in support of a change from Schedule 4 to Schedule 2 for acyclovir cold sore cream (5% w/w, 2g). The Committee noted that when the sponsor had applied for ADEC approval for the indication for "the treatment of herpes simplex viral infection of the lips" that Committee had agreed to the indication. The Committee agreed to waive the "2 year rule" in view of the fact that acyclovir has been used for many years as an eye ointment in Australia and had been available overseas for many years as a cold sore non-prescription preparation, without giving rise to public health concerns.

National Drugs and Poisons Schedule Committee: August 1997

The Committee noted advice from the Proprietary Medicines Association of Australia that the TGA Approved Name for acyclovir had been changed to aciclovir.

National Drugs and Poisons Schedule Committee: August 1998

The Committee agreed that Schedule 2 was appropriate for dermal preparations containing penciclovir. The Committee did not consider that there was sufficient justification to require Warning Statement 64 on either aciclovir or penciclovir cold sore creams.

National Drugs and Poisons Schedule Committee: February 1999

The Committee endorsed the modification to the existing schedule 2 entry for aciclovir to read: "ACICLOVIR FOR EXTERNAL USE FOR THE TREATMENT OF HERPES LABIALIS."

National Drugs and Poisons Schedule Committee: November 1999

The Schedule entry for aciclovir was amended to read: ACICLOVIR for external use for the treatment of herpes labialis.

National Drugs and Poisons Schedule Committee: November 2001

The Committee considered the proposal to exempt preparations containing 5% or less of aciclovir for dermal use from the requirements of scheduling. The Committee agreed to exempt dermal preparations containing aciclovir for use in the treatment of cold sores from the requirements of scheduling with appropriate pack size restriction which accommodated existing S2 products.

National Drugs and Poisons Schedule Committee: February 2002

The Committee reconsidered the Schedule 2 amendment for aciclovir made at the November 2001 meeting. The Committee confirmed that Decision 2001/33-12 from the November 2001 meeting, exempting 5% or less aciclovir for the treatment of Herpes labialis in pack sizes of 10 g or less, remains appropriate.

National Drugs and Poisons Schedule Committee: October 2002

The Committee considered the recommendations of NZ MCC on the harmonisation of aciclovir and decided that it should remain unharmonised and be placed on the 2-year review list of unharmonised substances.

National Drugs and Poisons Schedule Committee: October 2003

MCC was advised of the Committee's decision in October 2002 that aciclovir was to remain unharmonised.

National Drugs and Poisons Schedule Committee: February 2005

The Committee considered the harmonisation of scheduling for aciclovir in 5% preparations for the treatment of herpes labialis. The Committee agreed with the TTHWP's assessment and on the grounds of harmonisation, the Committee agreed to recommend to the New Zealand Ministry of Health that based on a history of safe use and in the interests of harmonisation, the 10 gram pack size of 5% aciclovir products within the general sales classification be harmonised with Australia.

Pre-meeting public submissions

Three submissions were received which supported the proposal on the basis that there is:

• no evidence that a departure from the existing scheduling policy is warranted for the combination of dermal hydrocortisone and aciclovir and that a Schedule 3 entry is appropriate;
• sound justification for the combination of hydrocortisone plus aciclovir to be covered by the existing Appendix H entry for hydrocortisone.

ACMS advice to the delegate

The ACMS recommended that the Schedule 3 entry for hydrocortisone be amended to allow for 1 per cent or less of hydrocortisone when compounded with aciclovir 5% w/w or less in primary packs of not more than 2 g for dermal use in adults and adolescents (12 years of age and older).

The ACMS recommended an implementation date of 1 October 2015.

Regarding the proposal to include aciclovir in Appendix H, the ACMS recommended that it is not necessary to create a new Appendix H entry for aciclovir.

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 the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

