Everolimus is available by the brand names, Afinitor and Zortress, among many more. It is an mTOR inhibitor indicated for the treatment of a variety of cancers and as an immunomodulatory drug after kidney, liver, and heart transplantation.
Medical Condition |
Everolimus Use |
Treatment Purpose |
|
Advanced Breast Cancer |
Afinitor only |
Treatment of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women in combination with exemestane after letrozole or anastrozole have failed. |
|
Liver Transplantation |
Zortress only |
Prophylaxis against allograft rejection in liver transplantation in combination with reduced doses of tacrolimus and corticosteroids. However, administration should not occur earlier than 30 days post-transplant. |
|
Neuroendocrine Tumors |
Afinitor only |
Treatment of locally advanced, metastatic, or unresectable progressive pancreatic neuroendocrine tumors (PNET), well-differentiated, nonfunctional GI or lung neuroendocrine tumors in patients with unresectable, locally advanced, or metastatic disease. |
|
Advanced Renal Cell Carcinoma |
Afinitor only |
Treatment of advanced renal cell cancer (RCC) in patients who have failed sunitinib or sorafenib. |
|
Renal Transplantation |
Zortress only |
Prophylaxis against organ rejection in renal transplant patients with low to moderate immunologic risk, in combination with reduced doses of cyclosporine, basiliximab induction, and concurrent corticosteroids. |
|
Tuberous Sclerosis Complex-Associated Partial-Onset Seizures |
Afinitor Disperz only |
Adjunctive treatment for partial-onset seizures associated with tuberous sclerosis complex (TSC) in adult and pediatric patients who are 2 years of age or older. |
|
Tuberous Sclerosis Complex-Associated Renal Angiomyolipoma |
Afinitor only |
Treatment of renal angiomyolipoma with TSC that does not require immediate surgery. |
|
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 who are 1 year of age or older and require therapeutic intervention but cannot be curatively resected. |
Off-Label Use in Adults |
||
|
Carcinoid Tumors |
Afinitor only |
Treatment of progressive and advanced carcinoid tumors. |
|
Heart Transplantation |
Zortress only |
Prophylaxis against organ rejection in heart transplant patients at least 3 months post-transplantation in combination with reduced doses of cyclosporine, basiliximab induction, and concurrent corticosteroids. |
|
Hodgkin Lymphoma |
Afinitor only |
Treatment of relapsed or refractory Hodgkin lymphoma. |
|
Lung Transplantation |
Zortress only |
Prophylaxis against organ rejection in lung transplant patients in combination with reduced doses of tacrolimus, basiliximab induction, and concurrent corticosteroids. |
|
Thymoma and Thymic Carcinomas |
Afinitor only |
Treatment of advanced and refractory thymoma and thymic carcinomas. |
|
Waldenström Macroglobulinemia |
Afinitor only |
Treatment of relapsed or refractory Waldenström macroglobulinemia. |
Everolimus Dose in Adults:
Please note that Afinitor Disperz, which is available in the form of tablets for oral suspension, is specifically indicated for the treatment of tuberous sclerosis complex (TSC)-associated partial-onset seizures and TSC-associated subependymal giant cell astrocytoma (SEGA), and should be used in conjunction with therapeutic monitoring.
Afinitor and Zortress, which are available in tablet form, are not interchangeable with Afinitor Disperz for these indications. It is important to avoid combining different formulations in an attempt to achieve the total desired dose.
Dosing According to medical condition:
|
Condition |
Medication |
Dosage |
Duration |
|
Breast cancer (advanced, hormone receptor-positive, HER2-negative) |
Afinitor |
Oral: 10 mg once daily (in combination with exemestane) |
Until disease progression or unacceptable toxicity |
|
Neuroendocrine tumors (GI, lung, or pancreatic origin) (advanced) |
Afinitor |
Oral: 10 mg once daily |
Until disease progression or unacceptable toxicity |
|
Renal cell cancer (advanced) |
Afinitor |
Oral: 10 mg once daily |
Until disease progression or unacceptable toxicity |
|
Renal cell carcinoma (advanced) |
Afinitor |
Oral: 5 mg once daily (in combination with Lenvatinib) |
Until disease progression or unacceptable toxicity (Motzer 2015) |
|
Liver transplantation (rejection prophylaxis, begin at least 30 days posttransplant) |
Zortress |
Oral: Initial: 1 mg twice daily (in combination with reduced dose tacrolimus and a corticosteroid) |
Adjust maintenance dose based on serum concentrations, tolerability, and response |
|
Renal transplantation (rejection prophylaxis) |
Zortress |
Oral: Initial: 0.75 mg twice daily (in combination with basiliximab induction, reduced dose cyclosporine and a corticosteroid) |
Adjust maintenance dose based on serum concentrations, tolerability, and response |
|
Tuberous sclerosis complex-associated partial-onset seizures (dosing based on body surface area [BSA]) |
Afinitor Disperz |
Oral: Initial: 5 mg/m2 once daily |
Until disease progression or unacceptable toxicity |
|
Therapeutic drug monitoring |
- |
Titrate dose to attain target trough concentrations (5-15 ng/mL); maximum dose increment not to exceed 5 mg; assess trough concentrations 1-2 weeks after initiation of therapy, with dosage modification(s), or when changing dosage forms, hepatic function change, or concurrent CYP3A4/P-glycoprotein (P-gp) inhibitor/inducer therapy; adjust dose using the following equation: New dose = Current dose x (Target concentration divided by Current concentration) |
|
|
Tuberous sclerosis complex-associated renal angiomyolipoma |
Afinitor |
Oral: 10 mg once daily |
Until disease progression or unacceptable toxicity |
|
Tuberous sclerosis complex-associated subependymal giant cell astrocytoma (dosing based on BSA) |
Afinitor or Afinitor Disperz |
Oral: Initial: 4.5 mg/m2 once daily |
Until disease progression or unacceptable toxicity |
|
Carcinoid tumors (advanced) |
Afinitor |
Oral: 10 mg once daily (in combination with octreotide LAR) |
Until disease progression or toxicity (Pavel 2011) |
|
Heart transplantation (≥3 months posttransplantation) |
- |
Oral: Initial: 0.75 mg twice daily; adjust everolimus dose based on everolimus trough concentrations |
Mortality was increased with 3 mg/day when used in combination with rabbit antithymocyte globulin (Eisen 2013) |
|
Hodgkin lymphoma (relapsed or refractory) |
- |
Oral: 10 mg once daily |
Until disease progression or toxicity (Johnston 2010) |
|
Lung transplantation (>1 month posttransplantation) |
- |
Oral: Initial: 0.75 to 1.5 mg twice daily; adjust everolimus dose based on everolimus trough concentrations |
- |
Note: This is a summary of dosage recommendations for various indications for everolimus (Afinitor/Zortress).
