Regulatory Decision Summary for Afinitor Disperz

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

everolimus

Therapeutic area:

Antineoplastic Agents

Type of submission:

Supplement to a New Drug Submission

Control number:

200814
What was the purpose of this submission?

 

Afinitor Disperz (everolimus) is an antineoplastic product with a number of cancer-related indications such as advanced breast cancer, neuroendocrine tumours of GI, lung, or pancreas in origin, and subependymal giant cell astrocytoma (SEGA) associated with Tuberous Sclerosis Complex (TSC). This submission was filed to add a new indication to the product monograph (PM) for everolimus as adjunctive therapy in the treatment of refractory seizures in patients with TSC.

 

Why was the decision issued?

 

This SNDS was submitted to seek the following indication, "Afinitor Disperz is indicated as adjunctive treatment of patients aged 2 years and older with refractory seizures associated with tuberous sclerosis complex (TSC)". A large percentage of patients with TSC experience a variety of seizures. Currently, other than conventional and second generation antiepileptic drugs (AEDs), there are no other approved products for the treatment of seizures in this population. Everolimus is a rapamycin derivative and a selective inhibitor of the mammalian target of rapamycin (mTOR). This molecule was initially developed as an immunosuppressive agent. Currently in Canada, everolimus has multiple cancer-related indications.

To support the proposed seizure related indication, the sponsor has provided study M2304, a placebo-controlled trial in TSC patients 2 to 56 years (mean and median age: 13 and 10, respectively). The design of the pivotal trial was in line with those used for the approval of standard antiepileptic drugs. Safety data were provided from this trial, its (ongoing) extension phase, and several other (oncology) studies. The most common adverse events reported in the seizure trials were stomatitis (55% and 64% in the low and high trough dose groups (LT and HT), respectively compared to 9% in placebo) and diarrhea (17% and 22%, compared to 5% in placebo). Everolimus treatment was associated with clinically relevant laboratory abnormalities including hypercholesterolemia (85% in LT and HT compared to 58% in placebo), hypertriglyceridemia (43%in LT and 38% in HT compared to 22% in placebo), neutropenia (25% in LT and 37% in HT compared to 23% in placebo) and anemia (26% in LT and 30% in HT compared to 21% in placebo). Everolimus causes many laboratory abnormalities in both children and adults. In some cases, incidences are substantially higher than placebo (e.g., 20 to 30 percent higher). This profile makes everolimus unsuitable for use in the general epilepsy population especially when there are currently a number of second and third generation AEDs on the market with greatly improved safety profiles as compared to conventional ones. Based on its safety profile, everolimus appears to be more toxic than the currently approved antiepileptic drugs (AEDs). However, as seizures in some TSC patients are not satisfactorily controlled with different AED regimens, there is a role for the use of everolimus in these patients.

The sponsors proposed wording for the INDICATIONS section was revised to remove the word "refractory" as there was no evidence to support the addition of this term. The PM for this product reflects issues associated with everolimus in the treatment of seizures in TSC patients, and is adequate to mitigate risks associated with everolimus. To avoid possible use of this drug for the treatment of seizures in non-TSC patients, a contraindication for this population was added to the PM.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.