Everolimus Dosage

Usual Adult Dose for Renal Cell Carcinoma

Recommended dose (Afinitor): 10 mg orally once daily to be taken at the same time every day.

Management of severe and/or intolerable adverse reactions may require a temporary dose reduction and/or interruption of therapy. If dose reduction is required, a dose of 5 mg orally once daily is recommended.

Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.

Usual Adult Dose for Organ Transplant - Rejection Prophylaxis

Initial dose (Zortress): 0.75 mg twice a day in combination with reduced dose cyclosporine, administered as soon as possible after transplantation. Adjust maintenance dose to achieve trough concentrations within the 3 to 8 ng/mL target range.

Once a day dosing to a target trough concentration of 2 to 5 ng/ml achieved a similar efficacy and safety profile when compared to twice a day dosing in a small (n=41) study in de novo renal transplant recipients. This dosing regimen has not been approved by the FDA.

Dose adjustments may be required based on everolimus blood levels, tolerability, individual response, change in concomitant medications and the clinical situation. Dose adjustments can be made at 4 to 5 day intervals. Administer consistently with or without food at the same time as cyclosporine.

Usual Adult Dose for Brain/Intracranial Tumor

Subependymal giant cell astrocytoma (SEGA):
Initial dose (Afinitor):
Body surface area 0.5 to 1.2 m2: 2.5 mg orally once daily

Body surface area 1.3 to 2.1 m2: 5 mg orally once daily

Body surface area 2.2 m2 or greater: 7.5 mg orally once daily

A dose adjustment may be required based on everolimus trough blood levels, tolerability, individual response, change in concomitant medications, and change in SEGA volume. Dose adjustments can be made at 2 week intervals. The optimal duration of therapy has not been determined.

Management of severe and/or intolerable adverse reactions may require a temporary dose reduction and/or interruption of therapy.

Usual Adult Dose for Pancreatic Cancer

Progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease: 10 mg orally once a day.

Usual Pediatric Dose for Brain/Intracranial Tumor

Subependymal giant cell astrocytoma (SEGA):
3 years or younger: Not recommended

3 years or older:
Initial dose (Afinitor):
Body surface area less than 0.58 m2: Not recommended

Body surface area 0.58 to 1.2 m2: 2.5 mg orally once daily

Body surface area 1.3 to 2.1 m2: 5 mg orally once daily

Body surface area 2.2 m2 or greater: 7.5 mg orally once daily

A dose adjustment may be required based on everolimus trough blood levels, tolerability, individual response, change in concomitant medications, and change in SEGA volume. Dose adjustments can be made at 2 week intervals. The optimal duration of therapy has not been determined.

Management of severe and/or intolerable adverse reactions may require a temporary dose reduction and/or interruption of therapy.

Renal Dose Adjustments

No clinical studies have been conducted with everolimus in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment.

Liver Dose Adjustments

Moderate hepatic impairment (Child-Pugh Class B): Reduce daily dose by one-half the recommended initial daily dose. Blood concentrations should be monitored to make further adjustments as necessary.

Severe hepatic impairment (Child-Pugh class C): Use in this patient population is not recommended. Everolimus has not been evaluated in patients with severe hepatic impairment

Dose Adjustments

Renal cell carcinoma and advanced pancreatic neuroendocrine tumors:
Concomitant administration of strong CYP450 3A4 inhibitors should be avoided.

For concomitant administration of moderate CYP450 3A4 and/or PgP inhibitor, the dose of everolimus should be reduced to 2.5 mg daily. The everolimus dose may be increased from 2.5 mg to 5 mg daily based on patient tolerance. If the moderate inhibitor is discontinued, approximately 2 to 3 days should elapse before increasing the everolimus dose. If the moderate inhibitor is discontinued, the dose of everolimus should be returned to the dose used prior to initiation of the moderate CYP450 3A4 and/or PgP inhibitor.

Concomitant administration of strong CYP450 3A4 inducers should be avoided.

For concomitant administration of a strong CYP450 3A4 inducer, an increase in the everolimus dose from 10 mg daily up to 20 mg daily, in 5 mg increments, should be considered. If the strong inducer is discontinued, the everolimus dose should be returned to the dose used prior to initiation of the strong CYP450 3A4 inducer.

Subependymal giant cell astrocytoma (SEGA):
Everolimus trough blood levels should be assessed approximately 2 weeks after starting therapy, after any change in dose, or after an initiation or change in coadministration of CYP450 3A4 and/or PgP inducers or inhibitors. Dosing should be adjusted to achieve trough levels of 5 to 10 ng/mL.

The daily dose may be increased or decreased by 2.5 mg every 2 weeks in order to achieve a trough level of 5 to 10 ng/mL. If a dose reduction is necessary in a patient receiving 2.5 mg daily, alternate day dosing should be considered.

For a trough level between 10 to 15 ng/ml, a dose reduction is not required if the drug is well tolerated and tumor response is evident.

For a trough level greater than 15 ng/mL, the dose of everolimus should be reduced.

Dialysis

Dialysis specific data is not available. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment.

Other Comments

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for everolimus under the brand name Zortress(R). It includes a communication plan. Additional information is available at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

Everolimus tablets may be administered with or without food.

Everolimus tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed.

In patients with subependymal giant cell astrocytoma (SEGA), SEGA volume should be evaluated approximately 3 months after starting everolimus and periodically thereafter.

Grapefruit, grapefruit juice, and St. John's Wort (Hypericum perforatum) should be avoided during administration of everolimus.

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