Please refer to the specific prescribing information and consult with a healthcare professional for complete and up-to-date dosing guidelines, including appropriate monitoring and dose adjustments. Dosage recommendations may vary depending on individual patient factors and treatment goals.
Everolimus Dose in Children:
Please note that Afinitor, Zortress tablets, and Afinitor Disperz oral suspension are not interchangeable.
Afinitor Disperz is specifically indicated for treating tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA) or TSC-associated partial-onset seizures.
Make sure to select the recommended dosage form based on the indication, and do not combine formulations to achieve the desired total dose.
|
Condition/Indication |
Drug |
Dosage (mg/m2/dose) |
Administration |
Monitoring |
Dose Adjustment |
|
TSC-associated SEGA |
Afinitor/Afinitor Disperz |
4.5 (initial) |
Oral, once daily |
Evaluate serum trough concentration periodically |
Adjust dose to attain serum trough concentrations between 5-15 ng/mL using the provided equation; maximum dose increment not to exceed 5 mg |
|
TSC-associated partial-onset seizures (adjunct therapy) |
Afinitor Disperz |
5 (initial) |
Oral, once daily |
Evaluate serum trough concentration periodically |
Adjust dose to attain serum trough concentrations between 5-15 ng/mL using the provided equation; maximum dose increment not to exceed 5 mg |
|
TSC therapeutic drug monitoring |
N/A |
N/A |
N/A |
Trough concentration measurement suggested at 1-2 weeks after initiation, dosage modification, or switch of dosage form; at 2 weeks after changes in hepatic function or concurrent CYP3A4 or P-gp strong inducer/moderate inhibitor therapy; every 3-6 months if BSA is changing and dose is stable; every 6-12 months if both dose and BSA are stable |
N/A |
Note: BSA refers to body surface area, and ng/mL refers to nanograms per milliliter. CYP3A4 refers to cytochrome P450 3A4, and P-gp refers to P-glycoprotein. SEGA stands for subependymal giant cell astrocytoma, and TSC stands for tuberous sclerosis complex.
Afinitor and Afinitor Disperz are brand names of the drug everolimus. Dosage adjustments should be done based on the provided equation and under the guidance of a healthcare professional.
Please refer to TSC Therapeutic Drug Monitoring for additional information. 2 days ago
|
Indication |
Medication |
Age Group |
Route |
Initial Dose |
Maintenance Concentration |
Reported Start Time |
Mean Doses in Trials |
Adverse Effects |
|
Renal transplantation rejection prophylaxis |
Zortress |
Children ≥1 year and Adolescents |
Oral |
0.8 mg/m2/dose twice daily (maximum single dose: 1.5 mg) |
3 to 6 ng/mL |
Variable |
1.53 mg/m2/day and 1.3-0.6 mg/m2/day in trials at 3 to 4 years post-transplant |
Hypertension and hyperlipidemia observed in one center (everolimus treatment group) |
Note: The information in the table is based on limited data available and various trials conducted in pediatric patients. Reported start time of therapy is variable, and mean doses in trials may vary.
Adverse effects observed include hypertension and hyperlipidemia in one center's everolimus treatment group.
Dosage Adjustment for Concomitant CYP3A4 and/or P-glycoprotein (P-gp) Inhibitors/Inducers:
For children and adolescents with TSC-associated SEGA or partial-onset seizures, dosage adjustments may be necessary when everolimus is co-administered with CYP3A4 and/or P-gp inducers or inhibitors.
-
CYP3A4 and P-gp Inducers:
- Strong inducers: Avoid concurrent use with strong CYP3A4 inducers (including St John's wort). If concomitant use cannot be avoided, double the daily everolimus dose in increments of ≤5 mg, with multiple increments possibly needed.
- When discontinuing strong CYP3A4 or P-gp inducers, wait for 5 days to elapse and then resume everolimus at the dose used prior to initiation of the initial strong inducer.
- Therapeutic drug monitoring: Monitor everolimus serum trough concentrations when modifying CYP3A4 or P-gp strong inducer therapy.
-
CYP3A4 and P-gp Inhibitors:
- Strong inhibitors: Avoid concurrent administration of P-gp and strong CYP3A4 inhibitors.
- Moderate inhibitors: Reduce everolimus dose by approximately 50%. If dose reduction is required for patients receiving the lowest available strength, consider alternate-day dosing. When discontinuing a moderate CYP3A4 or P-gp inhibitor, wait for 3 days to elapse and then resume everolimus at the dose used prior to initiation of the moderate inhibitor.
- Therapeutic drug monitoring: Monitor everolimus serum trough concentrations when modifying CYP3A4 or P-gp moderate inhibitor therapy.
