Decision to widen access to sirolimus

Medicines Decision

We're pleased to announce a decision to widen funded access to sirolimus from 1 February 2021 for people with the below indications:

We estimate that approximately 70 people across these three indications will benefit each year from this proposal, with expected reductions in lesion and tumour size, stabilisation or improvement in organ function, reduction in seizure frequency and improved quality of life for affected people.

Any changes to the original proposal?

This decision was subject to a consultation letter dated 7 October 2020.

We thank all those who provided consultation feedback. Following review of the feedback received we have made some changes to the Special Authority criteria we consulted on. More information about these changes can be found below.

Who we think will be most interested

  • People with lymphovascular malformations and their whānau
  • People with tuberous sclerosis complex and their whānau
  • Clinicians and health professionals involved in the treatment and management of people with lymphovascular malformations and tuberous sclerosis complex (TSC) including (but not limited to);
    • neurologists
    • paediatricians
    • nephrologists
    • surgeons (e.g. urology, general, vascular, thoracic, paediatric, orthopaedic, ENT)
  • Hospital and community pharmacists
  • Pharmaceutical suppliers and wholesalers

Detail about this decision

Funded access to sirolimus (brand name ‘Rapamune’®) will be amended in Section B of the Pharmaceutical Schedule from 1 February 2021 to include people with lymphovascular malformations, renal angiomyolipoma associated with TSC, and people with refractory epilepsy associated with TSC as follows (new criteria shown below). Equivalent changes will also be made in Part II of Section H of the Pharmaceutical Schedule. No changes were made to the criteria for any of the other funded uses of these treatments.

Sirolimus for lymphovascular malformations:

Initial application – (severe non-malignant lymphovascular malformations*) from any relevant practitioner. Approvals valid for 6 months for applications meeting the following criteria:

All of the following:

  1. Patient has severe non-malignant lymphovascular malformation*; and
  2. Any of the following:
    1. Malformations are not adequately controlled by sclerotherapy and surgery; or
    2. Malformations are widespread / extensive and sclerotherapy and surgery are not considered clinically appropriate; or
    3. Sirolimus is to be used to reduce malformation prior to consideration of surgery; and
  3. Patient is being treated by a specialist lymphovascular malformation multi-disciplinary team; and
  4. Patient has measurable disease as defined by RECIST version 1.1 (see Note).

Renewal – (severe non-malignant lymphovascular malformations*) from any relevant practitioner.

Approvals valid for 12 months for applications meeting the following criteria:

All of the following:

  1. Either:
    1. Patient’s disease has had either a complete response or a partial response to treatment, or patient has stable disease according to RECIST version 1.1 (see Note); or
    2. Patient’s disease has stabilised or responded clinically and disease response to treatment has been clearly documents in patient notes; and
  2. No evidence of progressive disease; and
  3. The treatment remains clinically appropriate and the patient is benefitting from the treatment.

Notes: Baseline assessment and disease responses to be assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (Eisenhauer et al. Eur J Cancer 2009;45:228-47(external link)).

Indications marked with * are unapproved indications

Sirolimus for renal angiomyolipoma associated with tuberous sclerosis complex:

Initial application – (renal angiomyolipoma(s) associated with tuberous sclerosis complex*) only from a nephrologist or urologist. Approvals valid for 6 months for applications meeting the following criteria:

Both:

  1. Patient has tuberous sclerosis complex*; and
  2. Evidence of renal angiomyolipoma(s) measuring 3 cm or greater and that have shown interval growth.

Renewal – (renal angiomyolipoma(s) associated with tuberous sclerosis complex*) from any relevant practitioner. Approvals valid for 12 months for applications meeting the following criteria:

All of the following:

  1. Documented evidence of renal angiomyolipoma reduction or stability by magnetic resonance imaging (MRI) or ultrasound; and
  2. Demonstrated stabilisation or improvement in renal function; and
  3. The patient has not experienced angiomyolipoma haemorrhage or significant adverse effects to sirolimus treatment; and
  4. The treatment remains appropriate and the patient is benefitting from treatment.

Note: Indications marked with * are unapproved indications

Sirolimus for the treatment of refractory epilepsy associated with tuberous sclerosis complex:

Initial application – (refractory seizures associated with tuberous sclerosis complex*) only from a Neurologist. Approvals valid for 6 months for applications meeting the following criteria:

All of the following:

  1. Patient has epilepsy with a background of documented tuberous sclerosis complex; and
  2. Either:
    1. Both:
      1. Vigabatrin has been trialled and has not adequately controlled seizures; and
      2. Seizures are not adequately controlled by, or the patient has experienced unacceptable side effects from, optimal treatment with at least two of the following: sodium valproate, topiramate, levetiracetam, carbamazepine, lamotrigine, phenytoin sodium, and lacosamide (see Note); or
    2. Both:
      1. Vigabatrin is contraindicated; and
      2. Seizures are not adequately controlled by, or the patient has experienced unacceptable side effects from, optimal treatment with at least three of the following: sodium valproate, topiramate, levetiracetam, carbamazepine, lamotrigine, phenytoin sodium, and lacosamide (see Note); and
  3. Seizures have a significant impact on quality of life; and
  4. Patient has been assessed and surgery is considered inappropriate for this patient, or patient has been assessed and would benefit from mTOR inhibitor treatment prior to surgery.

