Publication of interim decisions amending, or not amending, the current Poisons Standard, June 2018

Scheduling medicines and poisons

7 June 2018

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2.1 Prostaglandins

2. Joint meeting of the Advisory Committee on Chemicals and Medicines Scheduling (ACCS/ACMS #18)

2.1 Prostaglandins

Delegate's interim decision

The delegate's interim decision is that the current scheduling of all prostaglandins in the Poisons Standard remains appropriate.

Reasons:

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:

  1. the risks and benefits of the use of a substance:
    • Each substance was considered on its own risks and pattern of use
    • Risk: Including all prostaglandins for obstetrics/gynaecology use in Appendix D Item 1 would restrict prescribing this class of substance to authorised medical practitioners. Doctors who may require to use them in an emergency would not be able to access them.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Multiple therapeutic uses exist for prostaglandins as there are multiple compounds.
    • In the context of this agenda item, prostaglandins are used for:
      • The treatment of post-partum haemorrhage due to uterine atony;
      • For the therapeutic termination of pregnancy; and
      • For induction of labour.
  3. the toxicity of a substance:
    • Variable depending on prostaglandin however not relevant to putting increased controls on all of them.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Variable depending on prostaglandin however not relevant to putting increased controls on all of them.
  5. the potential for abuse of a substance:
    • Limited.
  6. any other matters that the Secretary considers necessary to protect public health:
    • Including all prostaglandins for obstetrics/gynaecology use in Appendix D Item 1 would restrict prescribing this whole class of substance to authorised medical practitioners. Doctors who may require to use them in an emergency would not be able to access them.
    • It is appropriate that the current prostaglandins in Appendix D remain there.
Scheduling proposal

The pre-meeting scheduling proposal for prostaglandins was published on the TGA website on 21 December 2017 at Consultation: Proposed Amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS-ACMS meetings, March 2018.

Background information for prostaglandins
Referred scheduling proposal

The delegate of the Secretary proposed an amendment to the scheduling of prostaglandins in the Poisons Standard by either:

  • Placing all applicable prostaglandins in Appendix D Item 1 and include a general entry in Appendix D Item 1 for 'PROSTAGLANDINS when used in obstetrics/gynaecology';
  • OR
  • Removing those prostaglandins currently listed in Appendix D Item 1
Scheduling application

The proposed amendments to the Poisons Standard are reflected below:

Appendix D, Item 1 - New Entries

CARBOPROST for obstetrics/gynaecology use.

CLOPROSTENOL for obstetrics/gynaecology use.

ETIPROSTON for obstetrics/gynaecology use.

FENPROSTALENE for obstetrics/gynaecology use.

FLUPROSTENOL for obstetrics/gynaecology use.

GEMEPROST for obstetrics/gynaecology use.

MISOPROSTOL for obstetrics/gynaecology use.

PROSTIANOL for obstetrics/gynaecology use.

Appendix D, Item 1 - Amend Entries

DINOPROST for obstetrics/gynaecology use.

DINOPROSTONE for obstetrics/gynaecology use.

PROSTAGLANDINS for obstetrics/gynaecology use.

The reasons for the proposal are:

  • Inconsistencies in prostaglandin entries in Schedule 4 and Appendix D Item 1.
Current scheduling status

Prostaglandins are listed in Schedule 4 of the Poisons Standard as follows:

Schedule 4

ALPROSTADIL.

BIMATOPROST.

CARBOPROST.

CLOPROSTENOL.

# DINOPROST.

# DINOPROSTONE.

ENPROSTIL.

EPOPROSTENOL.

ETIPROSTON.

FENPROSTALENE.

FLUPROSTENOL.

GEMEPROST.

ILOPROST.

LATANOPROST.

MISOPROSTOL.

PROSTAGLANDINS.

PROSTIANOL.

TAFLUPROST.

TRAVOPROST.

TREPROSTINIL.

UNOPROSTONE.

Some are also included in Appendices D, F and L as follows:

Appendix D, Item 1

DINOPROST for human use.

DINOPROSTONE for human use.

Appendix F, Part 3

MISOPROSTOL

Appendix L, Part 2

MISOPROSTOL.

