Everolimus: Drug information

For additional information see "Everolimus: Patient drug information" and "Everolimus: Pediatric drug information"

For abbreviations, symbols, and age group definitions show table

ALERT: US Boxed Warning

Immunosuppression (Zortress):

Increased susceptibility to infection and the possible development of malignancies such as lymphoma and skin cancer may result from immunosuppression.

Only health care providers experienced in immunosuppressive therapy and management of transplant patients should prescribe everolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Kidney graft thrombosis (Zortress):

An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, was reported, mostly within the first 30 days post-transplantation.

Nephrotoxicity (Zortress):

Increased nephrotoxicity can occur with use of standard doses of cyclosporine in combination with everolimus. Therefore, use reduced doses of cyclosporine should be used in combination with everolimus in order to reduce kidney dysfunction. It is important to monitor the cyclosporine and everolimus whole blood trough concentrations.

Mortality in heart transplant (Zortress):

Increased mortality, often associated with serious infection, within the first 3 months of post-transplantation was observed in a clinical trial of de novo heart transplant patients receiving immunosuppressive regimens with or without induction therapy. Use in heart transplantation is not recommended.

Brand Names: US

Afinitor;
Afinitor Disperz;
Torpenz;
Zortress

Brand Names: Canada

Afinitor;
Afinitor Disperz;
NAT-Everolimus;
PMS-Everolimus;
REDDY-Everolimus;
SANDOZ Everolimus;
TEVA-Everolimus

Pharmacologic Category

Antineoplastic Agent, mTOR Kinase Inhibitor;
Immunosuppressant Agent;
mTOR Kinase Inhibitor

Dosing: Adult

Note: Tablets (Afinitor, Zortress) and tablets for oral suspension (Afinitor Disperz) are not interchangeable; Afinitor Disperz is only indicated for the treatment of tuberous sclerosis complex (TSC)–associated partial-onset seizures and TSC-associated subependymal giant cell astrocytoma (SEGA), in conjunction with therapeutic monitoring. Do not combine formulations to achieve total desired dose. If possible, optimize glucose control and lipids prior to treatment initiation.

Prophylaxis: Antimicrobial prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and prophylaxis for cytomegalovirus (CMV) is recommended in transplant recipients. When concomitant corticosteroids or other immunosuppressive agents are required, administer PJP prophylaxis. Treatment of preexisting invasive fungal infections should be completed prior to starting everolimus treatment.

Breast cancer, advanced, hormone receptor positive, HER2 negative

Breast cancer, advanced, hormone receptor positive, HER2 negative (Afinitor): Oral: 10 mg once daily (in combination with exemestane); continue until disease progression or unacceptable toxicity (Ref).

Off-label dosing regimens:

Induction escalation combination therapy: Oral: 2.5 mg once daily for week 1, followed by 5 mg once daily for week 2, followed by 7.5 mg once daily for week 3, followed by 10 mg once daily thereafter (in combination with exemestane); continue until disease progression, unacceptable toxicity, or a maximum of 24 weeks of therapy (Ref).

Combination therapy: Oral: 10 mg once daily (in combination with tamoxifen); continue until disease progression or unacceptable toxicity (Ref) or10 mg once daily (in combination with fulvestrant); continue until disease progression, unacceptable toxicity, or a maximum of 12 cycles of therapy (Ref).

Carcinoid tumors, progressive, advanced

Carcinoid tumors, progressive, advanced (off-label use) (Afinitor): Oral: 10 mg once daily (in combination with octreotide LAR); continue until disease progression or toxicity (Ref).

Heart transplantation

Heart transplantation (≥3 months post-transplantation) (off-label use) (Zortress): Oral: Initial: 0.75 mg twice daily (in combination with concurrent immunosuppression; refer to study protocol for details); adjust everolimus dose based on everolimus trough concentrations (Ref).

Hodgkin lymphoma, relapsed or refractory

Hodgkin lymphoma, relapsed or refractory (off-label use) (Afinitor): Oral: 10 mg once daily; continue until disease progression or toxicity (Ref).

Kidney transplantation, rejection prophylaxis

Kidney transplantation, rejection prophylaxis (Zortress): Oral: Initial: 0.75 mg twice daily (in combination with basiliximab induction, cyclosporine [reduced dose required] and a corticosteroid); adjust maintenance dose per institutional protocol as needed at a 4- to 5-day interval (from prior dose adjustment) based on serum concentrations (see Reference Range), tolerability, and response.

Liver transplantation, rejection prophylaxis

Liver transplantation, rejection prophylaxis (begin at least 30 days post-transplant) (Zortress): Oral: Initial: 1 mg twice daily (in combination with tacrolimus [reduced dose required] and a corticosteroid; adjust maintenance dose per institutional protocol as needed at a 4- to 5-day interval (from prior dose adjustment) based on serum concentrations (see Reference Range), tolerability, and response.

Lung transplantation

Lung transplantation (>1 month post-transplantation) (off-label use) (Zortress): Oral: Initial: 0.75 to 1.5 mg twice daily (in combination with concurrent immunosuppression; refer to study protocol for details); adjust everolimus dose based on everolimus trough concentrations (Ref).

Cystic fibrosis lung transplant recipients: Oral: Consider initiating with 1.25 to 2 mg twice daily because bioavailability and absorption is reduced; administer at least 30 minutes prior to a meal and with a lipase supplement (Ref).

Neuroendocrine tumors, GI, lung, or pancreatic origin, advanced

Neuroendocrine tumors, GI, lung, or pancreatic origin, advanced (Afinitor): Oral: 10 mg once daily; continue treatment until disease progression or unacceptable toxicity (Ref).

Renal cell carcinoma, advanced, first-line combination therapy

Renal cell carcinoma, advanced, first-line combination therapy (Afinitor; off-label dose/combination):

In combination with lenvatinib (off-label combination): Note: May be used in combination with lenvatinib regardless of risk stratification in patients who are ineligible for (or who decline) initial treatment with immunotherapy-based combinations (Ref).

Oral: 5 mg once daily (in combination with lenvatinib); continue until disease progression or unacceptable toxicity (Ref).

Renal cell carcinoma, advanced, previously treated, combination therapy

Renal cell carcinoma, advanced, previously treated, combination therapy (Afinitor; off-label dose/combination):

In combination with lenvatinib (off-label combination): Note: May be used in combination with lenvatinib following prior antiangiogenic therapy, or in patients with progression after initial immunotherapy and have not previously received antiangiogenic therapy, or after initial combination therapy (immunotherapy plus an antiangiogenic agent) (Ref).

Oral: 5 mg once daily (in combination with lenvatinib); continue until disease progression or unacceptable toxicity (Ref).

Renal cell carcinoma, advanced, single-agent therapy

Renal cell carcinoma, advanced, single-agent therapy (Afinitor):

Note: May be used after failure of prior sorafenib or sunitinib therapy, but other therapies are generally preferred for the treatment of advanced disease (Ref).

Oral: 10 mg once daily; continue until disease progression or unacceptable toxicity (Ref).

Thymoma or thymic carcinoma, advanced or metastatic, relapsed or refractory

Thymoma or thymic carcinoma, advanced or metastatic, relapsed or refractory (later-line therapy) (Afinitor):

Note: Despite efficacy in the treatment of thymoma and thymic carcinoma, everolimus is not routinely used due to the risk of severe toxicity (pneumonitis) (Ref).

Oral: 10 mg once daily; continue until disease progression or toxicity (Ref).

Tuberous sclerosis complex–associated partial-onset seizures

Tuberous sclerosis complex–associated partial-onset seizures (dosing based on BSA) (Afinitor Disperz): Oral: Initial: 5 mg/m² once daily; continue until disease progression or unacceptable toxicity (Ref).

Therapeutic drug monitoring: Titrate dose to attain trough concentrations between 5 ng/mL to 15 ng/mL. Maximum dose increment at any titration must not exceed 5 mg; multiple dose titrations may be required to attain target trough concentration. Use the same assay and lab for therapeutic drug monitoring throughout treatment if possible. Adjust dose using the following equation:

New dose = Current dose × (Target concentration divided by Current concentration)

Assess trough concentrations 1 to 2 weeks after initiation of therapy, with dosage modification(s), or when changing dosage forms between tablets and tablets for oral suspension; 2 weeks after a change in hepatic function and initiation or discontinuation of concurrent CYP3A4/P-glycoprotein (P-gp) inhibitor/inducer therapy; every 3 to 6 months once stable dose is attained but BSA is changing; every 6 to 12 months once stable dose is attained and if BSA is stable throughout treatment.

Tuberous sclerosis complex–associated renal angiomyolipoma

Tuberous sclerosis complex–associated renal angiomyolipoma (Afinitor): Oral: 10 mg once daily, continue treatment until disease progression or unacceptable toxicity (Ref).

Tuberous sclerosis complex–associated subependymal giant cell astrocytoma

Tuberous sclerosis complex–associated subependymal giant cell astrocytoma (SEGA; dosing based on BSA) (Afinitor or Afinitor Disperz): Oral: Initial: 4.5 mg/m² once daily; continue until disease progression or unacceptable toxicity (Ref).

New dose = Current dose × (Target concentration divided by Current concentration)

Assess trough concentrations 1 to 2 weeks after initiation of therapy, with dosage modification(s), or when changing dosage forms between tablets and tablets for oral suspension; 2 weeks after a change in hepatic function and initiation or discontinuation of concurrent CYP3A4/P-gp inhibitor/inducer therapy; every 3 to 6 months once stable dose is attained but BSA is changing; every 6 to 12 months once stable dose is attained and if BSA is stable throughout treatment.

Waldenström macroglobulinemia, relapsed or refractory

Waldenström macroglobulinemia, relapsed or refractory (off-label use) (Afinitor): Oral: 10 mg once daily until disease progression or toxicity (Ref).

Missed doses: Afinitor/Afinitor Disperz missed doses may be administered up to 6 hours after regularly scheduled time; if more than 6 hours, skip the dose for that day and resume at next regularly scheduled time (do not administer double doses to make up for a missed dose).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosage adjustment for surgery: Temporarily withhold everolimus treatment ≥1 week prior to elective surgery; do not reinitiate therapy for ≥2 weeks following major surgery and until adequate wound healing.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (Ref).

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m²):

Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).

No dosage adjustment necessary (Ref).

Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable: No supplemental dose or dosage adjustment necessary (Ref).

Peritoneal dialysis: Unlikely to be significantly dialyzed: No dosage adjustment necessary (Ref).

CRRT: No dosage adjustment necessary (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).

Dosing: Liver Impairment: Adult

Mild impairment (Child-Turcotte-Pugh class A):

Breast cancer, neuroendocrine tumors, renal cell cancer (RCC), tuberous sclerosis complex (TSC)-associated renal angiomyolipoma: Reduce dose to 7.5 mg once daily; if not tolerated, may further reduce to 5 mg once daily.

Liver or kidney transplantation: Reduce initial dose by ~33%; individualize subsequent dosing based on therapeutic drug monitoring (target trough concentration: 3 to 8 ng/mL).

