Class: Antineoplastic Agents
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
Brands: Afinitor, Zortress

Introduction

Antineoplastic and macrolide immunosuppressive agent; inhibitor of mammalian target of rapamycin (mTOR) kinase.^{1 2 3 4 5 7 8 9 10 11 13}

Uses for Everolimus

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma following failure of sunitinib and/or sorafenib therapy.^{1 2 3 16}

Improves median progression-free survival;^{1 3 16} effects on overall survival remain to be established.^{12 16}

Slideshow: Top Prevention Tips: Springtime Allergies

Subependymal Giant Cell Astrocytoma

Treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients ≥3 years of age who require therapeutic intervention and are not candidates for curative surgical resection.^{1 17}

Reduces SEGA volume; improvement in disease-related symptoms and effect on overall survival have not been demonstrated.^{1 17}

Renal Allotransplantation

Prevention of rejection of renal allografts in adults with low to moderate immunologic risk.^{13 18} Used with basiliximab induction therapy and concurrent corticosteroids and reduced dosages of cyclosporine.^{13 18}

Safety and efficacy not established in renal transplant recipients with high immunologic risk or in recipients of other types of transplanted organs.¹³

Everolimus Dosage and Administration

General

Therapeutic Drug Monitoring in Patients with Subependymal Giant Cell Astrocytoma

• Routine monitoring of whole blood everolimus concentration using a validated assay is recommended for all patients.¹

• Measure trough concentrations approximately 2 weeks after initiation of or after any change in everolimus dosage, or after initiation or change in concomitant treatment with inducers or inhibitors of CYP3A4 or P-glycoprotein.¹

• Evaluate SEGA volume approximately 3 months after initiation of everolimus therapy and periodically thereafter.¹ Responses have been observed at trough concentrations as low as 3 ng/mL; therefore, additional dosage increases may not be necessary once acceptable efficacy has been achieved.¹ The optimal duration of therapy is not known.¹

Therapeutic Drug Monitoring in Renal Allotransplantation Patients

• The manufacturer recommends monitoring of blood everolimus and cyclosporine concentrations for all patients.¹³ Standard doses of cyclosporine in combination with everolimus are associated with an increased risk of nephrotoxicity and should not be used.¹³ (See Boxed Warnings and see Renal Effects under Cautions.)

• Carefully monitor clinical signs and symptoms, tissue biopsies, and laboratory parameters.¹³

• Carefully monitor blood everolimus concentrations in patients with hepatic impairment, patients receiving concomitant inducers or inhibitors of CYP3A4, when switching cyclosporine formulations, and when cyclosporine doses are reduced according to recommended target concentrations.¹³

Administration

Oral Administration

Administer orally once or twice daily^{1 2 3 13} at the same time every day (or approximately 12 hours apart when given twice daily),¹³ either consistently with food or consistently without food.¹

In patients with renal allografts, administer twice daily at the same time as cyclosporine.¹³

Swallow everolimus tablets whole with a glass of water; do not chew or crush.^{1 13}

In patients who are unable to swallow tablets, disperse everolimus (Afinitor) tablets in a glass containing approximately 30 mL of water by gently stirring immediately prior to drinking.¹ Rinse the glass with an additional 30 mL of water and completely swallow the rinse to ensure administration of the entire dose.¹

Dosage

Pediatric Patients

Subependymal Giant Cell Astrocytoma

Initial Dosage

Oral

Not studied in patients with body surface area <0.58 m² or <3 years of age.¹

Table 1. Recommended Initial Dosage in Children ≥3 years of Age with SEGA1

Body Surface Area (m2)	Initial Dosage
0.5–1.2	2.5 mg once daily
1.3–2.1	5 mg once daily
≥2.2	7.5 mg once daily

Laboratory Monitoring and Dosage Adjustments in SEGA

Adjust dosage at 2-week intervals as needed based on trough blood everolimus concentrations, tolerability, individual response, concomitant medications, and consideration of changes in SEGA volume.¹

Titrate dosage to attain trough everolimus concentrations of 5–10 ng/mL.¹ Higher trough concentrations may be associated with larger reductions in SEGA volume; however, responses have been observed at trough concentrations as low as 3 ng/mL, and additional dosage increases may not be necessary once acceptable efficacy has been achieved.¹ Limited safety experience available in patients with trough concentrations >10 ng/mL.¹

Patients with trough concentrations <5 ng/mL: May increase daily dosage by 2.5 mg every 2 weeks, subject to tolerability.¹ Limited safety experience available in patients with trough concentrations >10 ng/mL.¹

Patients with trough concentrations of 10–15 ng/mL who demonstrate tumor response and adequate tolerability: Dosage reduction not necessary.¹

Patients with trough concentrations >15 ng/mL: Reduce dosage.¹

If dosage reduction is necessary, may decrease daily dosage by 2.5 mg every 2 weeks to attain a target trough concentration of 5–10 ng/mL.¹ If dosage reduction is required in patients receiving 2.5 mg daily, use alternate-day dosing.¹

Optimal duration of therapy not known.¹

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderate inhibitors of CYP3A4, or inhibitors of P-glycoprotein.¹ (See Specific Drugs and Foods under Interactions.)