• Both hydrocortisone and aciclovir at the proposed topical concentrations have been individually available at Schedule 3 or exempt from scheduling for many years without any significant public health concerns. Data indicate a risk:benefit ratio consistent with a Schedule 3 listing for combination preparations for topical treatment of herpes labialis.
• Early access for consumers to this combination product from a pharmacist for recurrent cold sores is likely to be beneficial in reducing progression of symptoms and safe. Inclusion in Schedule 3 will mean that the product is accessed in consultation with a pharmacist for advice, education and checking appropriate use.
• Herpes labialis can be identified by the consumer. Topical aciclovir has been exempt from scheduling for over a decade without signals indicating significant risk at this scheduling level. Mandatory pharmacist assessment at the time of sale will reduce risk where hydrocortisone is combined with aciclovir for the same indication and ensures the patient will have sufficient information about the recommended duration of use.
• Toxicity is minimal at the proposed strength and duration of use.
• Both ingredients have been available without prescription (at the same strengths) for more than 10 years as dermal preparations with good safety profiles and large consumer experience. It is likely that risks would be similarly low in the combination product.
• Risks are minimised by the small pack size (2 g tube) and dermal application.
• Combination aciclovir 5% and hydrocortisone 1% dermal cream in packs of 2 g will be used for same indication and same route of administration, dose and timing (frequency, duration) as aciclovir 5% cream.
• The applicant's proposed labelling and Consumer Medicine Information promote appropriate use and health education.
• Very limited abuse potential - there is the same potential for possible off-label misuse (genital herpes) as for aciclovir 5% available on general sale.
• The combination product may be more effective in early treatment of cold sores, reducing progression rates and lesion area. Improving access to early treatment via a pharmacist reduces consumer treatment burden, and has the potential to improve self-management health outcomes. Allowing advertising to consumers would improve consumer awareness of timely access to the combination.

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 factors²;
• Other relevant information.

Delegate's interim decision

The delegate's interim decision is that:

• the Schedule 3 entry for hydrocortisone be amended to additionally allow for 1 per cent or less of hydrocortisone when compounded with aciclovir 5% w/w or less in primary packs of not more than 2 g for dermal use in adults and adolescents (12 years of age and older).
• that it is not necessary to create a new Appendix H entry for aciclovir.

The proposed implementation date for the Schedule 3 amendment is 1 October 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 the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; and d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the Amendment to Schedule 3 recommendation comprised the following:

• the risk:benefit ratio is consistent with a Schedule 3 listing for combination preparations for topical treatment of herpes labialis.
• early access for consumers to this combination product from a pharmacist for recurrent cold sores is likely to be beneficial in reducing progression of symptoms and safe. Inclusion in Schedule 3 will mean that the product is accessed in consultation with a pharmacist for advice, education and checking appropriate use.
• Herpes labialis can be identified by the consumer. Topical aciclovir has been exempt from scheduling for over a decade without signals indicating significant risk at this scheduling level. Mandatory pharmacist assessment at the time of sale will reduce risk where hydrocortisone is combined with aciclovir for the same indication and ensures the patient will have sufficient information about the recommended duration of use.
• minimal at the proposed strength and duration of use.
• risks are minimised by the small pack size (2 g tube) and dermal application.
• combination aciclovir 5% and hydrocortisone 1% dermal cream in packs of 2 g will be used for same indication and same route of administration, dose and timing (frequency, duration) as aciclovir 5% cream.

The reasons for the Amendment to Schedule 3 recommendation comprised the following:

• the proposed product contains 1% hydrocortisone and aciclovir at or below 5% in a pack of 2g or less for the treatment of herpes labialis. Therefore the aciclovir component of the new product continues to be within the existing limit (5% or less, 10g or less) for exemption from the requirements of the Poisons Standard. Products containing ingredients that are exempt from these requirements may be advertised to the public in accordance with the advertising requirements; and
• hydrocortisone is included in Appendix H without qualification and any product containing hydrocortisone when included in Schedule 3 (amended as proposed) may therefore be advertised to the public in accordance with the advertising requirements.
• accordingly, no additional change to the Poisons Standard is required to permit the advertising of the combination hydrocortisone/aciclovir product to the public.

Schedule entry

Schedule 3 - Amendment

HYDROCORTISONE and HYDROCORTISONE ACETATE, but excluding other salts and derivatives, in preparations for human therapeutic use containing 1 per cent or less of hydrocortisone:

1. for dermal use, in packs containing 30 g or less of such preparations, containing no other therapeutically active constituent other than an antifungal substance; or
2. for dermal use, in packs containing 2 g or less of such preparations, containing no other therapeutically active constituent other than aciclovir (5% w/w or less) in adults and adolescents (12 years of age and older); or
3. for rectal use when combined with a local anaesthetic substance but no other therapeutically active constituent except unscheduled astringents:
   1. in undivided preparations, in packs of 35 g or less; or
   2. in packs containing 12 or less suppositories;
   3. except when included in Schedule 2.

1.3 Diphenoxylate

Scheduling proposal

The medicines scheduling delegate (the delegate) has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):

• To down schedule diphenoxylate 2.5mg or less in packs of 8 or less dosage units, when combined with a quantity of atropine sulphate equivalent to at least 1 per cent of the dose of diphenoxylate from Schedule 3 to Schedule2; and
• To remove diphenoxylate from Appendix H.

