Proposal to widen access to sirolimus for lymphovascular malformations and tuberous sclerosis complex complications

Medicines Consultation Closed

We are seeking feedback on a proposal to widen funded access to sirolimus from 1 February 2021 for patients with indications as below:

Further details on this proposal, including how to provide feedback, can be found below.

Consultation closes at 5pm Friday 16 October 2020 and feedback can be emailed to consult@pharmac.govt.nz.

What would the effect be?

This proposal would mean that from 1 February 2021, funded access to sirolimus would be widened to include patients with lymphovascular malformations, renal angiomyolipoma associated with tuberous sclerosis complex (TSC) and refractory (i.e. treatment-resistant) epilepsy associated with TSC.  

We have received clinical advice that for people with severe non-malignant lymphovascular malformations, sirolimus would help lesion shrinkage and improve patients’ quality of life. Clinical advice also indicates that for people with clinically significant complications of TSC, there is evidence of benefit from mTOR inhibitors (e.g. sirolimus) such as reduction in tumour size, stabilisation or improvement in organ function, as well as improved quality of life. We have also received clinical advice that for people with treatment-resistant epileptic seizures resulting from TSC there is evidence of benefit from mTOR inhibitors to help to reduce seizure frequency and improve quality of life.

We estimate that approximately 70 patients across these three indications would benefit each year from this proposal under the proposed Special Authority criteria. We note that some people have received funded treatment with sirolimus for these indications in the past via Named Patient Pharmaceutical Assessment (NPPA) applications. 

Who we think will be 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 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

About sirolimus, lymphovascular malformations and tuberous sclerosis complex 

Sirolimus is a selective immune suppressing drug, which inhibits the mammalian target of rapamycin (mTOR) pathway. Sirolimus is currently funded for rescue therapy for organ transplant recipients. Sirolimus is not Medsafe approved for the indications included in this proposal.  

Lymphovascular malformations

Lymphovascular malformations are rare, non-malignant masses which arise during development of the lymphatic system. The masses (sometimes called tumours), consist of dilated lymphatic vessels and fluid-filled channels or spaces which develop when the lymphatic drainage system is blocked. Lymphovascular malformations can affect any area of the body, most commonly the head and neck, however, can also affect the chest, abdomen and groin. Left untreated, lymphovascular malformations can result in morbidity and mortality, such as significant deformity, infection and chronic pain. Currently, treatment options for people with lymphovascular malformations are based on symptomatic management and include; sclerotherapy, ablation, laser therapy, and surgical options such as debulking and/or total resection.

This proposal would mean that people with severe non-malignant lymphovascular malformations that are not adequately controlled by sclerotherapy and surgery, or are widespread/extensive and sclerotherapy and surgery are not considered clinically appropriate, or where sirolimus would be used to reduce malformation prior to consideration of surgery, have access to an effective treatment.

Tuberous sclerosis complex

TSC is a genetic disorder where benign tumour-like malformations develop in multiple organ systems. The size and number of these malformations generally increases with age.

Angiomyolipoma

The development of angiomyolipomas is common in TSC, becoming more common with increasing age. Renal angiomyolipomas are associated with impaired kidney function, and as they grow bigger in the kidney(s) (e.g. greater than 3 cm) there is an increased risk of spontaneous retroperitoneal haemorrhage and blood in the urine. Many patients with renal angiomyolipomas associated with TSC will not have symptoms; however, some angiomyolipomas will grow and can cause life-threatening harm. Available treatments for both bleeds and/or removal of individual angiomyolipoma’s risk morbidity, with embolisation and surgical nephrectomy risking kidney failure and potentially long-term dialysis.

This proposal would mean people with TSC and renal angiomyolipoma(s) measuring 3 cm or greater that have shown interval growth would be eligible to be treated with sirolimus. We note that there are a number of other TSC complications (e.g. lymphangioleiomyomatosis) which have not been formally assessed as part of this proposal. These complications will continue to be assessed through the Named Patient Pharmaceutical Assessment (NPPA) pathway.

Refractory epilepsy

Epilepsy is one of the most frequent and significant causes of morbidity in TSC. Seizures typically begin in infancy, and can range in frequency and severity, up to multiple seizures per day. Early onset epilepsy and untreated epilepsy is associated with an increased risk of neurodevelopmental disabilities, as well as severe negative impacts on physical and mental health including sleep, anxiety and risk of injury. Seizures associated with TSC are treated symptomatically with anti-epilepsy medicines or non-pharmacological methods such as ketogenic diet or surgery. For the purpose of this proposal, seizures are considered refractory in patients who continue to have a high and uncontrolled seizure frequency despite three or more lines of pharmacological treatment.

