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Everolimus: Pediatric drug information

Everolimus: Pediatric drug information
(For additional information see "Everolimus: Drug information" and see "Everolimus: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (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 use everolimus. Manage patients receiving the drug 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.

Renal 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 in combination with everolimus in order to reduce renal 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;
  • Zortress
Brand Names: Canada
  • Afinitor;
  • Afinitor Disperz;
  • PMS-Everolimus;
  • SANDOZ Everolimus;
  • TEVA-Everolimus
Therapeutic Category
  • Antineoplastic Agent, mTOR Kinase Inhibitor;
  • Immunosuppressant Agent
Dosing: Pediatric

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.

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 TSC Therapeutic Drug Monitoring for additional information.

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 TSC Therapeutic Drug Monitoring for additional information.

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) x (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.

Transplantation; renal, rejection prophylaxis: Zortress: Limited data available: Children ≥1 year and Adolescents: Oral: Initial: 0.8 mg/m2/dose twice daily (maximum single dose: 1.5 mg) to maintain concentration: 3 to 6 ng/mL; reported start time of therapy variable: Within 48 hours posttransplantation was used in a multicenter, international trial of 19 pediatric patients; others have reported initiation at 2 to 4 weeks after transplantation; trials evaluating use at 3 to 4 years posttransplant in pediatric patients (<16 years) reported mean doses of 1.53 mg/m2/day and 1.3 ± 0.6 mg/m2/day; no untoward adverse effects were observed, although one center observed a higher incidence of hypertension and hyperlipidemia in the everolimus treatment group (Brunkhorst 2015; Ettenger 2008; Hoyer 2003; Pape 2007; Pape 2010; Pape 2011; Van-Damme-Lombaerts 2002; Vester 2002).

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 dose 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: Hepatic Impairment: Pediatric

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

Mild to moderate hepatic impairment (Child-Pugh class A and B): 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 (Child-Pugh class C): 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).

Dosing: Adult

(For additional information see "Everolimus: Drug information")

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.

Infectio n prophylaxis: Antimicrobial prophylaxis for Pneumocystis jirovecii pneumonia (PCP) and prophylaxis for cytomegalovirus (CMV) is recommended in transplant recipients. When concomitant corticosteroids or other immunosuppressive agents are required, administer PCP 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 treatment until disease progression or unacceptable toxicity.

Carcinoid tumors, advanced

Carcinoid tumors, advanced (off-label use): Oral: 10 mg once daily (in combination with octreotide LAR) until disease progression or toxicity (Pavel 2011).

Heart transplantation

Heart transplantation (≥3 months posttransplantation) (off-label use): Oral: Initial: 0.75 mg twice daily; adjust everolimus dose based on everolimus trough concentrations (Eisen 2003; Eisen 2013; Hollis 2015). Note: Mortality was increased with 3 mg/day when used in combination with rabbit antithymocyte globulin (Eisen 2013).

Hodgkin lymphoma, relapsed or refractory

Hodgkin lymphoma, relapsed or refractory (off-label use): Oral: 10 mg once daily until disease progression or toxicity (Johnston 2010).

Liver transplantation, rejection prophylaxis

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

If trough is <3 ng/mL: Double total daily dose (using available tablet strengths).

If trough >8 ng/mL on 2 consecutive measures: Decrease dose by 0.25 mg twice daily.

Lung transplantation

Lung transplantation (>1 month posttransplantation) (off-label use): Oral: Initial: 0.75 to 1.5 mg twice daily; adjust everolimus dose based on everolimus trough concentrations (Glanville 2015; Snell 2006; Strueber 2016).

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 (De Pablo 2013).

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.

Renal cell cancer, advanced

Renal cell cancer, advanced (Afinitor): Oral: 10 mg once daily, continue treatment until disease progression or unacceptable toxicity.

Renal cell carcinoma, advanced (off-label dose/combination): Oral: 5 mg once daily (in combination with lenvatinib), continue until disease progression or unacceptable toxicity (Motzer 2015).

Renal transplantation, rejection prophylaxis

Renal 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 if needed at a 4- to 5-day interval (from prior dose adjustment) based on serum concentrations (see Reference Range), tolerability, and response.

If trough is <3 ng/mL: Double total daily dose (using available tablet strengths).

If trough >8 ng/mL on 2 consecutive measures: Decrease dose by 0.25 mg twice daily.

Thymoma and thymic carcinomas, advanced, refractory

Thymoma and thymic carcinomas, advanced, refractory (off-label use): Oral: 10 mg once daily until disease progression or toxicity (Zucali 2018).

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.

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 x (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.

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.

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 x (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): Oral: 10 mg once daily until disease progression or toxicity (Ghobrial 2010).

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 scheduled surgery; do not reinitiate therapy for ≥2 weeks following major surgery and until adequate wound healing.