Dosage Modification for Toxicity in SEGA

Patients presenting with radiographic changes suggestive of noninfectious pneumonitis who have few or no symptoms: May continue therapy without any dosage adjustment.¹

Patients with noninfectious pneumonitis experiencing moderate respiratory symptoms: Consider interrupting therapy and initiating corticosteroids (as indicated) until symptoms improve; if therapy is resumed, may reintroduce everolimus and reduce dosage to 50% of the dosage previously administered.¹

Patients with noninfectious pneumonitis experiencing severe respiratory symptoms: Discontinue therapy and initiate corticosteroids (as indicated) until clinical symptoms resolve; therapy may be reinitiated, depending on individual circumstances.¹ If therapy is resumed, reduce dosage to 50% of the dosage previously administered.¹

Adults

Renal Cell Carcinoma

Oral

10 mg once daily.¹

Continue therapy for as long as patient derives benefit from the drug or until unacceptable toxicity occurs.¹

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, or inhibitors of P-glycoprotein.¹ (See Specific Drugs and Foods under Interactions.)

Dosage Modification for Toxicity in Renal Cell Carcinoma

Patients with radiographic changes suggestive of noninfectious pneumonitis who have few or no symptoms: May continue therapy without any dosage adjustment.¹

Patients with noninfectious pneumonitis experiencing moderate respiratory symptoms: Consider interrupting therapy and initiating corticosteroids (as indicated) until symptoms improve; if therapy is resumed, may reintroduce everolimus and reduce dosage to 5 mg once daily.¹

Patients with noninfectious pneumonitis experiencing severe respiratory symptoms: Discontinue therapy and initiate corticosteroids (as indicated) until clinical symptoms resolve; therapy may be reinitiated, depending on individual circumstances.¹ If therapy is resumed, reduce dosage to 5 mg once daily based on individual clinical assessment.¹

Subependymal Giant Cell Astrocytoma

Initial Dosage

Oral

Not studied in patients with body surface area <0.58 m².¹

Table 2. Recommended Initial Dosage in Adults with SEGA1

Body Surface Area (m2)	Initial Dosage
0.5–1.2	2.5 mg once daily
1.3–2.1	5 mg once daily
≥2.2	7.5 mg once daily

Laboratory Monitoring and Dosage Adjustments in SEGA

Adjust dosage at 2-week intervals as needed based on trough blood everolimus concentrations, tolerability, individual response, concomitant medications, and consideration of changes in SEGA volume.¹

Titrate dosage to attain trough everolimus concentrations of 5–10 ng/mL.¹ Higher trough concentrations may be associated with larger reductions in SEGA volume; however, responses have been observed at trough concentrations as low as 3 ng/mL, and additional dosage increases may not be necessary once acceptable efficacy has been achieved.¹ Limited safety experience available in patients with trough concentrations >10 ng/mL.¹

Patients with trough concentrations <5 ng/mL: May increase daily dosage by 2.5 mg every 2 weeks, subject to tolerability.¹ Limited safety experience available in patients with trough concentrations >10 ng/mL.¹

Patients with trough concentrations of 10–15 ng/mL who demonstrate tumor response and adequate tolerability: Dosage reduction not necessary.¹

Patients with trough concentrations >15 ng/mL: Reduce dosage.¹

If dosage reduction is necessary, may decrease daily dosage by 2.5 mg every 2 weeks to attain a target trough concentration of 5–10 ng/mL.¹ If dosage reduction is required in patients receiving 2.5 mg daily, use alternate-day dosing.¹

Optimal duration of therapy not known.¹

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderate inhibitors of CYP3A4, or inhibitors of P-glycoprotein.¹ (See Specific Drugs and Foods under Interactions.)

