Brand names: Afinitor, Afinitor Disperz, Zortress
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- mTOR Inhibitors
ATC class: L04AA10
VA class: AN900
Chemical name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-Dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone
Molecular formula: C53H83NO14
CAS number: 159351-69-6
Warning
- Malignancies and Serious Infections
-
Only clinicians experienced in immunosuppressive therapy and management of transplant patients should prescribe everolimus (i.e., Zortress).
-
Patients should be managed in facilities with adequate laboratory and supportive medical resources; the clinician responsible for maintenance therapy should have complete information for patient follow-up.
-
Immunosuppression may result in increased susceptibility to infection and possible development of malignancies (e.g., lymphoma, skin cancer). (See Malignancies and Serious Infections under Cautions.)
- Kidney Graft Thrombosis
-
Increased risk of kidney arterial and venous thrombosis, resulting in graft loss; occurs principally within the first 30 days posttransplantation.
- Nephrotoxicity
-
Risk of nephrotoxicity may be increased with concomitant use of standard dosages of cyclosporine and everolimus. Reduce dosage of cyclosporine when used in combination with everolimus; monitor cyclosporine and everolimus whole blood trough concentrations. (See Renal Allotransplantation under Dosage and Administration and also see Nephrotoxicity under Cautions).
- Mortality in Cardiac Transplantation
-
Increased mortality, often associated with serious infections, observed within the first 3 months after transplantation in patients receiving everolimus in an immunosuppressive regimen with or without induction therapy in a clinical trial of de novo cardiac transplant patients; use of everolimus in cardiac transplantation is not recommended.
Introduction
Antineoplastic and macrolide immunosuppressive agent; inhibitor of mammalian target of rapamycin (mTOR) kinase.
Uses for Everolimus
Breast Cancer
Treatment (in combination with exemestane) of advanced hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer in postmenopausal women following failure of letrozole or anastrozole therapy.
Improves progression-free survival; effects on overall survival remain to be established.
Neuroendocrine Tumors of Pancreatic Origin (PNET)
Treatment of PNET in adults with unresectable, locally advanced, or metastatic disease (designated an orphan drug by FDA for this use).
Safety and efficacy not established in patients with carcinoid tumors† [off-label].
Improves progression-free survival; effects on overall survival remain to be established.
Renal Cell Carcinoma
Treatment of advanced renal cell carcinoma in adults following failure of sunitinib and/or sorafenib therapy.
Improves median progression-free survival; no substantial difference in overall survival between everolimus and placebo has been demonstrated.
Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC)
Treatment of renal angiomyolipoma with TSC, not requiring immediate surgery, in adults (designated an orphan drug by FDA for this use).
Improved renal angiomyolipoma response rate and skin lesion response rate in patients treated for a median of 8.3 months.
Subependymal Giant Cell Astrocytoma (SEGA) with TSC
Treatment of SEGA with TSC in patients ≥1 year of age when SEGA requires therapeutic intervention but cannot be curatively resected (designated an orphan drug by FDA for this use).
Reduces SEGA tumor volume; improvement in disease-related symptoms and overall survival has not been demonstrated.
Renal Allotransplantation
Prevention of rejection of renal allografts in adults with low to moderate immunologic risk. Used with basiliximab induction therapy and concurrent corticosteroids and reduced dosages of cyclosporine.
Therapeutic drug monitoring of everolimus and cyclosporine recommended for all patients.
Safety and efficacy not established in renal transplant recipients with high immunologic risk or in recipients of transplanted organs other than kidney and liver.
Hepatic Allotransplantation
Prevention of rejection of hepatic allografts in adults. Used ≥30 days posttransplant concurrently with tacrolimus (in reduced dosages) and corticosteroids.
Therapeutic drug monitoring of everolimus and tacrolimus recommended for all patients.
Safety and efficacy not established in recipients of transplanted organs other than kidney and liver.
Everolimus Dosage and Administration
General
Therapeutic Drug Monitoring in Patients with SEGA and TSC
-
The manufacturer recommends routine monitoring of whole blood trough everolimus concentrations for all patients. Use the same assay and laboratory when possible.
-
Measure trough concentrations approximately 2 weeks after initiation of everolimus treatment, any change in everolimus dosage, any change in concomitant treatment with inducers or inhibitors of CYP3A4 and/or P-glycoprotein, a change in hepatic function, or a change in dosage form between everolimus tablets (Afinitor) and everolimus tablets for oral suspension (Afinitor Disperz).
Therapeutic Drug Monitoring in Renal Allotransplantation Patients
-
The manufacturer recommends monitoring of blood everolimus and cyclosporine concentrations for all patients. Standard dosages of cyclosporine in combination with everolimus are associated with an increased risk of nephrotoxicity and should not be used.(See Boxed Warning and also see Nephrotoxicity under Cautions).
-
Carefully monitor clinical signs and symptoms, tissue biopsies, and laboratory parameters.
-
Carefully monitor blood everolimus concentrations in patients with hepatic impairment, patients receiving concomitant inducers or inhibitors of CYP3A4, when switching cyclosporine formulations, and/or when cyclosporine dosages are reduced according to recommended target concentrations.
Therapeutic Drug Monitoring in Hepatic Allotransplantation Patients
-
The manufacturer recommends monitoring of blood everolimus and tacrolimus concentrations for all patients.
-
Carefully monitor clinical signs and symptoms, tissue biopsies, and laboratory parameters.
-
Carefully monitor blood everolimus concentrations in patients with hepatic impairment and/or in patients receiving concomitant inducers or inhibitors of CYP3A4.
-
Cyclosporine not used in combination with everolimus in patients with hepatic transplant.
Administration
Oral Administration
Administer everolimus at the same time every day (or approximately 12 hours apart when given twice daily), either consistently with food or consistently without food.
Available as tablets (Afinitor, Zortress) and as tablets for oral suspension (Afinitor Disperz). Afinitor Disperz is recommended only for treatment of SEGA with TSC. Do not combine everolimus tablets (Afinitor) and everolimus tablets for oral suspension (Afinitor Disperz) to achieve the desired dose; use only one dosage form.
Tablets
Administer everolimus tablets (Afinitor, Zortress) orally once or twice daily.
In patients with renal or hepatic allografts, administer twice daily at the same time as cyclosporine or tacrolimus, respectively.
Swallow everolimus tablets whole with a glass of water; do not chew or crush.
Tablets for Oral Suspension
Administer everolimus tablets for oral suspension (Afinitor Disperz) once daily.
For administration using an oral syringe, place the prescribed dose (≤10 mg) in a 10-mL syringe; do not crush or break tablets. Draw approximately 5 mL of water and 4 mL of air into syringe; place syringe containing mixture in a container (tip up) for 3 minutes, until tablets are in suspension. Gently invert the syringe 5 times immediately prior to administration. Following administration, refill the syringe with 5 mL of water and 4 mL of air, swirl to suspend remaining particles, and administer entire contents of syringe. Prepare an additional syringe if a dose of >10 mg is required.