Dosing: Kidney Impairment: Adult

No dosage adjustment is necessary.

Dosing: Hepatic Impairment: Adult

Mild impairment (Child-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 renal 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-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 renal 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-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 renal 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).

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

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

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Afinitor: 2.5 mg, 5 mg, 7.5 mg [DSC], 10 mg

Generic: 2.5 mg, 5 mg, 10 mg

Tablet Soluble, Oral:

Afinitor Disperz: 2 mg, 3 mg, 5 mg

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/2018/021560s020lbl.pdf#page=32

Administration: Pediatric

To avoid potential contact with everolimus, caregivers should wear gloves when preparing suspension from tablets for oral suspension.

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: Swallow tablet whole with a glass of water; do not chew or crush; do not use 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. 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.

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

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 cancer, 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).

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 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 2016; USP-NF 2020).

Storage/Stability

Tablets and tablets for suspension: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light; protect from moisture. Store Afinitor and Afinitor Disperz in the original container. Discard suspension if not administered within 60 minutes after preparation.

Use

Afinitor: Treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) which requires intervention, but cannot be curatively resected (FDA approved in ages ≥1 year and adults); treatment of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women (in combination with exemestane and after letrozole or anastrozole failure (FDA approved in adults); treatment of advanced renal cell cancer (RCC), after sunitinib or sorafenib failure (FDA approved in adults); treatment of renal angiomyolipoma with TSC not requiring immediate surgery (FDA approved in adults); treatment of progressive pancreatic neuroendocrine tumors (PNET) (FDA approved in adults); treatment of progressive, well-differentiated, nonfunctional GI or lung neuroendocrine tumors in patients with unresectable, locally advanced, or metastatic disease (FDA approved in adults)

Afinitor Disperz: Treatment of SEGA associated with TSC which requires intervention, but cannot be curatively resected (FDA approved in ages ≥1 year and adults); adjunctive treatment of TSC-associated partial-onset seizures (FDA approved in ages ≥2 years and adults)

Zortress: Prophylaxis of organ rejection in patients at low-moderate immunologic risk receiving renal or liver transplants (FDA approved in adults)

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:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Administration issues:

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

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: liver transplant: 32%, kidney transplant: 9%), hypercholesterolemia (9% to 17%), hyperglycemia (kidney transplant: 12%), hyperkalemia (renal 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%)

Infection: Bacterial infection (liver transplant: 16%), hepatitis C (liver transplant: 11% to 14%), infection (kidney transplant: 62% to 64%; liver transplant: 50%), viral infection (liver transplant: 17%; kidney transplant: 10%)

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, renal artery thrombosis, 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, gout, hirsutism, hypercalcemia, hyperparathyroidism, hypertriglyceridemia, hyperuricemia, hypocalcemia, hypoglycemia, hyponatremia, hypothyroidism, iron deficiency, ovarian cyst, 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, perinephric abscess, perinephric hematoma, pollakiuria, proteinuria, pyuria, scrotal edema, urethritis, urinary retention, urinary urgency

Hematologic & oncologic: Benign neoplasm (≤4%), leukocytosis, lymphadenopathy, lymphorrhea, malignant neoplasm (≤4%), neutropenia, pancytopenia, thrombocythemia, 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, chills, depression, dizziness, drowsiness, hallucination, hemiparesis, hypoesthesia, lethargy, malaise, migraine, myasthenia, neuralgia, pain, paresthesia

Neuromuscular & skeletal: Arthralgia, asthenia, joint swelling, muscle spasm, musculoskeletal pain, myalgia, osteoarthritis, osteomyelitis, osteonecrosis, osteoporosis, spondylitis, tremor (8% to 10%)

Ophthalmic: Blurred vision, cataract, conjunctivitis

Renal: Hydronephrosis, increased blood urea nitrogen, interstitial nephritis, polyuria, pyelonephritis, renal failure syndrome (5% to 10%; may be acute), renal insufficiency, 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, hepatocellular neoplasm, lymphoproliferative disorder, thrombotic microangiopathy, thrombotic thrombocytopenic purpura

Hypersensitivity: Angioedema

Respiratory: Interstitial pulmonary disease

Frequency not defined:

Cardiovascular: Venous thrombosis

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

Hematologic & oncologic: Malignant lymphoma, malignant neoplasm of skin

Infection: Polyomavirus infection

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%), decreased serum fibrinogen (8% to 38%), 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%), 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: Irregular menses (10% to 11%), proteinuria (18%), urinary tract infection (9% to 31%)

Hematologic & oncologic: Anemia (41% to 92%; grades 3/4: 5% to 15%), 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%), behavioral problems (≤21%; includes abnormal behavior, 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%), asthenia (23% to 33%), 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%; may include interstitial pulmonary 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%), ovarian cyst (3%)

