Everolimus

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

REMS:

FDA approved a REMS for everolimus to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of everolimus and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

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

Uses for Everolimus

Renal Cell Carcinoma

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

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

Everolimus Dosage and Administration

Administration

Oral Administration

Administer orally once daily^{1 2 3} at the same time every day with or without food.¹

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

Dosage

Adults

Renal Cell Carcinoma

General Dosage

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 CYP3A4.¹ (See Interactions.)

Dosage Modification for Toxicity

Temporarily interrupt therapy or reduce everolimus dosage to 5 mg once daily if severe and/or intolerable adverse effects (e.g., noninfectious pneumonitis, invasive fungal infection) occur.¹

Noninfectious Pneumonitis

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

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

Patients experiencing severe respiratory symptoms: Discontinue everolimus therapy and initiate corticosteroids (as indicated) until clinical symptoms resolve; when therapy is resumed, reduce everolimus dosage to 5 mg once daily based on individual clinical assessment.¹

Invasive Fungal Infection

Discontinue everolimus and initiate appropriate antifungal therapy.¹

Special Populations

Hepatic Impairment

Moderate (Child-Pugh class B) hepatic impairment: Decrease dosage to 5 mg daily.¹

Severe (Child-Pugh class C) hepatic impairment: Use not recommended.¹ (See Hepatic Impairment under Precautions.)

Renal Impairment

Dosage adjustment not required.¹

Geriatric Patients

Dosage adjustment not required.¹

Cautions for Everolimus

Contraindications

• 
  

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

  
  

Warnings/Precautions

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

Noninfectious Pneumonitis

Potentially severe or fatal noninfectious pneumonitis reported.¹

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

If moderate or severe symptoms of noninfectious pneumonitis develop, temporarily interrupt therapy and reduce subsequent dosage.¹ (See Dosage Modification for Toxicity under Dosage and Administration.)

Immunosuppression

Immunosuppression may occur and may predispose patients to infections, particularly opportunistic infections.¹ Potentially severe or fatal localized and systemic infections (e.g., pneumonia, other bacterial infections, invasive aspergillosis or candidiasis) reported.¹

Monitor vigilantly for signs and symptoms of infection and institute appropriate treatment.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

Avoid use of live vaccines and close contact with individuals who have received live vaccines.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 topical preparations containing an antifungal agent 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

Hyperglycemia

Hyperglycemia reported.^{1 2 6}

Monitor fasting glucose concentrations prior to and periodically during therapy.¹ When possible, achieve optimal glycemic control prior to initiation of everolimus therapy.¹

Hyperlipemia

Hyperlipidemia (e.g., hypercholesterolemia, hypertriglyceridemia) reported.^{1 2 6}

Monitor serum lipids prior to and periodically during therapy.¹ When possible, achieve optimal lipid control prior to initiation of therapy.¹

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., moderate or 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 (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}

Women of childbearing potential should use an effective method of contraception during and for up to 8 weeks following discontinuance of therapy.¹

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

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

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing or the drug, taking into account the importance of the drug to the woman.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

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

Hepatic Impairment

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

Dosage adjustment recommended for patients with moderate (Child-Pugh class B) hepatic impairment.¹ (See Special Populations under Dosage and Administration)

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

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} nausea,^{1 2} peripheral edema,¹ anorexia,^{1 2} dyspnea,^{1 2} vomiting,^{1 2} pyrexia,¹ mucosal inflammation,^{1 2} headache,¹ epistaxis,¹ pneumonitis,^{1 2} pruritus,¹ dry skin,^{1 2} dysgeusia,¹ pain in extremity.¹

Interactions for Everolimus

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

Drugs and Foods Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased peak plasma concentrations and AUC of everolimus).¹ Avoid concomitant use with potent or moderately potent CYP3A4 inhibitors.¹ (See Specific Drugs and Foods under Interactions.)

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased peak plasma concentrations and AUC of everolimus).¹ Avoid concomitant use with potent CYP3A4 inducers; if concomitant use cannot be avoided, consider an increase in everolimus dosage.¹ (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4 and CYP2D6: Pharmacokinetic interaction unlikely.¹

Drugs Affecting the P-Glycoprotein Transport System

Inhibitors of P-glycoprotein: Potential pharmacokinetic interaction (increased peak plasma concentrations and AUC of everolimus).¹ Avoid concomitant use with P-glycoprotein inhibitors.¹

Inducers of P-glycoprotein: Potential pharmacokinetic interaction.¹ If concomitant use with potent P-glycoprotein inducers cannot be avoided, consider an increase in everolimus dosage.¹

Specific Drugs and Foods

Drug	Interaction	Comments
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Decreased plasma everolimus concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, increase everolimus dosage from 10 to 20 mg daily (titrated in 5-mg increments); if potent CYP3A4 inducer is discontinued, reduce everolimus dosage to the usual recommended dosage1 12
Antifungals, azole (fluconazole, ketoconazole, itraconazole, voriconazole)	Increased plasma everolimus concentrations1	Avoid concomitant use1
Antimycobacterials, rifamycins (rifabutin, rifampin)	Decreased plasma everolimus concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, increase everolimus dosage from 10 to 20 mg daily (titrated in 5-mg increments); if potent CYP3A4 inducer is discontinued, reduce everolimus dosage to the usual recommended dosage1 12
Aprepitant	Increased plasma everolimus concentrations1	Avoid concomitant use1
Calcium-channel blocking agents (diltiazem, verapamil)	Increased plasma everolimus concentrations1	Avoid concomitant use1
Delavirdine	Increased plasma everolimus concentrations1	Avoid concomitant use1
Dexamethasone	Decreased plasma everolimus concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, increase everolimus dosage from 10 to 20 mg daily (titrated in 5-mg increments); if potent CYP3A4 inducer is discontinued, reduce everolimus dosage to the usual recommended dosage1 12
Grapefruit juice	Increased plasma everolimus concentrations1	Avoid concomitant use1
HIV protease inhibitors (amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir)	Increased plasma everolimus concentrations1	Avoid concomitant use1
HMG-CoA reductase inhibitors (atorvastatin, pravastatin, simvastatin)	Pharmacokinetic interaction unlikely1
Macrolide antibiotics (clarithromycin, erythromycin, telithromycin)	Increased plasma everolimus concentrations1	Avoid concomitant use1
Nefazodone	Increased plasma everolimus concentrations1	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