For administration using a small drinking glass, place the prescribed dose (≤10 mg) in a glass (size ≤100 mL) containing approximately 25 mL of water; do not crush or break tablets. Allow mixture to suspend for 3 minutes. Gently stir the mixture with a spoon immediately prior to administration. Following administration, add 25 mL of water to the glass and stir with the same spoon to resuspend the remaining particles, and swallow entire contents of the glass. Prepare an additional glass if a dose of >10 mg is required.
Dosage
Pediatric Patients
SEGA with TSC
Initial Dosage
Oral4.5 mg/m2 once daily.
Not studied in patients <1 year of age.
Round dosage to the nearest strength of either everolimus tablets (Afinitor) or everolimus tablets for oral suspension (Afinitor Disperz). Subsequent dosing should be guided by therapeutic drug monitoring.
Continue therapy until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is not known.
Therapeutic Drug Monitoring and Dosage Adjustments in SEGA with TSC
OralAdjust dosage at 2-week intervals as needed to achieve and maintain trough blood everolimus concentrations of 5–15 ng/mL.
Higher trough concentrations may be associated with larger reductions in SEGA volume; however, responses have been observed at trough concentrations as low as 5 ng/mL, and additional dosage increases may not be necessary once acceptable efficacy has been achieved.
Patients with trough concentrations <5 ng/mL: Increase daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).
Patients with trough concentrations >15 ng/mL: Reduce daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).
If dosage reduction is required in patients receiving 2.5 mg (as Afinitor) or 2 mg (as Afinitor Disperz) daily, use alternate-day dosing.
Once a stable dosage is attained, monitor trough concentrations every 3–6 months in patients with changing body surface area and every 6–12 months in patients with stable body surface area for the duration of treatment.
Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderate inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein. (See Specific Drugs and Foods under Interactions).
Adults
Breast Cancer
Oral
10 mg once daily.
Continue therapy until disease progression or unacceptable toxicity occurs.
Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein. (See Specific Drugs and Foods under Interactions).
Neuroendocrine Tumors of Pancreatic Origin
Oral
10 mg once daily.
Continue therapy until disease progression or unacceptable toxicity occurs.
Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein. (See Specific Drugs and Foods under Interactions).
Renal Cell Carcinoma
Oral
10 mg once daily.
Continue therapy until disease progression or unacceptable toxicity occurs.
Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein. (See Specific Drugs and Foods under Interactions).
Renal Angiomyolipoma with TSC
Oral
10 mg once daily.
Continue therapy until disease progression or unacceptable toxicity occurs.
Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein. (See Specific Drugs and Foods under Interactions).
SEGA with TSC
Initial Dosage
Oral4.5 mg/m2 once daily.
Round dosage to the nearest strength of either everolimus tablets (Afinitor) or everolimus tablets for oral suspension (Afinitor Disperz). Subsequent dosing should be guided by therapeutic drug monitoring.
Continue therapy until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is not known.
Therapeutic Drug Monitoring and Dosage Adjustments in SEGA with TSC
OralAdjust dosage at 2-week intervals as needed to achieve and maintain trough blood everolimus concentrations of 5–15 ng/mL.
Higher trough concentrations may be associated with larger reductions in SEGA volume; however, responses have been observed at trough concentrations as low as 5 ng/mL, and additional dosage increases may not be necessary once acceptable efficacy has been achieved.
Patients with trough concentrations <5 ng/mL: Increase daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).
Patients with trough concentrations >15 ng/mL: Reduce daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).
If dosage reduction is required in patients receiving 2.5 mg (as Afinitor) or 2 mg (as Afinitor Disperz) daily, use alternate-day dosing.
Once a stable dosage is attained, monitor trough concentrations every 3–6 months in patients with changing body surface area and every 6–12 months in patients with stable body surface area for the duration of treatment.
Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderate inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein. (See Specific Drugs and Foods under Interactions).
Renal Allotransplantation
Initial Dosage
OralInitially, 0.75 mg twice daily, initiated as soon as possible following transplantation; used with basiliximab induction therapy and in combination with reduced-dosage cyclosporine and corticosteroids.
Administer oral prednisone once oral medications are tolerated. May taper corticosteroid dosage on an individualized basis based on patient’s clinical status and allograft function.
Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus in Renal Allotransplantation
OralAdjust dosage based on trough blood everolimus concentrations, tolerability, individual response, change in concomitant drug therapy, and clinical situation. (See Interactions). May adjust maintenance dosage based on trough everolimus concentrations obtained 4–5 days after a previous dosage change in either everolimus or cyclosporine.
Titrate dosage to attain therapeutic trough everolimus concentrations of 3–8 ng/mL. In clinical trials, whole blood trough concentrations ≥3 ng/mL were associated with a lower incidence of treated biopsy-proven acute rejection. Similar efficacy and more adverse effects observed in patients with trough everolimus concentrations of 6–12 ng/mL compared with patients with trough concentrations of 3–8 ng/mL.
Recommended therapeutic range of 3–8 ng/mL is based on a liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay method. May measure concentrations by chromatographic or immunoassay methodologies; however, the measured concentrations depend on the type of assay used, and individual patient sample concentration values from different assay methodologies may not be interchangeable. Consider assay results with knowledge of the specific assay used. Maintaining communication with the laboratory performing the assay is essential.
Therapeutic Drug Monitoring and Dosage Adjustment of Cyclosporine with Everolimus in Renal Allotransplantation
OralReduce cyclosporine dosage and target therapeutic range when used in combination with everolimus to minimize risk of nephrotoxicity. (See Nephrotoxicity under Cautions.)
Adjust cyclosporine dosage based on whole blood trough concentrations. The recommended therapeutic ranges for cyclosporine are 100–200 ng/mL through month 1 posttransplant, 75–150 ng/mL at months 2 and 3, 50–100 ng/mL at month 4, and 25–50 ng/mL from month 6 through month 12.
Administer cyclosporine (USP modified) as oral capsules twice daily unless administration of oral solution or IV cyclosporine cannot be avoided. Everolimus has not been evaluated in clinical trials with other formulations of cyclosporine.
Initiate cyclosporine as soon as possible and no later than 48 hours after reperfusion of the graft, and adjust the dosage to target concentrations from day 5 onward. Adjust the treatment regimen if progressive impairment of renal function occurs.
Data regarding everolimus dosages with reduced trough cyclosporine concentrations of 25–50 ng/mL after 12 months are limited.
Prior to dosage reduction of cyclosporine, verify steady-state whole blood trough everolimus concentrations of ≥3 ng/mL. Everolimus concentrations may decrease if cyclosporine exposure is reduced.
Hepatic Allotransplantation
Initial Dosage
OralInitially, 1 mg twice daily, initiated ≥30 days following transplantation; used in combination with reduced-dosage tacrolimus and corticosteroids.
May taper corticosteroid dosage on an individualized basis based on patient’s clinical status and allograft function.
Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus in Hepatic Allotransplantation
OralAdjust dosage based on trough blood everolimus concentrations, tolerability, individual response, change in concomitant drug therapy, and clinical situation. (See Interactions.) May adjust maintenance dosage based on trough everolimus concentrations obtained 4–5 days after a previous dosage change.