For children and adolescents undergoing renal transplantation, dosage adjustments may be necessary based on everolimus whole blood trough concentrations.
Table: The table below summarizes the dosing adjustments for everolimus based on concomitant use of CYP3A4 and/or P-gp inhibitors/inducers, toxicity, hepatic impairment, and renal impairment in children and adolescents with TSC-associated SEGA or partial-onset seizures:
|
Situation |
Dosing Adjustment |
|
CYP3A4 and/or P-gp inducers (strong) |
Avoid concomitant use; if unavoidable, double everolimus dose in increments of ≤5 mg |
|
Discontinuing strong inducer(s) |
Allow 5 days to elapse and resume everolimus at previous dose |
|
CYP3A4 and/or P-gp inhibitors (strong) |
Avoid concomitant use |
|
CYP3A4 and/or P-gp inhibitors (moderate) |
Reduce everolimus dose by ~50%; consider alternate-day dosing for lowest strength |
|
Discontinuing moderate inhibitor |
Allow 3 days to elapse and resume everolimus at previous dose |
|
Nonhematologic toxicities (noninfectious pneumonitis, stomatitis, metabolic toxicity, other) |
Interrupt treatment until symptoms improve; reinitiate at reduced dose if necessary |
|
Invasive systemic infection |
Withhold or permanently discontinue based on severity |
|
Hematologic toxicities (thrombocytopenia, neutropenia) |
Temporarily interrupt treatment until blood counts improve; reinitiate |
Dosage Adjustment for Toxicity:
For children and adolescents with TSC-associated SEGA or partial-onset seizures, dosage adjustments may be required for nonhematologic toxicities, such as noninfectious pneumonitis, stomatitis, metabolic toxicity, and other nonhematologic toxicities.
-
Noninfectious pneumonitis:
- Radiological changes suggestive of noninfectious pneumonitis with 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:
- Grade 2: Interrupt treatment until symptoms improve to ≤ grade 1; reinitiate at the 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 (platelets ≥25,000 to <50,000/mm^3): Temporarily interrupt treatment until platelet count improves to ≥50,000/mm^3; reinitiate at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest strength available. If thrombocytopenia recurs at grade 3, permanently discontinue treatment.
- Grade 4 (platelets <25,000/mm^3): Permanently discontinue treatment.
-
Neutropenia:
- Grade 2 (ANC ≥1000 to <1500/mm^3): Temporarily interrupt treatment until ANC improves to ≥1500/mm^3; reinitiate at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest strength available. If neutropenia recurs at grade 2, temporarily interrupt treatment until ANC improves to ≥1500/mm^3 and then reinitiate at same dose.
- Grade 3 (ANC ≥500 to <1000/mm^3): Temporarily interrupt treatment until ANC improves to ≥1000/mm^3; reinitiate at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest strength available. If neutropenia recurs at grade 3, permanently discontinue treatment.
- Grade 4 (ANC <500/mm^3): Permanently discontinue treatment.
Dosing adjustment for hepatic impairment:
- Children and Adolescents:
- TSC-associated SEGA or partial-onset seizures: Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: No dosage adjustment is necessary.
- Severe (Child-Pugh class C) hepatic impairment: Avoid use.
Dosing adjustment for renal impairment:
- Children and Adolescents:
- TSC-associated SEGA or partial-onset seizures: Mild (CrCl 50 to <80 mL/min/1.73 m^2) or moderate (CrCl 30 to <50 mL/min/1.73 m^2) renal impairment: No dosage adjustment is necessary.
- Severe (CrCl <30 mL/min/1.73 m^2) renal impairment: Avoid use.
Everolimus Dose in Pregnancy & Lactation:
- Everolimus, based on animal studies, may harm fetal development during pregnancy. Therefore, pregnancy status should be confirmed in females of reproductive age before starting everolimus therapy.
- Females should use effective contraception during treatment and for 8 weeks after the last dose, while males with female partners should use contraception for 4 weeks after the last dose.
- Everolimus may also cause menstrual irregularities, amenorrhea, increased luteinizing hormone and follicle-stimulating hormone in females, and azoospermia and oligospermia in males.
- Family planning should be considered by females of reproductive age before starting everolimus therapy. The Transplant Pregnancy Registry International (TPR) monitors pregnancies in transplant recipients and their partners.
Dose during Breastfeeding:
- Everolimus has been found in breast milk according to a study by Kociszewska-Najman in 2017.
- As per the manufacturer's recommendation, breastfeeding is not advised during everolimus therapy (Afinitor, Zortress), and for a period of 2 weeks after the last dose (Afinitor), to avoid potential serious adverse effects on the breastfed infant.
Everolimus Dose in Kidney Disease:
Dose in Adults:
No dosage adjustment is necessary.
Dose in Children:
All patients: No adjustment necessary at baseline; nephrotoxicity has been reported with use, monitor renal function.
