Class: mTOR inhibitor
- Tablets, oral 2.5 mg
- Tablets, oral 5 mg
- Tablets, oral 7.5 mg
- Tablets, oral 10 mg
- Tablets, oral 0.25 mg
- Tablets, oral 0.5 mg
- Tablets, oral 0.75 mg
Inhibitor of mammalian target of rapamycin (mTOR), which is a serine-threonine kinase. Everolimus binds to an intracellular protein, resulting in an inhibitory complex formation and inhibition of mTOR kinase activity.
T max is 1 to 2 h. C max and AUC are approximately 11.1 ng/mL and 75 + 31 ng•h/mL, respectively, for a 0.75 mg twice-daily dosage in renal transplant patients. Steady state is achieved within 2 wk with once-daily dosing. High-fat meals reduce C max and AUC of Zortress by 60% and 16%, respectively, and of Afinitor by 54% and 22%, respectively.
Protein binding is approximately 74%. Vd is 107 to 342 L.
Everolimus is a substrate for CYP3A4 and P-glycoprotein (P-gp). Six metabolites have been identified and are approximately 100 times less active than everolimus.
Elimination half-life is approximately 30 h. Recovery in the feces and urine is 80% and 5%, respectively.
Special PopulationsRenal Function Impairment
No influence of CrCl (11 to 178 mL/min) has been detected.Hepatic Function Impairment
The average AUC in subjects with moderate hepatic impairment is twice that found in subjects with healthy hepatic function.Elderly
A limited reduction in oral Cl of 0.33% per year was estimated in renal transplant patients.Gender
No effect of gender on pharmacokinetics has been observed.Race
The average exposure is higher in Japanese patients compared with non-Japanese patients. Oral Cl is 20% higher in black patients compared with white patients. The importance of these differences in safety and efficacy has not been established.
Indications and UsageAfinitor
Treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced, or metastatic disease; treatment of advanced renal cell carcinoma after failure of sunitinib or sorafenib; treatment of patients with subependymal giant cell astrocytoma associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgical resection; treatment of renal angiomyolipoma and tuberous sclerosis complex not requiring immediate surgery.Zortress
In combination with basiliximab induction and concurrently with reduced doses of cyclosporine and corticosteroids for the prophylaxis of organ rejection in adult patients receiving a kidney transplant who are at a low to moderate immunologic risk.
Hypersensitivity to everolimus, other rapamycin derivatives (eg, sirolimus), or any component of the product.
Dosage and AdministrationAdvanced Pancreatic Neuroendocrine Tumors/Advanced Renal Cell Carcinoma/Renal Angiomyolipoma With Tuberous Sclerosis Complex
PO 10 mg once daily. For the management of severe and/or intolerable adverse reactions, temporarily reduce dosage to 5 mg once daily and/or interrupt therapy. Continue treatment as long as clinical benefit is observed or unacceptable toxicity occurs.CYP3A4 and/or P-gp inhibitors
Avoid the use of concomitant strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) and grapefruit, grapefruit juice, and other foods that are known to inhibit CYP-450 and P-gp activity. Use caution when coadministered with moderate CYP3A4 and/or P-gp inhibitors (eg, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil). If patients require coadministration of a moderate CYP3A4 and/or P-gp inhibitor, reduce the everolimus dosage to 2.5 mg daily. An everolimus dosage increase from 2.5 to 5 mg may be considered based on patient tolerance. If the moderate inhibitor is discontinued, allow a washout period of approximately 2 to 3 days before the everolimus dose is increased. If the moderate inhibitor is discontinued, return the everolimus dose to the dose used prior to initiation of the moderate CYP3A4 and/or P-gp inhibitor.Strong CYP3A4 inducers
Avoid the use of concomitant strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort). Consider increasing the dose in 5 mg increments to 20 mg once daily. If the strong inducer is discontinued, return the everolimus dose to the dose used prior to initiation of the strong CYP3A4 inducer.Renal transplantation
PO Initially, 0.75 mg twice daily in combination with reduced-dose cyclosporine (modified) and corticosteroids, administered as soon as possible after transplant. Dose adjustments may be required based on achieved everolimus blood concentrations, tolerability, individual response, change in concomitant medications, and the clinical situation. Dose adjustments can be made at 4- to 5-day intervals.Subependymal Giant Cell Astrocytoma
Adults and children 3 y and older
PO Initial dosage is based on BSA: for 0.5 to 1.2 m 2 , administer 2.5 mg once daily; for 1.3 to 2.1 m 2 , administer 5 mg once daily; for 2.2 m 2 or more, administer 7.5 mg once daily. Make dose adjustments based on everolimus trough blood concentrations achieved, tolerability, individual response, and change in concomitant medications, including CYP3A4-inducing antiepileptic drugs, at 2-wk intervals. Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of everolimus therapy. If dosage reduction is required for patients receiving 2.5 mg daily, consider alternate-day dosing.CYP3A4 and/or P-gp inhibitors