TSC-associated partial-onset seizures and subependymal giant cell astrocytoma (SEGA): There is no initial dosage adjustment provided in the manufacturer's labeling; subsequent dosing is based on therapeutic drug monitoring (monitor 2 weeks after any change in hepatic status; target trough concentration: 5 to 15 ng/mL).

Moderate impairment (Child-Turcotte-Pugh class B):

Breast cancer, neuroendocrine tumors, RCC, TSC-associated renal angiomyolipoma: Reduce dose to 5 mg once daily; if not tolerated, may further reduce to 2.5 mg once daily.

Liver or kidney transplantation: Reduce initial dose by ~50%; individualize subsequent dosing based on therapeutic drug monitoring (target trough concentration: 3 to 8 ng/mL).

TSC-associated partial-onset seizures and SEGA: There is no initial dosage adjustment provided in the manufacturer's labeling; subsequent dosing is based on therapeutic drug monitoring (monitor 2 weeks after any change in hepatic status; target trough concentration: 5 to 15 ng/mL).

Severe impairment (Child-Turcotte-Pugh class C):

Breast cancer, neuroendocrine tumors, RCC, TSC-associated renal angiomyolipoma: If potential benefit outweighs risks, a dose of 2.5 mg once daily may be used (do not exceed 2.5 mg once daily).

Liver or kidney transplantation: Reduce initial dose by ~50%; individualize subsequent dosing based on therapeutic drug monitoring (target trough concentration: 3 to 8 ng/mL).

TSC-associated partial-onset seizures and SEGA: Reduce initial dose to 2.5 mg/m² once daily; subsequent dosing is based on therapeutic drug monitoring (monitor 2 weeks after any change in hepatic status; target trough concentration: 5 to 15 ng/mL).

Dosing: Adjustment for Toxicity: Adult

Oncology-related indications (Afinitor and Afinitor Disperz) :

**Everolimus Recommended Dosage Modifications for Adverse Reactions**
Adverse reaction	Severity	Everolimus dosage modification
Hematologic toxicity
Neutropenia	ANC ≥500/mm³ to <1,000/mm³ (Grade 3)	Withhold everolimus until recovery to ≤ grade 2; resume at same dose.
Neutropenia	ANC <500/mm³ (Grade 4)	Withhold everolimus until recovery to ≤ grade 2; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available.
Neutropenic fever	Grade 3	Withhold everolimus until recovery to ≤ grade 2 and no fever; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available.
Neutropenic fever	Grade 4	Permanently discontinue everolimus.
Thrombocytopenia	Platelets ≥50,000/mm³ to <75,000/mm³ (Grade 2)	Withhold everolimus until recovery to ≤ grade 1; resume at same dose.
	Platelets ≥25,000/mm³ to <50,000/mm³ (Grade 3)	Withhold everolimus until recovery to ≤ grade 1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available.
	Platelets <25,000/mm³ (Grade 4)	Withhold everolimus until recovery to ≤ grade 1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available.
Nonhematologic toxicity
Angioedema	Any	Permanently discontinue everolimus.
Hypersensitivity	Any (clinically significant)	Permanently discontinue everolimus.
Infections	Invasive; systemic	Withhold or permanently discontinue everolimus (based on severity of infection).
Metabolic adverse events (eg, hyperglycemia, dyslipidemia)	Grade 3	Withhold everolimus until recovery to ≤ grade 2; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available.
Metabolic adverse events (eg, hyperglycemia, dyslipidemia)	Grade 4	Permanently discontinue everolimus.
Noninfectious pneumonitis	Radiological changes; few or no symptoms	No dosage adjustment necessary; continue treatment and monitor appropriately.
	Grade 2	Withhold everolimus until recovery to ≤ grade 1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available. Corticosteroids may be indicated until clinical symptoms resolve. Toxicity does not resolve to grade 1 within 4 weeks: Permanently discontinue everolimus.
	Grade 3	First occurrence: Withhold everolimus until recovery to ≤ grade 1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available. Corticosteroids may be indicated until clinical symptoms resolve. Recurrent: Permanently discontinue everolimus.
	Grade 4	Permanently discontinue everolimus. Corticosteroids may be indicated until clinical symptoms resolve.
Stomatitis	Any	Avoid use of products containing alcohol, hydrogen peroxide, iodine, or thyme derivatives. Mouthwashes and topical treatments are recommended. Administering a dexamethasone (0.5 mg/5 mL) alcohol-free oral mouthwash (10 mL swish for 2 minutes and spit 4 times/day for at least 8 weeks) prophylactically when initiating everolimus treatment reduces the incidence and severity of stomatitis (avoid food or drink within 1 hour after dexamethasone) (Rugo 2017). Alternatively, retrospective data have suggested that patients unable to tolerate corticosteroid mouthwashes prophylactically may benefit from reactive (ie, initiated if mouth pain develops) treatment with dexamethasone mouthwashes (Ruddy 2023).
	Grade 2	First occurrence: Withhold everolimus until recovery to ≤ grade 1; resume at same dose. Recurrent: Withhold everolimus until recovery to ≤ grade 1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available.
	Grade 3	Withhold everolimus until recovery to ≤ grade 1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available.
	Grade 4	Permanently discontinue everolimus.
Other treatment related adverse events (excluding pneumonitis, stomatitis, or metabolic adverse events)	Grade 2	First occurrence (if intolerable): Withhold everolimus until recovery to ≤ grade 1; resume at same dose. Recurrent: Withhold everolimus until recovery to ≤ grade 1; resume at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available.
	Grade 3	First occurrence: Withhold everolimus until recovery to ≤ grade 1; consider resuming at 50% of previous dose; change to every other day dosing if reduced dose is lower than lowest strength available. Recurrent: Permanently discontinue everolimus.
	Grade 4	Permanently discontinue everolimus.

Liver or kidney transplantation (Zortress):

Evidence of polyoma virus infection or progressive multiple leukoencephalopathy: Consider reduced immunosuppression (taking into account the allograft risks associated with decreased immunosuppression).

Interstitial lung disease/non-infectious pneumonitis: Most cases resolve with treatment interruption (with or without corticosteroids).

Metabolic disorders (hyperlipidemia): Initiate dietary modifications, exercise, and lipid-lowering agents as clinically indicated.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Everolimus: Pediatric drug information")

Note: Tablets (Afinitor, Zortress) and/or tablets for oral suspension (Afinitor Disperz) are not interchangeable. Afinitor Disperz is indicated for the treatment of tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA) or TSC-associated partial-onset seizures. Select recommended dosage form based on the indication. Do not combine formulations to achieve total desired dose.

Transplantation; heart, rejection prophylaxis

Transplantation; heart, rejection prophylaxis: Limited data available: Dosing based on the TEAMMATE trial design; dosing initiated at 6 months post transplant; preliminary results (n=53, median age: 4.3 years) showed initial dose resulted in therapeutic levels in 45% of patients; median reported therapeutic dose: 1.6 mg/m²/day; further efficacy results are pending (Ref):

Infants, Children, and Adolescents: Initial:

BSA <0.6 m²: Oral: 0.25 mg every 12 hours.

BSA 0.6 m² to 0.9 m²: Oral: 0.5 mg every 12 hours.

BSA 0.9 m² to 1.2 m²: Oral: 0.75 mg every 12 hours.

BSA 1.2 m² to 1.5 m²: Oral: 1 mg every 12 hours.

BSA >1.5 m²: Oral: 1.25 mg every 12 hours.

Transplantation; renal, rejection prophylaxis

Transplantation; renal, rejection prophylaxis: Limited data available:

Children ≥1 year and Adolescents:

In combination with cyclosporine: Oral: Initial: 0.8 mg/m²/dose twice daily (maximum single dose: 1.5 mg) post-transplantation (Ref).

In combination with tacrolimus: Oral: Initial: 2 mg/m²/dose twice daily (Ref).

Tuberous sclerosis complex–associated subependymal giant cell astrocytoma

Tuberous sclerosis complex (TSC)–associated subependymal giant cell astrocytoma (SEGA):

Children ≥1 year and Adolescents: Afinitor; Afinitor Disperz: Oral: Initial: 4.5 mg/m²/dose once daily; continue until disease progression or unacceptable toxicity; evaluate serum trough concentration periodically; see "Tuberous Sclerosis Complex (TSC) Therapeutic Drug Monitoring" for additional information.

Tuberous sclerosis complex–associated partial-onset seizures, adjunct therapy

Tuberous sclerosis complex (TSC)–associated partial-onset seizures; adjunct therapy:

Children ≥2 years and Adolescents: Afinitor Disperz: Oral: Initial: 5 mg/m²/dose once daily; continue until disease progression or unacceptable toxicity; evaluate serum trough concentration periodically; see "Tuberous Sclerosis Complex (TSC) Therapeutic Drug Monitoring" for additional information.

Tuberous sclerosis complex (TSC) therapeutic drug monitoring: Children ≥1 year and Adolescents: Titrate dose to attain serum trough concentrations between target range of 5 ng/mL to 15 ng/mL. Use the same assay and lab for therapeutic drug monitoring throughout treatment if possible. Adjust dose using the following equation:

New dose (mg) = Current dose (mg) × (Target concentration [ng/mL] divided by Current concentration [ng/mL])

Maximum dose increment at any titration must not exceed 5 mg; multiple dose titrations may be required to attain target trough concentration.

Suggested timing of trough concentrations:

At 1 to 2 weeks following initiation, dosage modification, or switch of dosage form (tablets or tablets for oral suspension).

At 2 weeks following changes in hepatic function or modifications of concurrent CYP3A4 or p-glycoprotein (P-gp) strong inducer or moderate inhibitor therapy (initiated, dose change, or discontinued).

Every 3 to 6 months if BSA is changing and dose is stable.

Every 6 to 12 months if both dose and BSA are stable.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity:

Children and Adolescents:

TSC-associated SEGA or partial-onset seizures:

Nonhematologic toxicities:

Noninfectious pneumonitis:

Radiological changes suggestive of noninfectious pneumonitis but few or no symptoms: No dosage adjustment is necessary; continue treatment and monitor appropriately.

Grade 2: Interrupt treatment until symptoms improve to ≤ grade 1. Reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available. Corticosteroids may be indicated until clinical symptoms resolve. Permanently discontinue if toxicity does not resolve or improve to grade 1 within 4 weeks.

Grade 3: Interrupt treatment until symptoms improve to ≤ grade 1. Reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available. Corticosteroids may be indicated until clinical symptoms resolve. Permanently discontinue treatment if toxicity recurs at grade 3.

Grade 4: Permanently discontinue treatment. Corticosteroids may be indicated until clinical symptoms resolve.

Stomatitis (avoid the use of products containing alcohol, hydrogen peroxide, iodine, or thyme derivatives): Note: Mouthwashes and topical treatments are recommended. Administering an alcohol-free dexamethasone oral mouthwash (swish and spit) when initiating everolimus treatment reduces the incidence and severity of stomatitis.

Grade 2: Interrupt treatment until symptoms improve to ≤ grade 1; reinitiate at same dose. If stomatitis recurs at grade 2, interrupt treatment until symptoms improve to ≤ grade 1; reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available.

Grade 3: Interrupt treatment until symptoms improve to ≤ grade 1; then reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available.

Grade 4: Permanently discontinue treatment.