This proposal would mean that patients with refractory epilepsy resulting from TSC, who have trialled funded alternatives including vigabatrin (unless contraindicated), and for whom epilepsy surgery is inappropriate, would be eligible to be treated with sirolimus.

Why we’re proposing this

The Pharmacology and Therapeutics Advisory Committee (PTAC) considered funding applications for treatment of the above indications in November 2019 [PDF, 559 KB]. [PDF, 559 KB]

PTAC recommended that oral sirolimus for the treatment of severe non-malignant lymphovascular malformations be funded with a high priority. PTAC recommended a mTOR inhibitor (e.g. sirolimus or everolimus) be funded for the treatment of clinically significant complications resulting from TSC with a medium priority; recommending funding of a mTOR inhibitor for the treatment of refractory epileptic seizures associated with TSC with a high priority, subject to Special Authority criteria. The Committee considered that for these indications, mTOR inhibitors (e.g. sirolimus and everolimus) have the same or similar effect.

More information, including links to the PTAC records, can be found in the Application Tracker records:

Details about our proposal

Sirolimus would continue to be listed at the same price and subsidy in Section B and Part II of Section H of the Pharmaceutical Schedule.

Access to sirolimus (brand name ‘Rapamune’®) would be amended in Section B and Part II of Section H of the Pharmaceutical Schedule from 1 February 2021 to include people with lymphovascular malformations, angiomyolipoma associated with TSC, and patients with refractory epilepsy associated with TSC as follows (new criteria shown below):

Sirolimus for lymphovascular malformations

Special Authority for Subsidy

Initial application – (severe non-malignant lymphovascular malformations) 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:

2.1 Malformations are not adequately controlled by sclerotherapy and surgery; or
2.2 Malformations are widespread/extensive and sclerotherapy and surgery are not considered clinically appropriate; or
2.3 Sirolimus is to be used to reduce malformation prior to consideration of surgery; and

  1. Patient is being treated by a specialist lymphovascular malformation multi-disciplinary team; and
  2. Patient has measurable disease as defined by RECIST version 1.1 (see Notes(external link)).

Renewal – (severe non-malignant lymphovascular malformations) Approvals valid for 12 months for applications meeting the following criteria:

All of the following:

  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 Notes(external link)); and
  2. Either:

2.1 Response to treatment in target lesions has been determined by radiologic assessment (CT or MRI scan) following the most recent treatment period; or
2.2 Both:

2.2.1 Patient has measurable disease as defined by RECIST version 1.1; and
2.2.2 Patient’s disease has not progressed clinically and disease response to treatment has been clearly documented in patient notes; and

  1. No evidence of progressive disease according to RECIST criteria (see Notes(external link)); and
  2. The treatment remains clinically appropriate and the patient is benefitting from the treatment.

Notes(external link): 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)(external link))

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 application – (renal angiomyolipoma(s) associated with tuberous sclerosis complex) only from a relevant practitioner. Approvals valid for 6 months for applications meeting the following criteria:

All of the following:

  1. Documented evidence of renal angiomyolipoma reduction or stability by magnetic resonance imaging 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.

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:

2.1 Both:

2.1.1 Vigabatrin has been trialled and has not adequately controlled seizures; and
2.1.2 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, andlacosamide (see Note(external link));
or

2.2  Both:

2.2.1 Vigabatrin is contraindicated; and
2.2.2 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

  1. Seizures have a significant impact on quality of life; and
  2. The patient has been assessed and surgery is considered inappropriate for this patient, or the patient has been assessed and would benefit from mTOR inhibitor 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 patients 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 application (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 treatment sirolimus.

There are no proposed changes to other current Special Authority criteria for sirolimus.

To provide feedback

Send us an email:  consult@pharmac.govt.nz by 5pm Friday 16 October 2020.

All feedback received before the closing date will be considered by PHARMAC’s Board (or its delegate) prior to making a decision on this proposal.

Feedback we receive is subject to the Official Information Act 1982 (OIA) and we will consider any request to have information withheld in accordance with our obligations under the OIA. Anyone providing feedback, whether on their own account or on behalf of an organisation, and whether in a personal or professional capacity, should be aware that the content of their feedback and their identity may need to be disclosed in response to an OIA request.

We are not able to treat any part of your feedback as confidential unless you specifically request that we do, and then only to the extent permissible under the OIA and other relevant laws and requirements. If you would like us to withhold any commercially sensitive, confidential proprietary, or personal information included in your submission, please clearly state this in your submission and identify the relevant sections of your submission that you would like it withheld. PHARMAC will give due consideration to any such request.