Dosage Modification for Toxicity in SEGA

Patients presenting with radiographic changes suggestive of noninfectious pneumonitis who have few or no symptoms: May continue therapy without any dosage adjustment.¹

Patients with noninfectious pneumonitis experiencing moderate respiratory symptoms: Consider interrupting therapy and initiating corticosteroids (as indicated) until symptoms improve; if therapy is resumed, may reintroduce everolimus and reduce dosage to 50% of the dosage previously administered.¹

Patients with noninfectious pneumonitis experiencing severe respiratory symptoms: Discontinue therapy and initiate corticosteroids (as indicated) until clinical symptoms resolve; therapy may be reinitiated, depending on individual circumstances.¹ If therapy is resumed, reduce dosage to 50% of the dosage previously administered.¹

Renal Allotransplantation

Initial Dosage

Oral

Initially, 0.75 mg twice daily (1.5 mg/day) at the same time as reduced-dose cyclosporine, initiated as soon as possible following transplantation.¹³

Laboratory Monitoring and Dosage Adjustment of Everolimus in Renal Allotransplantation

Adjust dosage at 4- to 5-day intervals based on trough blood everolimus concentrations, tolerability, individual response, change in concomitant medications, and clinical situation.¹³

Titrate dosage to attain therapeutic trough everolimus concentrations of 3–8 ng/mL.¹³ In clinical trials, whole blood trough concentrations of ≥3 ng/mL were associated with a lower incidence of treated biopsy-proven acute rejection.¹³ 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.¹³

Administer oral prednisone once oral medications are tolerated.¹³ Individualize tapering of steroid dosages based on patient’s clinical status and allograft function.¹³

Laboratory Monitoring and Dosage Adjustment of Cyclosporine with Everolimus in Renal Allotransplantation

Reduce cyclosporine dosage and target concentration when used in combination with everolimus to minimize the risk of nephrotoxicity.¹³ (See Renal Effects under Cautions.)

Adjust cyclosporine dosage based on whole blood trough concentrations.¹³ The recommended therapeutic range for cyclosporine is 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 12.¹³

Administer cyclosporine (USP modified) as oral capsules twice daily unless administration of oral solution or IV cyclosporine cannot be avoided.¹³ Everolimus has not been evaluated in clinical trials with other formulations of cyclosporine.¹³

Initiate cyclosporine as soon as possible and no later than 48 hours after reperfusion of the graft, and adjust the dose to target concentrations from day 5 onward.¹³ Adjust the treatment regimen if progressive impairment of renal function occurs.¹³

Data regarding everolimus dosages with reduced trough cyclosporine concentrations of 25–50 ng/mL after 12 months are limited.¹³

Prior to dose reduction of cyclosporine, verify steady-state whole blood trough everolimus concentrations of ≥3 ng/mL.¹³ Everolimus concentrations may decrease if cyclosporine exposure is reduced.¹³

Special Populations

Hepatic Impairment

Moderate (Child-Pugh class B) hepatic impairment in patients with advanced renal cell carcinoma: Decrease dosage to 5 mg daily.¹

Moderate (Child-Pugh class B) hepatic impairment in patients with renal allografts: Decrease everolimus dosage to 50% of the recommended initial daily dose; make further dose adjustments based on therapeutic drug monitoring.¹³

Severe (Child-Pugh class C) hepatic impairment in patients with advanced renal cell carcinoma or SEGA: Use not recommended.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not required.^{1 13}

Geriatric Patients

Dosage adjustment not required.^{1 13}

Cautions for Everolimus

Contraindications

• Known hypersensitivity to everolimus, other rapamycin derivatives (e.g., sirolimus, temsirolimus), or any ingredient in the formulation.^{1 13}

Warnings/Precautions

Warnings

Immunosuppression

Possible increased risk of bacterial, fungal, viral, or protozoal infections, including opportunistic infections.^{1 13} Severe or fatal localized and systemic infections (e.g., pneumonia, other bacterial infections, invasive aspergillosis or candidiasis, viral infections including reactivation of hepatitis B virus) reported.^{1 13}

Monitor vigilantly for signs and symptoms of infection and institute appropriate treatment if infection develops; consider interruption or discontinuance of everolimus therapy.¹

If invasive systemic fungal infection occurs, discontinue everolimus and initiate appropriate antifungal therapy.¹ Complete treatment of a preexisting invasive fungal infection prior to initiating therapy with everolimus.¹

Lymphomas and Other Malignancies

Immunosuppressants, including everolimus, may increase risk of development of lymphomas or other malignancies, particularly of the skin.¹³ Risk appears to be related to intensity and duration of immunosuppression rather than to the use of any specific medication.¹³

Graft Thrombosis

Increased risk of kidney arterial and venous thrombosis, resulting in graft loss and occurring primarily within the first 30 days post-transplantation, reported.¹³

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) reported with everolimus and other rapamycin derivatives.^{1 13}

Other Warnings/Precautions

Noninfectious Pneumonitis

Potentially severe or fatal noninfectious pneumonitis reported.^{1 13}

Consider the 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.^{1 13}

If moderate or severe symptoms of noninfectious pneumonitis develop, interruption or discontinuance of therapy and dose reduction may be required.¹ (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.¹³

