Brand names: Afinitor, Afinitor Disperz, Zortress
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

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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.

Guidelines generally support the use of everolimus in combination with exemestane in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer in the second- or subsequent-line setting following treatment with a non-steroidal aromatase inhibitor.

Neuroendocrine Tumors

Treatment of progressive neuroendocrine tumors (NET) of pancreatic origin (PNET) in adults with unresectable, locally advanced, or metastatic disease (designated an orphan drug by FDA for this use).

Treatment of progressive, well-differentiated, non-functional NET of GI or lung origin (designated an orphan drug by FDA for this use).

Guidelines generally support consideration of everolimus among other options for the management of progressive PNET and NET of GI and lung origin.

Not indicated for use in patients with functional carcinoid tumors.

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma (RCC) in adults following failure of sunitinib and/or sorafenib therapy.

Guidelines generally support the use of everolimus in combination with lenvatinib^{† [off-label]} for the treatment of advanced RCC in patients who experience disease progression; some experts support the use of everolimus as monotherapy for certain patients with advanced RCC in the second- and subsequent-line treatment setting.

Renal Angiomyolipoma with Tuberous Sclerosis Complex

Treatment of renal angiomyolipoma with tuberous sclerosis complex (TSC), not requiring immediate surgery, in adults (designated an orphan drug by FDA for this use).

Guidelines generally support the use of everolimus as initial therapy for asymptomatic TSC-associated angiomyolipoma over 3 cm in diameter.

Subependymal Giant Cell Astrocytoma with TSC

Treatment of subependymal giant celll astrocytoma (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).

Guidelines generally support the use of everolimus in management of TSC-associated SEGA in patients who do not have an urgent indication for surgery, are not candidates for surgery, or prefer medical treatment.

TSC-Associated Partial-Onset Seizures

Adjunctive treatment of adult and pediatric patients aged ≥2 years with TSC-associated partial-onset seizures (designated an orphan drug by FDA for this use).

Guidelines generally support the use of everolimus for TSC-associated seizures alongside other options in this setting.

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.

Safety and efficacy not established in renal transplant recipients with high immunologic risk or in recipients of transplanted organs other than kidney and liver, or pediatric patients.

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guideline on renal transplantation generally recommends use of everolimus-containing immunosuppressive regimens only in patients unable to receive recommended standard therapy, and recommends against its combined use with a calcineurin inhibitor (CNI). A consensus guideline on maintenance immunosuppression in solid organ transplant recipient published in 2022 by the American College of Clinical Pharmacy (ACCP), American Transplantation Society (AST), and International Society for Heart and Lung Transplantation (ISHLT) generally recommends consideration of an mTOR inhibitor alongside or in place of certain immunosuppresants to minimize risk of renal dysfunction or in cases of intolerance of other agents in kidney transplant recipients, and notes that mTOR inhibitor-containing immunosuppression may reduce risks of de novo post-transplant malignancy and cytomegalovirus in this setting.

Hepatic Allotransplantation

Prevention of rejection of hepatic allografts in adults. Used ≥30 days posttransplant concurrently with tacrolimus (in reduced dosages) and corticosteroids.

Safety and efficacy not established in recipients of transplanted organs other than kidney and liver or pediatric patients.

In liver transplant recipients, the ACCP/AST/ISHLT 2022 guideline for maintenance immunosuppression in solid organ transplant recipients generally recommends consideration of an mTOR inhibitor alongside or in place of certain immunosuppresants to minimize risk of renal dysfunction or in cases of intolerance of other agents, and notes that mTOR inhibitor-containing immunosuppression may reduce risk of de novo post-transplant malignancy in this setting.

Heart Allotransplantation

Has been used for the prevention of heart transplant rejection^{† [off-label]}.

The 2022 ACCP/AST/ISHLT consensus guideline for maintenance immunosuppression in solid organ transplant recipients recommends consideration of mTOR inhibitors, including everolimus or sirolimus, alongside low-dose CNI, MPA, with or without corticosteroids, or as a replacement for CNI or antimetabolites, to minimize risk of kidney dysfunction in heart transplant recipients. The expert panel notes that mTOR inhibitors may protect against cytomegalovirus infection, may be useful in patients with cancer due to reduced risk of de novo and recurrent malignancy post-transplant, and are associated with prevention and reduced progression of cardiac allograft vasculopathy in heart transplant recipients.