Everolimus Dose Liver Disease:
Dose in Adults:
|
Impairment Level (Child-Pugh Class) |
Indication |
Dose Adjustment |
|
Mild |
Breast cancer, neuroendocrine tumors, renal cell cancer (RCC), tuberous sclerosis complex (TSC)-associated renal angiomyolipoma |
Reduce to 7.5 mg once daily; if not tolerated, may further reduce to 5 mg once daily |
|
Mild |
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) |
|
Mild |
TSC-associated partial-onset seizures and subependymal giant cell astrocytoma (SEGA) |
No initial dosage adjustment provided; subsequent dosing based on therapeutic drug monitoring (monitor 2 weeks after any change in hepatic status; target trough concentration: 5 to 15 ng/mL) |
|
Moderate |
Breast cancer, neuroendocrine tumors, RCC, TSC-associated renal angiomyolipoma |
Reduce to 5 mg once daily; if not tolerated, may further reduce to 2.5 mg once daily |
|
Moderate |
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) |
|
Moderate |
TSC-associated partial-onset seizures and SEGA |
No initial dosage adjustment provided; subsequent dosing based on therapeutic drug monitoring (monitor 2 weeks after any change in hepatic status; target trough concentration: 5 to 15 ng/mL) |
|
Severe |
Breast cancer, neuroendocrine tumors, RCC, TSC-associated renal angiomyolipoma |
If potential benefit outweighs risks, use 2.5 mg once daily (do not exceed 2.5 mg once daily) |
|
Severe |
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) |
|
Severe |
TSC-associated partial-onset seizures and SEGA |
Reduce initial dose to 2.5 mg/m2 once daily; subsequent dosing based on therapeutic drug monitoring (monitor 2 weeks after any change in hepatic status; target trough concentration: 5 to 15 ng/mL) |
Note: Dosing adjustments for everolimus based on impairment level (Child-Pugh class) are provided for different indications, including breast cancer, neuroendocrine tumors, renal cell cancer (RCC), tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, liver or renal transplantation, and TSC-associated partial-onset seizures and subependymal giant cell astrocytoma (SEGA).
The adjustments vary depending on the severity of impairment, with mild, moderate, and severe levels outlined in the table. Individualization of subsequent dosing is often recommended based on therapeutic drug monitoring, with target trough concentration ranges provided for different indications.
It's important to consult with a healthcare professional for appropriate dosing and monitoring of everolimus in patients with impaired liver function. Additionally, the potential benefit versus risks of everolimus should be carefully considered in severe impairment cases.
Do not exceed recommended dosages without proper medical supervision. The table serves as a quick reference guide and should not replace professional medical advice. Monitoring trough concentrations can help optimize dosing and reduce the risk of adverse effects.
Dose in Children:
Tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA) or partial-onset seizures:
Children and Adolescents:
|
Hepatic Impairment |
Condition |
Initial Dose |
Subsequent Dosing |
Therapeutic Drug Monitoring |
|
Child-Pugh class A |
TSC-associated SEGA or partial-onset seizures in children and adolescents |
No initial dosage adjustment provided |
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 |
|
Child-Pugh class B |
TSC-associated SEGA or partial-onset seizures in children and adolescents |
No initial dosage adjustment provided |
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 |
|
Child-Pugh class C |
TSC-associated SEGA or partial-onset seizures in children and adolescents |
Reduce initial dose to 2.5 mg/m2 once daily |
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 |
Note: Therapeutic drug monitoring is recommended for dosing adjustments in patients with hepatic impairment, and target trough concentrations of 5 to 15 ng/mL are recommended.
Monitoring should be performed after initiation of therapy, dosage modifications, or any change in hepatic status.
It is important to follow the dosing recommendations and monitoring guidelines provided by the manufacturer and consult with a healthcare professional for individualized dosing and monitoring in patients with hepatic impairment, especially in children and adolescents with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA) or partial-onset seizures.
Consultation with a healthcare professional is crucial to ensure safe and effective use of everolimus in patients with hepatic impairment.
Side effects caused by Everolimus:
Transplantation:
Reactions occur in kidney and liver transplantation unless otherwise specified.
Common side effects caused by Everolimus:
|
System/Organ |
Reaction |
Kidney Transplant (%) |
Liver Transplant (%) |
|
Cardiovascular |
Peripheral edema |
45 |
18-20 |
|
Hypertension |
17-30 |
- |
|
|
Central Nervous System |
Headache |
18-22 |
- |
|
Insomnia |
17 |
6-7 |
|
|
Procedural pain |
15 |
- |
|
|
Fatigue |
9-11 |
- |
|
|
Endocrine & Metabolic |
Diabetes mellitus (new onset) |
9 |
32 (liver) |
|
Hyperkalemia |
18 (renal) |
- |
|
|
Hypercholesterolemia |
9-17 |
- |
|
|
Hypomagnesemia |
14 (kidney) |
- |
|
|
Hypophosphatemia |
13 (kidney) |
- |
|
|
Hyperglycemia |
12 (kidney) |
- |
|
|
Hypokalemia |