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

Substance summary

The applicant has provided the following information regarding the substance:

• Diphenoxylate is chemically related to pethidine and acts by slowing intestinal motility and peristalsis allowing consolidation of intestinal content and protraction of its transit time, and extraction of moisture.
• Diphenoxylate is essentially devoid of 'morphine type subjective effects' at therapeutic doses. The potential for abuse appears to be limited.
• Diphenoxylate hydrochloride is well absorbed from the gastrointestinal tract and extensively metabolised in the liver to diphenoxin.

Atropine sulphate is included in the formulation as an anti-abusing agent contributing to the safe use of the product and is sub-therapeutic at 0.025 mg.

Atropine is an antimuscarinic agent which competitively antagonizes acetylcholine at postganglionic nerve endings, thus affecting receptors of the exocrine glands, smooth muscle, cardiac muscle and the central nervous system.

Scheduling status

DIPHENOXYLATE is currently listed in Schedules 8, 4 and 3.

Schedule 8

DIPHENOXYLATE except when included in Schedule 3 or 4.

Schedule 4

DIPHENOXYLATE in preparations containing, per dosage unit, 2.5 mg or less of diphenoxylate and a quantity of atropine sulfate equivalent to at least 1 per cent of the dose of diphenoxylate except when included in Schedule 3.

Schedule 3

DIPHENOXYLATE in packs of 8 or less dosage units, each dosage unit containing 2.5 mg or less of diphenoxylate and a quantity of atropine sulfate equivalent to at least 1 percent of the dose of diphenoxylate.

Diphenoxylate is also included under the entry Diphenoxylate in Appendix H and F with the following statements:

Appendix F

Scheduling history

National Health and Medical Research Council Poisons Scheduling Sub-committee (the Committee): November 1963

The Committee recommended that diphenoxylate in preparations containing 2.5 mg or less of diphenoxylate and not less than 25 micrograms of atropine (sulphate) per dosage unit be placed in Schedule 2.

National Health and Medical Research Council Poisons Scheduling Sub-committee: July 1964

Lomotil - The Public Health Advisory Committee requested the Committee to give an opinion as to whether or not there should be an upper limit specified for the amount of atropine sulphate which is required to be present in combination with the diphenoxylate. Information was to be sort from W.H.O.

National Health and Medical Research Council Poisons Scheduling Sub-committee: September 1964

Information received from W.H.O.: In setting the lower limit on the atropine the Narcotics Control Authorities were only interested in preventing abuse, not poisoning. The Committee advised the Public Health Advisory Committee that the amount of atropine which may be present in any schedule 2 preparation must be not greater than 0.25%.

National Health and Medical Research Council Poisons Scheduling Sub-committee: January 1965

Victoria raised concerns around indiscriminate use of preparations containing diphenoxylate which may result in intensification of bowel blockage when partial blockage was present plus upset blood chemistry. The Committee recommended that diphenoxylate remain in Schedule 2.

National Health and Medical Research Council Poisons Scheduling Sub-committee: December 1965

At the request of GD Searle and Co Ltd, the scheduling of the preparation of diphenoxylate hydrochloride with atropine sulphate (Lomotil) was reviewed. GD Searle had advised that Victoria had placed the preparation in Schedule 4. The Committee recommended that the entry in Schedule 2 regarding diphenoxylate be deleted and a similar entry be made in Schedule 4 to read: "Diphenoxylate is preparations containing 2.5 mg or less of diphenoxylate and note less than 25 micrograms of atropine sulphate per dosage units".

National Drugs and Poisons Schedule Committee: February 1998

The Committee considered a submission to down-schedule from Schedule 4 to Schedule 2 of packs of eight Lomotil® tablets (containing 2.5 mg of diphenoxylate and atropine sulfate 25 µg). The Committee decide that there was to be no change to the Schedule 4 entry for diphenoxylate.

National Drugs and Poisons Schedule Committee: May 1998

The Committee considered a request from Searle for reconsideration of the decision made in February 1998 meeting. The Committee did not support the rescheduling of Lomotil in small pack sizes to Schedule 2, but agreed that Schedule 3 would be the more appropriate classification.

National Drugs and Poisons Schedule Committee: August 1998

The Committee considered correspondence from the Australian College of Paediatrics, and the Director of Paediatrics at Canberra Hospital requesting reconsideration of the May 1998 Meeting decision to include diphenoxylate and atropine tablets in Schedule 3. The Committee agreed that the decision of the May 1998 Meeting to include diphenoxylate and atropine tablets in Schedule 3 was appropriate.

