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Scheduling delegate's final decisions, July 2016

Scheduling medicines and poisons

27 October 2016

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4.1 Ulipristal

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

4. Scheduling proposals referred to the July 2016 meeting of the Advisory Committee on Medicines Scheduling (ACMS#18)

4.1 Ulipristal

Note

  • Red strikethrough text indicates text that has been deleted.
  • Green italicised text indicates text that has been added.
Referred scheduling proposal

An application was submitted to reschedule ulipristal and create a new Schedule 3 entry for ulipristal for emergency post-coital contraception.

Scheduling application

General application.

The applicant's proposed amendments to the SUSMP are as follows:

Schedule 4 - Amend entry

ULIPRISTAL except when included in Schedule 3.

Schedule 3 - New Entry

ULIPRISTAL for emergency post-coital contraception.

The applicant's reasons for the request are:

  • The applicant believes the substance meets the criteria for inclusion in Schedule 3, on the same basis as the current scheduling of levonorgestrel;
  • The risk of pregnancy is highest when ovulation is due to happen in the first day or two after unprotected sexual intercourse (UPSI) or contraceptive failure (Brache 2013, Glasier 2010). However, the timing of ovulation is difficult to predict. Ovulation can occur as early as the 8th day and as late as the 60th day of the menstrual cycle (Wilcox 2000);
  • For both levonorgestrel and ulipristal, it is important to take the medicine as soon as possible after UPSI (ref: PI Postinor 1 and EllaOne). Ulipristal is more effective if taken in the first 24 hours following UPSI (PI EllaOne). More than a decade of experience with levonorgestrel has shown that pharmacy access enables women to use emergency contraception (EC) quickly and appropriately without medical supervision;
  • Ulipristal acetate 30 mg tablet was approved in the European Union (EU) on 15 May 2009 and first marketed there on 1 October 2009, and as of 20 January 2016, in 89 countries including in the United States on 1 December 2010. It was re-classified as a non-prescription medicinal product in the EU (centralised procedure) on 7 January 2015 and in Switzerland on 15 January 2016. It is currently available without a doctor's prescription in 25 European countries;
  • In Australia 'EllaOne ulipristal acetate 30 mg tablet blister pack' was approved by TGA on 6 March 2015 (AUST R 219535). It is now approved for supply on doctor's prescription as an alternative to levonorgestrel for EC. The TGA-approved Product Information (PI), the Australian Consumer Medicine Information (CMI) and the Australian Public Assessment Report (AusPAR) are included in this submission;
  • While being comparable to levonorgestrel in adverse event profile, clinical and biological evidence demonstrate that ulipristal acetate 30 mg is more effective than levonorgestrel, especially when taken within the first 24 hours after UPSI, at the time when the vast majority of women ask for EC. In addition, it is effective within 5 days (120 hours) of UPSI compared to 3 days (72 hours) for levonorgestrel;
  • In public health terms ulipristal offers a reduction in unintended pregnancies (and possibly abortions) and gives women additional options, for instance where more than 3 days has elapsed since UPSI (noting that for maximum efficacy ulipristal should be taken as soon as possible after UPSI). To put this in context we have calculated, based on sales of levonorgestrel to Australian pharmacies over 12 months to April 2014 and a meta-analysis of 2 comparative clinical trials conducted in the UK, Ireland and the USA, a theoretical figure of more than 5000 additional unintended pregnancies that could be prevented in Australia per year if ulipristal were to be used in place of levonorgestrel; and
  • These benefits will only be realised in Australia if ulipristal is made available as a Schedule 3 medicine on the same basis as levonorgestrel. Even if women somehow become aware that a better alternative is available from doctors (noting that prescription medicines cannot be advertised to the general public), they are unlikely to go to a doctor for EC while levonorgestrel is conveniently available from pharmacies.
Substance summary

Ulipristal is an orally-active synthetic selective progesterone receptor modulator that acts via high affinity binding to the human progesterone receptor. When used for emergency contraception the mechanism of action is inhibition or delay of ovulation via suppression of the lutenising hormone (LH) surge.

Ulipristal is indicated for emergency contraception within 120 hours (5 days) of unprotected sexual intercourse or contraceptive failure.