12 (kidney) |
- |
|
|
Gastrointestinal |
Constipation |
38 (kidney) |
- |
|
Nausea |
29 (kidney) |
14-15 (liver) |
|
|
Diarrhea |
19-24 |
- |
|
|
Vomiting |
15 (kidney) |
- |
|
|
Abdominal pain |
13-15 |
- |
|
|
Genitourinary |
Urinary tract infection |
22 (kidney) |
- |
|
Hematuria |
12 (kidney) |
- |
|
|
Dysuria |
11 (kidney) |
- |
|
|
Hematologic & Oncologic |
Anemia |
26 (kidney) |
- |
|
Leukopenia |
3-13 |
- |
|
|
Infection |
Infection |
62 (kidney) |
50 (liver) |
|
Viral infection |
10 (kidney) |
17 (liver) |
|
|
Bacterial infection |
- |
16 (liver) |
|
|
Hepatitis C |
- |
11-14 (liver) |
|
|
Local |
Incisional pain |
16 (kidney) |
11 (liver) |
|
Neuromuscular & Skeletal |
Limb pain |
12 (kidney) |
- |
|
Back pain |
11 (kidney) |
- |
|
|
Renal |
Increased serum creatinine |
18 (kidney) |
- |
|
Respiratory |
Upper respiratory tract infection |
16 (kidney) |
- |
|
Miscellaneous |
Postoperative wound complication |
35 (kidney) |
11 (liver) |
|
Fever |
13-19 |
- |
Less common side effects:
-
Cardiovascular:
- Hypertensive crisis
- Angina pectoris
- Atrial fibrillation
- Cardiac failure
- Chest discomfort
- Chest pain
- Deep vein thrombosis
- Edema
- Hypotension
- Palpitations
- Phlebitis
- Pulmonary embolism
- Renal artery thrombosis
- Syncope
- Tachycardia
- Venous thromboembolism
-
Central nervous system:
- Agitation
- Anxiety
- Chills
- Depression
- Dizziness
- Drowsiness
- Hallucination
- Hemiparesis
- Hypoesthesia
- Lethargy
- Malaise
- Migraine
- Myasthenia
- Neuralgia
- Pain
- Paresthesia
-
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
- Cyanocobalamin deficiency
- Dehydration
- Fluid retention
- Gout
- Hirsutism
- Hypercalcemia
- Hyperparathyroidism
- Hypertriglyceridemia
- Hyperuricemia
- Hypocalcemia
- Hypoglycemia
- Hyponatremia
- Hypothyroidism
- Iron deficiency
- Ovarian cyst
-
Gastrointestinal:
- Stomatitis (kidney transplant: 8%)
- Dyspepsia (kidney transplant: 4%)
- Upper abdominal pain (kidney transplant: 3%)
- Abdominal distention
- Anorexia
- Biliary obstruction
- Cholangitis
- Cholestasis
- Decreased appetite
- Dysphagia
- Epigastric distress
- Flatulence
- Gastritis
- Gastroenteritis
- Gastroesophageal reflux disease
- Gingival hyperplasia
- Hematemesis
- Hemorrhoids
- Hernia of abdominal cavity
- Inguinal hernia
- Intestinalobstruction
- Oral candidiasis
- Oral herpes simplex infection
- Oral mucosa ulcer
- Peritoneal effusion
- Peritonitis
-
Genitourinary:
- Erectile dysfunction (kidney transplant: 5%)
- Benign prostatic hyperplasia
- Bladder spasm
- Nocturia
- Perinephric abscess
- Perinephric hematoma
- Pollakiuria
- Proteinuria
- Pyuria
- Scrotal edema
- Urethritis
- Urinary retention
- Urinary urgency
-
Hematologic & oncologic:
- Neoplasm
- Leukocytosis
- Lymphadenopathy
- Lymphorrhea
- 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
-
Hypersensitivity:
- Angioedema
-
Infection:
- Bk virus (kidney transplant: 1%)
- Bacteremia
- Candidiasis
- Cytomegalovirus disease
- Herpes virus infection
- Influenza
- Sepsis
- Wound infection
-
Neuromuscular & skeletal:
- Tremor
- Arthralgia
- Asthenia
- Joint swelling
- Muscle spasm
- Musculoskeletal pain
- Myalgia
- Osteoarthritis
- Osteomyelitis
- Osteonecrosis
- Osteoporosis
- Spondylitis
-
Ophthalmic:
- Blurred vision
- Cataract
- Conjunctivitis
-
Renal:
- Renal failure syndrome (5% to 10%; may be acute)
- Hydronephrosis
- Increased blood urea nitrogen
- Interstitial nephritis
- Polyuria
- Pyelonephritis
- Renal insufficiency
- Renal tubular necrosis
-
Respiratory:
- Cough
- Atelectasis
- Bronchitis
- Dyspnea
- Epistaxis
- Lower respiratory tract infection
- Nasal congestion
- Nasopharyngitis
- Oropharyngeal pain
- Paranasal sinus congestion
- Pleural effusion
- Pneumonia
- Pulmonary edema
- Rhinorrhea
- Sinusitis
- Wheezing
Antineoplastic:
Antineoplastic indications include advanced hormone receptor-positive, advanced nonfunctional NET of gastrointestinal or lung origin, HER2-negative breast cancer, pancreatic neuroendocrine tumors, renal cell carcinoma, and tuberous sclerosis complex associated renal angiomyolipoma, subependymal giant cell astrocytoma, or seizures
Common side effects:
-
Cardiovascular:
- Edema
- Peripheral edema
- Hypertension
-
Central nervous system:
- Fatigue
- Malaise
- Headache
- Migraine
- Behavioral problems
- Insomnia
- Dizziness
-
Dermatologic:
- Skin rash
- Cellulitis
- Acne vulgaris
- Nail disease
- Pruritus
- Xeroderma
-
Endocrine & metabolic:
- Hypercholesterolemia
- Hyperglycemia
- Hypertriglyceridemia
- Decreased serum bicarbonate
- Hypophosphatemia
- Decreased serum calcium
- Hypokalemia
- Hypoalbuminemia
- Amenorrhea
-
Gastrointestinal:
- Stomatitis
- Diarrhea
- Abdominal pain
- Decreased appetite
- Vomiting
- Nausea
- Weight loss
- Anorexia
- Dysgeusia
- Mucositis
- Constipation
- Xerostomia
-
Genitourinary:
- Urinary tract infection
- Irregular menses
-
Hematologic & oncologic:
- Anemia
- Increase in fasting plasma glucose
- Prolonged partial thromboplastin time
- Lymphocytopenia
- Leukopenia
- Neutropenia
- Thrombocytopenia
-
Hepatic:
- Increased serum alkaline phosphatase
- Increased serum aspartate aminotransferase
- Increased serum alanine aminotransaminase
-
Infection:
- Infection
-
Neuromuscular & skeletal:
- Asthenia
- Arthralgia
- Back pain
- Limb pain