Scheduling history

Prostaglandins

In August 1975, the Poisons Schedule Sub-Committee (PSSC) considered a previous deferred item to include prostaglandins in Schedule 7 due to concerns of use in cattle and sheep and whether an entry should be made to cover research work. The PSSC agreed that prostaglandins should be included in Schedule 7 as they are new substances, have a wide range of biological activities and their functions are not fully understood. The PSSC also recommended only allowing availability to medical practitioners and veterinary surgeons with a specialised knowledge and experience with these types of substances, and only for approved research purposes.

In May 1981, the Poisons Schedule Committee (PSC) noted that the Schedule 7 entry for prostaglandins may not be appropriate, and they should be rescheduled from Schedule 7 to Schedule 4. This was deferred to the next meeting.

In November 1981, after agreeing to the inclusion of fenprostalene in Schedule 4 for animal use, the PSC agreed to amend the Schedule 7 entry for prostaglandins to include the words 'except when included in Schedule 4'.

In February 1982, the PSC discussed concerns raised by State and Territories in regards to the difficulties encountered with the Schedule 7 entry of prostaglandins being only for human use. It was agreed that they should continue being handled by State and Territories through appropriate amendments to regulations, rather than amending the Poisons Standard (SUSMP).

In November 1982, the PSC considered a letter regarding the scheduling of prostaglandins proposing that these therapeutic drugs require additional controls on possession and supply applied to them. It was recommended that a Schedule 4 and Appendix D listing would be more appropriate than their existing Schedule 7 entry. The committee agreed to the recommendation and deleted its Schedule 7 entry and created new entries in Schedule 4 and Appendix D with the control 'these substances should be available only to medical practitioners and veterinary surgeons with a specialised knowledge and experience with these types of substances, and for approved research purposes'.

In February 1985, the PSC discussed a recommendation to increase restrictions on the availability of prostaglandins due to an adverse reaction. The committee agreed that the current scheduling remained appropriate. The committee agreed that Appendix D was to be amended and split into two parts, and prostaglandins added to Appendix D, Part 1 - 'drugs to be available only from or on prescription of person or classes of person specifically authorised'.

In August 1986, the Drugs and Poisons Schedule Committee (DPSC) considered the issue of including specific prostaglandin entries in Schedule 4 and amending the Appendix D rider. This was due to a new prostaglandin product indicated to treat gastric or duodenal ulcers, but contraindicated for use in pregnancy and restricted for use by the Appendix D 'prostaglandins' class entry for specialist prescriptions. The matter was deferred to November 1986.

In November 1986, the DPSC reviewed the issue raised in the previous meeting. It was agreed that prostaglandin preparations for routine therapy should be available in Schedule 4, whereas the more specialised use products, (obstetrics, gynaecology, endocrinology) should be confined to specialist use. In situations where no specialist was available (rural areas etc.), medical practitioners authorised by State/Territory Health authorities would be permitted to use them. The committee agreed to individual entries in Appendix D, although the class entry for prostaglandins would be retained in Schedule 4, but deleted from Appendix D. It was also agreed to delete 'for treatment of animals' from existing individual prostaglandin entries in Schedule 4 as there was no need to refer to veterinary specialists.

In February 1993, the DPSC noted that no rationale had been stated to place dinoprostone in Appendix D. It was agreed that a rationalisation of the class of prostaglandins needed to be considered by the committee at a future meeting.

Alprostadil

In May 1982, the PSC agreed that alprostadil was already covered by the general Schedule 7 entry for prostaglandins.

In November 1986, the DPSC agreed to include alprostadil in Schedule 4.

In November 1997, the National Drugs and Poisons Scheduling Committee (NDPSC) considered an inclusion of alprostadil in Appendix D to prevent misuse. The committee decided to defer the decision as more information was required.

Bimatoprost

In October 2002, the NDPSC considered the scheduling of bimatoprost. The committee agreed to include bimatoprost in Schedule 4 on the grounds that the condition being treated required professional diagnosis, management and monitoring of the indicated condition and any side effects.

Carboprost

In November 1998, the NDPSC agreed to create a new Schedule 4 entry for carboprost due to consolidation of scheduling proposals arising from the Trans-Tasman Harmonisation of Scheduling of Drugs and Poisons Working Party.

Cloprostenol

In November 1975, the PSSC considered an application for the scheduling of cloprostenol. The sub-committee recommended a new Schedule 4 entry be created for the treatment of animals, and to amend the Schedule 7 entry for prostaglandins to exempt cloprostenol when included in Schedule 4.