Lung Allotransplantation

Has been used for the prevention of lung transplant rejection^{† [off-label]} .

The 2022 ACCP/AST/ISHLT consensus guideline for maintenance immunosuppression in solid organ transplant recipients recommends consideration of mTOR inhibitors, including everolimus or sirolimus, alongside low-dose CNI, MPA, with or without corticosteroids to minimize risk of kidney dysfunction in lung transplant recipients. The expert panel notes that mTOR inhibitors may protect against cytomegalovirus infection and that their use in place of antimetabolites may reduce risk of bronchiolitis obliterans syndrome in this setting.

Pancreas Allotransplantation

Has been used for the prevention of pancreas transplant rejection^{† [off-label]}.

The 2022 ACCP/AST/ISHLT consensus guideline for maintenance immunosuppression in solid organ transplant recipients recommends consideration of mTOR inhibitors, including everolimus or sirolimus, as a replacement for CNI to minimize risk of kidney dysfunction in pancreas transplant recipients. The expert panel notes that mTOR inhibitors may be useful in the setting of MPA intolerance; in patients with MPA-induced GI toxicity, replacement with an mTOR inhibitor may be considered if the mTOR inhibitor is used in combination with tacrolimus with or without corticosteroids to minimize risk of rejection.

Vascularized Composite Allotransplantation

Has been used for the prevention of vascularized composite transplant rejection^{† [off-label]} in a limited number of patients undergoing hand transplantation and uterus transplantation; larger studies are required to define the standard of care in this setting.

Everolimus Dosage and Administration

General

Pretreatment Screening

• Fasting glucose and lipid profiles, CBCs, and renal function tests should be monitored prior to everolimus therapy.

• Complete all routine vaccinations prior to initiating treatment with everolimus.

• Complete treatment of preexisting invasive fungal infections prior to initiating treatment with everolimus.

• Verify pregnancy status of females of reproductive potential prior to initiation of everolimus.

Patient Monitoring

• Monitor renal function annually during therapy with everolimus for non-transplant indications. In patients with increased risk factors for renal failure, monitor renal function at least every 6 months.

• Monitor renal function and for proteinuria during everolimus therapy in all transplant patients.

• Monitor CBC every 6 months during the first year of treatment with everolimus, and annually thereafter.

• Monitor lipid profile annually during everolimus therapy.

• Monitor fasting glucose concentrations annually during everolimus therapy in non-diabetic patients. In diabetic patients, monitor fasting blood glucose as clinically indicated.

• Monitor for signs and symptoms of infection during treatment.

• Monitor for the development of angioedema during treatment with everolimus, particularly in patients on concomitant angiotensin converting enzyme (ACE) inhibitor therapy.

• Monitor everolimus whole blood trough drug concentrations routinely in all patients receiving everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) with tuberous sclerosis complex (TSC) and partial-onset seizures associated with TSC, and in all renal and hepatic transplant patients. Use the same assay and laboratory when possible.

• In patients with SEGA or partial-onset seizures associated with TSC, measure trough concentrations 1–2 weeks after initiation of everolimus treatment, with any change in everolimus dosage, or with a change in dosage form between everolimus tablets (Afinitor) and everolimus tablets for oral suspension (Afinitor Disperz); measure trough concentration 2 weeks after the initiation or discontinuance of inducers or inhibitors of CYP3A4 and/or P-glycoprotein, or a change in hepatic function.

Premedication and Prophylaxis

• Administer antimicrobial prophylaxis against Pneumocystis jirovecipneumonia (PJP) in patients receiving everolimus for non-transplant indications when concomitant corticosteroids or immunosuppressives are used. Administer antimicrobial prophylaxis against PJP and cytomegalovirus (CMV) in renal and hepatic transplant recipients.

• Initiate dexamethasone alcohol-free mouthwash for the first 8 weeks during initiation of everolimus treatment in adult patients to reduce the severity and incidence of stomatitis.

Dispensing and Administration Precautions

• Handling and Disposal:Everolimus is classified as a hazardous drug by the Centers for Disease Control and Prevention National Institute for Occupational Safety and Health (NIOSH). Everolimus tablets for oral suspension (Afinitor Disperz) can cause fetal harm; 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 drug.