Titrate dosage to attain therapeutic trough everolimus concentrations of 3–8 ng/mL. In clinical trials, whole blood trough concentrations ≥3 ng/mL were associated with a lower incidence of treated biopsy-proven acute rejection. Similar efficacy and more adverse effects observed in patients with trough everolimus concentrations of 6–12 ng/mL compared with patients with trough concentrations of 3–8 ng/mL.
Therapeutic Drug Monitoring and Dosage Adjustment of Tacrolimus with Everolimus in Hepatic Allotransplantation
OralReduce tacrolimus dosage and target therapeutic range when used in combination with everolimus to minimize risk of nephrotoxicity. (See Nephrotoxicity under Cautions.)
Adjust tacrolimus dosage based on whole blood trough concentrations. Recommended therapeutic range for tacrolimus is 3–5 ng/mL by 3 weeks after the first dose of everolimus (approximately month 2 posttransplant) through month 12 posttransplant.
Administer tacrolimus as oral capsules twice daily unless administration of IV tacrolimus cannot be avoided.
Data regarding everolimus dosages with reduced trough tacrolimus concentrations of 3–5 ng/mL after 12 months are limited. Prior to dosage reduction of tacrolimus, verify steady-state whole blood trough everolimus concentrations of ≥3 ng/mL.
Tacrolimus does not affect everolimus concentrations.
Dosage Modification for Toxicity
Adjustment of everolimus dosage and/or interruption of therapy may be required according to toxicity. The suggested dosage is approximately 50% lower than the previously administered daily dosage, if dosage reduction is required.
Noninfectious Pneumonitis
In patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.
Toxicity Grade |
Number of Appearances |
Comments |
---|---|---|
Grade 1 (asymptomatic, radiographic findings only) |
Any appearance |
No dosage adjustment necessary; monitor appropriately |
Grade 2 (symptomatic, not interfering with activities of daily living) |
1st appearance |
Consider interrupting therapy until symptoms improve to grade 1 or less and initiating corticosteroids, then resume everolimus at lower daily dosage; discontinue therapy if failure to recover within 4 weeks |
Grade 3 (symptomatic, interfering with activities of daily living, oxygen indicated) |
1st appearance |
Interrupt therapy until resolved to grade 1 or less, then may resume at lower daily dosage; rule out infection and consider initiating corticosteroids |
2nd appearance |
Consider therapy discontinuance |
|
Grade 4 (life-threatening, ventilatory support indicated) |
1st appearance |
Discontinue therapy permanently, rule out infection, and consider initiating corticosteroids |
Stomatitis
In patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.
Toxicity Grade |
Number of Appearances |
Comments |
---|---|---|
Grade 1 (minimal symptoms, normal diet) |
Any appearance |
Continue therapy without dosage adjustment |
Grade 2 (symptomatic, can eat and swallow modified diet) |
1st appearance |
Interrupt therapy until resolved to grade 0–1, then resume at original daily dosage |
2nd appearance |
Interrupt therapy until resolved to grade 0–1, then resume at lower daily dosage |
|
Grade 3 (symptomatic, unable to adequately aliment or hydrate orally) |
1st appearance |
Interrupt therapy until resolved to grade 0–1, then resume at lower daily dosage |
Grade 4 (symptoms associated with life-threatening consequences) |
1st appearance |
Discontinue therapy permanently |
Other Nonhematologic Toxicity
Excluding metabolic events; in patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.
Toxicity Grade |
Number of Appearances |
Comments |
---|---|---|
Grade 1 (mild symptoms) |
Any appearance |
If toxicity is tolerable, continue therapy without dosage adjustment |
Grade 2 (moderate symptoms) |
1st appearance |
If toxicity is tolerable, continue therapy without dosage adjustment. If toxicity is intolerable, interrupt therapy until resolved to grade 0–1, then resume at original dosage |
2nd appearance |
Interrupt therapy until resolved to grade 0–1, then resume at lower dosage |
|
Grade 3 (severe symptoms) |
1st appearance |
Interrupt therapy until resolved to grade 0–1, then consider reinitiating therapy at lower dosage |
2nd appearance |
Consider therapy discontinuance |
|
Grade 4 (life-threatening symptoms) |
1st appearance |
Discontinue therapy permanently |
Metabolic Events
Metabolic events include hyperglycemia and dyslipidemia; in patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.
Toxicity Grade |
Number of Appearances |
Comments |
---|---|---|
Grade 1 (mild symptoms) |
Any appearance |
Continue therapy without dosage adjustment |
Grade 2 (moderate symptoms) |
Any appearance |
Continue therapy without dosage adjustment |
Grade 3 (severe symptoms) |
1st appearance |
Interrupt therapy temporarily, then resume at lower dosage |
Grade 4 (life-threatening symptoms) |
1st appearance |
Discontinue therapy permanently |
Special Populations
Hepatic Impairment
Breast Cancer, Neuroendocrine Tumors of Pancreatic Origin, Renal Cell Carcinoma, or Renal Angiomyolipoma with TSC
Oral
Mild (Child-Pugh class A) hepatic impairment: 7.5 mg daily; may decrease dosage to 5 mg daily if not well tolerated.
Moderate (Child-Pugh class B) hepatic impairment: 5 mg daily; may decrease dosage to 2.5 mg daily if not well tolerated.
Severe (Child-Pugh class C) hepatic impairment: If potential benefit outweighs risk, may use maximum dosage of 2.5 mg daily.
If hepatic status changes during treatment, adjust dosage accordingly.
SEGA with TSC
Oral
Mild or moderate (Child-Pugh class A or B) hepatic impairment: Adjustment of initial dosage may not be necessary; base subsequent dosage on therapeutic drug monitoring.
Severe (Child-Pugh class C) hepatic impairment: Decrease initial dosage by approximately 50%; base subsequent dosage on therapeutic drug monitoring.
Renal or Hepatic Allotransplantation
Oral
Mild (Child-Pugh class A) hepatic impairment: Decrease initial dosage by approximately 33%; adjust subsequent dosage to attain trough concentrations of 3–8 ng/mL.
Moderate or severe (Child-Pugh class B or C) hepatic impairment: Decrease initial dosage by approximately 50%; adjust subsequent dosage to attain trough concentrations of 3–8 ng/mL.
Renal Impairment
Dosage adjustment not required.
Geriatric Patients
Dosage adjustment not required. Close monitoring and appropriate dosage adjustments for adverse effects are recommended for Afinitor and Afinitor Disperz.
Cautions for Everolimus
Contraindications
-
Known hypersensitivity to everolimus, other rapamycin derivatives (e.g., sirolimus, temsirolimus), or any ingredient in the formulations.
Warnings/Precautions
Warnings
Malignancies and Serious Infections
Immunosuppressants, including everolimus, can increase susceptibility to infection (bacterial, fungal, viral, or protozoal infections, including opportunistic infections). Severe or fatal localized and systemic infections (e.g., pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections [e.g., aspergillosis, candidiasis], viral infections including HBV reactivation) reported.