Avoid the use of strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) and grapefruit, grapefruit juice, and other foods that are known to inhibit CYP-450 and P-gp activity. Use caution when coadministered with moderate CYP3A4 and/or P-gp inhibitors (eg, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil). If patients require coadministration of a moderate CYP3A4 and/or P-gp inhibitor, reduce the everolimus dose by approximately 50% to maintain trough concentrations of 5 to 10 ng/mL. If dosage reduction is required for patients receiving 2.5 mg daily, consider alternate-day dosing. Individualize subsequent dosing based on therapeutic drug monitoring. Assess everolimus trough concentrations approximately 2 wk after the addition of a moderate CYP3A4 and/or P-gp inhibitor. If the moderate inhibitor is discontinued, return the everolimus dose to the dose used prior to initiation of the moderate CYP3A4 and/or P-gp inhibitor, and reassess the everolimus trough concentration approximately 2 wk later.Strong CYP3A4 inducers
Avoid the use of concomitant strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort). For patients requiring a concomitant strong CYP3A4 inducer, double the everolimus dose. Individualize subsequent dosing based on therapeutic drug monitoring. If the strong inducer is discontinued, return the everolimus dose to the dose used prior to initiation of the strong CYP3A4 inducer, and assess the everolimus trough concentrations approximately 2 wk later.Hepatic Function Impairment
Advanced pancreatic neuroendocrine tumors/advanced renal cell carcinoma/renal angiomyolipoma with tuberous sclerosis complex Mild hepatic impairment (Child-Pugh class A)
7.5 mg daily; may decrease to 5 mg if not well tolerated.Moderate hepatic impairment (Child-Pugh class B)
5 mg daily; may decrease to 2.5 mg if not well tolerated.Severe hepatic impairment (Child-Pugh class C)
Do not exceed 2.5 mg daily.Renal transplantation
The daily dose needs to be reduced by half the recommended initial daily dose in patients with moderate hepatic impairment (Child-Pugh class B); monitor blood concentrations to make further adjustments as necessary.Subependymal giant cell astrocytoma
Adjustment to the starting dose may not be needed for patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Individualize subsequent dosing based on therapeutic drug monitoring. Do not use in patients with severe hepatic impairment (Child-Pugh class C).Therapeutic Drug Monitoring
Subependymal giant cell astrocytoma
Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients using a validated assay. Assess trough concentrations approximately 2 wk after starting treatment. Titrate dosing to attain trough concentrations of 5 to 10 ng/mL. If concentrations are between 10 and 15 ng/mL and the patient has demonstrated adequate tolerability and tumor response, no dose reductions are needed. Reduce the dose of everolimus if trough concentrations greater than 15 ng/mL are observed. If concentrations are less than 5 ng/mL, the daily dose may be increased by 2.5 mg every 2 wk, subject to tolerability. The daily dose may be reduced by 2.5 mg every 2 wk to attain a target of 5 to 10 ng/mL. If dose reduction is required for patients receiving 2.5 mg daily, use alternate-day dosing. Assess trough concentrations approximately 2 wk after any change in dose or after an initiation or change in coadministration of CYP3A4 and/or P-gp inducers or inhibitors.Renal transplantation Everolimus
Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients using appropriate assay methodology. The recommended everolimus therapeutic range is 3 to 8 ng/mL. Pay careful attention to clinical signs and symptoms, tissue biopsies, and laboratory parameters. It is important to monitor everolimus blood concentrations in patients with hepatic impairment during coadministration of CYP3A4 inducers or inhibitors, when switching cyclosporine formulations, and/or when cyclosporine dosing is reduced according to recommended target concentrations. Optimally, base dose adjustments of everolimus on trough concentrations obtained 4 or 5 days after a previous dosing change. There is an interaction between cyclosporine and everolimus, and, consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced.Cyclosporine
When given in a regimen with everolimus, reduce cyclosporine doses and the target range for whole blood trough concentrations to minimize the risk of nephrotoxicity. The recommended cyclosporine therapeutic ranges when administered with everolimus are 100 to 200 ng/mL through month 1 posttransplant, 75 to 150 ng/mL at mo 2 and 3 posttransplant, 50 to 100 ng/mL at mo 4 posttransplant, and 25 to 50 ng/mL from mo 6 through 12 posttransplant. The median trough concentrations observed in the clinical trial ranged between 161 and 185 ng/mL through month 1 posttransplant and between 111 and 140 ng/mL at mo 2 and 3 posttransplant. The median trough concentration was 99 ng/mL at mo 4 posttransplant and ranged between 46 and 75 ng/mL from mo 6 through 12 posttransplant. If impairment of renal function is progressive, adjust the treatment regimen. In renal transplant patients, base the cyclosporine dose on cyclosporine whole blood trough concentrations.