Latent Viral Infections

Increased risk of reactivation of latent viral infections, including polyoma virus infections.¹³ BK virus-associated nephropathy (BKVAN) may result in deteriorating renal function and renal graft loss.¹³

Monitor renal transplant patients for BKVAN, and consider reduction in immunosuppression in patients who develop evidence of BKVAN.¹³

Immunization

Avoid use of live vaccines and close contact with individuals who have received live vaccines.^{1 13} Consider the timing of routine vaccinations in pediatric patients with SEGA before initiating everolimus therapy.¹

Oral Ulceration

Mouth ulcers, stomatitis, and oral mucositis, mostly grade 1 and 2, reported.¹

Topical therapy recommended if oral ulceration occurs.¹ Avoid alcohol- or peroxide-containing mouthwashes because they may exacerbate the condition.¹ Do not use antifungal agents unless fungal infection has been diagnosed.¹

Renal Effects

Increases in S_cr concentrations, usually mild, reported.^{1 2} Acute renal failure also reported.¹

Monitor renal function (e.g., BUN, S_cr) prior to and periodically during therapy.¹

Increased nephrotoxicity can occur with use of standard dosages of cyclosporine in combination with everolimus in renal transplant patients.^{13 19 20} Use reduced dosages of cyclosporine in combination with everolimus and monitor whole blood trough concentrations of everolimus and cyclosporine.¹³

Increased risk of proteinuria in patients receiving everolimus and cyclosporine; higher risk in patients with higher whole blood trough everolimus concentrations.¹³ Monitor for proteinuria.¹³

Wound Healing and Fluid Accumulation

Delayed wound healing and increased incidence of wound-related complications, including wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma, reported; may require surgical treatment.¹³ 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.¹³

Hyperglycemia and Diabetes Mellitus

Hyperglycemia reported.^{1 2 6} Monitor fasting glucose concentrations prior to and periodically during therapy; when possible, optimal glycemic control should be achieved prior to initiation of everolimus.¹

Following renal allotransplantation, increased risk of developing new-onset diabetes mellitus reported.¹³ Closely monitor glucose concentrations in patients receiving everolimus following renal allotransplantation.¹³

Hyperlipidemia

Hyperlipidemia (e.g., hypercholesterolemia, hypertriglyceridemia), possibly requiring treatment, reported;^{1 2 6 13} increased risk in patients with higher whole blood trough everolimus concentrations.¹³

Monitor fasting serum lipids prior to and periodically during therapy.¹ When possible, achieve optimal lipid control prior to initiation of therapy.¹ Treat patients who develop hyperlipidemia while receiving everolimus according to National Cholesterol Education Program guidelines.¹³

Normalization of serum lipids with antihyperlipidemic agents may not be possible in patients receiving everolimus.¹³ 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 on everolimus.¹³ Safety and efficacy of everolimus in patients with baseline cholesterol concentrations >350 mg/dL not established.¹³

GI Effects

Everolimus may cause diarrhea and malabsorption in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption; avoid everolimus use in such patients.¹³

Hematologic Effects

Anemia, lymphopenia, neutropenia, and thrombocytopenia reported.^{1 2 6} Monitor CBC prior to and periodically during therapy.¹

Interactions

Concomitant use with certain drugs (e.g., potent inhibitors of CYP3A4) or foods (e.g., grapefruit juice) is not recommended or requires adjustment of everolimus dosage (e.g., potent inducers of CYP3A4).^{1 13} (See Interactions.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.¹ No adequate and well-controlled studies in humans.^{1 12 13}

Women of childbearing potential should use an effective method of contraception during and for up to 8 weeks following discontinuance of everolimus.^{1 13}

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Impairment of Fertility

Possible impairment of male fertility (decreased fertility observed in male rats); azoospermia or oligospermia may be observed.^{1 13}

Adequate Patient Evaluation and Monitoring

Monitor fasting glucose and lipid profiles, CBC, and renal function tests prior to and periodically during therapy.¹

Specific Populations

Pregnancy

Afinitor: Category D.¹

Zortress: Category C.¹³ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 13} Patients with renal cell carcinoma or SEGA should discontinue nursing or the drug, taking into account the importance of the drug to the woman.¹ Avoid use in renal transplant patients.¹³

Pediatric Use

Safety and efficacy of everolimus for the treatment of SEGA associated with tuberous sclerosis have been evaluated in pediatric patients ≥3 years of age.¹ Safety and efficacy not established in children <3 years of age with SEGA.¹

Safety and efficacy of everolimus for the prevention of renal allograft rejection not established in pediatric patients <18 years of age.¹³

Consider the timing of routine vaccinations in pediatric patients with SEGA before initiation of everolimus therapy.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Limited clinical experience with use of everolimus following renal allotransplantation in patients ≥65 years of age.¹³

Hepatic Impairment

Not studied in patients with severe (Child-Pugh class C) hepatic impairment; use not recommended.¹

Dosage adjustment recommended for patients with advanced renal carcinoma or renal allotransplantation and moderate (Child-Pugh class B) hepatic impairment.^{1 13} (See Special Populations under Dosage and Administration.)