Antimicrobial prophylaxis for Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia and cytomegalovirus (CMV) is recommended in transplant recipients.
Monitor vigilantly for signs and symptoms of infection and institute appropriate treatment if infection develops; consider interruption or discontinuance of everolimus therapy.
If invasive systemic fungal infection occurs, discontinue everolimus and initiate appropriate antifungal therapy. Complete treatment of a preexisting invasive fungal infection prior to initiating everolimus therapy.
The manufacturer of everolimus (Zortress) states that the drug should be used only by clinicians experienced in immunosuppressive therapy and the management of transplant patients. (See Boxed Warning.)
Immunosuppressants, including everolimus, may increase risk of development of lymphomas or other malignancies, particularly of the skin. Risk appears to be related to intensity and duration of immunosuppression rather than to the use of any specific drug. (See Advice to Patients.)
Kidney Graft Thrombosis
Increased risk of kidney arterial and venous thrombosis, resulting in kidney graft loss; occurs primarily within the first 30 days after renal transplantation.
Nephrotoxicity
Increased risk of nephrotoxicity when used concurrently with standard cyclosporine dosages; use reduced cyclosporine dosages. (See Specific Drugs and Foods under Interactions.)
Increases in Scr and proteinuria reported in patients receiving everolimus (Afinitor). Cases of renal failure (including acute renal failure), some with fatal outcome, also observed. Monitor renal function (including BUN, urinary proteins, and/or Scr) prior to and periodically during therapy.
Not studied with standard tacrolimus dosages in hepatic transplant recipients; use in combination with reduced-dosage tacrolimus to minimize potential risk of nephrotoxicity.
Monitor renal function in all transplant patients. Consider switching to other immunosuppressive therapies if renal function does not improve after dosage adjustments or if renal dysfunction is thought to be drug related.
Increased risk of proteinuria reported in transplant patients receiving everolimus (Zortress); higher risk observed in patients with higher whole blood trough concentrations of the drug. Monitor transplant patients for proteinuria.
Increased Mortality in Cardiac Transplantation
Increased mortality within the first 3 months posttransplantation observed in de novo cardiac transplant patients receiving everolimus (Zortress) in an immunosuppressive regimen with or without induction therapy in a clinical trial; use not recommended in cardiac transplantation.
Sensitivity Reactions
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, dyspnea, flushing, chest pain, and/or angioedema, reported with everolimus and other rapamycin derivatives. (See Angioedema under Cautions.)
Other Warnings/Precautions
Interstitial Lung Disease/Noninfectious Pneumonitis
Potentially severe or fatal noninfectious pneumonitis reported.
Consider diagnosis of noninfectious pneumonitis in patients presenting with nonspecific respiratory signs and symptoms (e.g., hypoxia, pleural effusion, cough, dyspnea) and in whom other causes (e.g., infection, cancer) have been excluded.
If moderate or severe symptoms of noninfectious pneumonitis develop, interruption or discontinuance of therapy and subsequent dosage reduction may be required. (See Dosage Modification for Toxicity under Dosage and Administration.)
In renal transplant patients, noninfectious pneumonitis may respond to interruption of everolimus therapy with or without glucocorticoid therapy.
Consider diagnosis of interstitial lung disease in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom other causes (e.g., infection, cancer, other non-drug causes) have been excluded. In renal or hepatic transplant patients, interstitial lung disease generally resolves following interruption of everolimus therapy with or without glucocorticoid therapy; however, fatal cases reported.
Oral Ulceration
Mouth ulcers, stomatitis, and oral mucositis, mostly grade 1 and 2, reported.
Topical therapy recommended if oral ulceration occurs. Manage grade 1 stomatitis with non-alcoholic or salt water (0.9%) mouthwash several times daily. Manage grade 2 and 3 stomatitis with topical analgesic mouth treatments with or without topical corticosteroids.
Avoid alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes because they may exacerbate the condition.
Do not use antifungal agents unless fungal infection has been diagnosed. (See Specific Drugs and Foods under Interactions.)
Depending on severity, interruption of therapy, dosage reduction, and/or drug discontinuance may be required. (See Dosage Modification for Toxicity under Dosage and Administration.)
Hepatic Artery Thrombosis (HAT)
mTOR inhibitors are associated with an increased risk of HAT. Most cases occurred within the first 30 days posttransplant and most resulted in graft loss or death. Do not administer everolimus earlier than 30 days after liver transplantation.
Polyoma Virus Infections
Increased risk of reactivation of latent viral infections, including polyoma virus infections. Polyoma virus infections in transplant recipients may be serious or fatal; these include polyoma virus-associated neuropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multiple leukoencephalopathy (PML). PVAN may result in deteriorating renal function and renal graft loss.
Monitoring transplant patients may help detect patients at risk of PVAN. Consider reduction in total immunosuppression in patients who develop evidence of PVAN or PML. Also consider risk that reduced immunosuppression represents to the functioning allograft.
Immunization
Avoid use of live vaccines and close contact with individuals who have received live vaccines.
Consider the timing of routine vaccinations in pediatric patients with SEGA who do not require immediate treatment before initiating everolimus therapy. Prior to initiation of everolimus therapy, complete the recommended childhood series of live virus vaccinations according to the US Public Health Service Advisory Committee on Immunization Practices (ACIP) guidelines. An accelerated vaccination schedule may be appropriate.
Angioedema
Angioedema reported with everolimus and other mTOR inhibitors. Concomitant use of other drugs known to cause angioedema (e.g., ACE inhibitors) may increase this risk. Monitor patients for possible symptoms; if angioedema occurs, treat promptly. (See Specific Drugs and Foods under Interactions.)
Delayed Wound Healing and Fluid Accumulation
Increased risk of delayed wound healing and increased incidence of wound-related complications, including wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma, reported; wound-related complications may require surgical treatment.
Generalized fluid accumulation, including peripheral edema (e.g., lymphedema), and other types of localized fluid accumulation (e.g., pericardial and pleural effusions, ascites) also reported.
Monitor patients for delayed wound healing and fluid accumulation; if present, treat promptly to minimize potential complications. (See Advice to Patients.)
Hyperglycemia and Diabetes Mellitus
Hyperglycemia reported. Monitor fasting glucose concentrations prior to and periodically during everolimus (Afinitor) therapy; when possible, achieve optimal glycemic control prior to initiation of everolimus.
Following transplantation, increased risk of developing new-onset diabetes mellitus reported. Closely monitor glucose concentrations in patients receiving everolimus (Zortress) following renal and hepatic allotransplantation.
Hyperlipidemia
Hyperlipidemia (e.g., hypercholesterolemia, hypertriglyceridemia), possibly requiring treatment, reported; increased risk in patients with higher whole blood trough everolimus concentrations.
Monitor fasting serum lipids prior to and periodically during everolimus (Afinitor, Zortress) therapy. When possible, achieve optimal lipid control prior to initiation of therapy. Treat patients who develop hyperlipidemia while receiving everolimus according to current standards of care.