In renal transplantation, there are limited data regarding everolimus dosing with reduced cyclosporine trough concentrations of 25 to 50 ng/mL after 12 mo. Prior to dose reduction of cyclosporine, it should be ascertained that the steady-state everolimus whole blood trough concentration is at least 3 ng/mL. There is an interaction of cyclosporine on everolimus, and, consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced.
- Administer at the same time each day, either consistently with or without food. In patients receiving a renal transplant, administer everolimus consistently, approximately 12 h apart with or without food, to minimize variability in absorption; administer at the same time as cyclosporine.
- Do not chew or crush tablets.
- Afinitor : For patients unable to swallow tablets, everolimus tablets should be dispersed completely in a glass of water (containing approximately 30 mL) by gently stirring immediately prior to drinking. The glass should be rinsed with the same volume of water and the rinse should be completely swallowed to ensure that the entire dose is administered.
- In patients receiving a renal transplant, initiate oral prednisone once oral medication is tolerated. Steroid doses may be further tapered on an individualized basis depending on the clinical status of the patient and function of graft. Administer cyclosporine as oral capsules twice daily unless cyclosporine oral solution or IV administration of cyclosporine cannot be avoided. Initiate cyclosporine as soon as possible and no later than 48 h after reperfusion of the graft, and adjust the dose to target concentrations from day 5 onwards.
- Consider procedures for proper handling and disposal of anticancer drugs.
Store between 59° and 86°F. Protect from light and moisture. Store in the original container.
Drug InteractionsACE inhibitors (eg, captopril)
The risk of angioedema may be increased with coadministration of ACE inhibitors and everolimus. If an interaction is suspected, stop one or both drugs.Boceprevir, telaprevir
Everolimus plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. An everolimus dose reduction may be needed. Additional plasma concentration and clinical monitoring is warranted.Cyclosporine
Everolimus blood concentrations may be increased. Monitor everolimus concentrations and the clinical response of the patient when the cyclosporine dose is altered. Adjust the everolimus dose as needed.Digoxin
Everolimus blood concentrations may be increased. Use with caution.Efavirenz
Everolimus blood concentrations may be reduced, decreasing the efficacy. Closely monitor everolimus blood concentrations when efavirenz is started or stopped and adjust the everolimus dose as needed.Food
High-fat meals reduce the C max and AUC; however, everolimus may be taken without regard to meals.Grapefruit
Grapefruit or grapefruit juice may increase everolimus exposure. Advise patients taking everolimus to avoid grapefruit.Live vaccines (eg, intranasal influenza, rubella)
Avoid administration of live vaccines during treatment with everolimus.Lovastatin, simvastatin
The risk of adverse reactions (eg, rhabdomyolysis) may be increased. Coadministration of lovastatin or simvastatin with everolimus is discouraged. Coadministration of everolimus and atorvastatin (a CYP3A4 substrate) or pravastatin (a P-gp substrate) to healthy volunteers did not affect the pharmacokinetics of atorvastatin, pravastatin, or everolimus, or total HMG-CoA reductase bioreactivity in the plasma. However, these results cannot be extrapolated to other HMG-CoA reductase inhibitors.Moderate CYP3A4 and P-gp inhibitors (eg, aprepitant, diltiazem, fluconazole, fosamprenavir, macrolide antibiotics [eg, erythromycin], nicardipine, verapamil)
Moderate CYP3A4 inhibitors and P-gp inhibitors (eg, erythromycin, verapamil) increase everolimus C max and AUC by approximately 2- and 4-fold, respectively. If everolimus is coadministered with moderate inhibitors of CYP3A4 and P-gp, closely monitor everolimus blood concentrations and adjust the everolimus dose as needed.Nevirapine
Everolimus blood concentrations may be reduced, decreasing the efficacy. If nevirapine is coadministered, closely monitor everolimus blood concentrations when nevirapine is started or stopped and adjust the everolimus dose as needed.St. John's wort
Everolimus blood concentrations may be reduced, decreasing the efficacy. If coadministration of St. John's wort cannot be avoided, closely monitor everolimus blood concentrations when St. John's wort is started or stopped and adjust the everolimus dose as needed.Strong CYP3A4 and P-gp inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)
Ketoconazole, a strong CYP3A4 inhibitor and P-gp inhibitor, increases everolimus C max and AUC by 3.9- and 15-fold, respectively, and prolongs the half-life by 89%. Avoid coadministration of strong CYP3A4 inhibitors.Strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine)
Strong CYP3A4 inducers may reduce everolimus C max and AUC by approximately 60%. Avoid coadministration of strong CYP3A4 inducers.