Metabolic toxicity (eg, hyperglycemia, dyslipidemia):

Grade 3: Temporarily interrupt treatment until symptoms improve to ≤ grade 2; reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available.

Grade 4: Permanently discontinue treatment.

Other nonhematologic toxicities (excluding pneumonitis, stomatitis, and metabolic toxicity):

Grade 2: If toxicity becomes intolerable, temporarily interrupt treatment until improvement to ≤ grade 1 and reinitiate at the same dose; if toxicity recurs at grade 2, temporarily interrupt treatment until improvement to ≤ grade 1 and then reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available.

Grade 3: Temporarily interrupt treatment until improvement to ≤ grade 1; consider reinitiating treatment at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available. If toxicity recurs at grade 3, permanently discontinue treatment.

Grade 4: Permanently discontinue treatment.

Angioedema: Permanently discontinue everolimus.

Hypersensitivity (clinically significant): Permanently discontinue everolimus.

Invasive systemic infection: Withhold or permanently discontinue (based on the severity of infection).

Hematologic toxicities:

Thrombocytopenia:

Grade 2 (platelets ≥50,000 to <75,000/mm³): Temporarily interrupt treatment until improvement to ≤ grade 1; reinitiate at the same dose.

Grade 3 (platelets ≥25,000 to <50,000/mm³): Temporarily interrupt treatment until improvement to ≤ grade 1; reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available.

Grade 4 (platelets <25,000/mm³): Temporarily interrupt treatment until improvement to ≤ grade 1; reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available.

Neutropenia:

Grade 3 (ANC ≥500 to <1,000/mm³): Temporarily interrupt treatment until improvement to ≤ grade 2; reinitiate at the same dose.

Grade 4 (ANC <500/mm³): Temporarily interrupt treatment until improvement to ≤ grade 2; reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available.

Neutropenic fever:

Grade 3: Temporarily interrupt treatment until improvement to ≤ grade 2 and no fever; reinitiate at 50% of previous dose; change to every-other-day dosing if the reduced dose is lower than the lowest strength available.

Grade 4: Permanently discontinue treatment.

Transplantation, renal:

Evidence of polyoma virus infection or PML: Consider reduced immunosuppression (taking into account the allograft risks associated with decreased immunosuppression).

Interstitial lung disease/noninfectious pneumonitis: Most cases resolve with treatment interruption (with or without corticosteroids).

Dosing: Kidney Impairment: Pediatric

All patients: No adjustment necessary at baseline; nephrotoxicity has been reported with use; monitor renal function.

Dosing: Liver Impairment: Pediatric

Tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA) or partial-onset seizures:

Afinitor, Afinitor Disperz: Children and Adolescents:

Mild to moderate hepatic impairment: There is no initial dosage adjustment provided in the manufacturer's labeling; subsequent dosing should be based on therapeutic drug monitoring (monitor serum drug concentration 2 weeks after initiation, dosage modifications, or after any change in hepatic status; target trough concentration: 5 to 15 ng/mL).

Severe hepatic impairment: Reduce initial dose to 2.5 mg/m² once daily; subsequent dosing is based on therapeutic drug monitoring (monitor 2 weeks after initiation, dosage modifications, or after any change in hepatic status; target trough concentration: 5 to 15 ng/mL).

Adverse Reactions (Significant): Considerations

Angioedema

Angioedema (eg, lingual) following initiation of everolimus has been reported. Angioedema is limited to case reports in the oncology literature (Ref). Angioedema may respond to hypersensitivity treatment (eg, corticosteroids, antihistamines) and mechanistic target of rapamycin (mTOR) inhibitor discontinuation (Ref).

Mechanism: Non–dose-related; immunologic; alteration in the bradykinin pathway and impaired endothelial response to bradykinin (Ref).

Onset: Varied. In solid organ transplant, angioedema presented between 2 to 60 days after initiation of everolimus (Ref); similar varied onset observed in patients receiving everolimus for treatment of a malignancy (mean: 21 days to 1 month after initiation) (Ref).

Risk factors:

• Concurrent administration of angiotensin converting enzyme inhibitors (ACEIs) (Ref)

• History of angioedema with ACEIs (Ref)

Edema

Everolimus-associated edema can manifest in several ways, including peripheral edema, eyelid edema, lymphocele, or effusions (Ref).

Mechanism: Non–dose-related; several pathways of altered lymphatic drainage have been hypothesized, specifically endothelial dysfunction through activation of protein kinase C-α; reduced vascular endothelial growth factor expression and interruption of vascular endothelial p120-cadherin leading to increased capillary permeability; and alterations in endothelial cells involved in lymphatic drainage mediated through the mTOR pathway (Ref).

Onset: Varied. In a review of solid organ transplant recipients, edema presented between 1 day to 3 years after initiation (Ref); similar varied onset was observed in solid tumors (eg, breast cancer) with a mean of 12 months after initiation (Ref).

Risk factors:

Solid organ transplant recipients:

• Glomerular filtration rate <35 mL/minute (Ref)

• History of acute rejection (Ref)

• Dose, exposure-related (Ref)

• Concurrent administration of dihydropyridine calcium channel blockers (Ref)

• High salt diet (Ref)

Endocrine and metabolic effects

Everolimus is associated with several endocrine and metabolic-related effects, including:

• Hyperglycemia: Reported in various studies (Ref).

• Acute pancreatitis: Case reports in the setting of solid tumor treatment (Ref).

• Ketoacidosis: Reported in the setting of oncologic indications (Ref).

• Hypertriglyceridemia: Reported in malignancy (Ref) and solid organ transplant (Ref).

• Hypercholesterolemia: Increased cholesterol requiring intervention has been reported (Ref).

Mechanism: Dose-related; related to pharmacologic action. Everolimus has been shown to decrease β-cell mass and function and increase glycogen turnover which may reduce endogenous insulin secretion and promote insulin resistance yielding hyperglycemia (Ref). The mechanism for everolimus-induced hyperlipidemia and increased triglycerides is unknown but may be related to reduced clearance of lipids, specifically apolipoproteins (eg, B100) generated in the liver (Ref).

Onset: Varied. Hyperglycemia has been reported 3 to 8 weeks after exposure in cancer patients (Ref); hyperglycemia onset in solid organ transplant recipients is difficult to decipher in the setting of concurrent immunosuppressants which also cause hyperglycemia (Ref). Cholesterol and triglycerides have been reported to increase within 4 weeks of exposure in oncology patients (Ref) and 2 to 3 months in solid organ transplant recipients (Ref). Acute pancreatitis occurred within 2 months after initiation of therapy in case reports (Ref).

Risk factors:

• Concurrent use of tacrolimus or corticosteroids increases risk of hyperglycemia specifically in solid organ transplant recipients (Ref)

• Dose-related; increased exposure increases the risk of development of endocrine-associated complications (Ref)

• High triglyceride levels ≥500 mg/dL increases risk of acute pancreatitis (Ref)

• Preexisting dysfunction in glucose metabolism, diabetes, or diabetes risk factors (Ref)

• Preexisting hyperlipidemia (Ref)

• Tumor type (eg, renal cell carcinoma, neuroendocrine tumors) (Ref)

• Viral infections (eg, cytomegalovirus, hepatitis C virus) (Ref)

Hematologic abnormalities

Everolimus exposure can cause anemia, thrombocytopenia, leukopenia, and lymphocytopenia, which may resolve upon discontinuation of therapy (Ref). The incidence of everolimus-related hematologic abnormalities in patients with cancer appear to be more prevalent than in solid organ transplant recipients; this difference may be dose-related (Ref).

Mechanism: Dose- and time-related; related to cumulative dose; mechanistic target of rapamycin (mTOR) inhibitors block the cell cycle and decrease interleukin-2 receptor and co-stimulatory pathways which may also be important for hematopoietic cell proliferation (Ref). mTOR inhibitor-related anemia may also result from decreased iron absorption from the gastrointestinal tract and alteration in iron uptake into erythrocytes (Ref).

Onset: Varied. Changes in hematologic parameters occurred as early as 2 weeks in oncology patients and solid organ transplant recipients (Ref).

Risk factors:

mTOR inhibitor-related anemia in solid organ transplant:

• Dose-related, resolution upon discontinuation (Ref)

• Increased age (Ref)

• Low iron (Ref)

• Concurrent malignancy (Ref)

• Presence of inflammation (Ref)

• Kidney insufficiency (Ref)

• Concurrent viral infection (Ref)

• Concurrent use of mycophenolate (Ref)

Kidney abnormalities

Non-oliguric kidney damage requiring dialysis and nephrotic syndrome have been reported in patients with cancer with resolution after cessation of everolimus (Ref). Glomerulonephritis in a kidney transplant recipient presenting as proteinuria has also been reported (Ref). Mild to moderate proteinuria was reported in patients with renal cell carcinoma receiving everolimus as first-line therapy in one retrospective review; median time to resolution of proteinuria in this population was 2 months (range: 1 to 12 months) (Ref).

Mechanism: Dose-related; related to the pharmacologic action; may be related to everolimus accumulation in kidney cells; however, the exact mechanism is unknown but proposed loss of podocyte integrity or kidney epithelial cell apoptosis through immunologic pathways (Ref). In solid organ transplant recipients transitioned from a calcineurin inhibitor to everolimus, proteinuria may be related to alterations in glomerular permeability to serum proteins by increased blood flow and glomerular pressure after withdrawal of the calcineurin inhibitor (Ref).

Onset: Varied. Changes in kidney function were observed between 2 weeks to 5 years after initiation (Ref); in renal cell carcinoma, the median time to onset of proteinuria was 2 months (range: 1 to 15 months) (Ref).

Risk factors:

• Dose-related, higher trough concentrations (eg, >8 ng/mL) in solid organ transplant (Ref)

• Pretreatment proteinuria (>800 mg/day) (Ref)

• Preexisting kidney insufficiency (eg, eGFR <40 mL/minute) (Ref)

• Active viral infection (Ref)

• Diabetes (Ref)

Non-infective pneumonitis

Everolimus-induced non-infective pneumonitis is a diagnosis of exclusion (Ref). Patients may present with cough, shortness of breath, fever, malaise, or chest radiograph findings consistent with pneumonitis (Ref). Rate and degree of reduced lung diffusion capacity for carbon monoxide (corrected for hemoglobin) was shown to predict the severity of interstitial lung disease (ILD) in a pilot study and discriminate ILD from other underlying pulmonary disorders (Ref). The onset of symptoms correlates with recent exposure to everolimus and symptoms resolve with cessation of everolimus (Ref). Of note, in a single center experience, radiographic findings (18F-fluoro-deoxy-glucose combined with positron emission tomography/computerized tomography [¹⁸F-FDG PET/CT] imaging) of hypermetabolic pulmonary pleuroparenchymal anomalies were observed in most patients with metastatic breast cancer receiving everolimus (Ref).

Mechanism: Non–dose-related; immunologic; evidence of high number of CD4+ cells and eosinophils on bronchial alveolar lavage (Ref) and direct mTOR inhibitor toxicity to lung tissue (Ref).

Onset: Varied. Respiratory symptoms occurred as early as 5 days after initiation up to 6 years postexposure (Ref).