Normalization of serum lipids with antihyperlipidemic agents may not be possible in patients receiving everolimus (Zortress). Consider the risk/benefit of everolimus therapy prior to initiating therapy in patients with baseline hyperlipidemia and of continued therapy in patients who develop severe refractory hyperlipidemia while receiving the drug. Safety and efficacy of everolimus in patients with baseline cholesterol concentrations >350 mg/dL not established.
Patients with Hereditary Disorders
Everolimus may cause diarrhea and malabsorption in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption; avoid use in such patients.
Hematologic Effects
Anemia, lymphopenia, neutropenia, and thrombocytopenia reported. Monitor CBC prior to and periodically during therapy.
Increased Risk of Thrombotic Microangiopathy (TMA)/Thrombotic Thrombocytopenic Purpura (TTP)/Hemolytic Uremic Syndrome (HUS)
Concurrent use of everolimus and cyclosporine may increase the risk of TMA/TTP/HUS. Monitor hematologic parameters in patients concurrently receiving everolimus and cyclosporine.
CYP3A4- and P-glycoprotein-mediated Interactions
Concomitant use of everolimus with certain drugs (e.g., moderate or potent inhibitors of CYP3A4, potent inducers of CYP3A4, moderate inhibitors of P-glycoprotein) or foods (e.g., grapefruit juice) is not recommended or requires close monitoring of whole blood trough everolimus concentrations and/or adjustment of everolimus dosage. (See Interactions.)
Fetal/Neonatal Morbidity and Mortality
Can cause fetal harm; teratogenicity and embryolethality demonstrated in animals. No adequate and well-controlled studies in humans.
Women of childbearing potential should use a highly effective method of contraception during and for up to 8 weeks following discontinuance of everolimus.
If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
Impairment of Male Fertility
Possible impairment of male fertility (decreased fertility observed in male rats); azoospermia or oligospermia may be observed.
Adequate Patient Evaluation and Monitoring
Monitor fasting glucose and lipid profiles, CBC, and renal function tests prior to and periodically during therapy.
Specific Populations
Pregnancy
Afinitor and Afinitor Disperz: Category D. Women of childbearing potential should use highly effective contraception during and for up to 8 weeks after discontinuance of therapy.
Zortress: Category C. Women of childbearing potential should use effective contraception during and for up to 8 weeks after discontinuance of therapy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
National Transplantation Pregnancy Registry (NTPR) at 877-955-6877 or [Web].
Lactation
Everolimus and/or its metabolites distribute into milk in rats; not known whether distributed into human milk.
Patients with breast cancer, PNET, renal angiomyolipoma, renal cell carcinoma, or SEGA: Discontinue nursing or the drug.
Renal and hepatic transplant patients: Avoid breast-feeding.
Pediatric Use
Safety and efficacy for treatment of SEGA with TSC have been evaluated in pediatric patients ≥1 year of age. Safety and efficacy not established in children <1 year of age with SEGA and TSC. Safety and efficacy for treatment of renal angiomyolipoma with TSC in the absence of SEGA not established in pediatric patients.
Safety and efficacy for prevention of renal or hepatic allograft rejection not established in pediatric patients <18 years of age.
In pediatric patients with SEGA not requiring immediate therapy, complete recommended childhood series of live virus vaccinations prior to initiating everolimus therapy; accelerated vaccination schedule may be appropriate. (See Immunization under Cautions.)
Long-term effects on growth and pubertal development not known.
Geriatric Use
Patients with advanced hormone receptor-positive, HER2-negative breast cancer, advanced renal cell carcinoma, or advanced PNET: No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. (See Geriatric Patients under Dosage and Administration.)
Transplant recipients: Limited clinical experience with use of everolimus following transplantation in patients ≥65 years of age.
Hepatic Impairment
Patients with breast cancer, PNET, advanced renal carcinoma, or renal angiomyolipoma, or renal or hepatic allograft recipients: Dosage adjustment recommended in those with mild, moderate, or severe (Child-Pugh class A, B, or C) hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)
Patients with SEGA: Adjustment of initial dosage may not be required in those with mild or moderate (Child-Pugh class A or B) hepatic impairment; however, individualize subsequent dosage based on therapeutic drug monitoring. Initial dosage adjustment recommended for those with severe (Child-Pugh class C) hepatic impairment; individualize subsequent dosage based on therapeutic drug monitoring. (See Hepatic Impairment under Dosage and Administration.)
Renal Impairment
Safety and efficacy in patients with renal impairment not studied specifically to date. (See Renal Impairment under Dosage and Administration and also see Elimination: Special Populations under Pharmacokinetics.)
Common Adverse Effects
In patients with advanced HER2-negative breast cancer: Stomatitis (e.g., mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, lip ulceration), infections, rash, fatigue or asthenia, diarrhea, decreased appetite, nausea, weight loss, cough, dysgeusia, headache, dyspnea, arthralgia, peripheral edema, pneumonitis (e.g., interstitial lung disease, lung infiltration, pulmonary fibrosis), epistaxis, vomiting, pyrexia, back pain, constipation, pruritus, insomnia, dry mouth, alopecia, hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, hypertriglyceridemia, decreased albumin, neutropenia, hypokalemia, increased Scr.
In patients with advanced PNET: Stomatitis, rash, diarrhea, fatigue/malaise, edema (peripheral or generalized), abdominal pain, fever, headache/migraine, decreased appetite, vomiting, weight loss, nasopharyngitis/rhinitis/upper respiratory tract infection, cough, nail disorders, epistaxis, pruritus, dyspnea, dysgeusia, pneumonitis, urinary tract infection, arthralgia, back pain, pain in extremity, insomnia, constipation, dry skin, hypertension, dizziness, dry mouth, oropharyngeal pain, diabetes mellitus, muscle spasms, anemia, increased alkaline phosphatase, hyperglycemia, hypercholesterolemia, decreased bicarbonate, increased AST, increased ALT, lymphopenia, thrombocytopenia, leukopenia, hypophosphatemia, hypertriglyceridemia, hypocalcemia, neutropenia, hypokalemia, increased Scr, hypoalbuminemia.
In patients with renal cell carcinoma: Stomatitis, infections, asthenia, fatigue, diarrhea, cough, rash, anemia, hypercholesterolemia, increased Scr, hypertriglyceridemia, hyperglycemia, lymphopenia.
In patients with renal angiomyolipoma with TSC: Stomatitis, hypercholesterolemia, acne, cough, vomiting, diarrhea, arthralgia, amenorrhea, peripheral edema, upper respiratory tract infection, anemia, hypertriglyceridemia.
In patients with SEGA with TSC: Stomatitis (e.g., mouth and lip ulceration), respiratory tract infection, elevated cholesterol, increased ALT and AST, elevated PTT, neutropenia, reduced hemoglobin, pyrexia, fatigue, vomiting, diarrhea, constipation, gastroenteritis, psychiatric disorders (e.g., anxiety, aggression, other behavioral disturbances), hyperglycemia, cellulitis, rash, acne, increased Scr, hypertriglyceridemia, pharyngitis.