Hypertension (13%); pleural effusion (7%); tachycardia (3%); CHF (1%).
Fatigue/malaise (45%); asthenia (33%); headache/migraine (30%); convulsion (29%); personality change (18%); dizziness, insomnia (14%); anxiety, fatigue, somnolence (7%); paresthesia (5%).
Rash (59%); dermatitis acneiform (25%); nail disorders (22%); pruritus (21%); body tinea, dry skin, skin infection (18%); contact dermatitis (14%); acne (11%); hand-foot syndrome (5%); erythema, onychoclasis, pityriasis rosea, skin lesion (4%).
Sinusitis (39%); otitis media (36%); epistaxis (22%); allergic rhinitis, nasal congestion, otitis externa (14%); oropharyngeal pain (11%); eyelid edema, ocular hyperemia, pharyngolaryngeal pain (4%); rhinorrhea (3%); conjunctivitis (2%).
Stomatitis (86%); diarrhea (50%); abdominal pain (36%); nausea (32%); decreased appetite (30%); vomiting (29%); anorexia (25%); dysgeusia (19%); gastroenteritis (18%); constipation, gastric infection (14%); dry mouth (11%); gastritis (7%); hemorrhoids (5%); dysphagia (4%); pancreatitis (postmarketing).
UTI (16%); proteinuria (7%); renal failure (3%); male infertility (postmarketing).
Decreased Hgb (92%); increased AST (89%); increased cholesterol (77%); increased fasting glucose (75%); increased alkaline phosphatase (74%); increased triglycerides (73%); increased glucose (57%); decreased bicarbonate (56%); decreased WBC (54%); decreased lymphocytes (51%); increased creatinine (50%); increased ALT (48%); decreased platelets (45%); decreased phosphate (40%); decreased calcium (37%); decreased glucose (32%); decreased neutrophils (30%); decreased potassium (23%); decreased sodium (16%); decreased albumin (13%); increased bilirubin (10%); increased potassium (7%).
Edema (general and peripheral) (39%); weight decrease (28%); diabetes mellitus (10%); exacerbation of preexisting diabetes mellitus (2%).
Arthralgia, back pain (15%); pain in extremity (14%); muscle spasms (10%).
Upper respiratory tract infection (82%); cough (30%); nasopharyngitis/rhinitis (25%); dyspnea (24%); pneumonitis (17%); pharyngitis (11%); pharyngeal inflammation (7%).
Infections and infestations (37%); pyrexia (32%); cellulitis (21%); mucosal inflammation (19%); excoriation (14%); chest pain (5%); abnormal chest x-ray, chills (4%); hemorrhage, jaw pain (3%); angioedema (postmarketing).
Increased susceptibility to infection and the possible development of malignancies, such as lymphoma and skin cancer, may result from immunosuppression.
Only health care providers experienced in immunosuppressive therapy and management of transplant patients should prescribe everolimus. Manage patients in facilities equipped and staffed with adequate laboratory and supportive medical resources.
In renal transplant patients, 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.
An increased risk of kidney arterial and venous thrombosis resulting in graft loss was reported, mostly within 30 days posttransplantation.
Increased mortality, often associated with serious infection, within the first 3 months posttransplantation was observed. Use in heart transplantation is not recommended.
Monitor everolimus and cyclosporine whole blood trough concentrations. Monitor renal function, including BUN or serum creatinine, CBC, fasting blood glucose, and lipid profile prior to therapy and periodically thereafter. When possible, achieve glucose and lipid control prior to starting therapy. Monitor patients for signs and symptoms of infection and proteinuria. Evaluate subependymal giant cell astrocytoma volume approximately 3 mo after starting therapy and periodically thereafter.
Category D ( Afinitor ); Category C ( Zortress ). May cause fetal harm.
Undetermined. Avoid breast-feeding.
Safety and efficacy not established in kidney transplant, advanced pancreatic neuroendocrine tumors, or advanced renal cell carcinoma patients younger than 18 y. Everolimus has not been studied in children with subependymal giant cell astrocytoma younger than 3 y.