Administration

Oral Administration

Administer orally 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 and as adjunctive treatment for partial-onset seizures with TSC.

Do not combine dosage forms to achieve desired dose; use only one dosage form.

If a dose of Afinitor or Afinitor Disperz is missed, the dose can be administered up to 6 hours later. If more than 6 hours has passed since the missed dose, skip dose and resume usual schedule the following day.

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 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. Wear gloves when preparing suspension.

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

Oral

Pediatric patients ≥1 year of age: Recommended initial dosage is 4.5 mg/m² once daily.

Subsequent dosing should be guided by therapeutic drug monitoring.

Continue therapy until disease progression or unacceptable toxicity occurs.

Partial-Onset Seizures with TSC

Oral

Pediatric patients ≥2 years of age: 5 mg/m² once daily.

Subsequent dosing should be guided by therapeutic drug monitoring.

Continue therapy until disease progression or unacceptable toxicity occurs.

Adults

Breast Cancer

Oral

10 mg once daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Adjust dosage when used in conjunction with P-gp and strong inducers of CYP3A4 or moderately strong inhibitors of CYP3A4.

Neuroendocrine Tumors of Pancreatic, GI, or Lung Origin

Oral

10 mg once daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Adjust dosage when used in conjunction with P-gp and strong inducers of CYP3A4 or moderately strong inhibitors of CYP3A4.

Renal Cell Carcinoma

Oral

10 mg once daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Adjust dosage adjustments when used in conjunction with P-gp and strong inducers of CYP3A4 or moderately strong inhibitors of CYP3A4.

Renal Angiomyolipoma with TSC

Oral

10 mg once daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Adjust dosage adjustments when used in conjunction with P-gp and strong inducers of CYP3A4 or moderately strong inhibitors of CYP3A4.

SEGA with TSC

Oral

Recommended initial dosage 4.5 mg/m² once daily.

Subsequent dosing should be guided by therapeutic drug monitoring.

Continue therapy until disease progression or unacceptable toxicity occurs.

Partial-onset Seizures with TSC

Oral

Recommended initial dosage 5 mg/m² once daily.

Subsequent dosing should be guided by therapeutic drug monitoring.

Continue therapy until disease progression or unacceptable toxicity occurs.

Renal Allotransplantation

Oral

Initially, 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.

If trough concentrations decrease to <3 ng/mL, double the dosage using the available tablet strengths (0.25 mg, 0.5 mg, 0.75 mg, or 1 mg). If 2 consecutive trough concentrations are >8 ng/mL, decrease the dosage by 0.25 mg twice daily.

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.

Hepatic Allotransplantation

Oral

Initially, 1 mg twice daily, initiated ≥30 days following transplantation; used in combination with reduced-dosage tacrolimus and corticosteroids.

If trough concentrations decrease to <3 ng/mL, double the dosage using the available tablet strengths (0.25 mg, 0.5 mg, 0.75 mg, or 1 mg). If 2 consecutive trough concentrations are >8 ng/mL, decrease the dosage by 0.25 mg twice daily.

May taper corticosteroid dosage on an individualized basis based on patient’s clinical status and allograft function.

Heart Allotransplantation†

Oral

Optimum dosage not established; initial dosage of 0.75 mg twice daily in combination with other immunosuppressive agents, with subsequent adjustment based on trough everolimus concentrations when necessary, has been found to be effective in clinical studies.

Lung Allotransplantation†

Oral

Optimum dosage not established; initial dosage of 0.75 mg twice daily to 1.5 mg twice daily in combination with other immunosuppressive agents, with subsequent adjustment based on trough everolimus concentrations when necessary, has been found to be effective in clinical studies.

Pancreas Allotransplantation†

Oral

Optimum dosage not established; initial dosage of 0.75 mg twice daily in combination with other immunosuppressive agents, with subsequent adjustment based on trough everolimus concentrations when necessary, has been described.

Vascularized Composite Allotransplantation†

Oral

Optimum dosage not established; initial dosage of 0.75 mg twice daily in combination with other immunosuppressive agents, with subsequent adjustment based on trough everolimus concentrations when necessary, has been described.