In renal transplant patients: Infections, peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection, hyperlipidemia, diarrhea, pyrexia, headache, hyperkalemia, increased Scr, hypercholesterolemia, insomnia, incision site pain, upper respiratory tract infection, dyslipidemia, procedural pain, vomiting, abdominal pain, hypomagnesemia, hypophosphatemia, extremity pain, hematuria, hyperglycemia, hypokalemia, back pain, dysuria.
In hepatic transplant patients: Infections, diarrhea, headache, peripheral edema, hypertension, nausea, leukopenia, abdominal pain, pyrexia.
Interactions for Everolimus
Metabolized principally by CYP3A4; competitive inhibitor of CYP3A4 and mixed inhibitor of CYP2D6 in vitro. Also a substrate and moderate inhibitor of the efflux transporter P-glycoprotein (P-gp).
Drugs and Foods Affecting Hepatic Microsomal Enzymes
CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased peak plasma concentrations and AUC of everolimus). Avoid concomitant use with potent CYP3A4 inhibitors. Reduced everolimus dosage may be required in patients who require coadministration of a moderate CYP3A4 inhibitor.
CYP3A4 inducers: Potential pharmacokinetic interaction (decreased peak plasma concentrations and AUC of everolimus). Avoid concomitant use with potent CYP3A4 inducers; if concomitant use cannot be avoided, consider an increase in everolimus dosage.
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP3A4 and CYP2D6: Potential pharmacokinetic interaction (increased plasma substrate concentrations). Use with caution in patients receiving CYP3A4 or CYP2D6 substrates.
Drugs Affecting the P-Glycoprotein Transport System
Inhibitors of P-gp: Potential pharmacokinetic interaction (increased peak plasma concentrations and AUC of everolimus). Use with caution. Reduced everolimus dosage may be required.
Nephrotoxic Agents
Potential for increased risk of nephrotoxicity with concomitant cyclosporine therapy in renal transplant patients. Use other drugs known to impair renal function concomitantly with caution.
Specific Drugs and Foods
Drug or Food |
Interaction |
Comments |
---|---|---|
ACE inhibitors |
Possible increased risk of angioedema |
Consider use of alternative antihypertensive agents if necessary |
Anticonvulsants (carbamazepine, phenobarbital, phenytoin) |
Decreased plasma everolimus concentrations |
Breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma: Avoid concomitant use; if cannot avoid, increase everolimus dosage from 10 to 20 mg daily (titrated in 5-mg increments), based on pharmacokinetic data; if the anticonvulsant is discontinued, reduce everolimus dosage to previous level SEGA: Avoid concomitant use if alternative therapy is available; if cannot avoid, increase everolimus dosage twofold, assess trough concentrations in 2 weeks, and adjust dosage to maintain trough concentrations of 5–15 ng/mL; if the anticonvulsant is discontinued, reduce everolimus dosage to previous level and reassess trough everolimus concentrations in approximately 2 weeks |
Antifungals, azole (fluconazole, itraconazole, ketoconazole, voriconazole) |
Increased plasma everolimus concentrations |
Itraconazole, ketoconazole, voriconazole: Avoid concomitant use Fluconazole: Use concomitantly with caution Fluconazole in patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance. If fluconazole is discontinued, allow interval of 2–3 days before increasing everolimus dosage to the previous level Fluconazole in patients with SEGA: Reduce everolimus dosage by approximately 50%; administer every other day in patients receiving the lowest available strength. Assess trough everolimus concentrations approximately 2 weeks after dosage reduction. If fluconazole is discontinued, increase everolimus dosage to previous level and reassess trough everolimus concentration in approximately 2 weeks |
Antilipemic agents (HMG-CoA reductase inhibitors [statins], fibric acid derivatives) |
Pharmacokinetic interaction with atorvastatin, pravastatin, or simvastatin unlikely |
Renal or hepatic transplant patients: Monitor for rhabdomyolysis and other adverse effects associated with antilipemic therapy |
Antimycobacterials, rifamycins (rifabutin, rifampin, rifapentine) |
Decreased plasma everolimus concentrations |
Breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma: Avoid concomitant use, if cannot avoid, increase everolimus dosage from 10 to 20 mg daily (titrated in 5-mg increments) based on pharmacokinetic data; if the rifamycin is discontinued, reduce everolimus dosage to previous level SEGA: Avoid concomitant use if alternative therapy is available; if cannot avoid, increase everolimus dosage twofold, assess trough concentrations in 2 weeks, and adjust dosage to maintain trough concentrations of 5–15 ng/mL; if the rifamycin is discontinued, reduce everolimus dosage to previous level and reassess trough everolimus concentrations in approximately 2 weeks Renal or hepatic transplant patients: Concomitant use with rifampin or rifabutin not recommended |
Aprepitant |
Increased plasma everolimus concentrations |
Use concomitantly with caution Breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance. If aprepitant is discontinued, allow interval of 2–3 days before increasing everolimus dosage to previous level and reassess trough everolimus concentrations in approximately 2 weeks SEGA: Reduce everolimus dosage by approximately 50%; administer every other day in patients receiving the lowest available strength. Assess trough everolimus concentrations approximately 2 weeks after dosage reduction. If aprepitant is discontinued, increase everolimus dosage to the previous level and reassess trough everolimus concentration in approximately 2 weeks |
Calcium-channel blocking agents (diltiazem, verapamil) |
Increased plasma everolimus concentrations |
Use concomitantly with caution; if concomitant use required, reduced everolimus dosage may be necessary Breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance. If moderate CYP3A4 inhibitor (e.g., diltiazem, verapamil) is discontinued, allow interval of 2–3 days before increasing everolimus dosage to previous level SEGA: Reduce everolimus dosage by approximately 50%; administer every other day in patients receiving the lowest available strength. Assess trough everolimus concentrations approximately 2 weeks after dosage reduction. If moderate CYP3A4 inhibitor is discontinued, increase everolimus dosage to previous level and reassess trough everolimus concentration in approximately 2 weeks |
Cyclosporine |
Increased plasma concentrations of everolimus Increased risk of nephrotoxicity with concomitant use of everolimus and standard-dose cyclosporine Increased risk of proteinuria Possible increased risk of thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome |
Renal transplant patients: Use reduced-dose cyclosporine therapy to minimize risk of nephrotoxicity; monitor cyclosporine and everolimus concentrations in all patients Monitor renal function; consider alternative immunosuppressive therapies if renal function does not improve after dosage adjustments or if renal dysfunction is thought to be drug related Dosage adjustment of everolimus may be required if cyclosporine dosage is altered Monitor hematologic parameters and for proteinuria |
Exemestane |
Increased plasma exemestane concentrations; however, steady-state estradiol concentrations not altered and no increase in exemestane-related adverse effects observed |
|
Grapefruit or grapefruit juice |
Increased plasma everolimus concentrations |
Avoid concomitant use |
HCV protease inhibitors (boceprevir, telaprevir) |
Increased plasma everolimus concentrations |
Avoid concomitant use |
HIV protease inhibitors (atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir) |
Increased plasma everolimus concentrations |