Risk factors:

• Asian heritage; Japanese heritage (Ref)

• Dose-related (increased exposure increases the risk of development of pneumonitis, although not confirmed) (Ref)

• Increased weight (Ref)

• Kidney insufficiency (Ref)

Radiation sensitization/recall

Radiation recall phenomenon has been reported in patients who previously underwent radiation therapy and subsequently received everolimus as part of their cancer treatment regimen (Ref). Specifically, case reports identify recall syndrome involving nonspecific inflammation (eg, pulmonary infiltrates, gastric ulcers, tissue erosion, esophagitis) in areas of radiation exposure after receiving everolimus (Ref). Resolution of symptoms occurred after cessation of therapy and appropriate supportive care (eg, corticosteroids) (Ref).

Mechanism: Non–dose-related; idiosyncratic; may be related to mechanistic target of rapamycin inhibition of DNA repair and angiogenesis (Ref).

Onset: Varied. Case reports identify symptoms as early as 1 week after initiating therapy and up to 16 weeks postexposure (Ref).

Risk factors:

• Previous or concurrent radiation exposure (Ref)

Stomatitis

Mechanistic target of rapamycin (mTOR) inhibitor-associated stomatitis lesions are superficial, well-demarcated, singular or multiple ulcers that present with regular, round boarders in the mouth and generally occur on nonkeratinized areas (eg, inside of the lips, cheeks, tongue, soft palate) (Ref). Lesions are typically ≤0.5 cm in diameter (Ref). Most cases are mild to moderate in severity (Ref). Pain and impaired oral function can be dose-limiting (Ref). Therapy interruption or discontinuation was required to allow lesions to heal (Ref).

Mechanism: Dose-related; related to the pharmacologic action; may be related to composition of normal oral flora (eg, Bacteroidales species), genetic predisposition coding for proinflammatory cytokines (eg, serotonin transcriptase), or direct mTOR inhibitor toxicity to oral mucosa (Ref).

Onset: Intermediate; mTOR inhibitor associated-stomatitis symptoms usually develop between 5 and 7 days after initiation of therapy (Ref).

Risk factors:

• Dose-related (Ref)

• Stress and anxiety (Ref)

• Nutritional deficiency (Ref)

• Hormonal alteration (Ref)

• Conversion to everolimus post-solid organ transplant from a calcineurin inhibitor (eg, tacrolimus, cyclosporine) (Ref)

Thrombosis

Mechanistic target of rapamycin (mTOR) inhibitors may induce a procoagulant state in some patients, resulting in thromboembolic events (eg, pulmonary embolism, deep vein thrombosis, allograft thrombosis) (Ref). These events have been described most frequently in liver transplant recipients, but events have been reported in all solid organ transplant recipients (Ref). There are also reports of thromboembolic events in oncology uses; specifically, thromboembolic events that led to discontinuation occurred in ~5% of patients undergoing treatment with everolimus plus hormonal therapy (eg, tamoxifen) for breast cancer (Ref).

Mechanism: Non–dose related; prothrombotic; everolimus increases von Willebrand factor which is evidence of endothelial cell activation and platelet activation (Ref). Increases in thrombin formation and impairment in fibrinolysis both contribute to clot formation in the setting of everolimus (Ref). mTOR inhibition can also contribute to up regulation of tissue factor which can contributor to clot formation (Ref).

Onset: Varied. Thromboembolic events occurred at an average of 376 days (range: 123 to 1,034 days) after initiation of therapy (Ref).

Risk factors:

• History of thrombophilia (Ref)

• Use early post-liver transplant (<30 days) (Ref)

• Concurrent use of hormonal therapy (eg, tamoxifen) (Ref)

Wound healing impairment

Mechanistic target of rapamycin (mTOR) inhibitor-related wound healing impairment complications can manifest in several ways, including surgical wound dehiscence, lymphoceles, wound infection, seroma, hematoma, effusions, incisional site discharge, primary nonclosure, or delayed healing (Ref). The definition of a wound healing impairment is not well defined; therefore, the true mTOR inhibitor-related incidence is unknown (Ref).

Mechanism: Dose-related; related to the pharmacologic action; mTOR inhibitors suppress fibroblast proliferation, neointimal hyperplasia, and angiogenesis, which all may lead to impaired wound healing (Ref).

Onset: Varied. The exact time to event is challenging to decipher as evaluation of a transplant procedure-related wound event is typically collated at specific times after a procedure (eg, 1 month, 12 months) and details of primary wound non-healing or a wound-related complication are based on symptom detection (eg, lymphocele) and varying definitions in the literature (Ref).

Risk factors:

• Dose-related; higher doses or increased systemic exposure as evidenced by high systemic levels suggest a higher frequency of wound healing complications, including those that required intervention, specifically in kidney transplant recipients (Ref)

• History of diabetes mellitus (Ref)

• Increased body mass index (≥30 kg/m²) (Ref)

• Increased age (Ref)

• High corticosteroid exposure (Ref)

• History of a left ventricular assist device in heart transplant recipients (Ref)

• Redo sternotomy in heart transplant recipients (Ref)

• Active bacterial or fungal infection (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Transplantation:

Reactions occur in kidney and liver transplantation unless otherwise specified. Reported as a part of combination therapy.

>10%:

Cardiovascular: Hypertension (17% to 30%), peripheral edema (kidney transplant: 45%; liver transplant: 18% to 20%)

Endocrine & metabolic: Diabetes mellitus (new onset: kidney transplant: 9%; liver transplant: 32%), hypercholesterolemia (9% to 17%), hyperglycemia (kidney transplant: 12%), hyperkalemia (kidney transplant: 18%), hypokalemia (kidney transplant: 12%), hypomagnesemia (kidney transplant: 14%), hypophosphatemia (kidney transplant: 13%)

Gastrointestinal: Abdominal pain (13% to 15%), constipation (kidney transplant: 38%), diarrhea (19% to 24%), nausea (kidney transplant: 29%; liver transplant: 14% to 15%), vomiting (kidney transplant: 15%)

Genitourinary: Dysuria (kidney transplant: 11%), hematuria (kidney transplant: 12%), urinary tract infection (kidney transplant: 22%)

Hematologic & oncologic: Anemia (kidney transplant: 26%), leukopenia (3% to 13%)

Hepatic: Hepatitis C (liver transplant: 11% to 14%)

Infection: Bacterial infection (liver transplant: 16%), infection (kidney transplant: 62% to 64%; liver transplant: 50%), viral infection (kidney transplant: 10%; liver transplant: 17%)

Nervous system: Fatigue (9% to 11%), headache (18% to 22%), insomnia (kidney transplant: 17%; liver transplant: 6% to 7%)

Neuromuscular & skeletal: Back pain (kidney transplant: 11%), limb pain (kidney transplant: 12%)

Renal: Increased serum creatinine (kidney transplant: 18%)

Respiratory: Upper respiratory tract infection (kidney transplant: 16%)

Miscellaneous: Fever (13% to 19%), wound healing impairment (kidney transplant: 35%; liver transplant: 11%; includes dehiscence, incisional hernia, lymphocele, seroma)

1% to 10%:

Cardiovascular: Angina pectoris, atrial fibrillation, chest discomfort, chest pain, deep vein thrombosis, edema, heart failure, hypertensive crisis, hypotension, palpitations, phlebitis, pulmonary embolism, syncope, tachycardia, venous thromboembolism

Dermatologic: Acne vulgaris, acneiform eruption, alopecia, cellulitis, diaphoresis, ecchymoses, folliculitis, hypertrichosis, night sweats, onychomycosis, pruritus, skin rash, tinea pedis

Endocrine & metabolic: Acidosis, amenorrhea, cushingoid appearance, dehydration, fluid retention, hirsutism, hypercalcemia, hyperparathyroidism, hypertriglyceridemia, hyperuricemia, hypocalcemia, hypoglycemia, hyponatremia, hypothyroidism, iron deficiency, vitamin B₁₂ deficiency

Gastrointestinal: Abdominal distention, anorexia, biliary obstruction, cholangitis, cholestasis, decreased appetite, dyspepsia (kidney transplant: 4%), dysphagia, epigastric distress, flatulence, gastritis, gastroenteritis, gastroesophageal reflux disease, gingival hyperplasia, hematemesis, hemorrhoids, hernia of abdominal cavity, inguinal hernia, intestinal obstruction, oral candidiasis, oral herpes simplex infection, oral mucosa ulcer, peritoneal effusion, peritonitis, stomatitis (kidney transplant: 8%), upper abdominal pain (kidney transplant: 3%)

Genitourinary: Benign prostatic hypertrophy, bladder spasm, erectile dysfunction (kidney transplant: 5%), nocturia, ovarian cyst, perinephric abscess, perinephric hematoma, pollakiuria, polyuria, proteinuria, pyuria, scrotal edema, urethritis, urinary retention, urinary urgency

Hematologic & oncologic: Benign neoplasm (≤4%), leukocytosis, lymphadenopathy, lymphorrhea, malignant neoplasm (≤4%), neutropenia, pancytopenia, thrombocytopenia

Hepatic: Abnormal hepatic function tests (liver transplant: 7% to 8%), ascites (liver transplant: 4%), hepatitis (noninfectious), increased liver enzymes, increased serum alkaline phosphatase, increased serum bilirubin

Infection: Bacteremia, BK virus (kidney transplant: 1%), candidiasis, cytomegalovirus disease (1%), fungal infection (liver transplant: 2%), herpes virus infection, influenza, sepsis, wound infection

Nervous system: Agitation, anxiety, asthenia, chills, depression, dizziness, drowsiness, hallucination, hemiparesis, hypoesthesia, lethargy, malaise, migraine, myasthenia, neuralgia, pain, paresthesia, tremor (8% to 10%)

Neuromuscular & skeletal: Arthralgia, gout, joint swelling, muscle spasm, musculoskeletal pain, myalgia, osteoarthritis, osteomyelitis, osteonecrosis, osteoporosis, spondylitis

Ophthalmic: Blurred vision, cataract, conjunctivitis

Renal: Hydronephrosis, increased blood urea nitrogen, interstitial nephritis, kidney failure (5% to 10%; may be acute), kidney impairment, pyelonephritis, renal artery thrombosis, renal tubular necrosis

Respiratory: Atelectasis, bronchitis, cough (kidney transplant: 7%), dyspnea, epistaxis, lower respiratory tract infection, nasal congestion, nasopharyngitis, oropharyngeal pain, paranasal sinus congestion, pleural effusion (liver transplant: 5%), pneumonia, pulmonary edema, rhinorrhea, sinusitis, wheezing

<1%:

Cardiovascular: Pericardial effusion

Gastrointestinal: Pancreatitis

Hematologic & oncologic: Hemolytic-uremic syndrome, lymphoproliferative disorder, thrombotic microangiopathy, thrombotic thrombocytopenic purpura

Hepatic: Hepatocellular neoplasm

Hypersensitivity: Angioedema

Respiratory: Interstitial lung disease

Frequency not defined:

Cardiovascular: Venous thrombosis

Dermatologic: Malignant neoplasm of skin

Endocrine & metabolic: Decreased plasma testosterone, increased follicle-stimulating hormone

Hematologic & oncologic: Malignant lymphoma

Antineoplastic:

Antineoplastic indications include advanced nonfunctional neuroendocrine tumors (NET) of gastrointestinal or lung origin in adults; pancreatic NET in adults; advanced renal cell carcinoma in adults; and tuberous sclerosis complex associated renal angiomyolipoma or subependymal giant cell astrocytoma in pediatric patients and adults.