Therapeutic Drug Monitoring

Therapeutic Drug Monitoring and Dosage Adjustments in Pediatric and Adult Patients with SEGA and Partial-onset Seizures with TSC

Adjust dosage at 1–2 week intervals as needed to achieve and maintain trough whole blood everolimus concentrations of 5–15 ng/mL.

Higher trough concentrations may be associated with larger reductions in SEGA volume and a greater reduction in absolute seizure frequency.

Adjust dosage using this equation if trough concentrations are not within goal range of 5–15 ng/mL: New dosage = current dosage multiplied by (target trough concentration divided by current trough concentration.

For each dosage titration, increase dosage increment by no greater than 5 mg; multiple dosage titrations at 1–2 week intervals may be necessary to attain target trough concentrations.

Measure trough concentrations 2 weeks after any change in hepatic function, or during the initiation or discontinuance of a potent inducer or moderate inhibitor of CYP3A4 and P-glycoprotein.

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.

Make dosage adjustments when used in conjunction with moderate inhibitors or potent inducers of CYP3A4 and inhibitors of P-glycoprotein.

Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus in Renal Allotransplantation in Adults

Adjust dosage based on trough whole blood everolimus concentrations, tolerability, individual response, change in concomitant drug therapy, and clinical situation. 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.13, Maintaining communication with the laboratory performing the assay is essential.

Therapeutic Drug Monitoring and Dosage Adjustment of Cyclosporine with Everolimus in Renal Allotransplantation in Adults

Reduce cyclosporine dosage and target therapeutic range when used in combination with everolimus to minimize risk of nephrotoxicity.

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.

Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus in Hepatic Allotransplantation in Adults

Adjust dosage based on trough whole blood everolimus concentrations, tolerability, individual response, change in concomitant drug therapy, and clinical situation. 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 in Adults

Reduce tacrolimus dosage and target therapeutic range when used in combination with everolimus to minimize risk of nephrotoxicity.

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 Modifications for Toxicity

Adjustment of everolimus dosage and/or interruption of therapy may be required for patients with breast cancer, NET, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures, according to the toxicity. If dosage reduction is required, the suggested dosage is approximately 50% lower than the previously administered daily dosage, if dosage reduction is required. Everolimus may be changed to every other day dosing if the reduced dose is lower than the lowest available strength.

Noninfectious Pneumonitis

Grade 2: Interrupt therapy until improvement to grade 1 or less, then resume at lower dosage. Permanently discontinue everolimus if resolution or improvement to grade 1 does not occur within 4 weeks.

Grade 3: Interrupt therapy until improvement to grade 1 or less, then resume at lower dosage. If grade 3 toxicity recurs, permanently discontinue.

Grade 4: Permanently discontinue everolimus.

Stomatitis

Grade 2: Interrupt therapy until improvement to grade 1 or less, then resume at original dosage. If grade 2 toxicity recurs, interrupt therapy until improvement to grade 1 or less, then resume at lower dosage.

Grade 3: Interrupt therapy until improvement to grade 1 or less, then resume at lower dosage.

Grade 4: Permanently discontinue everolimus.

Other Nonhematologic Toxicity

Grade 2: If toxicity is intolerable, interrupt therapy until improvement to grade 1 or less, then resume at original dosage. If grade 2 toxicity recurs, interrupt therapy until improvement to grade 1 or less, then resume at lower dosage.

Grade 3: Interrupt therapy until improvement to grade 1 or less, then resume at lower dosage. If grade 3 toxicity recurs, permanently discontinue.

Grade 4: Permanently discontinue everolimus.

Metabolic Events

Grade 3: Interrupt therapy until improvement to grade 2 or less, then resume at lower dosage.

Grade 4: Permanently discontinue everolimus.

Thrombocytopenia

Grade 2: Interrupt therapy until improvement to grade 1 or less, then resume at original dosage.

Grade 3 or 4: Interrupt therapy until improvement to grade 1 or less, then resume at lower dosage.

Neutropenia

Grade 3: Interrupt therapy until improvement to grade 2 or less, then resume at original dosage.

Grade 4: Interrupt therapy until improvement to grade 2 or less, then resume at lower dosage.

Febrile Neutropenia

Grade 3: Interrupt therapy until improvement to grade 2 or less and no fever, then resume at lower dosage.

Grade 4: Permanently discontinue everolimus.