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

Genitourinary: Abnormal uterine bleeding (6%), azoospermia (1%), dysmenorrhea (6%), 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: Renal failure syndrome (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, hypersensitivity angiitis, septic shock, thrombosis of vascular graft (kidney)

Dermatologic: Erythroderma

Gastrointestinal: Acute pancreatitis, cholecystitis, cholelithiasis

Genitourinary: Male infertility, oligospermia

Hematologic & oncologic: Lymphedema

Hypersensitivity: Anaphylaxis

Infection: Aspergillosis, polyomavirus infection, reactivation of HBV

Nervous system: Complex regional pain syndrome, progressive multifocal leukoencephalopathy

Renal: Nephrotoxicity

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

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. Monitor blood counts at baseline, every 6 months for the first year of treatment, and annually thereafter.

• 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 renal arterial and venous thrombosis has been reported in renal transplantation, generally within the first 30 days after transplant; may result in graft loss.

• Hepatic artery thrombosis: 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 renal function and renal graft loss, has been observed with use in renal transplantation. JC virus-associated progressive multiple leukoencephalopathy (PML) may also be associated with everolimus use in transplantation. Reduced immunosuppression (taking into account 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 {PCP}] 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), renal 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 PCP when evaluating clinical symptoms. Everolimus treatment may be continued (without dose adjustment in patients who develop radiological changes suggestive of non-infectious pneumonitis with few or no symptoms [imaging appears to overestimate the incidence of clinical pneumonitis]). When concomitant corticosteroids or other immunosuppressive agents are required, administer PCP prophylaxis. 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 on in the postoperative period (Andreassen 2014; Andreassen 2016; Costanzo 2010; Hirt 2013; Hollis 2015).

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

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

• Transplantation (solid organ): The safety and efficacy of everolimus in renal transplantation recipients with high-immunologic risk or in solid organ transplant other than renal or liver have not been established. In liver transplant recipients, tacrolimus has minimal or no pharmacokinetic impact on everolimus concentrations. 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 combination therapy: Due to the increased risk for nephrotoxicity in renal transplantation, avoid standard doses of cyclosporine in combination with everolimus; reduced cyclosporine doses are recommended when everolimus is used in combination with cyclosporine. Therapeutic monitoring of cyclosporine and everolimus concentrations is recommended. Everolimus and cyclosporine combination therapy may result in increased proteinuria and may increase the risk for thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TMA/TTP/HUS). In liver transplantation, the tacrolimus dose and target range should be reduced to minimize the risk of nephrotoxicity. Eliminating calcineurin inhibitors from the immunosuppressive regimen may result in acute rejection.

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.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

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

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

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

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

Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

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

Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

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

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

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

Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. 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 (Adenovirus Vector): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA vaccine at least 28 days after the primary vaccine dose. Patients should also receive 2 booster doses of mRNA vaccine - one 2 months after the 2nd (additional) dose and another 4 months after the first booster dose. Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series, and a booster dose 3 months after the 3rd dose in the primary series, to patients taking immunosuppressive medications. Patients 12 years of age and older should also receive a 2nd booster 4 months after the first booster. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy

CycloSPORINE (Systemic): May increase the 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 the serum concentration of Everolimus. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers if possible. If coadministration cannot be avoided, monitor for decreased everolimus serum concentrations and effects, and adjust everolimus dose as needed. Risk D: Consider therapy modification

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

CYP3A4 Inhibitors (Strong): May increase the 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 enhance the neutropenic effect 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 enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect 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

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

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

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

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

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

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

Inducers of CYP3A4 (Strong) and P-glycoprotein: May decrease the 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 enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect 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 the 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 the serum concentration of Everolimus. Risk X: Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect 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 the 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

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the 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

Lonafarnib: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lonafarnib. Management: Avoid concurrent use of lonafarnib with weak CYP3A4 inhibitors. If concurrent use is unavoidable, reduce the lonafarnib dose to or continue at a dose of 115 mg/square meter. Monitor for evidence of arrhythmia, syncope, palpitations, or similar effects. Risk D: Consider therapy modification

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

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

Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

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

Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Pacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk X: Avoid combination

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

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

Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

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

Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

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

Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to 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 enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect 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

Rubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Simvastatin: CYP3A4 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Weak) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy

Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect 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 the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy

Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase the 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 Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy

St John's Wort: May decrease the serum concentration of Everolimus. Management: Concurrent use of Afinitor brand everolimus with St Johns wort (SJW) is not recommended. Zortress brand everolimus prescribing information cautions that SJW may decrease everolimus concentrations, though no specific dose adjustment is recommended. Risk X: Avoid combination

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

Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect 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 combination

Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

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

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

Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the 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 enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modification

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

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

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.

Dietary Considerations

Avoid grapefruit and grapefruit juice.