>10%:

Cardiovascular: Edema (≤39%), hypertension (4% to 13%), peripheral edema (≤39%)

Dermatologic: Acne vulgaris (10% to 22%), nail disease (5% to 22%), pruritus (12% to 21%), skin rash (21% to 59%), xeroderma (13%)

Endocrine & metabolic: Amenorrhea (15% to 17%), decreased serum bicarbonate (56%), hypercholesterolemia (66% to 85%), hyperglycemia (13% to 75%), hypertriglyceridemia (27% to 73%), hypoalbuminemia (13% to 18%), hypocalcemia (37%), hypokalemia (23% to 27%), hypophosphatemia (9% to 49%), irregular menses (10% to 11%), weight loss (5% to 28%)

Gastrointestinal: Abdominal pain (5% to 36%), anorexia (25%), constipation (10% to 14%), decreased appetite (6% to 30%), diarrhea (14% to 50%; grades 3/4: 2% to 9%), dysgeusia (5% to 19%), gastroenteritis (10% to 12%), mucosal swelling (19%), nausea (8% to 26%; grades 3/4: 2% to 3%), stomatitis (44% to 78%; grades 3/4: 4% to 9%), vomiting (15% to 29%; grade 3: 1% to 4%), xerostomia (8% to 11%)

Genitourinary: Proteinuria (18%), urinary tract infection (9% to 31%)

Hematologic & oncologic: Anemia (41% to 92%; grades 3/4: 5% to 15%), decreased serum fibrinogen (8% to 38%), leukopenia (37% to 49%; grades 3/4: 2%), lymphocytopenia (20% to 66%; grades 3/4: 1% to 18%), neutropenia (14% to 46%; grades 3/4: ≤9%), prolonged partial thromboplastin time (63% to 72%; grade 3: 3%), prolonged prothrombin time (40%), thrombocytopenia (19% to 45%; grades 3/4: 1% to 3%)

Hepatic: Increased serum alanine aminotransaminase (18% to 48%), increased serum alkaline phosphatase (32% to 74%), increased serum aspartate aminotransferase (23% to 57%)

Infection: Infection (37% to 58%)

Nervous system: Aggressive behavior (≤21%), anxiety (≤21%), asthenia (23% to 33%), behavioral changes (≤21%; including agitation, obsessive compulsive disorder, panic attack), dizziness (7% to 12%), fatigue (≤45%), headache (≤30%), insomnia (6% to 14%), malaise (≤45%), migraine (≤30%)

Neuromuscular & skeletal: Arthralgia (13% to 15%), back pain (15%), limb pain (8% to 14%), myalgia (11%)

Renal: Increased serum creatinine (5% to 50%)

Respiratory: Cough (≤30%), dyspnea (≤24%), dyspnea on exertion (≤20%), epistaxis (5% to 22%), nasopharyngitis (≤25%), oropharyngeal pain (11%), pneumonia (6% to 19%), pneumonitis (1% to 17%; including interstitial lung disease, pulmonary alveolar hemorrhage, pulmonary alveolitis, pulmonary fibrosis, pulmonary infiltrates, pulmonary toxicity, restrictive pulmonary disease), productive cough (≤25%), respiratory tract infection (31%), rhinitis (≤25%), upper respiratory tract infection (≤25%)

Miscellaneous: Fever (20% to 31%)

1% to 10%:

Cardiovascular: Chest pain (5%), heart failure (1%), pulmonary embolism (2%), tachycardia (3%), thrombosis (1%)

Dermatologic: Acneiform eruption (3%), cellulitis (6%), erythema of skin (4%), onychoclasis (4%), palmar-plantar erythrodysesthesia (5%), skin lesion (4%)

Endocrine & metabolic: Diabetes mellitus (10%; new onset: <1%), exacerbation of diabetes mellitus (2%), heavy menstrual bleeding (6% to 10%), increased follicle-stimulating hormone (3%), increased luteinizing hormone (1% to 4%), menstrual disease (6% to 10%)

Gastrointestinal: Dysphagia (4%), hemorrhoids (5%)

Genitourinary: Abnormal uterine bleeding (6%), azoospermia (1%), dysmenorrhea (6%), ovarian cyst (3%), vaginal hemorrhage (8%)

Hematologic & oncologic: Hemorrhage (3%)

Hepatic: Hyperbilirubinemia (3%)

Hypersensitivity: Angioedema (≤1%), hypersensitivity reaction (3%)

Nervous system: Chills (4%), depression (5%), paresthesia (5%)

Neuromuscular & skeletal: Jaw pain (3%), muscle spasm (10%)

Ophthalmic: Conjunctivitis (2%), eyelid edema (4%)

Otic: Otitis media (6%)

Renal: Kidney failure (3%)

Respiratory: Pharyngolaryngeal pain (4%), pleural effusion (7%), rhinorrhea (3%), streptococcal pharyngitis (10%)

<1%:

Cardiovascular: Deep vein thrombosis

Infection: Candidiasis

Miscellaneous: Wound healing impairment

Postmarketing (any indication):

Cardiovascular: Arterial thrombosis, shunt thrombosis (kidney)

Dermatologic: Erythroderma

Endocrine & metabolic: Ketoacidosis (Ref)

Gastrointestinal: Acute pancreatitis (Ref), cholecystitis, cholelithiasis

Genitourinary: Male infertility, oligospermia

Hematologic & oncologic: Lymphedema

Hypersensitivity: Anaphylaxis, hypersensitivity angiitis

Infection: Aspergillosis, polyomavirus infection, reactivation of HBV, septic shock

Nervous system: Complex regional pain syndrome, progressive multifocal leukoencephalopathy

Renal: Glomerulonephritis (Ref), nephrotoxicity

Miscellaneous: Radiation recall phenomenon (with prior to, during, or subsequent radiation treatment) (Ref)

Contraindications

Clinically significant hypersensitivity to everolimus, other rapamycin derivatives, or any component of the formulation.

Canadian labeling: Additional contraindications (not in the US labeling): Treatment of seizures (any type) in populations other than those with a definite tuberous sclerosis complex (TSC) diagnosis.

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: Everolimus is associated with the development of angioedema; concomitant use with other agents known to cause angioedema (eg, ACE inhibitors) may increase the risk.

• Bone marrow suppression: Decreases in hemoglobin, neutrophils, platelets, and lymphocytes have been reported, including grade 3 and 4 events.

• Edema: Generalized edema (including peripheral edema and lymphedema) and local fluid accumulation (eg, pericardial effusion, pleural effusion, ascites) may occur.

• Graft thrombosis: An increased risk of kidney arterial and venous thrombosis has been reported in kidney transplantation, generally within the first 30 days after transplant; may result in graft loss.

• Hepatic artery thrombosis: Mammalian target of rapamycin (mTOR) inhibitors are associated with an increase in hepatic artery thrombosis, most cases have been reported within 30 days after transplant and usually proceeded to graft loss or death. Do not use everolimus prior to 30 days post liver transplant.

• Hypersensitivity: Severe hypersensitivity reactions (anaphylaxis, dyspnea, flushing, chest pain, and angioedema) have been reported.

• Infections: Everolimus has immunosuppressant properties, which may result in increased susceptibility to infection. Everolimus may predispose patients to bacterial, fungal, viral, or protozoal infections, including opportunistic infections. Polyoma virus infection in transplant recipients may be serious and/or fatal. Polyoma virus-associated nephropathy (primarily due to BK virus), which may result in serious cases of deteriorating kidney function and kidney graft loss, has been observed with use in kidney transplantation. JC virus-associated progressive multiple leukoencephalopathy (PML) may also be associated with everolimus use in transplantation. Reduced immunosuppression (considering the risks of rejection) should be considered with evidence of polyoma virus infection or PML. Localized and systemic infections (including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections [eg, aspergillosis, candidiasis, or Pneumocystis jirovecii pneumonia {PJP}] and viral infections [eg, hepatitis B reactivation]) have occurred. Grade 3 and 4 infections have been reported; some infections have been severe (eg, sepsis, septic shock, or resulting in multisystem organ failure) or fatal. Serious infections have been reported at a higher frequency in patients <6 years of age. Treatment of preexisting invasive fungal infections should be completed prior to starting everolimus treatment. Combination immunosuppressant therapy in solid organ transplantation should be used with caution due to the risk of over immunosuppression, which may lead to increased susceptibility to infection.

• Malignancy: Immunosuppressant use may result in the development of malignancy, including lymphoma and skin cancer. The risk is associated with treatment intensity and the duration of therapy. To minimize the risk for skin cancer, limit exposure to sunlight and ultraviolet light; wear protective clothing, and use effective sunscreen.

• Metabolic effects: Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported, including grade 3 and 4 events. Higher serum everolimus concentrations are associated with an increased risk for hyperlipidemia. Everolimus has not been studied in transplant recipients with baseline cholesterol >350 mg/dL. Increases in serum glucose are common; may alter insulin and/or oral hypoglycemic therapy requirements in patients with diabetes. The risk for new-onset diabetes is increased with everolimus use after transplantation. Antihyperlipidemic therapy may not normalize levels.

• Mucositis/stomatitis: Everolimus is commonly associated with mouth ulcers, mucositis, and stomatitis. Stomatitis typically occurs within the first 8 weeks of therapy. Due to the high potential for drug interactions, avoid the use of systemic antifungals unless fungal infection has been diagnosed.

• Nephrotoxicity: Elevations in serum creatinine (generally mild), kidney failure, and proteinuria have been observed with everolimus. Grade 3 and 4 serum creatinine elevations and proteinuria have been reported. Risk of nephrotoxicity may be increased when administered with calcineurin inhibitors (eg, cyclosporine, tacrolimus); dosage adjustment of calcineurin inhibitor is necessary. The risk of proteinuria is increased when everolimus is used in combination with cyclosporine, and with higher serum everolimus concentrations.

• Pulmonary toxicity: Noninfectious pneumonitis, interstitial lung disease (ILD), and/or noninfectious fibrosis have been observed with mTOR inhibitors, including everolimus; some cases were fatal. Promptly evaluate worsening respiratory symptoms. Cases of ILD have been reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. Consider opportunistic infections such as PJP when evaluating clinical symptoms. Pneumonitis has been reported even at reduced everolimus doses.

• Radiation sensitization/recall: Radiation sensitization and recall (some cases may be severe or involve cutaneous and visceral organs [eg, radiation esophagitis, pneumonitis]) have been reported in patients treated with radiation prior to, during, or after treatment with everolimus.

• Wound healing impairment: Vascular endothelial growth factor receptor inhibitors are associated with impaired wound healing; therefore, everolimus may affect wound healing. The safety of resuming everolimus treatment after resolution of wound healing complications has not been established.