Increases in peak plasma concentrations dose-proportional following single doses of 5–10 mg.^{1 4 10} 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

Steady-state concentrations achieved within 2 weeks of once-daily dosing.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.^a However, food had no apparent effect on the post absorption phase concentration-time profile.^a

Distribution

Extent

Crosses the placenta and is distributed into milk in rats.¹

Plasma Protein Binding

Approximately 74%.¹

Special Populations

Moderate hepatic impairment does not alter plasma protein binding.¹

Elimination

Metabolism

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

Elimination Route

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

Half-life

Approximately 30 hours.^{1 4}

Special Populations

Moderate hepatic impairment increases AUC twofold.¹

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.¹ However, relevance to safety and efficacy of everolimus in Japanese patients not established.¹

Clearance is 20% higher in black patients than in Caucasian patients.¹ However, relevance to safety and efficacy of everolimus in black patients 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

Actions

• 
  

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

  
  


• 
  

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

  
  


• 
  

  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}

  
  


• 
  

  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}

  
  

Advice to Patients

• 
  

  Importance of providing patient a copy of manufacturer’s patient information.¹

  
  


• 
  

  Importance of taking everolimus tablets as directed; take at the same time each day, swallowing the tablets whole with a glass of water.¹

  
  


• 
  

  If a dose of everolimus 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 Do not take a double dose to make up for a missed dose.¹

  
  


• 
  

  Importance of informing patients about risks, including serious allergic reactions (e.g., anaphylaxis), noninfectious pneumonitis, and increased susceptibility to infection.¹ 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

  
  


• 
  

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

  
  


• 
  

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

  
  


• 
  

  Importance of avoiding use of live vaccines and close contact with those who have received live vaccines.¹

  
  


• 
  

  Importance of avoiding grapefruit juice during everolimus therapy.¹

  
  


• 
  

  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).¹

  
  


• 
  

  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

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (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	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 10/2011. 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

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis Pharmaceuticals Inc. Afinitor (everolimus) tablets prescribing information. East Hanover, NJ: 2009 Mar.

2. Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008; 372:449-56. [PubMed 18653228]

3. Kay A, Motzer R, Figlin R, et al. Updated data from a phase III randomized trial of everolimus (RAD001) versus PBO in metastatic renal cell carcinoma (mRCC). Abstract No. 278. Presented at ASCO Genitourinary Symposium, Orlando FL, 28 Mar 2009.

4. Dasanu CA, Clark BA, Alexandrescu DT et al. mTOR-blocking agents in advanced renal cancer: an emerging therapeutic option. Expert Opin Investig Drugs. 2009; 18:175-87. [PubMed 19236264]

5. Tanaka C, O'Reilly T, Kovarik JM et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol. 2008; 26:1596-602. [PubMed 18332467]

6. Hudes GR. Targeting mTOR in renal cell carcinoma. Cancer. 2009; 115:2313-2320. [PubMed 19402072]

7. Motzer RJ, Bukowski RM. Targeted therapy for metastatic renal cell carcinoma. J Clin Oncol. 2006; 24:5601-8. [PubMed 17158546]

8. Atkins MB, Ernstoff MS, Figlin RA et al. Innovations and challenges in renal cell carcinoma: summary statement from the Second Cambridge Conference. Clin Cancer Res. 2007; 13:667s-670s. [PubMed 17255291]

9. Cho D, Signoretti S, Regan M et al. The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res. 2007; 13:758s-763s. [PubMed 17255306]

10. O'Donnell A, Faivre S, Burris HA et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol. 2008; 26:1588-95. [PubMed 18332470]

11. Reddy GK, Mughal TI, Rini BI. Current data with mammalian target of rapamycin inhibitors in advanced-stage renal cell carcinoma. Clin Genitourin Cancer. 2006; 5:110-3. [PubMed 17026798]

12. Novartis Pharmaceuticals Corporation, East Hanover, NJ: Personal communication.

a. Novartis Pharmaceuticals Inc. Afinitor (everolimus) tablets prescribing information. East Hanover, NJ: 2010 May.

More Everolimus resources

• Everolimus Side Effects (in more detail)
• Everolimus Dosage
• Everolimus Use in Pregnancy & Breastfeeding
• Everolimus Drug Interactions
• Everolimus Support Group
• 1 Review for Everolimus - Add your own review/rating

• Everolimus Professional Patient Advice (Wolters Kluwer)


• Everolimus MedFacts Consumer Leaflet (Wolters Kluwer)


• everolimus Advanced Consumer (Micromedex) - Includes Dosage Information


• Afinitor Consumer Overview


• Afinitor Prescribing Information (FDA)


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• Zortress MedFacts Consumer Leaflet (Wolters Kluwer)


• Zortress Consumer Overview

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