-
Renal:
- Increased serum creatinine
-
Respiratory:
- Respiratory tract infection
- Cough
- Nasopharyngitis
- Rhinitis
- Upper respiratory tract infection
- Dyspnea
- Epistaxis
- Pneumonitis
- Oropharyngeal pain
-
Miscellaneous:
- Fever
Less common side effects:
-
Cardiovascular:
- Chest pain
- Tachycardia
- Cardiac failure
- Deep vein thrombosis
-
Central nervous system:
- Depression
- Paresthesia
- Chills
- Aggressive behavior
-
Dermatologic:
- Alopecia
- Palmar-plantar erythrodysesthesia
- Erythema
- Onychoclasis
- Skin lesion
- Acneiform eruption
-
Endocrine & metabolic:
- Diabetes mellitus
- Heavy menstrual bleeding
- Menstrual disease
- Decreased serum fibrinogen
- Increased luteinizing hormone
- Increased follicle-stimulating hormone
- Ovarian cyst
- Exacerbation of diabetes mellitus
-
Gastrointestinal:
- Gastroenteritis
- Hemorrhoids
- Dysphagia
-
Genitourinary:
- Vaginal hemorrhage
- Dysmenorrhea
- Uterine hemorrhage
- Cystitis
- Proteinuria
-
Hematologic & oncologic:
- Hemorrhage
-
Hepatic:
- Increased serum bilirubin
-
Hypersensitivity:
- Hypersensitivity reaction
- Angioedema
-
Infection:
- Candidiasis
- Hepatitis C
- Sepsis
-
Neuromuscular & skeletal:
- Muscle spasm
- Jaw pain
-
Ophthalmic:
- Eyelid edema
- Conjunctivitis
-
Otic:
- Otitis media
-
Renal:
- Renal failure syndrome
-
Respiratory:
- Streptococcal pharyngitis
- Pleural effusion
- Pneumonia
- Bronchitis
- Pharyngolaryngeal pain
- Rhinorrhea
- Sinusitis
-
Miscellaneous:
- Postoperative wound complication
Contraindication to Everolimus Include:
Everolimus, other rapamycin derivatives, or any ingredient in the formulation causing clinically significant hypersensitivity is not suitable for treatment.
The Canadian labeling adds an extra contraindication not present in the US labeling, stating that the medication is not recommended for treating seizures in individuals who do not have a confirmed diagnosis of tuberous sclerosis complex (TSC).
Warnings/Precautions
Concerns related to adverse effects:
|
Side Effect |
Information |
|
Angioedema |
May occur; permanently discontinue if it does. Increased risk with concomitant use of other angioedema-causing agents. |
|
Bone marrow suppression |
May cause decreases in blood counts, including grade 3 and 4 events. Monitor blood counts regularly and withhold or permanently discontinue treatment based on severity. |
|
Edema |
Generalized edema and local fluid accumulation may occur. |
|
Graft thrombosis |
Increased risk of renal arterial and venous thrombosis; may result in graft loss. |
|
Hepatic artery thrombosis |
Associated with an increase in hepatic artery thrombosis; do not use everolimus prior to 30 days post liver transplant. |
|
Hypersensitivity |
Severe hypersensitivity reactions have been reported; permanently discontinue if it occurs. |
|
Infections |
Everolimus has immunosuppressant properties which may result in increased susceptibility to infection. Opportunistic infections and serious infections have been reported. Monitor for signs and symptoms of infection and withhold or permanently discontinue treatment based on severity. |
|
Malignancy |
May result in the development of malignancy, including lymphoma and skin cancer. Minimize risk by limiting exposure to sunlight and ultraviolet light. |
|
Metabolic effects |
May cause hyperglycemia, hyperlipidemia, and hypertriglyceridemia, including grade 3 and 4 events. Monitor glucose and lipid profile regularly and manage with appropriate medical therapy. |
|
Mucositis/stomatitis |
Commonly associated with mouth ulcers, mucositis, and stomatitis. Manage with mouthwash and/or topical therapy. |
|
Nephrotoxicity |
May cause elevations in serum creatinine. Monitor renal function regularly. |
The information also notes that everolimus has a US Boxed Warning for graft thrombosis, infections, and malignancy.
It may also cause metabolic effects, mucositis/stomatitis, and nephrotoxicity. The medication has immunosuppressant properties and may increase the risk of infections, including opportunistic infections, in transplant patients.
The risk of developing malignancy is associated with the intensity and duration of therapy. The medication is commonly associated with mouth ulcers, mucositis, and stomatitis, which can be managed with mouthwash and/or topical therapy.
The medication may cause elevations in serum creatinine and may require regular monitoring of renal function.
Disease-related concerns:
The concerns related to the use of everolimus include increased mortality (usually associated with infections) within the first 3 months after heart transplantation, increased exposure in patients with hepatic impairment, risk of diarrhea and malabsorption in patients with hereditary galactose intolerance, and an increased incidence of rash, infection, and dose interruptions in patients with renal insufficiency who received mTOR inhibitors.
The safety and efficacy of everolimus in solid organ transplantation other than renal or liver have not been established. The recommended doses for everolimus in different medical conditions have also been provided.
The dosage adjustments are not required based on renal impairment. Tacrolimus has minimal or no pharmacokinetic impact on everolimus concentrations in liver transplant patients.