Special Populations

Hepatic Impairment

Breast Cancer, Neuroendocrine Tumors of Pancreatic, GI, or Lung 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.

SEGA or Partial-onset Seizures with TSC

Oral

Severe (Child-Pugh class C) hepatic impairment: Decrease initial dosage to 2.5 mg/m²; base subsequent dosage on therapeutic drug monitoring.

Renal or Hepatic Allotransplantation

Oral

Mild (Child-Pugh class A) hepatic impairment: Decrease initial daily 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 daily 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

Management of Immunosuppression

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.)

Malignancies and Serious Infections

Immunosuppressants, including everolimus, can increase susceptibility to infection (bacterial, fungal, viral, or protozoal infections, including opportunistic infections) (see Boxed Warning). Severe or fatal localized and systemic infections reported.

Antimicrobial prophylaxis for Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PJP) and cytomegalovirus (CMV) is recommended in transplant recipients. The manufacturer of Afinitor and Afinitor Disperz recommends administration of prophylaxis against PJP when concomitant corticosteroids or immunosuppressives are used with everolimus.

Monitor for signs and symptoms of infection and institute appropriate treatment if infection develops; consider interruption or discontinuance of everolimus therapy. Complete treatment of a preexisting invasive fungal infection prior to initiating everolimus therapy.

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. In patients with an increased risk for skin cancer, limit exposure to sunlight and ultraviolet light with use of protective clothing and sunscreen with a high protection factor.

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 (see Boxed Warning).

Renal Effects

Increased risk of nephrotoxicity when used concurrently with standard cyclosporine dosages; use reduced cyclosporine dosages (see Boxed Warning). Not studied with standard tacrolimus dosages in hepatic transplant recipients; use in combination with reduced-dosage tacrolimus to minimize potential risk of nephrotoxicity.

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.

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.

Increases in S_cr and proteinuria reported in patients receiving everolimus (Afinitor and Afinitor Disperz). Cases of renal failure (including acute renal failure), some with fatal outcome, also observed. Monitor renal function prior to initiating everolimus and annually thereafter. In patients with increased risk factors for renal dysfunction, monitor renal function at least every 6 months.

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 (see Boxed Warning.).

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), as well as the presence of opportunistic infections such as PJP. Administer prophylaxis against PJP when corticosteroids and other immunosuppressive treatments are required.

If radiological changes suggestive of noninfectious pneumonitis develop in patients with minimal or no symptoms, continue Afinitor and Afinitor Disperz without dosage alteration. If grade 2–4 symptoms of noninfectious pneumonitis develop, interruption or discontinuance of therapy and subsequent dosage reduction may be required.

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.

Stomatitis

Mouth ulcers, stomatitis, and oral mucositis, mostly grade 1 and 2, reported. Stomatitis generally occurs within the first 8 weeks of starting treatment.

Topical therapy recommended if oral ulceration occurs. Initiation of dexamethasone 0.1 mg/mL alcohol-free oral solution as a mouthwash when starting everolimus has been shown to reduce the incidence and severity of stomatitis in adult patients.

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.

Depending on severity, interruption of therapy, dosage reduction, and/or drug discontinuance may be required.

Hepatic Artery Thrombosis (HAT)

Mammanlian target of rapmaycin (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.

Risk of Infection or Reduced Immune Response with 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 who do not require immediate treatment before initiating everolimus therapy. Prior to initiation of everolimus therapy, complete the recommended childhood series ofvaccinations according to the US Public Health Service Advisory Committee on Immunization Practices (ACIP) guidelines. An accelerated vaccination schedule may be appropriate.

Severe Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, dyspnea, flushing, chest pain, and/or angioedema, reported with everolimus and other rapamycin derivatives. Permanently discontinue everolimus if clinically significant hypersensitivity reactions develop.

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. The manufacturer recommends permanent discontinuation of Afinitor and Afinitor Disperz if angioedema occurs.

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.

The manufacturer of Afinitor and Afinitor Disperz recommends withholding everolimus for at least 1 week prior to elective surgery, and for at least 2 weeks after completion of the procedure until adequate wound healing has been established. Safety of resuming everolimus following the resolution of wound healing complications is not known.

Metabolic Disorders

Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia reported.