Disease-related concerns:

• Heart transplantation: Increased mortality (usually associated with infections) within the first 3 months after transplant was noted in a study of patients with de novo heart transplant receiving immunosuppressive regimens containing everolimus (with or without induction therapy). Use in heart transplantation is not recommended. The boxed warning in the labeling (Zortress) is based on severe infectious complications, rather than efficacy (reduction in the incidence of cardiac allograft vasculopathy). Despite labeled warnings for this off-label indication, some centers continue to use everolimus (with reduced calcineurin inhibitor exposure). However, everolimus initiation in heart transplantation is delayed until 3 to 6 months post-transplantation due to impaired wound healing and pericardial effusions early in the postoperative period (Andreassen 2014; Andreassen 2016; Hirt 2013; Hollis 2015; ISHLT [Velleca 2023]).

• Hereditary galactose intolerance: Avoid use in patients with galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption; may result in diarrhea and malabsorption.

• Kidney impairment: An increased incidence of rash, infection and dose interruptions have been reported in patients with kidney insufficiency (CrCl ≤60 mL/minute) who received mTOR inhibitors for the treatment of renal cell carcinoma (Gupta 2011). Serum creatinine elevations and proteinuria have been reported.

• Transplantation (solid organ): Everolimus should only be used by physicians experienced in immunosuppressive therapy and management of transplant recipients. Adequate laboratory and supportive medical resources must be readily available.

Concurrent drug therapy issues:

• Calcineurin inhibitor (CNI) combination therapy: Due to the increased risk for nephrotoxicity in solid organ transplantation, avoid standard doses of CNI (cyclosporine or tacrolimus) in combination with everolimus; reduced CNI doses are recommended. Therapeutic monitoring of CNI and everolimus concentrations is recommended.

Dosage form specific issues:

• Tablet formulations: Tablets (Afinitor, Zortress) and tablets for oral suspension (Afinitor Disperz) are not interchangeable; Afinitor Disperz is only indicated in conjunction with therapeutic monitoring for the treatment of tuberous sclerosis complex-associated partial-onset seizures and SEGA. Do not combine formulations to achieve total desired dose.

Other warnings/precautions:

• Assay method: For indications requiring whole blood trough concentrations to determine dosage adjustments, a consistent method should be used; concentration values from different assay methods may not be interchangeable.

• Immunizations: Patients should not be immunized with live viral vaccines during or shortly after treatment and should avoid close contact with recently vaccinated (live vaccine) individuals. In pediatric patients, complete recommended series of live virus childhood vaccinations prior to everolimus treatment (if immediate everolimus treatment is not indicated); an accelerated vaccination schedule may be appropriate.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Afinitor: 2.5 mg, 5 mg, 7.5 mg, 10 mg

Torpenz: 2.5 mg, 5 mg, 7.5 mg, 10 mg

Zortress: 0.25 mg, 0.5 mg, 0.75 mg, 1 mg

Generic: 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg

Tablet Soluble, Oral:

Afinitor Disperz: 2 mg, 3 mg, 5 mg

Generic: 2 mg, 3 mg, 5 mg

Generic Equivalent Available: US

Yes

Pricing: US

Tablet,Dispersible (Afinitor Disperz Oral)

2 mg (per each): $780.12

3 mg (per each): $787.91

5 mg (per each): $820.08

Tablet,Dispersible (Everolimus Oral)

2 mg (per each): $575.67

3 mg (per each): $581.44

5 mg (per each): $605.16

Tablets (Afinitor Oral)

2.5 mg (per each): $784.06

5 mg (per each): $820.12

7.5 mg (per each): $820.09

10 mg (per each): $820.04

Tablets (Everolimus Oral)

0.25 mg (per each): $10.01 - $10.57

0.5 mg (per each): $20.02 - $21.14

0.75 mg (per each): $30.03 - $31.71

1 mg (per each): $40.06 - $42.29

2.5 mg (per each): $578.94 - $611.37

5 mg (per each): $605.56 - $639.49

7.5 mg (per each): $605.56 - $639.49

10 mg (per each): $605.56 - $737.94

Tablets (Torpenz Oral)

2.5 mg (per each): $665.47

5 mg (per each): $696.07

7.5 mg (per each): $696.07

10 mg (per each): $696.07

Tablets (Zortress Oral)

0.25 mg (per each): $12.90

0.5 mg (per each): $25.85

0.75 mg (per each): $38.74

1 mg (per each): $51.59

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Afinitor: 2.5 mg, 5 mg, 10 mg

Generic: 2.5 mg, 5 mg, 10 mg

Tablet Soluble, Oral:

Afinitor Disperz: 2 mg, 3 mg, 5 mg

Administration: Adult

Oral: May be administered with or without food; to reduce variability, take consistently with regard to food.

Tablets: Swallow whole with a glass of water. Do not break, chew, or crush (do not administer tablets that are crushed or broken). Avoid contact with or exposure to crushed or broken tablets.

Tablets for oral suspension: Administer as a suspension only; wear gloves when preparing suspension. Administer immediately after preparation; discard if not administered within 60 minutes after preparation. Prepare suspension in water only. Do not break or crush tablets.

Preparation in an oral syringe: Place dose into 10 mL oral syringe (maximum: 10 mg/syringe; use an additional syringe for doses >10 mg). Draw ~5 mL of water and ~4 mL of air into oral syringe; allow to sit (tip up) in a container until tablets are in suspension (3 minutes). Gently invert syringe 5 times immediately prior to administration; administer contents, then add ~5 mL water and ~4 mL of air to same syringe, swirl to suspend remaining particles and administer entire contents.

Preparation in a small glass: Place dose into a small glass (≤100 mL) containing ~25 mL water (maximum: 10 mg/glass; use and additional glass for doses >10 mg); allow to sit until tablets are in suspension (3 minutes). Stir gently with spoon immediately prior to administration; administer contents, then add ~25 mL water to same glass, swirl with same spoon to suspend remaining particles and administer entire contents.

Breast cancer, neuroendocrine tumors, renal cell carcinoma, tuberous sclerosis complex (TSC)-associated partial onset-seizures, renal angiomyolipoma, and subependymal giant cell astrocytoma (SEGA): Administer at the same time each day.

Solid organ transplantation: Administer consistently ~12 hours apart; administer at the same time as cyclosporine or tacrolimus.

Note: Some everolimus products are provided in blister cards that also contain desiccant tablets; counsel patients to discard desiccants (desiccants should not be ingested).

Administration: Pediatric

Note: To avoid potential contact with everolimus, caregivers should wear gloves when preparing suspension from tablets for oral suspension. Some everolimus products are provided in blister cards which also contain desiccant tablets; counsel patients to discard desiccants (desiccants should not be ingested).

Oral: May be taken with or without food; to reduce variability, take consistently with regard to food.

Timing of doses:

Afinitor/Afinitor Disperz: Administer at the same time each day.

Missed doses: May be taken up to 6 hours after regularly scheduled time; if >6 hours, resume at next regularly scheduled time (do not administer double doses to make up for a missed dose).

Zortress: Administer consistently ~12 hours apart and at the same time as tacrolimus or cyclosporine.

Tablets:

Afinitor: Swallow tablet whole with a glass of water; do not break or crush tablets.

Zortress: Swallow tablet whole; do not crush per the manufacturer. In pediatric heart transplant trials for patients unable to swallow tablets, each tablet was crushed in an oral syringe using the plunger, mixed with 5 mL of water within the same syringe, allowed to dissolve, and administered. Each dose was followed by another 5 mL pulled up into the same oral syringe. Gloves should be worn during preparation. Refer to TEAMMATE trial protocol for detailed information (Ref).

Tablets for oral suspension (eg, Afinitor Disperz): Administer as a suspension only. Administer immediately after preparation; discard if not administered within 60 minutes after preparation. Prepare suspension in water only. Do not break or crush tablets. May be prepared in an oral syringe or small glass.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2024 [table 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication;

Zortress: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021560s033lbl.pdf

Use: Labeled Indications

Breast cancer, advanced (Afinitor only): Treatment of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal patients (in combination with exemestane and after letrozole or anastrozole failure).

Kidney transplantation (Zortress only): Prophylaxis of organ rejection in adult kidney transplant recipients at low to moderate immunologic risk (in combination with basiliximab induction and concurrent with corticosteroids and reduced doses of cyclosporine).

Liver transplantation (Zortress only): Prophylaxis of allograft rejection in liver transplantation in adults (in combination with corticosteroids and reduced doses of tacrolimus; everolimus should not be administered earlier than 30 days post-transplant).

Neuroendocrine tumors (Afinitor only): Treatment of locally advanced, metastatic or unresectable progressive pancreatic neuroendocrine tumors (PNET) in adults; treatment of progressive, well-differentiated, nonfunctional GI or lung origin neuroendocrine tumors in adults with unresectable, locally advanced or metastatic disease.

Limitations of use: Not indicated for the treatment of functional carcinoid tumors.

Renal cell carcinoma, advanced (Afinitor only): Treatment of advanced renal cell carcinoma (RCC) after sunitinib or sorafenib failure in adults.

Tuberous sclerosis complex–associated partial-onset seizures (Afinitor Disperz only): Adjunctive treatment of partial-onset seizures associated with tuberous sclerosis complex (TSC) in adult and pediatric patients ≥2 years of age.

Tuberous sclerosis complex–associated renal angiomyolipoma (Afinitor only): Treatment of renal angiomyolipoma, associated with TSC, not requiring immediate surgery in adults.

Tuberous sclerosis complex–associated subependymal giant cell astrocytoma (Afinitor or Afinitor Disperz only): Treatment of subependymal giant cell astrocytoma (SEGA) associated with TSC in adults and pediatric patients ≥1 year of age which requires therapeutic intervention, but cannot be curatively resected.

Use: Off-Label: Adult

Carcinoid tumors, progressive, advanced (Afinitor only); Heart transplantation, ≥3 months post-transplantation (Zortress only); Hodgkin lymphoma, relapsed or refractory (Afinitor only); Lung transplantation (Zortress only); Thymoma or thymic carcinoma, advanced or metastatic, relapsed or refractory (Afinitor only); Waldenström macroglobulinemia, relapsed or refractory (Afinitor only)

Medication Safety Issues

Sound-alike/look-alike issues:

Everolimus may be confused with sirolimus (conventional), sirolimus (protein bound), tacrolimus, temsirolimus

Afinitor may be confused with afatinib

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral; immunosuppressant agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).

Administration issues:

Tablets (Afinitor, Zortress) and tablets for oral suspension (Afinitor Disperz) are not interchangeable; do not combine formulations to achieve total desired dose.