Note: “Optimal treatment” is defined as treatment, which is indicated and clinically appropriate for the patient, given in adequate doses for the patient’s age, weight and other features affecting the pharmacokinetics of the drug, with good evidence of adherence. Women of childbearing age are not required to have a trial of sodium valproate.

Renewal – (refractory seizures associated with tuberous sclerosis complex*) only from a Neurologist. Approvals valid for 12 months where demonstrated significant and sustained improvement in seizure rate (e.g. 50% reduction in seizure frequency) or severity and/or patient quality of life compared with baseline prior to starting sirolimus treatment.

Note: Indications marked with * are unapproved indications

We’re really grateful for the time people took to respond to this consultation.  Responses were generally supportive of the proposal. A summary of the main themes raised in feedback, our responses to the feedback received, and changes we have made after listening to you are set out below.

THEME

PHARMAC COMMENT

Noted, with regard to refractory seizures as a complication of TSC, that vigabatrin is only suitable if the patient has infantile spasm and is not suitable for other seizure types.

PTAC recommended [PDF, 559 KB] PHARMAC develop Special Authority criteria for this group using input from paediatric neurologists.

The Paediatric Neurology Network advised that vigabatrin be trialled unless contraindicated as it has a specific mechanism of action that involves mTOR (mammalian target of rapamycin) and therefore may be more effective in TSC.

PHARMAC staff note, that, as proposed, the Special Authority criteria do not require vigabatrin to be trialled if it is contraindicated.

Requests to consider changes to, or clarifications to, the Special Authority criteria:

1.     Request for clarification that the specialism ‘Neurologist’ (as required by the Special Authority criteria for refractory epilepsy associated with TSC) refers to both paediatric and adult neurologists, noting the majority of applications for this indication are likely to be from paediatric neurologists.

2.     Request to extend the Special Authority renewal time frame for treatment of renal angiomyolipoma’s with sirolimus from 6 months to 12 months once a patient is stabilised on sirolimus.

3.     Request for changes to the Special Authority renewal criteria for lymphovascular malformations to allow further funding if the lesion is clearly responding clinically and there is organ function improvement, removing the requirement for MRI assessment for each renewal.

This request considered that, whilst the RECIST tool is reasonable for assessment of response, some children require general anaesthesia for MRI, which carries risks and may not be required if clinical imaging is unlikely to alter management.

 

 

 

1.     For the purposes of the Special Authority, ’Neurologist’ refers both to paediatric and adult neurologists. 

 

 

2.     After careful consideration, the Special Authority and Hospital Restrictions accordingly have been amended to this extended timeframe.

  

3.     After careful consideration the restriction criteria for lymphovascular malformations have been amended so clinical imaging is no longer required for renewal; however, these renewal criteria still require disease to have responded or stabilised, with no evidence of disease progression.

Noted that the application for the renal angiomyolipoma indication was initially for everolimus, with superior evidence of this treatment compared to sirolimus.

 

Request for everolimus be funded in the event that a patient does not tolerate sirolimus or does not experience the expected improvement in their condition.

 

PHARMAC staff sought specific advice from PTAC on the use of both sirolimus and everolimus in this setting.

PTAC considered [PDF, 559 KB] the clinical effectiveness of mTOR inhibitors such as everolimus or sirolimus to be a class effect, with either suitable to be considered for funding. In line with this advice, both everolimus and sirolimus have been considered for funding. The application for the use of everolimus for renal angiomyolipoma(external link) has also been assessed and remains an option for funding in the future.

PHARMAC staff note that assessment of the patient group who are intolerant to or experience insufficient treatment benefit from sirolimus would be required to consider funding for this group; however, funding of everolimus for these people could be considered via the NPPA policy.

Requests for wider access to sirolimus for treatment of other possible manifestations of TSC.

PHARMAC understands that many people with TSC experience a range of manifestations and considers it likely that most people would meet one of the Special Authority criteria for access to mTOR treatment.

It is acknowledged that there may be some people who do not meet these criteria. We note that consideration for funding via the NPPA policy is available.

It is noted that a funding application for sirolimus ointment for treatment of facial angiofibroma’s(external link), has been received and is under assessment for funding.  

Noted that Rapamune is not licenced for these indications and noted the importance of reporting for healthcare professionals using sirolimus for unlicensed indications.

 

PHARMAC staff note that sirolimus is not registered for use in these indications. This means sirolimus would need to be prescribed and used in accordance with section 25 of the Medicines Act 1981 when used in these unapproved indications.

If you have any questions about this decision, you can email us at enquiry@pharmac.govt.nz; or call our toll free number (9 am to 5 pm, Monday to Friday) on 0800 660 050.