In February 1982, the PSC discussed concerns raised by state and territories in regards to the difficulties encountered around prostaglandins. The subcommittee agreed to keep cloprostenol in Schedule 4 entry for the treatment of animals.

In November 1986, the DPSC agreed to delete from the Schedule 4 entry of cloprostenol the words 'for the treatment of animals'.

Dinoprost

In February 1982, the PSC agreed to create a new Schedule 4 entry for dinoprost for the treatment of animals.

In November 1986, the DPSC agreed to amend the Schedule 4 entry for dinoprost by deleting the words 'for the treatment of animals' and to also include dinoprost in Appendix D with the wording 'for human use' and 'this substance should be available only on the prescription or order of authorised medical practitioners.

In August 1997, the NDPSC considered a submission to remove dinoprost and dinoprostone from Appendix D which restricts its prescribing. The discussion was deferred to allow states and territories time to consult with jurisdictions and legislation.

In November 1997, the NDPSC agreed that dinoprost and dinoprostone should not be removed from Appendix D due to state and territory regulations.

Dinoprostone

In February 1991, the DPSC agreed to include dinoprostone in Schedule 4 and Appendix D for human use.

In February 1993, the DPSC noted that no rationale had been stated to place dinoprostone in Appendix D and how confusion has arisen as to why it is more difficult to obtain than gemeprost and other prostaglandins in Schedule 4. It was noted that general practitioners (GPs) do not support the Appendix D inclusion. It was agreed that this needed to be considered at a future meeting.

In August 1997, the National Drugs and Poisons Scheduling Committee (NDPSC) considered a submission to remove dinoprost and dinoprostone from Appendix D which restricts its prescribing. The discussion was deferred to allow States and Territories time to consult with jurisdictions and legislation.

In November 1997, the NDPSC agreed that dinoprost and dinoprostone should not be removed from Appendix D due to State and Territory regulations.

Enprostil

In November 1998, the NDPSC agreed to create a new Schedule 4 entry for enprostil due to consolidation of scheduling proposals arising from the Trans-Tasman Harmonisation of Scheduling of Drugs and Poisons Working Party.

Epoprostenol

In November 1999, the NDPSC agreed to include epoprostenol in Schedule 4 to harmonise with the Prescription Medicine classification in New Zealand.

Etiproston

In May 1996, the NDPSC considered an application for etiproston as a veterinary injectable. The committee noted that etiproston was covered by the class Schedule 4 entry for prostaglandins, but agreed that for clarification a separate Schedule 4 entry for etiproston was appropriate.

Fenprostalene

In November 1981, the PSC considered an application for fenprostalene, a synthetic analogue of the naturally occurring prostaglandin PGF2 alpha, to create a new entry in Schedule 4, even though the group entry for prostaglandins is in Schedule 7. The committee agreed that fenprostalene is well classified in Schedule 4 for animal use.

In November 1986, the DPSC agreed to delete from entry the words 'for the treatment of animals'.

Fluprostenol

In February 1982, the PSC agreed to create a new Schedule 4 entry for fluprostenol for the treatment of animals.

In November 1986, the DPSC agreed to delete from the Schedule 4 entry of fluprostenol the words 'for the treatment of animals'.

Gemeprost

In November 1986, the DPSC was advised that general practitioners should have access to gemeprost as it has a place in routine dilation and curettage (D & C) procedures. A new Schedule 4 entry was created.

In February 1991, the DPSC considered correspondence to include gemeprost in Appendix D, restricting its use to specialised physicians and/or institutions due to the potential for misuse. The members agreed that more research is required to investigate if gemeprost is being misused and to report back to a future meeting.

In November 1997, the NDPSC again considered an inclusion of gemeprost in Appendix D. The committee noted that this would achieve consistency among the group and was important due to the possible use of gemeprost by GPs to induce abortion. The committee noted that gemeprost was also indicated for surgical purposes, and placing gemeprost in Appendix D may remove access by GPs. The committee decided to defer the decision as more information was required.

In November 1998, the NDPSC revisited the consideration to include gemeprost in Appendix D. The committee agreed that inclusion of gemeprost in Appendix D would disadvantage certain States and Territories due to various mechanisms placed on Appendix D. The committee did not support the inclusion of gemeprost in Appendix D.

Iloprost

In November 1998, the NDPSC agreed to create a new Schedule 4 entry for iloprost due to consolidation of scheduling proposals arising from the Trans-Tasman Harmonisation of Scheduling of Drugs and Poisons Working Party.