|
Medical Condition |
Recommended Dose |
|
Heart transplantation |
Use not recommended, everolimus initiation delayed until 3 to 6 months post-transplantation |
|
Hepatic impairment (breast cancer, neuroendocrine tumors, RCC, or TSC-associated renal angiomyolipoma) |
Reduced doses recommended for mild, moderate, and severe hepatic impairment |
|
Hepatic impairment (transplant patients) |
Reduced doses recommended for Child-Pugh class A, B, or C; monitor whole blood trough levels closely |
|
Hepatic impairment (TSC-associated partial onset seizures and SEGA) |
Reduced doses recommended in severe hepatic impairment; monitor whole blood trough levels |
|
Hereditary galactose intolerance |
Avoid use |
|
Renal impairment |
Monitor renal function (BUN, serum creatinine, urinary protein) at baseline and periodically, dosage adjustments not required based on renal impairment |
|
Solid organ transplantation other than renal or liver |
Safety and efficacy not established |
|
Liver transplant |
Tacrolimus has minimal or no pharmacokinetic impact on everolimus concentrations. |
Drug Interaction:
|
Drug |
Interaction |
Risk |
|
Everolimus |
May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors |
C: Monitor therapy |
|
Hyperglycemia-Associated Agents |
May diminish the therapeutic effect of Antidiabetic Agents |
C: Monitor therapy |
|
ARIPiprazole |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole |
C: Monitor therapy |
|
Bosentan |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers) |
C: Monitor therapy |
|
Chloramphenicol (Ophthalmic) |
May enhance the adverse/toxic effect of Myelosuppressive Agents |
C: Monitor therapy |
|
Clofazimine |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors) |
C: Monitor therapy |
|
CloZAPine |
Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine |
C: Monitor therapy |
|
Coccidioides immitis Skin Test |
Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test |
C: Monitor therapy |
|
CYP3A4 Inducers (Moderate) |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers) |
C: Monitor therapy |
|
Deferasirox |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers) |
C: Monitor therapy |
|
Denosumab |
May enhance the adverse/toxic effect of Immunosuppressants |
C: Monitor therapy |
|
Dofetilide |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide |
C: Monitor therapy |
|
Erdafitinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers) |
C: Monitor therapy |
|
Erdafitinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors) |
C: Monitor therapy |
|
Erdafitinib |
May increase the serum concentration of P-glycoprotein/ABCB1 Substrates |
C: Monitor therapy |
|
Flibanserin |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin |
C: Monitor therapy |
|
Fosaprepitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors) |
C: Monitor therapy |
|
Ivosidenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers) |
C: Monitor therapy |
|
Larotrectinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors) |
C: Monitor therapy |
|
NiMODipine |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine |
C: Monitor therapy |
|
Ocrelizumab |
May enhance the immunosuppressive effect of Immunosuppressants |
C: Monitor therapy |
|
Palbociclib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors) |
Risk C: Monitor therapy |
|
P-glycoprotein/ABCB1 Inhibitors |
May increase the serum concentration of Everolimus |
Risk C: Monitor therapy |
|
Pidotimod: |
Immunosuppressants may diminish the therapeutic effect of Pidotimod. |
Risk C: Monitor therapy |
|
Promazine: |
May enhance the myelosuppressive effect of Myelosuppressive Agents. |
Risk C: Monitor therapy |
|
Ranolazine: |
May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. |
Risk C: Monitor therapy |
|
Rifabutin: |
May decrease the serum concentration of Everolimus. |
Risk C: Monitor therapy |
|
Rifapentine: |
May decrease the serum concentration of Everolimus. |
Risk C: Monitor therapy |
|
Sarilumab: |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
Risk C: Monitor therapy |
|
Siltuximab: |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
Risk C: Monitor therapy |
|
Simeprevir: |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
Risk C: Monitor therapy |
|
Siponimod: |
Immunosuppressants may enhance the immunosuppressive effect of Siponimod. |
Risk C: Monitor therapy |
|
Tertomotide: |
Immunosuppressants may diminish the therapeutic effect of Tertomotide. |
Risk C: Monitor therapy |
|
Tocilizumab: |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
Risk C: Monitor therapy |
|
Trastuzumab: |
May enhance the neutropenic effect of Immunosuppressants. |
Risk C: Monitor therapy |
|
Baricitinib: |
Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses ofmethotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. |
Risk D: Consider therapy modification |
|
CycloSPORINE (Systemic): |
May increase the serum concentration of Everolimus. Management: When using everolimus for renal cell carcinoma, avoid concurrent cyclosporine. When using everolimus as post-transplant immunosuppression, concurrent cyclosporine should be used at lower doses and with lower target serum cyclosporine concentrations. |
Risk D: Consider therapy modification |
|
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, double the daily dose of everolimus using increments of 5 mg or less. Monitor everolimus serum concentrations closely when indicated. |
Risk D: Consider therapy modification |
|
CYP3A4 Inhibitors (Moderate): |
May increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations. |
Risk D: Consider therapy modification |
|
Dabrafenib: |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). |
Risk D: Consider therapy modification |
|
Echinacea: |
May diminish the therapeutic effect of Immunosuppressants. |
Risk D: Consider therapy modification |
|
Efavirenz: |
May decrease the serum concentration of Everolimus. Management: Closely monitor everolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of everolimus may be required. |
Risk D: Consider therapy modification |
|
Enzalutamide: |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. |
Risk D: Consider therapy modification |
|
Fingolimod: |
Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). |
Risk D: Consider therapy modification |
|
Inhibitors of CYP3A4 (Moderate) and P-glycoprotein: |
May increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations. |
Risk D: Consider therapy modification |
|
Leflunomide: |
Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. |
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 |
|
Lorlatinib: |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. |
Risk D: Consider therapy modification |
|
Mitotane: |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. |
Risk D: Consider therapy modification |
|
Nivolumab: |
Immunosuppressants may diminish the therapeutic effect of Nivolumab. |
Risk D: Consider therapy modification |
|
Pitolisant: |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. |
Risk D: Consider therapy modification |
|
Roflumilast: |