Atazanavir, indinavir, nelfinavir, ritonavir, saquinavir: Avoid concomitant use Fosamprenavir: Use concomitantly with caution Fosamprenavir in patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance. If fosamprenavir is discontinued, allow interval of 2–3 days before increasing everolimus dosage to previous level Fosamprenavir in patients with SEGA: Reduce everolimus dosage by approximately 50%; administer every other day in patients receiving the lowest available strength. Assess trough everolimus concentrations approximately 2 weeks after dosage reduction. If fosamprenavir is discontinued, increase everolimus dosage to previous level and reassess trough everolimus concentration in approximately 2 weeks |
HMG CoA reductase inhibitors (statins) (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) |
Clinically important pharmacokinetic interactions with atorvastatin, pravastatin, or simvastatin unlikely; however, cannot extrapolate these results to other statins Use of statins such as lovastatin or simvastatin was strongly discouraged in clinical trials of everolimus with cyclosporine in renal transplant patients because of an adverse interaction with cyclosporine |
Atorvastatin or pravastatin: Dosage adjustments not necessary Monitor patients receiving everolimus, cyclosporine, and a statin for possible development of rhabdomyolysis and other adverse effects |
Immunosuppressive agents |
Increased risk of lymphoma and other malignancies and susceptibility to infection |
Use with caution |
Macrolide antibiotics (clarithromycin, erythromycin, telithromycin) |
Increased plasma everolimus concentrations |
Clarithromycin or telithromycin: Avoid concomitant use Erythromycin: Use concomitantly with caution Erythromycin in patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance. If erythromycin is discontinued, allow interval of 2–3 days before increasing everolimus dosage to previous level Erythromycin in patients with SEGA: Reduce everolimus dosage by approximately 50%; administer every other day in patients receiving the lowest available strength. Assess trough everolimus concentrations approximately 2 weeks after dose reduction. If erythromycin is discontinued, increase everolimus dosage to previous level and reassess trough everolimus concentration in approximately 2 weeks Erythromycin in transplant patients: Monitor everolimus concentration and adjust everolimus dosage as necessary |
Midazolam |
Increased peak plasma concentrations and AUC of midazolam; elimination half-life of midazolam and metabolic AUC ratio not affected |
Dosage adjustment of midazolam not necessary |
Nefazodone |
Increased plasma everolimus concentrations |
Avoid concomitant use |
Octreotide |
Long-acting parenteral formulation of octreotide acetate: trough plasma concentrations of octreotide increased by approximately 50% |
|
St. John’s wort (Hypericum perforatum) |
Unpredictable decreases in everolimus exposure |
Avoid concomitant use |
Tacrolimus |
Hepatic transplants: Everolimus not studied with standard-dosage tacrolimus Increased risk of nephrotoxicity with concomitant use of standard-dosage tacrolimus |
Hepatic transplant patients: Use reduced-dosage tacrolimus and reduce target therapeutic range for tacrolimus to minimize risk of nephrotoxicity; monitor tacrolimus and everolimus concentrations in all patients Everolimus dosage adjustment generally not necessary Monitor renal function; consider alternative immunosuppressive therapies if renal function does not improve after dosage adjustments or if renal dysfunction is thought to be drug related |
Vaccines |
Possible decreased immune response to vaccination |
Avoid use of live vaccines |
Everolimus Pharmacokinetics
Absorption
Bioavailability
Peak everolimus concentrations attained within 1–2 hours following oral administration of doses ranging from 5–70 mg in patients with advanced solid tumors.
Increases in peak plasma concentrations dose-proportional following single doses of 5–10 mg. Peak plasma concentrations and AUC also dose-proportional at steady state following oral dosages of 0.5–2 mg twice daily in renal allograft patients. Increases in peak plasma concentrations less than dose-proportional following single doses of ≥20 mg; considered unlikely to be clinically important. Increases in AUC dose-proportional over dosage range of 5–70 mg.
AUC of everolimus tablets for oral suspension (Afinitor Disperz) was equivalent to that of everolimus tablets (Afinitor); peak concentrations were 20–36% lower for everolimus tablets for oral suspension. Predicted trough concentrations at steady state were similar between these dosage forms following daily administration.
In patients with advanced solid tumors, steady-state concentrations achieved within 2 weeks of once-daily dosing. In renal allograft patients, steady-state concentrations achieved by day 4 with an accumulation in blood concentrations of twofold to threefold compared with exposure following the first dose.
In patients with SEGA and TSC, everolimus trough concentrations were dose-proportional at daily dosages of 1.35–14.4 mg/m2.
Food
Administration of 10-mg tablet with a high-fat meal in healthy individuals reduced peak plasma concentrations and AUC of everolimus by 54 and 22%, respectively; light fat meals reduced peak plasma concentrations and AUC of everolimus by 42 and 32%, respectively. However, food had no apparent effect on the postabsorption phase concentration-time profile.
Special Populations
Mild, moderate, and severe hepatic impairment increased AUC by 1.6-, 3.2-, and 3.6-fold, respectively, in a single-dose study. In another study, average AUC in individuals with moderate hepatic impairment was twice that found in those with normal hepatic function.
Distribution
Extent
Crosses the placenta. Everolimus and/or its metabolites readily distributed into milk in rats at a concentration 3.5 times higher than in maternal serum.
Plasma Protein Binding
Approximately 74%.
Special Populations
Moderate hepatic impairment does not alter plasma protein binding.
Elimination
Metabolism
Metabolized by CYP3A4 to inactive metabolites; also a substrate for P-glycoprotein.
Elimination Route
Excreted in feces (80%) and urine (5%) as inactive metabolites.
Half-life
Approximately 30 hours.
Special Populations
No significant correlation between Clcr (range: 25–178 mL/minute) and everolimus clearance; renal impairment not expected to influence drug exposure.
In patients with SEGA, everolimus clearance normalized to body surface area may be higher in pediatric patients compared with adults.
Higher exposure to everolimus among Japanese patients compared with non-Japanese patients; relevance to safety and efficacy not established.
Clearance is 20% higher in black patients than in Caucasian patients; relevance to safety and efficacy not established.
Stability
Storage
Oral
Tablets
Original container at 25°C (may be exposed to 15–30°C); protect from light and moisture.
Tablets for Oral Suspension
Original container at 25°C (may be exposed to 15–30°C); protect from light and moisture.
Actions
-
Inhibits mammalian target of rapamycin (mTOR) kinase.
-
Inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.
-
Binds with high affinity to the intracellular protein FK506 binding protein-12 (FKBP-12), forming a drug-protein complex with mTOR complex 1 (mTORC1 or everolimus:FKBP-12) that binds to and inhibits the activation of mTOR.
-
Disruption of mTOR reduces the activity of downstream effectors (i.e., S6 ribosomal protein kinase [S6K1], eukaryotic elongation factor 4E-binding protein [4E-BP1]), thereby blocking progression of cells from G1 into S phase and, subsequently, inducing cell growth arrest and apoptosis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor, resulting in ligand-independent activation of the receptor.