Metabolism/Transport Effects

Substrate of CYP3A4 (Major), P-glycoprotein (Major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (Weak);

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor

Abrocitinib: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid

ALPRAZolam: CYP3A4 Inhibitors (Weak) may increase serum concentration of ALPRAZolam. Risk C: Monitor

Angiotensin-Converting Enzyme Inhibitors: Everolimus may increase adverse/toxic effects of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor

Antidiabetic Agents: Hyperglycemia-Associated Agents may decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor

Antihepaciviral Combination Products: May increase serum concentration of Everolimus. Risk X: Avoid

Antithymocyte Globulin (Equine): Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor

Antithyroid Agents: Myelosuppressive Agents may increase neutropenic effects of Antithyroid Agents. Risk C: Monitor

Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Baricitinib. Risk X: Avoid

BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of BCG Products. Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid

Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Brincidofovir. Risk C: Monitor

Brivudine: May increase adverse/toxic effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid

Cannabidiol: May increase serum concentration of Everolimus. Risk C: Monitor

Chikungunya Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Chikungunya Vaccine (Live). Risk X: Avoid

Chloramphenicol (Ophthalmic): May increase adverse/toxic effects of Myelosuppressive Agents. Risk C: Monitor

Chloramphenicol (Systemic): Myelosuppressive Agents may increase myelosuppressive effects of Chloramphenicol (Systemic). Risk X: Avoid

Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Cladribine. Risk X: Avoid

Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor

Clotrimazole (Oral): May increase serum concentration of Everolimus. Risk C: Monitor

CloZAPine: Myelosuppressive Agents may increase adverse/toxic effects of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor

Coccidioides immitis Skin Test: Coadministration of Immunosuppressants (Miscellaneous Oncologic Agents) and Coccidioides immitis Skin Test may alter diagnostic results. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider Therapy Modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor

COVID-19 Vaccine (mRNA): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider Therapy Modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of COVID-19 Vaccine (Subunit). Risk C: Monitor

CycloSPORINE (Systemic): May increase serum concentration of Everolimus. Management: When everolimus is used as a post-transplant immunosuppressant (Zortress brand), lower cyclosporine doses and lower target serum cyclosporine concentrations must be used. Monitor both everolimus and cyclosporine serum concentrations closely when combined. Risk D: Consider Therapy Modification

CYP3A4 Inducers (Moderate): May decrease serum concentration of Everolimus. Risk C: Monitor

CYP3A4 Inducers (Strong): May decrease serum concentration of Everolimus. Management: Concomitant use of everolimus and strong CYP3A4 inducers is generally not recommended. However, if combined, monitor for decreased everolimus concentrations and effects, and adjust everolimus dose as needed. Risk D: Consider Therapy Modification

CYP3A4 Inhibitors (Moderate): May increase serum concentration of Everolimus. Risk C: Monitor

CYP3A4 Inhibitors (Strong): May increase serum concentration of Everolimus. Management: Consider avoiding use of strong CYP3A4 inhibitors with everolimus. If combined, closely monitor for increased everolimus serum concentrations and toxicities. Everolimus dose reductions will likely be required. Risk D: Consider Therapy Modification

Deferiprone: Myelosuppressive Agents may increase neutropenic effects of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider Therapy Modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Dengue Tetravalent Vaccine (Live). Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid

Denosumab: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider Therapy Modification

Deucravacitinib: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid

Dofetilide: CYP3A4 Inhibitors (Weak) may increase serum concentration of Dofetilide. Risk C: Monitor

Etrasimod: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid

Fenofibrate and Derivatives: Everolimus may increase nephrotoxic effects of Fenofibrate and Derivatives. Fenofibrate and Derivatives may decrease serum concentration of Everolimus. Risk C: Monitor

Fexinidazole: Myelosuppressive Agents may increase myelosuppressive effects of Fexinidazole. Risk X: Avoid

Filgotinib: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid

Finerenone: CYP3A4 Inhibitors (Weak) may increase serum concentration of Finerenone. Risk C: Monitor

Flibanserin: CYP3A4 Inhibitors (Weak) may increase serum concentration of Flibanserin. Risk C: Monitor

Flucloxacillin: May decrease serum concentration of Everolimus. Risk C: Monitor

Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification

Grapefruit Juice: May increase serum concentration of Everolimus. Risk X: Avoid

Inducers of CYP3A4 (Strong) and P-glycoprotein: May decrease serum concentration of Everolimus. Management: Afinitor: Double the everolimus daily dose, using increments of 5 mg or less, with careful monitoring; multiple increments may be necessary. Zortress: Avoid if possible and monitor for decreased everolimus concentrations if combined. Risk D: Consider Therapy Modification

Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Inebilizumab. Risk C: Monitor

Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider Therapy Modification

Inhibitors of CYP3A4 (Moderate) and P-glycoprotein: May increase serum concentration of Everolimus. Management: Afinitor: For TSC-associated SEGA or TSC-associated seizures reduce everolimus dose 50%. For other Afinitor indications, reduce everolimus dose to 2.5 mg/day, increase to 5 mg/day if tolerated. Zortress: Monitor for increased everolimus concentrations. Risk D: Consider Therapy Modification

Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase serum concentration of Everolimus. Risk X: Avoid

Ixabepilone: CYP3A4 Inhibitors (Weak) may increase serum concentration of Ixabepilone. Risk C: Monitor

Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider Therapy Modification

Lemborexant: CYP3A4 Inhibitors (Weak) may increase serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Linezolid: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor

Lomitapide: CYP3A4 Inhibitors (Weak) may increase serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider Therapy Modification

Maribavir: May increase serum concentration of Everolimus. Risk C: Monitor

Midazolam: CYP3A4 Inhibitors (Weak) may increase serum concentration of Midazolam. Risk C: Monitor

Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Mumps- Rubella- or Varicella-Containing Live Vaccines may increase adverse/toxic effects of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid

Nadofaragene Firadenovec: Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid

Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Natalizumab. Risk X: Avoid

NiMODipine: CYP3A4 Inhibitors (Weak) may increase serum concentration of NiMODipine. Risk C: Monitor

Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ocrelizumab. Risk C: Monitor

Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ofatumumab. Risk C: Monitor

Olaparib: Myelosuppressive Agents may increase myelosuppressive effects of Olaparib. Risk C: Monitor

P-glycoprotein/ABCB1 Inducers: May decrease serum concentration of Everolimus. Risk C: Monitor

P-glycoprotein/ABCB1 Inhibitors: May increase serum concentration of Everolimus. Risk C: Monitor

Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Pidotimod. Risk C: Monitor

Pimecrolimus: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid

Pimozide: CYP3A4 Inhibitors (Weak) may increase serum concentration of Pimozide. Risk X: Avoid

Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Pneumococcal Vaccines. Risk C: Monitor

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid

Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may increase hypersensitivity effects of Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider Therapy Modification

Promazine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor

Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider Therapy Modification

Ritlecitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ritlecitinib. Risk X: Avoid

Ropeginterferon Alfa-2b: Myelosuppressive Agents may increase myelosuppressive effects of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider Therapy Modification

Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ruxolitinib (Topical). Risk X: Avoid

Simvastatin: CYP3A4 Inhibitors (Weak) may increase serum concentration of Simvastatin. CYP3A4 Inhibitors (Weak) may increase active metabolite exposure of Simvastatin. Risk C: Monitor

Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider Therapy Modification

Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase serum concentration of Sirolimus (Conventional). Risk C: Monitor

Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m² when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Sphingosine 1-Phosphate (S1P) Receptor Modulators: May increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor

St John's Wort: May decrease serum concentration of Everolimus. Management: Consider alternatives to this combination. Concurrent use of the Afinitor brand of everolimus with St John's wort should be strictly avoided. If combined with the Zortress brand of everolimus, monitor for reduced everolimus concentrations and effects. Risk D: Consider Therapy Modification

Tacrolimus (Systemic): Everolimus may decrease serum concentration of Tacrolimus (Systemic). Risk C: Monitor

Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Tacrolimus (Topical). Risk X: Avoid

Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid

Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Tertomotide. Risk X: Avoid

Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Tofacitinib. Risk X: Avoid

Triazolam: CYP3A4 Inhibitors (Weak) may increase serum concentration of Triazolam. Risk C: Monitor

Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Typhoid Vaccine. Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid

Ublituximab: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Ublituximab. Risk C: Monitor

Ubrogepant: CYP3A4 Inhibitors (Weak) may increase serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider Therapy Modification

Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may increase immunosuppressive effects of Upadacitinib. Risk X: Avoid

Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Vaccines (Live). Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid

Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before or during therapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider Therapy Modification

Vimseltinib: May increase serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Management: Avoid concomitant use of vimseltinib and P-gp substrates when possible. If combined, administer vimseltinib at least 4 hours before the P-gp substrate. Risk D: Consider Therapy Modification

Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Yellow Fever Vaccine. Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid

Zoster Vaccine (Live/Attenuated): Immunosuppressants (Miscellaneous Oncologic Agents) may increase adverse/toxic effects of Zoster Vaccine (Live/Attenuated). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may decrease therapeutic effects of Zoster Vaccine (Live/Attenuated). Risk X: Avoid

Food Interactions

Grapefruit and grapefruit juice may increase levels of everolimus. Absorption with food may be variable. Management: Avoid grapefruit juice. Administer with or without food, but be consistent with regard to food.

Reproductive Considerations

Verify pregnancy status prior to initiating therapy in patients who could become pregnant. Patients who could become pregnant should be advised to avoid pregnancy and use highly effective birth control during treatment and for 8 weeks after the last everolimus dose. Patients whose partners could become pregnant should use effective contraception during treatment and for 4 weeks after the last everolimus dose.

Everolimus may cause infertility. In females, menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone and follicle-stimulating hormone have occurred. Azoospermia and oligospermia have been observed in males.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to everolimus may cause fetal harm. Information related to the use of everolimus in pregnancy is limited (Yamamura 2017).

The Transplant Pregnancy Registry International (TPR) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPR encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.

Breastfeeding Considerations

Everolimus is present in breast milk (Kociszewska-Najman 2017).

Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy (Afinitor, Afinitor Disperz, Zortress) and for 2 weeks following the last dose (Afinitor, Afinitor Disperz).

Dietary Considerations

Avoid grapefruit and grapefruit juice.

Monitoring Parameters

CBC with differential (baseline, every 6 months during the first year of treatment, and then annually thereafter); liver function (baseline and periodic); kidney function including serum creatinine, urinary protein, and BUN (baseline and annually; monitor kidney function every 6 months in patients with additional risk factors for kidney failure); fasting serum glucose (baseline and annually in nondiabetic patients and more frequently as indicated in patients with diabetes or if on concomitant medications affecting glucose), HbA_1c, and lipid profile (baseline and annually thereafter). Evaluate pregnancy status prior to initiating therapy in patients who could become pregnant. Monitor for signs and symptoms of infection, noninfectious pneumonitis (promptly evaluate worsening respiratory symptoms), stomatitis, or secondary malignancy. Monitor closely for radiation recall when everolimus is administered concomitantly or sequentially with radiation treatment. Monitor adherence.

Solid organ transplantation: Monitor everolimus whole blood trough concentrations (based on an LC/MS/MS assay method), especially in patients with hepatic impairment, with concomitant CYP3A4 inhibitors and inducers or cannabidiol, and when cyclosporine or tacrolimus formulations or doses are changed; dosage adjustments should be made on trough concentrations obtained 4 to 5 days after a previous dosage adjustment; monitor cyclosporine or tacrolimus concentrations; monitor for proteinuria.