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. Monitor fasting glucose concentrations prior to and annually periodically during everolimus (Afinitor and Afinitor Disperz) therapy; when possible, achieve optimal glycemic control prior to initiation of everolimus. In diabetic patients, monitor fasting blood glucose more frequently as clinically indicated.

Monitor fasting serum lipids prior to and periodically during everolimus (Afinitor, Zortress) therapy (annually for patients receiving Afinitor and Afinitor Disperz). 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.

Depending on severity of metabolic disorders, interruption of Afinitor or Afinitor Disperz therapy, dosage reduction, and/or drug discontinuance may be required.

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.

Myelosuppression

Anemia, lymphopenia, neutropenia, and thrombocytopenia reported. Monitor CBC prior to and every 6 months during the first year of therapy. Thereafter, CBC can be monitored annually. Depending on severity, interruption of therapy, dosage reduction, and/or drug discontinuance may be required.

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.

Radiation Sensitization and Recall

Radiation sensitization and recall involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis), including some severe cases, have been reported in patients receiving radiation prior to, during, and after initiation of everolimus (Afinitor and Afinitor Disperz). Monitor patients closely if everolimus is administered during or in sequence with radiation therapy.

Interaction with Potent Inhibitors and Inducers of Cytochrome P-450 Isoenzyme 3A4

Concomitant use of everolimus (Zortress) with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir) and strong inducers of CYP3A4 (e.g., rifampin, rifabutin) is not recommended or requires close monitoring of whole blood trough everolimus concentrations and/or adjustment of everolimus dosage.

Fetal/Neonatal Morbidity and Mortality

Can cause fetal harm; teratogenicity and embryolethality demonstrated in animals. No adequate and well-controlled studies in humans.

Females of childbearing potential should use an effective method of contraception during and for up to 8 weeks following discontinuance of everolimus.

Advise male partners of such females to use effective contraception during everolimus treatment, and for 4 weeks after discontinuance of the drug.

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.

Drug Interactions

Closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity when cannabidiol is administered concurrently with everolimus (Zortress). A dose reduction of everolimus (Zortress) should be considered as needed when coadministration occurs.

Grapefruit and grapefruit juice inhibit cytochrome CYP3A4 and P-gp activity and should therefore be avoided with concomitant use of everolimus.

Specific Populations

Pregnancy

Based on animal studies and the mechanism of action of everolimus, may cause fetal harm. Verify pregnancy status of females of reproductive potential prior to initiation.

Women of childbearing potential should use effective contraception during and for up to 8 weeks after discontinuance of therapy.

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.

Avoid breast-feeding. Some manufacturers state to avoid breastfeeding during treatment with everolimus and for 2 weeks following the last dose.

Females and Males of Reproductive Potential

Everolimus may impair male and female fertility.

Confirm pregnancy status prior to initiation of everolimus.

Advise females of reproductive potential to use effective contraceptive methods during everolimus therapy and for up to 8 weeks after discontinuance of the drug. Advise males who are partners of such females to use effective methods of contraception while receiving the drug and for at least 4 weeks after discontinuing therapy.

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. Although it remains inconclusive, the use of everolimus does not appear to adversely affect growth and pubertal development.

Safety and efficacy for the adjunctive treatment of partial-onset seizures with TSC have been evaluated in pediatric patients ≥2 years of age. Safety and efficacy not established in pediatric patients < 2 years of age with TSC-associated partial-onset seizures.

Incidence of infections, including serious infections, in pediatric patients <6 years of age reported at a higher frequency in comparison to patients ≥6 years of age.

Safety and efficacy for treatment of renal angiomyolipoma with TSC in the absence of SEGA, hormone-receptor positive, HER2-negative breast cancer, NET, and renal cell carcinoma 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.

Geriatric Use

Patients with 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.

Transplant recipients: Limited clinical experience with use of everolimus following transplantation in patients ≥65 years of age.

Hepatic Impairment

Patients with breast cancer, NET, advanced renal carcinoma, TSC-associated 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.

Patients with TSC-associated SEGA or partial-onset seizures: Initial dosage adjustment recommended for those with severe (Child-Pugh class C) hepatic impairment; individualize subsequent dosage based on therapeutic drug monitoring.

Renal Impairment

No significant correlation has been demonstrated between Cl_cr and everolimus pharmacokinetics.