Adjustment of the initial dose in patients with SEGA who have moderate (Child-Pugh class B) hepatic impairment may not be required; however, individualize subsequent dosage based on therapeutic drug monitoring.¹

Dosage adjustment not required in renal transplant patients with mild (Child-Pugh Class A) hepatic impairment.¹³

Renal Impairment

Safety and efficacy in patients with renal impairment not studied specifically to date.¹ (See Special Populations under Pharmacokinetics: Elimination.)

Common Adverse Effects

In patients with renal cell carcinoma: Stomatitis,^{1 2 3} infections,^{1 2} asthenia,^{1 2 3} fatigue,^{1 2 3} diarrhea,^{1 2 3} cough,^{1 2} rash,^{1 2 3 6} anemia,¹ hypercholesterolemia,¹ increased creatinine concentrations,¹ hypertriglyceridemia,¹ hyperglycemia,¹ lymphopenia.¹

In patients with SEGA: Stomatitis,¹ upper respiratory tract infection,¹ elevated cholesterol concentrations,¹ increased ALT and AST concentrations,¹ reduced hemoglobin concentrations,¹ sinusitis,¹ otitis media,¹ hypoglycemia,¹ pyrexia,¹ hypertriglyceridemia,¹ leukocytopenia.¹

In renal transplant patients: Infections (e.g., urinary tract infection),¹³ peripheral edema,¹³ constipation,¹³ hypertension,¹³ nausea,¹³ anemia,¹³ hyperlipidemia.¹³

Interactions for Everolimus

Metabolized principally by CYP3A4; competitive inhibitor of CYP3A4 and mixed inhibitor of CYP2D6 in vitro.^{1 13} Also a substrate and moderate inhibitor of the efflux transporter P-glycoprotein.^{1 13}

Drugs and Foods Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased peak plasma concentrations and AUC of everolimus).^{1 13} Avoid concomitant use with potent CYP3A4 inhibitors.^{1 13} Reduced everolimus dosage may be required in patients who require coadministration of a moderate CYP3A4 inhibitor.^{1 13}

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased peak plasma concentrations and AUC of everolimus).^{1 13} Avoid concomitant use with potent CYP3A4 inducers; if concomitant use cannot be avoided, consider an increase in everolimus dosage.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4 and CYP2D6: Potential pharmacokinetic interaction (increased plasma substrate concentrations).¹³ Everolimus unlikely to affect metabolism of these substrates.¹ Use with caution in patients receiving CYP3A4 or CYP2D6 substrates.¹³

Drugs Affecting the P-Glycoprotein Transport System

Inhibitors of P-glycoprotein: Potential pharmacokinetic interaction (increased peak plasma concentrations and AUC of everolimus).¹ Use with caution in patients receiving P-glycoprotein inhibitors.¹ Reduced everolimus dosage may be required in patients who require coadministration of a P-glycoprotein inhibitor.¹

Nephrotoxic Agents

Potential for increased risk of nephrotoxicity with concomitant cyclosporine therapy in renal transplant patients.¹³ Use other drugs known to impair renal function concomitantly with caution.¹³

