AFINITOR DISPERZ

, Therapeutic drug monitoring for patients treated for SEGA). ● The optimal duration of AFINITOR therapy for patients with SEGA is not known; however, SEGA re-growth has been reported to occur once therapy is discontinued (see 4 DOSAGE AND ADMINISTRATION, SEGA volume monitoring for patients treated with AFINITOR and 14 CLINICAL TRIALS, SEGA associated with Tuberous Sclerosis Complex).

● Non-clinical data suggests that there is a risk of delayed developmental landmarks and delayed reproductive development in patients taking everolimus ( see Special Populations, Pediatrics below and 16 NON-CLINICAL TOXICOLOGY). ● Dosage forms (AFINITOR and AFINITOR DISPERZ) are not interchangeable (see 4 DOSAGE AND ADMINISTRATION, Dosing Considerations, Switching dosage forms) Renal Angiomyolipoma associated with TSC: ● Treatment with AFINITOR should be initiated by a qualified healthcare professional experienced in the treatment of patients with TSC.

The optimal time to initiate therapy is not known. ● The optimal duration of AFINITOR therapy for patients who have renal angiomyolipoma associated with TSC is not known (see 14 CLINICAL TRIALS, Renal Angiomyolipoma associated with Tuberous Sclerosis Complex).

● Clinical trial data suggest that there is a potential risk of secondar y amenorrhoea in females taking everolimus (see 7 WARNINGS AND PRECAUTIONS, Reproductive Health: Female and Male Potential). 1 Dosing Considerations AFINITOR and AFINITOR DISPERZ should be prescribed by a qualified healthcare professional who is experienced in the use of antineoplastic therapy and/or in the treatment of patients with TSC.

AFINITOR (everolimus) is available in two dosage forms, tablets (AFINITOR) and tablets for oral suspension (AFINITOR DISPERZ). AFINITOR and AFINITOR DISPERZ are not interchangeable and should not be combined to achieve the desired dose.

4 Administration). AFINITOR Tablets AFINITOR (tablets) may be used in all approved oncology indications and for the renal angiomyolipoma associated with tuberous sclerosis complex (TSC) and subependymal giant cell astrocytoma (SEGA) associated with TSC indications.

For patients with SEGA associated with TSC, AFINITOR must be used in conjunction with therapeutic drug monitoring (see Therapeutic drug monitoring for patients treated for SEGA and/or seizures associated with TSC below). AFINITOR (tablets) have not been studied and should not be used in patients with seizures associated with TSC.

). Monitoring of fasting lipid profile is recommended prior to the start of AFINITOR or AFINITOR DISPERZ therapy and periodically thereafter. Consider dose reduction, dose interruption or discontinuation, as well as management with appropriate medical therapy (see 4 DOSAGE AND ADMINISTRATION, Dosing Considerations, Table 2).

Hyperglycaemia:

Hyperglycaemia has been reported in patients taking AFINITOR. Monitoring of fasting serum glucose is recommended prior to the start of AFINITOR or AFINITOR DISPERZ therapy and periodically thereafter (see Monitoring and Laboratory Tests below).

More frequent monitoring is recommended when AFINITOR or AFINITOR DISPERZ is co - administered with other drugs that may induce hyperglycaemia. Optimal glycaemic control should be achieved before starting a patient on AFINITOR or AFINITOR DISPERZ.

New onset type 2 diabetes has occurred with AFINITOR treatment (see 8 ADVERSE REACTIONS). Functional carcinoid tumour In a randomized, double-blind, multi-centre trial in 429 patients with functional carcinoid tumours, AFINITOR plus depot octreotide was compared to placebo plus depot octreotide.

The study did not meet the primary efficacy endpoint (PFS) and the OS interim analysis numerically favoured the placebo plus depot octreotide arm. Therefore, the use of AFINITOR in patients with functional carcinoid tumours is not recommended outside an investigational study.