Common Adverse Effects

Adverse effects (≥30%) in patients with breast cancer, neuroendocrine tumors, or advanced renal cell carcinoma: stomatitis (including mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration), infections (including urinary tract infections, upper and lower respiratory tract infections, skin, and GI tract infections), rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, decreased appetite.

Adverse effects (≥30%) in patients with renal angiomyolipoma with tuberous sclerosis complex (TSC): stomatitis (including mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and stomatitis).

Adverse effects (≥30%) in patients with subependymal giant cell astrocytoma (SEGA) with TSC: stomatitis (including mouth and lip ulceration, and stomatitis) and respiratory tract infections (including respiratory tract infection, upper respiratory tract infection, and viral respiratory tract infection).

Adverse effects (≥30%) in patients with partial-onset seizures with TSC: stomatitis (including stomatitis, mouth ulceration, apththous ulcer, lip and tongue ulceration, mucosal inflammation, and gingival pain).

Adverse effects (≥20%) in renal transplant patients: peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection, hyperlipidemia.

Adverse effects (>10%) in hepatic transplant patients: diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, leukopenia, hypercholesterolemia.

Drug Interactions

Metabolized principally by CYP3A4; competitive inhibitor of CYP3A4 and CYP2D6 in vitro. Also a substrate of the efflux transporter P-glycoprotein (P-gp).

Inhibitors or Inducers of CYP3A4 and P-gp

P-gp and strong CYP3A4 inhibitors: Avoid concomitant use.

P-gp and moderate CYP3A4 inhibitors: Reduced everolimus dosage required in patients who require coadministration. If concomitant use is required in patients with breast cancer, neuroendocrine tumors (NET), renal cell carcinoma, or tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce dosage to 2.5 mg; may increase if tolerated to 5 mg daily. Resume original everolimus dosage 3 days after discontinuance of the P-gp and CYP inhibitor. If concomitant use is required in patients with TSC-associated subependymal giant cell astrocytoma (SEGA) or partial-onset seizures, reduce the initial daily dosage by 50%; subsequent dosing based on therapeutic drug monitoring. Resume original everolimus dosage 3 days after discontinuance of the P-gp and CYP inhibitor and reassess trough concentration 2 weeks later.

P-gp and strong CYP3A4 inducers: Avoid concomitant use. If concomitant use cannot be avoided in patients with breast cancer, NET, renal cell carcinoma, or TSC-associated renal angiomyolipoma, double the daily dosage (from 10 mg daily up to 20 mg daily, titrated in ≤5 mg increments). Resume original everolimus dosage 5 days after discontinuance of the P-gp and potent CYP3A4 inducer.

If concomitant use cannot be avoided in patients with TSC-associated SEGA or partial-onset seizures, double the dosage of everolimus, titrating in ≤5-mg increments. Assess trough concentrations 2 weeks after doubling the dosage, and adjust as necessary for a trough concentration of 5–15 ng/mL. If a second potent CYP3A4 inducer is added to the existing regimen and the dosage has already been adjusted, additional dosage modification may not be necessary. Resume original everolimus dosage 5 days after discontinuance of the P-gp and potent inducer and reassess everolimus trough concentrations 2 weeks later.

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.

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

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.

Administration of 9-mg tablets for oral suspension with a high-fat in healthy individuals reduced everolimus peak plasma concentrations and AUC by 60 and 12%, respectively; administration with a low-fat meal reduced peak plasma concentrations and AUC by 50 and 30%, respectively.

Special Populations

Mild, moderate, and severe hepatic impairment increased AUC by 1.8-, 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 Cl_cr (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.

In patients with cancer, no apparent relationship observed between oral clearance and age or sex.

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

• Provide the patient with a copy of the manufacturer’s patient information (Afinitor and Afinitor Disperz) or medication guide (Zortress).

• Take everolimus tablets at about the same time each day (or twice daily approximately 12 hours apart), either consistently with food or consistently without food. Swallow the tablets (Afinitor or Zortress) whole with a glass of water and do not crush or chew the tablets.

• Inform patients that everolimus tablets for oral suspension (Afinitor Disperz) should be taken as a suspension only and should not be swallowed whole. The suspension should be taken orally once daily at the same time each day, either consistently with food or consistently without food. Review procedures for preparation of everolimus tablets for oral suspension (Afinitor Disperz) with patients.