Tuberous sclerosis complex (TSC)-associated partial onset seizures and subependymal giant cell astrocytoma (SEGA): Monitor everolimus whole blood trough concentrations 1 to 2 weeks after treatment initiation, with dosage modification(s), or when changing dosage forms between tablets and tablets for oral suspension, 2 weeks after a change in hepatic function and initiation or discontinuation of concurrent CYP3A4/P-glycoprotein (P-gp) inhibitor/inducer therapy. Maintain trough concentrations between 5 and 15 ng/mL; once stable dose is attained and if body surface area (BSA) is stable throughout treatment, monitor trough concentrations every 6 to 12 months (monitor every 3 to 6 months if BSA is changing).

Patients with cancer: The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Reference Range

Recommended range for everolimus whole blood trough concentrations:

Liver and kidney transplantation: 3 to 8 ng/mL (based on an LC/MS/MS assay method).

Tuberous sclerosis complex-associated partial-onset seizures and subependymal giant cell astrocytoma (SEGA): 5 to 15 ng/mL. High concentrations may be associated with larger reductions in SEGA volumes, responses have been observed at concentrations as low as 5 ng/mL.

Heart transplantation (off-label use): 3 to 8 ng/mL with reduced dose calcineurin inhibitor (Eisen 2013; Hollis 2015; ISHLT [Velleca 2023]) or 6 to 10 ng/mL following calcineurin inhibitor withdrawal (Andreassen 2014; ISHLT [Velleca 2023]).

Lung transplantation (off-label use): 3 to 8 ng/mL with reduced dose cyclosporine (Glanville 2015; Strueber 2016).

Mechanism of Action

Everolimus is a macrolide immunosuppressant and a mechanistic target of rapamycin (mTOR) inhibitor which has antiproliferative and antiangiogenic properties, and reduces lipoma volume in patients with angiomyolipoma. Reduces protein synthesis and cell proliferation by binding to the FK binding protein-12 (FKBP-12), an intracellular protein, to form a complex that inhibits activation of mTOR (mechanistic target of rapamycin) serine-threonine kinase activity. Also reduces angiogenesis by inhibiting vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF-1) expression. Angiomyolipomas may occur due to unregulated mTOR activity in TSC-associated renal angiomyolipoma (Budde 2012); everolimus reduces lipoma volume (Bissler 2013).

Pharmacokinetics (Adult Data Unless Noted)

Absorption: Rapid (Kirchner 2004)

Distribution: Apparent V_d: 128 to 589 L (Zortress); volume of distribution in pediatric renal transplant recipients (3 to 16 years) lower than adults (Van Damme-Lombaerts 2002)

Protein binding: ~74% (Afinitor and Zortress)

Metabolism: Extensively metabolized in the liver via CYP3A4; forms 6 weak metabolites (Afinitor and Zortress)

Bioavailability:

Tablets: ~30% (Tabernero 2008 [Afinitor]); Systemic exposure reduced by 22% with a high-fat meal and by 32% with a light-fat meal (Afinitor); Systemic exposure reduced 16% with a high-fat meal (Zortress)

Tablets for suspension (Afinitor): AUC equivalent to tablets although peak concentrations are 20% to 36% lower; steady state concentrations are similar; Systemic exposure reduced by 12% with a high-fat meal and by 30% with a low-fat meal

Half-life elimination: ~30 hours (Afinitor and Zortress); in pediatric renal transplant recipients (3 to 16 years), half-life similar to adult data (Van Damme-Lombaerts 2002)

Time to peak, plasma: 1 to 2 hours (Afinitor and Zortress)

Excretion: Feces (80%, based on solid organ transplant studies); Urine (~5%, based on solid organ transplant studies); clearance in pediatric renal transplant recipients lower than adults possibly due to distributive differences (Van Damme-Lombaerts 2002)

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Hepatic function impairment:

Afinitor, Afinitor Disperz: In one study, subjects with mild (Child-Turcotte-Pugh class A), moderate (Child-Turcotte-Pugh class B), and severe (Child-Turcotte-Pugh class C) impairment had a 1.8-fold, 3.2-fold, and 3.6-fold higher AUC, respectively, compared to patients with normal function. In another study, the average AUC in subjects with moderate (Child-Turcotte-Pugh class B) impairment was twice that of subjects with normal function.

Zortress: The average AUC in subjects with mild (Child-Turcotte-Pugh class A) impairment was 1.6-fold higher than that of patients with normal hepatic function (following a 10 mg dose); in moderate (Child-Turcotte-Pugh class B) impairment the AUC was 2.1- to 3.3-fold higher than that of patients with normal hepatic function (following a 2 mg or 10 mg dose); in severe (Child-Turcotte-Pugh class C) impairment the AUC was 3.6-fold higher than that of patients with normal hepatic function (following a 10 mg dose).

Pediatric: In patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA) or TSC-associated partial-onset seizures, mean serum C_min values when normalized to mg/m² dose in pediatric patients (age <18 years) were lower than those observed in adults, suggesting everolimus clearance (adjusted to body surface area) was higher in pediatric patients compared to adults.

Race/ethnicity: Average everolimus exposure may be higher in Japanese individuals (based on an Afinitor cross-study comparison). Oral everolimus clearance is 20% higher (on average) in Black patients compared with White patients.

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Afinitor;
(AR) Argentina: Afinitor | Certican | Everolimus ethypharm | Gineva | Xilcator;
(AT) Austria: Afinitor | Certican | Everolimus hcs | Everolimus mylan | Everolimus ratiopharm | Everolimus stada | Votubia;
(AU) Australia: Afinitor | Certican | Everocan | Everolimus sandoz;
(BD) Bangladesh: Certican;
(BE) Belgium: Afinitor | Everolimus eg | Everolimus krka | Votubia;
(BG) Bulgaria: Afinitor | Certican | Everolimus mylan | Everolimus sandoz | Everolimus teva | Votubia;
(BR) Brazil: Afinitor | Certican | Everolimo | Exher | Osys;
(CH) Switzerland: Afinitor | Certican | Votubia;
(CI) Côte d'Ivoire: Afinitor;
(CL) Chile: Afinitor | Lysenda;
(CO) Colombia: Afinitor | Certican | Sumirol;
(CZ) Czech Republic: Afinitor | Certican | Everolimus krka | Everolimus sandoz | Everolimus teva | Everolimus vipharm | Verimmus | Votubia;
(DE) Germany: Afinitor | Certican | Everofin | Everolimus accord | Everolimus AL | Everolimus beta | Everolimus biocon | Everolimus ethypharm | Everolimus mylan | Everolimus zentiva | Votubia;
(DK) Denmark: Afinitor;
(DO) Dominican Republic: Afinitor | Certican;
(EC) Ecuador: Afinitor | Certican;
(EE) Estonia: Afinitor | Everolimus krka | Everolimus norameda | Votubia;
(EG) Egypt: Afinitor | Certican;
(ES) Spain: Afinitor | Certican | Everolimus accord | Everolimus dr. reddys | Everolimus ethypharm | Everolimus mylan | Everolimus stada | Everolimus tillomed | Votubia;
(ET) Ethiopia: Afinitor;
(FI) Finland: Aderolio | Afinitor | Certican | Everolimus avansor | Everolimus krka | Everolimus mylan | Everolimus sandoz | Everolimus stada | Votubia;
(FR) France: Afinitor | Certican | Everolimus arrow | Everolimus biogaran | Everolimus eg | Everolimus hcs | Everolimus mylan | Everolimus reddy pharma | Everolimus sandoz | Everolimus teva | Everolimus zentiva | Votubia;
(GB) United Kingdom: Afinitor | Certican | Everolimus dr. reddy's | Everolimus ethypharm | Everolimus sandoz | Votubia;
(GR) Greece: Afinitor | Certican | Votubia;
(HK) Hong Kong: Afinitor | Certican;
(HR) Croatia: Afinitor | Certican | Votubia;
(HU) Hungary: Afinitor | Everolimus accord | Everolimus alvogen | Everolimus krka | Everolimus onkogen | Everolimus sandoz | Everolimus vipharm | Verimmus | Votubia;
(ID) Indonesia: Afinitor | Certican;
(IE) Ireland: Afinitor;
(IN) India: Advacan | Afinitor | Boletraaz | Certican | Ersteine | Everbliss | Evergraf | Evermil | Everotas | Evertor | Natlimus | Rolimus | Torinat | Xolimus;
(IT) Italy: Afinitor | Everolimus dr reddys | Everolimus eg | Everolimus medac | Everolimus sandoz | Votubia;
(JO) Jordan: Afinitor | Certican;
(JP) Japan: Afinitor | Certican;
(KE) Kenya: Afinitor | Certican | Everbliss;
(KR) Korea, Republic of: Afinitor | Certican | Certirobell;
(KW) Kuwait: Afinitor | Certican;
(LB) Lebanon: Afinitor | Certican | Everolimus arrow;
(LT) Lithuania: Afinitor | Everolimus norameda | Votubia;
(LU) Luxembourg: Everolimus eg;
(LV) Latvia: Afinitor | Certican | Everolimus norameda | Votubia;
(MA) Morocco: Afinitor;
(MT) Malta: Afinitor;
(MX) Mexico: Afinitor | Certican;
(MY) Malaysia: Afinitor | Certican;
(NG) Nigeria: Certican;
(NL) Netherlands: Afinitor | Certican | Everolimus accord | Everolimus sandoz | Everolimus teva | Votubia;
(NO) Norway: Afinitor | Certican | Votubia;
(NZ) New Zealand: Afinitor;
(PE) Peru: Afinitor | Certican | Forpanil;
(PH) Philippines: Afinitor;
(PK) Pakistan: Afinitor | Evercan | Evergraf | Evrilus;
(PL) Poland: Afinitor | Certican | Everolimus accord | Everolimus stada | Everolimus vipharm | Votubia;
(PR) Puerto Rico: Afinitor | Afinitor disperz | Zortress;
(PT) Portugal: Afinitor | Certican | Everolimus mylan | Everolimus teva | Votubia;
(PY) Paraguay: Afinitor | Certican | Everolimus eposino | Rocas;
(QA) Qatar: Afinitor | Certican | Votubia;
(RO) Romania: Afinitor | Certican | Verimmus | Votubia;
(RU) Russian Federation: Afinitor | Certican;
(SA) Saudi Arabia: Afinitor;
(SE) Sweden: Afinitor | Certican | Everolimus avansor | Everolimus krka | Everolimus mylan | Everolimus sandoz | Everolimus stada | Everolimus teva | Everolimus zentiva | Votubia;
(SG) Singapore: Afinitor;
(SI) Slovenia: Afinitor | Certican | Votubia;
(SK) Slovakia: Afinitor | Everolimus accord | Everolimus krka | Everolimus sandoz | Everolimus stada | Everolimus vipharm | Verimmus | Votubia;
(TH) Thailand: Afinitor | Certican;
(TN) Tunisia: Afinitor | Certican;
(TR) Turkey: Afinitor | Evaxmus | Votubia;
(TW) Taiwan: Afinitor | Certican | Votubia;
(UA) Ukraine: Afinitor | Certican;
(UG) Uganda: Afinitor | Certican;
(UY) Uruguay: Afinitor | Certican;
(ZA) South Africa: Afinitor | Everzor;
(ZW) Zimbabwe: Afinitor

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Refer to manufacturer's labeling.
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Everolimus: Drug information