Hypersensitivity reactions (eg, anaphylaxis, angioedema [eg, swelling of the airways or tongue with or without respiratory impairment], chest pain, dyspnea, flushing) have been observed.
Dosage reduction in patients with moderate hepatic impairment is recommended. Because use in patients with severe hepatic impairment has not been evaluated, avoid administration.
Special Risk Patients
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take everolimus.
An increased risk of kidney arterial and venous thrombosis resulting in graft loss has been reported, usually within 30 days posttransplantation.
Increased serum cholesterol and triglycerides have been reported.
Because everolimus has immunosuppressive properties, patients may be predisposed to infections, including opportunistic pathogens. Some have been severe (eg, leading to respiratory failure) or fatal.
Lymphomas and other malignancies
May occur, particularly of the skin.
Azoospermia or oligospermia may be observed.
Everolimus with standard-dose cyclosporine increases the risk of nephrotoxicity, resulting in a lower glomerular filtration rate. Reduced doses of cyclosporine are required.
May occur. Fatal outcomes have been observed. Consider the possibility in patients who present with symptoms consistent with infectious pneumonia (eg, hypoxia, pleural effusion, cough, dyspnea).
Mouth ulcers, oral mucositis, and stomatitis may occur.
Everolimus with cyclosporine in transplant patients has been associated with increased proteinuria.
Has occurred, some with fatal outcomes.
Would healing/fluid accumulation
Everolimus delays wound healing and increases the occurrence of wound-related complications. Generalized fluid accumulation, including peripheral edema, pericardial and pleural effusions, and ascites, may also occur.
Clinical experience is limited.
- Advise renal transplant patients to read the Medication Guide before starting therapy and with each refill.
- Warn patients of the possibility of developing noninfectious pneumonitis. Advise patients to report promptly any new or worsening respiratory symptoms.
- Inform patients that they may be more susceptible to infections and that cases of hepatitis B reactivation have been associated with everolimus therapy. Advise them to promptly report any such signs or symptoms to their health care provider.
- Inform patients of the possibility of developing mouth ulcers, stomatitis, and oral mucositis. In such cases, mouthwashes and/or topical treatments are recommended, but these should not contain alcohol or peroxide.
- Inform patients of the possibility of developing kidney failure.
- Inform patients of the need to monitor blood chemistry and hematology prior to the start of therapy and periodically thereafter.
- Advise patients to inform their health care providers of all concomitant medications, including nonprescription medications and dietary supplements. Some medications can increase or decrease the blood concentrations of everolimus.
- Advise women of childbearing potential that everolimus may cause fetal harm and to use an effective method of contraception during therapy with everolimus and for 8 wk after ending treatment.
- Inform patients to take everolimus at the same time every day, either consistently with or without food.
- Advise patients not to crush or chew the tablets and to not take tablets that are crushed or broken.
- Instruct patients that if they miss a dose, they may still take it up to 6 h after the time they would normally take it. If more than 6 h have elapsed, instruct them to skip the dose for that day. The next day, they should take everolimus at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.
- Inform patients to avoid grapefruit and grapefruit juice.
- Advise patients to avoid live vaccines and close contact with those who have received live vaccines.
- Advise patients to limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protection factor.
- Inform renal transplant patients that everolimus has been associated with an increased risk of kidney arterial and venous thrombosis, resulting in graft loss, usually within 30 days posttransplantation.
- Inform renal transplant patients that impaired or delayed wound healing and fluid accumulation may occur, and that the need for careful observation of their incision site may be necessary.
- Inform patients that use has been associated with increased serum cholesterol and triglycerides, which may require treatment and monitoring of blood lipid concentrations.
- Inform patients that use has been associated with an increased risk of proteinuria and diabetes mellitus.
- Inform patients that use may increase the risk of diabetes mellitus and to contact their health care provider if they develop symptoms.
- Advise patients not to take everolimus if they have hereditary disorders of galactose intolerance (Lapp lactase deficiency or glucose-galactose malabsorption).
Copyright © 2009 Wolters Kluwer Health.
More Everolimus resources
- Everolimus Monograph (AHFS DI)
- everolimus Advanced Consumer (Micromedex) - Includes Dosage Information
- everolimus MedFacts Consumer Leaflet (Wolters Kluwer)
- Afinitor Consumer Overview
- Afinitor Prescribing Information (FDA)
- Zortress Prescribing Information (FDA)
- Zortress MedFacts Consumer Leaflet (Wolters Kluwer)
- Zortress Consumer Overview