Latanoprost

In May 1997, the NDPSC considered an application for a latanoprost eye drop was submitted and agreed to include latanoprost in Schedule 4.

Misoprostol

In May 1986, the DPSC agreed to include misoprostol in Schedule 4 after the Australian Drug Evaluation Committee (ADEC) had recommended approval of a product containing misoprostol.

In November 1986, the DPSC noted the warning statement for misoprostol regarding pregnant women in a handbook, and agreed to liaise with the sponsor and regulators regarding suitable warning labels.

In February 1990, the DPSC considered the need for misoprostol to be labelled with a warning statement for pregnant women. The committee agreed to include misoprostol in Appendix F, Part 2 with a new Warning Statement 53 'CAUTION (name of substance) should not be used by pregnant women)'.

In October 2007, the NDPSC considered an issue raised of inconsistencies between listings in Appendix D and ADEC's 'Prescribing Medicines in Pregnancy' handbook. It was noted that misoprostol is listed in ADEC's Category X but is not in Appendix D. The committee decided that misoprostol did not warrant inclusion in Appendix D as the original packaging requires a label warning statement due to its inclusion in Appendix F Part 3.

Prostianol

In February 1982, the PSC agreed to create a new Schedule 4 entry for prostianol for the treatment of animals.

In November 1986, the DPSC agreed to delete from entry the words 'for the treatment of animals'.

Tafluprost

In December 2010, the delegate considered an application to register tafluprost eye drops and decided that a Schedule 4 entry was appropriate. The delegate noted reproductive toxicity data and raised concerns during pregnancy and decided to refer it to the Advisory Committee on Medicines Scheduling (ACMS).

In February 2011, the ACMS considered a proposal to include tafluprost in Appendices D and L. The committee recommended that the scheduling of tafluprost remain unchanged (i.e. in Schedule 4 with no new Appendix D or L entry).

Travoprost

In June 2002, the NDPSC considered the scheduling of travoprost. The committee agreed to include travoprost in Schedule 4 on the grounds that the condition being treated required diagnosis and management by a medical professional.

Treprostinil

In June 2004, the NDPSC considered the scheduling of treprostinil. The committee agreed to include treprostinil in Schedule 4 on the grounds that the condition being treated necessitated appropriate medical diagnosis and the safe use of this medicine required administration, ongoing patient management and monitoring by a medical professional.

Unoprostone

In November 2000, the NDPSC considered a request to include unoprostone in Schedule 4 to harmonise with NZ. The committee agreed to create a Schedule 4 entry for unoprostone as it is a new substance that treats a condition that requires medical management and on the grounds of harmonisation.

Australian regulations

The Australian Register of Therapeutic Goods (ARTG) has 82 registered products with prostaglandins:

  • Alprostadil - 5 registered products for injection as powder preparations or solutions for erectile dysfunction;
  • Bimatoprost - 11 registered products as solutions for eye drops;
  • Dinoprost - 3 registered products for injection as solution preparations for pregnancy termination;
  • Dinoprostone - 4 registered products as gel preparations for labour induction;
  • Epoprostenol - 8 registered products for injection as powder preparations or solutions for pulmonary hypertension;
  • Gemeprost - 1 registered product as gel preparation for pregnancy termination;
  • Iloprost - 1 registered product in nebuliser solution for pulmonary hypertension;
  • Latanoprost - 36 registered products as solutions for eye drops;
  • Misoprostol - 7 registered products in tablet form for gastrointestinal ulceration and/or bleeding;
  • Tafluprost - 1 registered product as a solution for eye drops; and
  • Travoprost - 5 registered products as a solution for eye drops.
  • Currently no registered products listed on the ARTG for the following prostaglandins: carboprost, cloprostenol, enprostil, etiproston, fenprostalene, fluprostenol, prostianol, treprostinil and unoprostone.

There is no reference to prostaglandins in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018, as they are scheduled substances and are not eligible for use in ARTG listed medicines.

The APVMA PubCRIS database has 14 registered and 4 approved products with prostaglandins.