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, everolimus may cause fetal harm if administered during pregnancy. 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.

Monitoring Parameters

CBC with differential (baseline, every 6 months during the first year of treatment, and then annually); liver function (baseline and periodic); renal function (eg, SCr, BUN, urinary protein) (baseline and annually thereafter; every 6 months patients with additional risk factors for renal failure); fasting serum glucose (baseline and annually in nondiabetic patients and more frequently as indicated in diabetic patients), HbA1c, and lipid profile (baseline and annually thereafter); monitor for signs and symptoms of infection, noninfectious pneumonitis, stomatitis, or malignancy; pregnancy test (in patients who can become pregnant prior to initiating therapy). Monitor adherence.

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

Transplantation; liver or renal: Monitor whole blood trough concentrations (based on an LC/MS/MS assay method), especially in patients with hepatic impairment, with concomitant CYP3A4/P-gp inhibitors and inducers, and when cyclosporine formulations or doses are changed; dosage adjustments should be made on trough concentrations obtained 4 to 5 days after previous dosage adjustment; monitor cyclosporine concentrations and proteinuria.

Reference Range

Recommended range for everolimus whole blood trough concentrations:

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

Transplantation; liver or renal: 3 to 8 ng/mL (based on LC/MS/MS assay method); in pediatric studies, reported target range: 3 to 6 ng/mL

Mechanism of Action

Everolimus is a macrolide immunosuppressant and a mechanistic target of rapamycin (mTOR) inhibitor which has antiproliferative and antiangiogenic properties, and also 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 Vd: 128 to 589 L (Zortress); volume of distribution in pediatric renal transplant patients (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 patients (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 patients lower than adults possibly due to distributive differences (Van Damme-Lombaerts 2002)

Pharmacokinetics: Additional Considerations

Hepatic function impairment:

Afinitor: In one study, subjects with mild, moderate, and severe 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 impairment was twice that of subjects with normal function.

Zortress: The average AUC in subjects with mild impairment was 1.6-fold higher than that of patients with normal hepatic function (following a 10 mg dose); in moderate 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 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 Cmin 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: Average everolimus exposure may be higher in Japanese patients (based on an Afinitor cross-study comparison). Oral everolimus clearance is 20% higher (on average) in Black patients compared with White patients.

Extemporaneous Preparations

Tablets for oral suspension (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.

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 an 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.

Administer immediately after preparation; discard if not administered within 60 minutes after preparation.

Afinitor and Afinitor Disperz (everolimus) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; September 2017.

Tablets (Afinitor): Although the manufacturer recommends that the tablets be swallowed whole, an oral liquid may be prepared using tablets (for patients unable to swallow tablets whole). Disperse tablet in ~30 mL (1 oz) of water; gently stir. Administer and rinse container with additional 30 mL (1 oz) water and administer to ensure entire dose is administered. Administer immediately after preparation.

Afinitor (everolimus) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; July 2012.
Pricing: US

Tablet,Dispersible (Afinitor Disperz Oral)

2 mg (per each): $640.34

3 mg (per each): $646.74

5 mg (per each): $673.14

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): $643.56

5 mg (per each): $673.18

7.5 mg (per each): $673.15

10 mg (per each): $673.10

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): $578.55 - $611.37

5 mg (per each): $605.16 - $639.49

7.5 mg (per each): $605.16 - $639.49

10 mg (per each): $605.56 - $605.82

Tablets (Zortress Oral)

0.25 mg (per each): $11.14

0.5 mg (per each): $22.30

0.75 mg (per each): $33.42

1 mg (per each): $44.51

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.

Brand Names: International
  • Advacan (IN);
  • Afinitor (AE, AR, AT, AU, BB, BE, BH, BR, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EE, EG, ES, FR, GB, GT, HK, HN, HR, ID, IE, IL, IS, JO, JP, KR, KW, LB, LK, LT, LU, LV, MT, MY, NI, NO, NZ, PA, PL, QA, RO, SA, SE, SG, SI, SK, SV, TH, TR, TW, UA, VN, ZW);
  • Certican (AE, AR, AT, AU, BE, BG, BH, BR, CH, CL, CN, CO, CU, CY, CZ, DE, DK, EC, EE, EG, ES, FI, FR, GR, HK, HN, HR, ID, IE, IL, IN, IS, IT, JO, JP, KR, KW, LB, LT, MT, MY, NL, NO, PE, PH, PK, PL, PT, PY, QA, RO, SA, SE, SG, SI, SK, TH, TR, TW, UA, UY, VE);
  • Vetubia (HR, RO);
  • Votubia (AT, BE, BH, CH, CY, CZ, DE, DK, EE, ES, FR, GB, IE, LU, LV, MT, NO, PL, QA, SE, TW);
  • Xevirol (BD)


For country abbreviations used in Lexicomp (show table)
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