Specific Drugs and Foods

Drug	Interaction	Comments
ACE inhibitors	Possible increased risk of angioedema13
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Decreased plasma everolimus concentrations1	Renal cell carcinoma: 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 level1 12 SEGA: Avoid concomitant use; if cannot avoid, increase everolimus dosage twofold, then individualize dosage based on monitoring; if the anticonvulsant is discontinued, reduce everolimus dosage to previous level and reassess trough everolimus concentrations in approximately 2 weeks1
Antifungals, azole (fluconazole, itraconazole, ketoconazole, voriconazole)	Increased plasma everolimus concentrations1 13	Itraconazole, ketoconazole, voriconazole: Avoid concomitant use1 13 Fluconazole: Use concomitantly with caution1 13 Fluconazole in patients with renal cell carcinoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance.1 If fluconazole is discontinued, allow interval of 2–3 days before increasing everolimus dosage to the previous level1 Fluconazole in patients with SEGA: Reduce everolimus dosage by approximately 50% to maintain trough everolimus concentrations of 5–10 ng/mL; consider alternate-day dosing in patients receiving 2.5 mg daily.1 Assess trough everolimus concentrations approximately 2 weeks after initiation of fluconazole; individualize subsequent everolimus dosage based on monitoring.1 If fluconazole is discontinued, increase everolimus dosage to previous level and reassess trough everolimus concentration in approximately 2 weeks1
Antilipemic agents (HMG-CoA reductase inhibitors [statins], fibric acid derivatives)	Pharmacokinetic interaction with atorvastatin, pravastatin, or simvastatin unlikely1	Renal transplant patients: Monitor for rhabdomyolysis and other adverse effects associated with antilipemic therapy13
Antimycobacterials, rifamycins (rifabutin, rifampin, rifapentine)	Decreased plasma everolimus concentrations1 13	Renal cell carcinoma: 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 level1 12 SEGA: Avoid concomitant use. If cannot avoid, increase everolimus dosage twofold, then individualize dosage based on monitoring; if the rifamycin is discontinued, reduce everolimus dosage to previous level and reassess trough everolimus concentrations in approximately 2 weeks1 Renal transplant patients: Concomitant use with rifampin or rifabutin not recommended13
Aprepitant	Increased plasma everolimus concentrations1	Use concomitantly with caution1 Renal cell carcinoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance.1 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 weeks1 SEGA: Reduce everolimus dosage by approximately 50% to maintain trough everolimus concentrations of 5–10 ng/mL; consider alternate day dosing in patients receiving 2.5 mg daily.1 Assess trough everolimus concentrations approximately 2 weeks after initiation of aprepitant; individualize subsequent everolimus dosage based on monitoring.1 If aprepitant is discontinued, increase everolimus dosage to the previous level and reassess trough everolimus concentration in approximately 2 weeks1
Calcium-channel blocking agents (diltiazem, verapamil)	Increased plasma everolimus concentrations1 13	Use concomitantly with caution; if concomitant use required, reduced everolimus dosage may be required1 Renal cell carcinoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance.1 If moderate CYP3A4 inhibitor is discontinued, allow interval of 2–3 days before increasing everolimus dosage to previous level1 SEGA: Reduce everolimus dosage by approximately 50% to maintain trough everolimus concentrations of 5–10 ng/mL; consider alternate-day dosing in patients receiving 2.5 mg daily.1 Assess trough everolimus concentrations approximately 2 weeks after initiation of moderate CYP3A4 inhibitor; individualize subsequent everolimus dosage based on monitoring.1 If moderate CYP3A4 inhibitor is discontinued, increase everolimus dosage to previous level and reassess trough everolimus concentration in approximately 2 weeks1
Cyclosporine	Increased plasma concentrations of everolimus13 19 20 Increased risk of nephrotoxicity with concomitant use of everolimus and standard-dose cyclosporine13 Increased risk of proteinuria13 Possible increased risk of thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome13	Renal transplant patients: Use reduced-dose cyclosporine therapy and monitor renal function; consider alternate immunosuppressive therapies if renal function does not improve after dosage adjustments or if renal dysfunction is thought to be drug-related13 Dosage adjustment of everolimus may be required if cyclosporine dosage is altered13 Monitor hematologic parameters and for proteinuria13
Grapefruit or grapefruit juice	Increased plasma everolimus concentrations1 13	Avoid concomitant use1 13
HIV protease inhibitors (amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir)	Increased plasma everolimus concentrations1	Atazanavir, indinavir, nelfinavir, ritonavir, saquinavir: Avoid concomitant use1 13 Amprenavir or fosamprenavir: Use concomitantly with caution1 13 Amprenavir or fosamprenavir in patients with renal cell carcinoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance.1 If amprenavir or fosamprenavir is discontinued, allow interval of 2–3 days before increasing everolimus dosage to previous level1 Amprenavir or fosamprenavir in patients with SEGA: Reduce everolimus dosage by approximately 50% to maintain trough everolimus concentrations of 5–10 ng/mL; consider alternate day dosing in patients receiving 2.5 mg daily.1 Assess trough everolimus concentrations approximately 2 weeks after initiation of amprenavir or fosamprenavir; individualize subsequent everolimus dosage based on monitoring.1 If amprenavir or fosamprenavir is discontinued, increase everolimus dosage to previous level and reassess trough everolimus concentration in approximately 2 weeks1
Immunosuppressive agents	Increased immunosuppression and risk of infection13	Use with caution13
Macrolide antibiotics (clarithromycin, erythromycin, telithromycin)	Increased plasma everolimus concentrations1 13	Clarithromycin or telithromycin: Avoid concomitant use1 13 Erythromycin: Use concomitantly with caution1 13 Erythromycin in patients with renal cell carcinoma: Reduce everolimus dosage to 2.5 mg daily; may increase dosage to 5 mg daily based on patient tolerance.1 If erythromycin is discontinued, allow interval of 2–3 days before increasing everolimus dosage to previous level1 Erythromycin in patients with SEGA: Reduce everolimus dosage by approximately 50% to maintain trough everolimus concentrations of 5–10 ng/mL; consider alternate-day dosing in patients receiving 2.5 mg daily.1 Assess trough everolimus concentrations approximately 2 weeks after initiation of erythromycin; individualize subsequent everolimus dosage based on monitoring.1 If erythromycin is discontinued, increase everolimus dosage to previous level and reassess trough everolimus concentration in approximately 2 weeks1 If erythromycin is used in renal transplant patients, monitor everolimus concentration and adjust everolimus dosage as necessary13
Nefazodone	Increased plasma everolimus concentrations1	Avoid concomitant use1
St. John’s wort (Hypericum perforatum)	Unpredictable decreases in everolimus exposure1	Avoid concomitant use1
Vaccines	Possible decreased immune response to vaccination1	Avoid use of live vaccines1