• Advise patients to store everolimus (Afinitor or Afinitor Disperz) tablets in the original package and keep 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. Advise patients to keep everolimus (Zortress) tablets dry and protected from light.

• If a dose of everolimus (Afinitor or Afinitor Disperz) is missed by 6 hours or less, advise the patient to take the dose as soon as it is remembered, and the next dose at the regularly scheduled time; if a dose is missed by more than 6 hours, omit the dose, and take the next dose at the regularly scheduled time. Do not administer a double dose to make up for a missed dose.

• Risk of serious allergic reactions, including anaphylaxis; advise patients to report signs or symptoms immediately.

• Risk of noninfectious pneumonitis, which may be fatal; inform patients to promptly report any new or worsening respiratory symptoms (e.g., cough, shortness of breath, difficulty breathing, wheezing).

• Risk of increased susceptibility to infection, which may be fatal; inform patients to promptly report any signs or symptoms of infection (e.g., fever, chills).

• Risk of malignancy, including lymphoma and skin cancer. Advise patients to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using sunscreen with a high sun protection factor.

• Risk of new-onset diabetes mellitus; advise patients to report any signs or symptoms of diabetes mellitus (e.g., frequent urination, increased thirst or hunger).

• Risk of mouth ulcers, stomatitis, and oral mucositis. Inform patients to report any signs or symptoms of oral ulceration (e.g., pain, discomfort, or open sores in the mouth). Use of alcohol-free mouthwashes and/or topical treatments is recommended to treat oral ulceration; however, alcohol-, peroxide-, iodine-, or thyme-containing preparations should be avoided since they may exacerbate the condition.

• Risk of kidney arterial and venous thrombosis leading to graft loss in renal transplant recipients; usually occurs within first 30 days after transplantation. Inform patients to promptly report 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, vomiting).

• Inform patients of the risk of proteinuria in those receiving everolimus following transplantation.

• Risk of angioedema; risk may be increased by concomitant use of other drugs known to cause angioedema (e.g., angiotensin-converting enzyme inhibitors). Advise patients to seek prompt medical attention in case of symptoms of angioedema (e.g., sudden swelling of face, mouth, throat, tongue, or hands; hives or welts; itchy or painful swollen skin; trouble breathing).

• Risk of impaired wound healing and fluid accumulation. Advise patients to inform their healthcare provider of any planned surgical procedure. Importance of careful observation of incision site in patients who have undergone renal or hepatic allotransplantation. Advise patients to promptly inform a 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, CBCs, and renal and liver function tests are required; remind patients about the importance of adherence to laboratory appointment schedules.

• Need for therapeutic drug monitoring in patients receiving everolimus for the treatment of subependymal giant cell astrocytoma (SEGA), partial-onset seizures, or for the prevention of rejection of renal or hepatic allografts; remind patients about the importance of adherence to laboratory appointment schedules.

• Inform patients to avoid use of live vaccines and close contact with those who have received live vaccines while taking everolimus.

• Advise patients to inform clinicians of hereditary disorders of galactose intolerance (Lapp lactase deficiency or glucose-galactose malabsorption); Zortress therapy should be avoided in patients with these conditions.

• Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to everolimus treatment. Advise patients to inform their healthcare provider if they have had or are planning to receive radiation therapy.

• Advise patients to inform their 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 hepatitis B virus infection, personal or family history of skin cancer). Remind patients to avoid grapefruit and grapefruit juice while receiving everolimus therapy.

• Advise patients to inform their clinicians if they are pregnant or plan to become pregnant or plan to breast-feed; advise females of childbearing potential to avoid pregnancy and to use an effective contraceptive method during therapy and for 8 weeks following discontinuance of therapy. Advise males with female partners of reproductive potential to use effective contraception during therapy and for 4 weeks following discontinuance of therapy. Advise women to avoid breastfeeding while receiving everolimus therapy, and for 2 weeks after discontinuation of treatment. Advise patients of the potential risk for impaired female and male fertility.

• Inform patients that everolimus tablets for oral suspension (Afinitor Disperz) can cause fetal harm; 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 drug.

• Inform patients of other precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at https://www.ahfsdruginformation.com.

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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Frequently asked questions

• How much does Afinitor cost per month?
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