National Drugs and Poisons Schedule Committee: November 1998

The Committee considered a submission from Searle requesting the inclusion of diphenoxylate (as Lomotil) in Appendix H. The Committee was not convinced by the arguments in support of Schedule 3 advertising and decided that it should not be included in Appendix H.

National Drugs and Poisons Schedule Committee: February 1999

The Committee considered a submission from Searle requesting a reconsideration of the decision of the November 1998 Meeting that Lomotil^® tablets (diphenoxylate 2.5 mg and atropine 0.025 mg) when included in Schedule 3 should not be permitted to be advertised. The Committee reaffirmed its previous decision – diphenoxylate should not be included in Appendix H.

National Drugs and Poisons Schedule Committee: May 2000

The Committee considered submissions from Searle requesting that diphenoxylate in combination with atropine be rescheduled from Schedule 3 to Schedule 2, or if that was not supported, be included in Appendix H. The Committee did not support the rescheduling of diphenoxylate from Schedule 3 to Schedule 2, however, the proposal to include diphenoxylate in Appendix H was supported.

Pre-meeting public submissions

Two submissions were received. Both did not support the proposal as there is a risk of consumers incorrectly selecting diphenoxylate, particularly to treat diarrhoea in children or in pregnancy, and thus its use requires pharmacy intervention. One submission suggested removing the substance from Appendix H, as it carries a higher risk profile compared to other substances with similar indications.

ACMS advice to the delegate

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

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 the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

• Diphenoxylate carries a higher risk profile than other medications with similar indications. It can produce euphoria and other psychoactive effects in very high doses. In deliberate overuse, it is potentially habit-forming and can lead to significant tolerance and physical dependence if taken continuously for a protracted period.
• Like all anti-peristaltic agents, diphenoxylate may prolong / worsen diarrhoea associated with organisms that penetrate the intestinal mucosa.
• Diphenoxylate presents risks to patients with ulcerative colitis, as agents that inhibit motility have been reported to induce toxic megacolon.
• Diphenoxylate may interact with monoamine oxidase (MAO) inhibitors, potentially causing hypertensive crisis.
• Caution is required in patients with advanced hepatorenal disease, abnormal liver function, children aged under 12 years, the elderly, patients with other medical conditions, eg. diabetes, impaired renal or hepatic function, pregnancy and lactation.
• Risks also include adverse effects, as noted in the TGA's Database of Adverse Event Notifications (DAEN), the New Zealand Centre for Adverse Reactions Monitoring (CARM) database and the Product information (PI). OTC products containing diphenoxylate require a number of label warnings - the Required Advisory Statements for Medicines Labels (RASML) requires label warnings re drowsiness (and avoid alcohol), advice that treatment should not be continued beyond 48 hours, or in pregnancy or lactation, except on the advice of a doctor, and the contraindication "Do not give to children under 12 years of age".

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 factors³;
• Other relevant information.

Delegate's interim decision

The delegate's interim decision is that the current scheduling of diphenoxylate, including its Appendix H entry, remains appropriate.

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 the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the 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:

• Diphenoxylate carries a higher risk profile than other medications with similar indications. It can produce euphoria and other psychoactive effects in very high doses. In deliberate overuse, it is potentially habit-forming and can lead to significant tolerance and physical dependence if taken continuously for a protracted period.
• Like all anti-peristaltic agents, diphenoxylate may prolong / worsen diarrhoea associated with organisms that penetrate the intestinal mucosa.
• Diphenoxylate presents risks to patients with ulcerative colitis, as agents that inhibit motility have been reported to induce toxic megacolon.
• Diphenoxylate may interact with monoamine oxidase (MAO) inhibitors, potentially causing hypertensive crisis.
• Caution is required in patients with advanced hepatorenal disease, abnormal liver function, children aged under 12 years, the elderly, patients with other medical conditions, eg. diabetes, impaired renal or hepatic function, pregnancy and lactation.
• Risks also include adverse effects, as noted in the TGA's Database of Adverse Event Notifications (DAEN), the New Zealand Centre for Adverse Reactions Monitoring (CARM) database and the Product information (PI). OTC products containing diphenoxylate require a number of label warnings - the Required Advisory Statements for Medicines Labels (RASML) requires label warnings re drowsiness (and avoid alcohol), advice that treatment should not be continued beyond 48 hours, or in pregnancy or lactation, except on the advice of a doctor, and the contraindication "Do not give to children under 12 years of age".

1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
2. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
3. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)