Gastrointestinal AFINITOR (everolimus) and AFINITOR DISPERZ Pr oduct Monograph Page 22 of 123 Stomatitis, including mouth ulceration, is a common adverse event in patients treated with AFINITOR. Across the clinical trial experience, 44% to 86% of the patients receiving AFINITOR experienced stomatitis (see 8 ADVERSE REACTIONS).

Stomatitis mostly occurs within the first 8 weeks of treatment. For mouth ulcers and stomatitis, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine- or thyme-containing mouthwashes should be avoided as they may exacerbate the condition.

and 14 CLINICAL TRIALS).  the treatment of patients with metastatic renal cell carcinoma (RCC) of clear cell morphology, after failure of initial treatment with either of the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-receptor TKIs) sunitinib or sorafenib.

The effectiveness of AFINITOR is based on PFS. Prolongation of OS was not demonstrated for AFINITOR in RCC nor were quality-of-life differences shown between patients receiving AFINITOR versus placebo in the pivotal phase III trial (see 14 CLINICAL TRIALS).

AFINITOR (everolimus) and AFINITOR DISPERZ Pr oduct Monograph Page 6 of 123  the treatment of adult patients (≥ 18 years of age) with renal angiomyolipoma associated with tuberous sclerosis complex (TSC), who do not require immediate surgery.

3 months in the pivotal phase III placebo-controlled trial (see 14 CLINICAL TRIALS). AFINITOR and AFINITOR® DISPERZ® are indicated for:  the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) that have demonstrated serial growth, who are not candidates for surgical resection and for whom immediate surgical intervention is n ot required.

The effectiveness of AFINITOR is based on an analysis of change in SEGA volume. Prescribers should take into consideration that surgical resection can be curative, while treatment with AFINITOR has been shown only to reduce the SEGA volume.

The pharmacokinetic properties of AFINITOR and AFINITOR DISPERZ have been evaluated in clinical comparative bioavailability trials (see 10 CLINICAL PHARMACOLOGY, Pharmacokinetics). AFINITOR DISPERZ has not been studied in clinical safety and efficacy trials.

AFINITOR DISPERZ is indicated for:  as adjunctive treatment of seizures associated with Tuberous Sclerosis Complex (TSC) in patients 2 years and older, with a definite diagnosis of TSC, who are not satisfactorily controlled with current therapies.

and 14 CLINICAL TRIALS). AFINITOR DISPERZ is the only formulation that should be used for the treatment of patients with seizures associated with TSC. 3 Pediatrics).

Pediatrics (>1 to <18 years of age):

Based on the data submitted and reviewed by Health Canada, the safety and efficacy of AFINITOR and AFINITOR DISPERZ in pediatric patients with SEGA > 1 year of age has been established. Therefore, Health Canada has authorized an indication for pediatric patients with SEGA > 1 year of age.

3 Pediatrics). 2 Geriatrics Geriatrics (≥ 65 years of age): In the advanced breast cancer study, no overall differences in effectiveness were observed between elderly and younger patients. 4 Geriatrics and 14 CLINICAL TRIALS). In two other randomized trials (metastatic RCC and advanced PNET), no overall differences in safety or effectiveness were observed between elderly and younger patients (see 14 CLINICAL TRIALS).

In the randomized advanced GI/Lung NET study, no overall differences in effectiveness were observed between elderly and younger patients. 5-fold the incidence in older patients receiving everolimus relative to those aged <65 years included cardiac failure, lower respiratory tract infections (pneumonia, lung infection, bronchitis), cough and decreased appetite.

2 CONTRAINDICATIONS  AFINITOR (everolimus) and AFINITOR DISPERZ are contraindicated in patients who are hypersensitive to the drug, to other rapamycin derivatives or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

For a complete listing, see 6 DOSAGE FORMS, STRENGTHS COMPOSITION AND PACKAGING (see also 7 WARNINGS AND PRECAUTIONS).  AFINITOR (everolimus) and AFINITOR DISPERZ are contraindicated for the treatment of seizures (of any type) in populations other than those with a definite diagnosis of TSC (see 14 CLINICAL TRIALS).