May enhance the immunosuppressive effect of Immunosuppressants. |
Risk D: Consider therapy modification |
|
Sipuleucel-T: |
Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. |
Risk D: Consider therapy modification |
|
Stiripentol: |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. |
Risk D: Consider therapy modification |
|
Tofacitinib: |
Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. |
Risk D: Consider therapy modification |
|
Vaccines (Inactivated): |
Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. |
Risk D: Consider therapy modification |
|
Venetoclax: |
May increase the serum concentration of Everolimus. Management: Administer everolimus at least 6 hours before venetoclax when concomitant therapy is required. |
Risk D: Consider therapy modification |
|
Antihepaciviral Combination Products: |
May increase the serum concentration of Everolimus. |
Risk X: Avoid combination |
|
BCG (Intravesical): |
Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). |
Risk X: Avoid combination |
|
BCG (Intravesical): |
Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). |
Risk X: Avoid combination |
|
Cladribine: |
May enhance the immunosuppressive effect of Immunosuppressants. |
Risk X: Avoid combination |
|
Cladribine: |
May enhance the myelosuppressive effect of Myelosuppressive Agents. |
Risk X: Avoid combination |
|
Conivaptan: |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
Risk X: Avoid combination |
|
CYP3A4 Inhibitors (Strong): |
May increase the serum concentration of Everolimus. |
Risk X: Avoid combination |
|
Deferiprone: |
Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. |
Risk X: Avoid combination |
|
Dipyrone: |
May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased |
Risk X: Avoid combination |
|
Fusidic Acid (Systemic): |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
Risk X: Avoid combination |
|
Grapefruit Juice: |
May increase the serum concentration of Everolimus. |
Risk X: Avoid combination |
|
Idelalisib: |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
Risk X: Avoid combination |
|
Natalizumab: |
Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. |
Risk X: Avoid combination |
|
Pimecrolimus: |
May enhance the adverse/toxic effect of Immunosuppressants. |
Risk X: Avoid combination |
|
Pimozide: |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. |
Risk X: Avoid combination |
|
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 (Topical): |
May enhance the adverse/toxic effect of Immunosuppressants. |
Risk X: Avoid combination |
|
Vaccines (Live): |
Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. |
Risk X: Avoid combination |
|
Voriconazole: |
May increase the serum concentration of Everolimus. |
Risk X: Avoid combination |
Everolimus administration in adults:
The medication Afinitor/Afinitor Disperz can be taken with or without food, but to reduce variability, it should be taken consistently with regard to food.
Missed doses may be taken up to 6 hours after the regularly scheduled time.
Tablets should be swallowed whole with a glass of water and should not be crushed or broken.
Tablets for oral suspension should be administered immediately after preparation in water only, and if not administered within 60 minutes, they should be discarded.
A dose of up to 10 mg can be placed in a 10 mL oral syringe and suspended in water and air, while doses above 10 mg require an additional syringe.
For breast cancer, neuroendocrine tumors, renal cell cancer, tuberous sclerosis complex (TSC)-associated partial onset-seizures, renal angiomyolipoma, and subependymal giant cell astrocytoma (SEGA), the medication should be administered at the same time each day.
For solid organ transplantation, the medication should be administered consistently approximately 12 hours apart, and at the same time as cyclosporine or tacrolimus.
Administration: Pediatric
To prevent potential contact with everolimus, caregivers must wear gloves when preparing the oral suspension from tablets.
It is recommended to take the oral dose with or without food consistently. Afinitor/Afinitor Disperz should be administered at the same time daily, and if a dose is missed, it can be taken up to six hours after the scheduled time.
Zortress should be administered at the same time as tacrolimus or cyclosporine, approximately twelve hours apart.
Tablets should be swallowed whole with a glass of water, and crushed or broken tablets should be avoided.
Tablets for oral suspension must be given as a suspension, immediately after preparation, using water only, and must not be crushed or broken.
Oral suspension can be prepared in an oral syringe or small glass.
Monitoring & Parameters:
The recommended monitoring parameters for patients taking everolimus include CBC with differential, liver function, serum creatinine, urinary protein, BUN, fasting serum glucose, HbA1c, lipid profile, and renal function. Signs and symptoms of infection, non-infectious pneumonitis, stomatitis, or malignancy should also be monitored.
Additionally, a pregnancy test should be conducted for females of reproductive potential prior to starting therapy, and adherence should be monitored.
For patients undergoing solid organ transplantation, everolimus whole blood trough concentrations should be monitored, especially in those with hepatic impairment, concurrent CYP3A4 inhibitors and inducers, and when cyclosporine or tacrolimus formulations or doses are altered.
Dosage adjustments should be made based on trough concentrations obtained 4 to 5 days after the previous dosage adjustment. Cyclosporine or tacrolimus concentrations should also be monitored, along with proteinuria.
For patients with TSC-associated partial onset seizures and SEGA, everolimus whole blood trough concentrations should be monitored 1 to 2 weeks after treatment initiation, with dosage modification(s), or when changing dosage forms, 2 weeks after a change in hepatic function and initiation or discontinuation of concurrent CYP3A4/P-gp inhibitor/inducer therapy.
The trough concentrations should be maintained between 5 and 15 ng/mL, and stable patients should be monitored every 6 to 12 months, or every 3 to 6 months if BSA is changing.
MOA: Mechanism of Action of Everolimus
Everolimus is an immunosuppressant macrolide and an mTOR inhibitor with antiproliferative and antiangiogenic effects.
It works by binding to the intracellular protein FKBP-12, forming a complex that inhibits mTOR serine-threonine kinase activity, leading to reduced protein synthesis and cell proliferation.
It also reduces angiogenesis by suppressing the expression of VEGF and HIF-1. In TSC-associated renal angiomyolipoma, mTOR activity is unregulated, leading to the development of angiomyolipomas. Everolimus reduces lipoma volume, as demonstrated in studies conducted by Bissler in 2013.
Pharmacodynamics and Pharmacokinetics
|
Property |
Description |
|
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) |
International Brands of Everolimus:
- Afinitor
- Afinitor Disperz
- Advacan
- Certican
- Vetubia
- Votubia
- Xevirol
- Zortress