  • Cloprostenol - 10 registered and 4 approved products in parenteral liquid / solution, for the regulation of bovine, equine and porcine oestrus cycles or farrowing.
  • Dinoprost - 3 registered products in parenteral liquid / solution, for the regulation of bovine, equine and porcine oestrus cycles, abortion or parturition.
  • Etiproston - 1 registered products in parenteral liquid / solution, for the regulation of bovine oestrus cycles, abortion or parturition or the treatment of endometritis.

In the last 30 years there have been 1,962 reported cases of adverse events related to prostaglandins in the Database of Adverse Events Notification (DAEN) - Medicines: Of the 21 listed prostaglandins, a total of 870 cases with a single suspected medicine have been reported and 33 cases where death was a reported outcome.

International regulations
  • Alprostadil - New Zealand (NZ): Prescription; and the United States of America (USA): Prescription.
  • Bimatoprost - Canada: Prescription and USA: Prescription.
  • Carboprost - USA: Prescription.
  • Cloprostenol - Canada: Prescription.
  • Dinoprost - European Union (EU): Annex II, No 2377/90 and USA: discontinued.
  • Dinoprostone - Canada: Prescription, EU: Annex II, No 2377/90 and USA: Prescription.
  • Epoprostenol - Canada: Prescription and USA: Prescription.
  • Etiproston - EU: Annex II, bovine, porcine.
  • Fenprostalene - EU: withdrawn.
  • Fluprostenol - Canada: Prescription.
  • Iloprost - NZ: Prescription and USA: Prescription.
  • Latanoprost - NZ: Prescription, Canada: Prescription, EU: Prescription and USA: Prescription.
  • Misoprostol - NZ: Prescription, EU: Prescription and USA: Prescription.
  • Tafluprost - NZ: Prescription, EU: Prescription and USA: Prescription.
  • Travoprost - NZ: Prescription, EU: Prescription and USA: Prescription.
  • Treprostinil - Canada: Prescription, EU: Prescription and USA: Prescription.
  • Unoprostone - Canada: Prescription and USA: Prescription.
Substance summary
Table 2.1A: Chemical information for prostaglandins
Property Prostaglandins
CAS name Multiple
CAS number Multiple
Chemical structure Chemical structure of prostaglandins
Molecular formula Multiple
Molecular weight Multiple
IUPAC and/or common and/or other names Multiple

Prostaglandins are a diverse family of lipid compounds derived from arachidonic acid via the action of cyclooxygenase enzymes (COX). They have hormone-like effects that maintain homeostatic functions and have pathogenic and inflammatory actions.

The physiological actions of prostaglandins vary from one tissue to another and can determine blood vessel diameter (vasodilators or vasoconstrictors), have roles in thrombosis (pro- or anti- clot formation), pain sensitisation, parturition, gastric mucous production and bicarbonate secretion, calcium movement and renal filtration, among many other functions.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is a common means of reducing the production of prostaglandins via the inhibition of COX enzymes.

Pre-meeting public submissions

One (1) public submission was received in support of the proposal.

The main point provided in support of the amendment was:

  • The public submission endorsed the option of placing all applicable prostaglandins in Appendix D, Item 1 in the Poisons Standard and to include a general entry in Appendix D, Item 1 for 'PROSTAGLANDINS for obstetrics/gynaecology use'. This will increase uniformity and help manage medication safety.

The public submission will be made available on the TGA website.

Summary of ACCS advice to the delegate

The committee recommended that the current scheduling of all prostaglandins remains appropriate.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance.

The reasons for the advice were:

  1. the risks and benefits of the use of a substance:
    • Each substance was considered on its own risks and pattern of use
    • Risk: Including all prostaglandins for obstetrics/gynaecology use in Appendix D Item 1 would restrict prescribing this class of substance to authorised medical practitioners. People who may require these in an emergency cannot access them.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Multiple therapeutic uses exist for prostaglandins as there are multiple compounds.
    • There are a variety of therapeutic uses for prostaglandins.
    • In the context of this agenda item, prostaglandins are used for:
      • The treatment of post-partum haemorrhage due to uterine atony;
      • For the therapeutic termination of pregnancy; and
      • For induction of labour.
  3. the toxicity of a substance:
    • Variable.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Variable.
  5. the potential for abuse of a substance:
    • Limited.
  6. any other matters that the Secretary considers necessary to protect public health:
    • Nil.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACCS-ACMS advice;
  • Public submission received;
  • Scheduling Policy Framework (SPF 2018); and
  • Section 52E (1) of the Therapeutic Goods Act 1989, in particular: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

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