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Everolimus (Monograph)

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

Medically reviewed by Drugs.com on Mar 27, 2023. Written by ASHP.

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

Therapeutic Drug Monitoring in Renal Allotransplantation Patients

Therapeutic Drug Monitoring in Hepatic Allotransplantation Patients

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
Oral

4.5 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
Oral

Adjust 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
Oral

4.5 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
Oral

Adjust 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
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.

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
Oral

Adjust 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
Oral

Reduce 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
Oral

Initially, 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
Oral

Adjust 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
Oral

Reduce 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.

Table 1. Recommended Dosage Modifications for Noninfectious Pneumonitis with Everolimus1

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.

Table 2. Recommended Dosage Modifications for Stomatitis with Everolimus1

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.

Table 3. Recommended Dosage Modifications for Nonhematologic Toxicity with Everolimus1

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.

Table 4. Recommended Dosage Modifications for Metabolic Events with Everolimus1

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

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.

Drug Interactions

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

Advice to Patients

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.

Everolimus

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 2024, 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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