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.^{1 13}

Increases in peak plasma concentrations dose-proportional following single doses of 5–10 mg.^{1 4 10} Peak plasma concentrations and area under the concentration-time curve (AUC) values also dose-proportional at steady state following oral dosages of 0.5–2 mg twice daily in renal allograft patients.¹³ Increases in peak plasma concentrations less than dose-proportional following single doses of ≥20 mg;^{1 4 10} considered unlikely to be clinically important.¹⁰ Increases in AUC dose-proportional over dosage range of 5–70 mg.¹

In patients with advanced solid tumors, steady-state concentrations achieved within 2 weeks of once-daily dosing.¹ 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.¹³

In patients with SEGA, intrapatient steady-state everolimus trough concentrations were dose-proportional at daily dosages of 1.5–14.6 mg/m².¹

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.¹ However, food had no apparent effect on the postabsorption phase concentration-time profile.¹

Distribution

Extent

Crosses the placenta and is distributed into milk in rats.^{1 13}

Plasma Protein Binding

Approximately 74%.^{1 13}

Special Populations

Moderate hepatic impairment does not alter plasma protein binding.^{1 13}

Elimination

Metabolism

Metabolized by CYP3A4 to inactive metabolites;^{1 10 12 13} also a substrate for P-glycoprotein.^{1 13}

Elimination Route

Excreted in feces (80%) and urine (5%) as inactive metabolites.^{1 12 13}

Half-life

Approximately 30 hours.^{1 4 13}

Special Populations

Moderate hepatic impairment increases AUC twofold.^{1 13}

No significant correlation between Cl_cr (range: 25–178 mL/minute) and everolimus clearance; renal impairment not expected to influence drug exposure.¹

Higher exposure to everolimus among Japanese patients compared with non-Japanese patients; relevance to safety and efficacy not established.¹

Clearance is 20% higher in black patients than in Caucasian patients; relevance to safety and efficacy not established.¹

Stability

Storage

Oral

Tablets

Original container at 25°C (may be exposed to 15–30°C); protect from light and moisture.^{1 13}

Actions

• Inhibits mammalian target of rapamycin (mTOR) kinase.^{1 2 3 4 5 7 8 9 10 11}

• Inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.¹³

• Binds with high affinity to the intracellular protein FK506 binding protein-12 (FKBP-12), forming a drug-protein complex (mTORC1 or everolimus: FKBP-12) that binds to and inhibits the activation of mTOR.^{1 2 5 6 9 10 13}

• 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.^{4 6 9 10 11 13}

• The everolimus: FKBP-12 complex has no effect on calcineurin activity.¹³

• Also inhibits expression of hypoxia-inducible factor (e.g., HIF-1α), thereby reducing the expression of vascular endothelial growth factor (VEGF).^{1 7 9}

• Reduces cell proliferation, angiogenesis, and glucose uptake in vitro and/or in vivo.^{1 5 10}

• 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.¹ In the genetic disorder tuberous sclerosis, inactivating mutations in the TSC1 or TSC2 gene leads to hematoma formation throughout the body.¹ SEGA may develop in patients with tuberous sclerosis.^{1 17}

Advice to Patients

• Importance of providing patient a copy of manufacturer’s patient information (Afinitor) or medication guide (Zortress).^{1 13 14 15}

• Importance of taking everolimus tablets as directed either consistently with food or consistently without food; take at the same time each day (or twice daily approximately 12 hours apart), swallowing the tablets whole with a glass of water.^{1 13 14 15}

• For patients who are unable to swallow tablets, disperse everolimus (Afinitor) tablets in a glass of water (containing approximately 30 mL) by gently stirring immediately prior to drinking.^{1 14} Rinse the glass with an additional 30 mL of water and completely swallow the rinse to ensure administration of the entire dose.^{1 14}