-
The everolimus:FKBP-12 complex has no effect on calcineurin activity.
-
Also inhibits expression of hypoxia-inducible factor (e.g., HIF-1α), thereby reducing the expression of vascular endothelial growth factor (VEGF).
-
Reduces cell proliferation, angiogenesis, and glucose uptake in vitro and/or in vivo.
-
In breast cancer, constitutive activation of the phosphoinositide 3-kinase inhibitor (PI3K)/Akt/mTOR pathway can lead to endocrine resistance. Estrogen-dependent and HER2-positive breast cancer cells are sensitive to the inhibitory effects of everolimus in vitro. Concomitant use of everolimus with Akt, HER2, or aromatase inhibitors (e.g., anastrozole, exemestane, letrozole) enhances the anti-tumor activity of everolimus in a synergistic manner.
-
Loss or inactivation of tuberin-sclerosis complexes 1 and 2 (TSC1 and TSC2), 2 of the regulators of mTORC1 signaling, leads to activation of downstream signaling. In the genetic disorder tuberous sclerosis, inactivating mutations in the TSC1 or TSC2 gene lead to hematoma formation throughout the body. SEGA may develop in patients with tuberous sclerosis.
Advice to Patients
-
Importance of providing patient a copy of manufacturer’s patient information (Afinitor and Afinitor Disperz) or medication guide (Zortress).
-
Importance of taking everolimus tablets as directed either consistently with food or consistently without food; take at the same time each day (or twice daily approximately 12 hours apart), swallowing the tablets whole with a glass of water.
-
Everolimus tablets for oral suspension (Afinitor Disperz) should be taken as a suspension only and should not be swallowed. Importance of reviewing procedures for preparation of everolimus tablets for oral suspension with patients.
-
Importance of storing everolimus (Afinitor or Afinitor Disperz) tablets in the original package and keeping the blister package and tablets dry and protected from light. Importance of opening the blister package (scissors may be used to avoid spillage) immediately prior to taking everolimus. Importance of keeping everolimus (Zortress) tablets dry and protected from light.
-
If a dose of everolimus (Afinitor or Afinitor Disperz) is missed by ≤6 hours, take dose as soon as it is remembered, and take the next dose at the regularly scheduled time; if a dose is missed by >6 hours, omit the dose and take the next dose at the regularly scheduled time. Do not take a double dose to make up for a missed dose.
-
Importance of informing patients about risks, including serious allergic reactions (e.g., anaphylaxis), noninfectious pneumonitis, and increased susceptibility to infection. Importance of patients promptly reporting any facial swelling, new or worsening respiratory symptoms (e.g., cough, shortness of breath, difficulty breathing, wheezing), or any signs or symptoms of infection (e.g., fever, chills).
-
Risk of reactivation of HBV infection. Importance of promptly reporting any signs and symptoms of possible HBV infection (e.g., loss of appetite, pale stool or dark urine, yellowing of the skin, pain in upper right side of the stomach).
-
Risk of malignancy, including lymphoma and skin cancer. Importance of limiting exposure to sunlight and ultraviolet light by wearing protective clothing and using sunscreen with a high protection factor.
-
Risk of new-onset diabetes mellitus; importance of reporting any signs or symptoms of diabetes mellitus (e.g., frequent urination, increased thirst or hunger).
-
Risk of mouth ulcers, stomatitis, and oral mucositis. Importance of reporting any signs or symptoms of oral ulceration (e.g., pain, discomfort, open sores in mouth). Use of mouthwashes and/or topical treatments is recommended; however, avoid alcohol-, peroxide-, iodine-, or thyme-containing preparations.
-
Risk of kidney arterial and venous thrombosis leading to graft loss in renal transplant recipients; usually occurs within first 30 days after transplantation. Importance of promptly reporting any signs and symptoms of possible kidney thrombosis (e.g., pain in groin, lower back, side, or stomach, decreased urination, blood in urine or dark colored urine, fever, nausea, or vomiting).
-
Risk of PVAN, which may result in deteriorating renal function and renal graft loss.
-
Risk of proteinuria in patients receiving everolimus following transplantation.
-
Risk of angioedema; risk may be increased by other drugs known to cause angioedema (e.g., ACE inhibitors). Importance of seeking prompt medical attention if symptoms (e.g., sudden swelling of face, mouth, throat, tongue, or hands; hives or welts; itchy or painful swollen skin; trouble breathing) develop.
-
Risk of impaired wound healing and fluid accumulation. Importance of careful observation of incision site in patients who have undergone renal or hepatic allotransplantation; promptly inform healthcare provider if incision is red, warm, or painful; if there is blood, fluid, or pus in incision; if incision opens up; or in case of swelling of incision.
-
Risk of increased blood glucose, triglyceride, and/or cholesterol concentrations; risk of adverse renal and hematologic effects. Fasting glucose and lipid profiles, CBC, and renal and liver function tests are required; importance of adherence to laboratory appointment schedules.
-
Need for therapeutic drug monitoring in patients receiving everolimus for the treatment of SEGA or for the prevention of rejection of renal or hepatic allografts; importance of adherence to laboratory appointment schedules.
-
Importance of avoiding use of live vaccines and close contact with those who have received live vaccines.
-
Importance of avoiding grapefruit and grapefruit juice during everolimus therapy.
-
Importance of informing clinicians of hereditary disorders of galactose intolerance (Lapp lactase deficiency or glucose-galactose malabsorption); avoid Zortress therapy in patients with these conditions.
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., antifungals, antivirals, anticonvulsants [carbamazepine, phenytoin, barbiturates]) and herbal products (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., hepatic impairment, diabetes mellitus or hyperglycemia, hyperlipidemia, infection, history of HBV infection, personal or family history of skin cancer).
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women of childbearing potential to avoid pregnancy and to use a highly effective contraceptive method during therapy and for 8 weeks following discontinuance of therapy. Necessity of advising women to avoid breastfeeding while receiving everolimus therapy. Risk of male infertility (low or no sperm count). Everolimus tablets for oral suspension (Afinitor Disperz) can cause harm to an unborn baby; the suspension should be prepared by an adult who is not pregnant or planning to become pregnant. Anyone who prepares everolimus tablets for suspension (Afinitor Disperz) for another person should wear gloves to avoid possible contact with the medicine.
-
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets |
0.25 mg |
Zortress |
Novartis |
0.5 mg |
Zortress |
Novartis |
||
0.75 mg |
Zortress |
Novartis |
||
2.5 mg |
Afinitor |
Novartis |
||
5 mg |
Afinitor |
Novartis |
||
7.5 mg |
Afinitor |
Novartis |
||
10 mg |
Afinitor |
Novartis |
||
Tablets for oral suspension |
2 mg |
Afinitor Disperz |
Novartis |
|
3 mg |
Afinitor Disperz |
Novartis |
||
5 mg |
Afinitor Disperz |
Novartis |
AHFS DI Essentials™. © Copyright 2023, Selected Revisions April 6, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
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