The structure of ulipristal is shown in Figure 4.1 and a summary of its chemical properties are described in Table 4.1.

Figure 4.1: Structure of ulipristal

Figure 4.1: Structure of ulipristal

Table 4.1: General chemical information for ulipristal
Australian Approved Name (AAN) ulipristal acetate
Chemical name 17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione
Molecular formula C30H37NO4
Molecular weight 475.62 g/mol
CAS No. 126784-99-4
Specific questions raised by the delegate

The delegate asked the committee if it was appropriate for ulipristal to be available as a Schedule 3 medicine for emergency post-coital contraception and, if not, how it differs from levonorgestrel for emergency post-coital contraception.

Current scheduling status

Ulipristal is currently listed in Schedule 4 of the SUSMP.

Schedule 4

ULIPRISTAL.

Relevant scheduling history

In May 2015, the delegate considered an application from the Therapeutic Goods Administration (TGA) for the scheduling of ulipristal, a new chemical entity for a human therapeutic medicine. The delegate decided to make a delegate-only decision to include ulipristal in Schedule 4. The Advisory Committee on Medicines Scheduling was not consulted. Ulipristal was included in the SUSMP on 1 June 2015.

Pre-meeting public submissions

Sixteen (16) public submissions were received and all supported the application.

The key points made in the submissions were that rescheduling will provide more choice to women who require emergency contraception, that rescheduling would be consistent with the classification of the current available emergency contraception levonorgestrel, of which ulipristal has a similar safety profile, and that ulipristal is available without a doctor's prescription in at least 25 European countries.

The public submissions are available on the TGA website.

Summary of ACMS advice to the delegate

The committee advised that the proposal to down-schedule ulipristal to Schedule 3 was appropriate.

The ACMS advised an implementation date of 1 February 2017.

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.

The reasons for the advice included:

  • Substantial benefit in providing another emergency contraception (EC) option for women with the ability to be used up to 5 days after unprotected sexual intercourse;
  • Benefit outweighs risk for ulipristal's proposed use;
  • Access to EC via a Schedule 3 listing has been established in Australia for over 10 years. There is no evidence of use outside of the intended or increased extent of use of EC as a result of a Schedule 3 listing;
  • Consistent with overseas use and Schedule 4 use in Australia. Existing Schedule 3 alternative medicines are available, but they are less efficacious;
  • The safety and toxicity profile of ulipristal is similar to levonorgestrel;
  • The Product Information (PI) states that breastfeeding mothers need to cease to feed for 1 week post- exposure; this will need to be managed via the packaging, labelling and education of pharmacists;
  • Toxicity is minimal in recommended dose (1 tablet);
  • Single dose packaging and labelling are appropriate for Schedule 3;
  • There is no evidence of potential for abuse; and
  • There is minimal risk of use as an abortifacient with current doses.
Delegate's considerations

The delegate considered the following in regards to this application:

  • Scheduling proposal;
  • Public submissions received;
  • ACMS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling Policy Framework (SPF 2015); and
  • Other relevant information.
Delegate's interim decision

The delegate has considered and agrees with the advice and reasons of the ACMS to create a new Schedule 3 entry for ulipristal. There is substantial benefit in providing another, more effective, emergency contraception (EC) option for women with the ability to be used up to 5 days after unprotected sexual intercourse. The single dose packaging and labelling are appropriate for Schedule 3 given the safety and toxicity profile of ulipristal and its similarity to levonorgestrel. Over the 10 years in which EC has been available over the counter in Australia there has been no evidence of misuse or increased extent of use, and there is minimal risk of use as an abortifacient with currently available doses.

The proposed implementation date is 1 February 2017.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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.

Schedule 4 - Amend Entry

ULIPRISTAL except when included in Schedule 3.

Schedule 3 - New Entry

ULIPRISTAL for emergency post-coital contraception.

Public submissions on the interim decision

Seven (7) submissions were received and all supported the interim decision.

The key points made in the submissions were that the new Schedule 3 status would facilitate timely and easy access to highly effective emergency contraception, that ulipristal has a well demonstrated safety profile, that it is more effective than levonorgestrel, that it is used as emergency contraception in over 90 countries, and it is available in 25 European countries without a prescription.

Delegate's final decision

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

The implementation date is 1 February 2017.

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