• Importance of storing everolimus (Afinitor) tablets in the original package and keeping the blister package and tablets dry and protected from light.^{1 14} Importance of opening the blister package (scissors may be used to avoid spillage) immediately prior to taking everolimus.¹⁴ Importance of keeping everolimus (Zortress) tablets dry and protected from light.¹⁵

• If a dose of everolimus (Afinitor) is missed by ≤6 hours, take dose as soon as it is remembered, and take the next dose at the regularly scheduled time; if a dose is missed by >6 hours, omit the dose and take the next dose at the regularly scheduled time.^{1 14} Do not take a double dose to make up for a missed dose.^{1 14}

• Importance of informing patients about risks, including serious allergic reactions (e.g., anaphylaxis), noninfectious pneumonitis, and increased susceptibility to infection.^{1 13 14 15} Importance of patients promptly reporting any facial swelling,¹² new or worsening respiratory symptoms (e.g., cough, shortness of breath, difficulty breathing, wheezing), or any signs or symptoms of infection (e.g., fever, chills).^{1 13 14 15}

• Risk of reactivation of hepatitis B virus infection.^{1 14} Importance of promptly reporting any signs and symptoms of possible hepatis B virus infection (e.g., loss of appetite, pale stool or dark urine, yellowing of the skin, pain in upper right side).^{1 14}

• Risk of malignancy, including lymphoma and skin cancer.^{13 15} Importance of limiting exposure to sunlight and ultraviolet light by wearing protective clothing and using sunscreen with a high protection factor.^{13 15}

• Risk of new-onset diabetes mellitus; importance of reporting any signs or symptoms of diabetes mellitus (e.g., frequent urination, increased thirst or hunger).^{13 15}

• Risk of mouth ulcers, stomatitis, or oral mucositis.^{1 14} Importance of reporting any signs or symptoms of oral ulceration (e.g., pain, discomfort, or open sores in the mouth).^{1 14} Use of mouthwashes and/or topical treatments is recommended; however, avoid alcohol- or peroxide-containing preparations.^{1 14}

• Risk of kidney arterial and venous thrombosis leading to graft loss in renal transplant recipients; usually occurs within first 30 days after transplantation.^{13 15} Importance of promptly reporting any signs and symptoms of possible kidney thrombosis (e.g., pain in groin, lower back, side, or stomach, decreased urination, blood in urine or dark colored urine, fever, nausea, or vomiting).¹⁵

• Risk of BK virus-associated nephropathy (BKVAN), which may result in deteriorating renal function and renal graft loss.^{13 15}

• Risk of proteinuria in patients receiving everolimus following renal allotransplantation.^{13 15}

• Risk of angioedema; risk may be increased by concomitant use of ACE inhibitors.^{13 15} Importance of seeking prompt medical attention if symptoms (e.g., sudden swelling of face, mouth, throat, tongue, or hands, hives or welts, itchy or painful swollen skin, trouble breathing) develop.^{13 15}

• Risk of impaired wound healing and fluid accumulation.^{13 15} Importance of careful observation of incision site in patients who have undergone renal allotransplantation; promptly inform healthcare provider if incision is red, warm, or painful; if there is blood, fluid, or pus in incision; if incision opens up; or in case of swelling of incision.^{13 15}

• Risk of increased blood glucose, triglyceride, and/or cholesterol concentrations; risk of adverse renal and hematologic effects.^{1 13 15} Fasting glucose and lipid profiles, CBC, and renal and liver function tests are required; importance of adherence to laboratory appointment schedules.^{1 13 14 15}

• Need for therapeutic drug monitoring in patients receiving everolimus for the treatment of SEGA or for the prevention of rejection of renal allografts; importance of adherence to laboratory appointment schedules.^{1 13 14 15}

• Importance of avoiding use of live vaccines and close contact with those who have received live vaccines.^{1 13 14 15}

• Importance of avoiding grapefruit and grapefruit juice during everolimus therapy.^{1 13 14 15}

• Importance of informing clinicians of hereditary disorders of galactose intolerance (Lapp-lactase deficiency or glucose-galactose malabsorption); avoid Zortress therapy in patients with these conditions.^{13 15}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs 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).^{1 14 15}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women of childbearing potential to avoid pregnancy and to use effective contraceptive methods during therapy and for 8 weeks following discontinuance of therapy.^{1 13 14 15} Risk of male infertility (low or no sperm count).¹⁵

• Importance of informing patients of other important precautionary information.^{1 13} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

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
		10 mg	Afinitor	Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Zortress 0.25MG Tablets (NOVARTIS): 30/$195.99 or 90/$555.97