Everolimus (DB01590): A Comprehensive Monograph on its Pharmacology, Clinical Applications, and Safety Profile

Introduction and Drug Profile

Overview and Identification

Everolimus is a seminal small molecule drug, a derivative of sirolimus, that functions as a potent and selective inhibitor of the mammalian target of rapamycin (mTOR) kinase, a central regulator of cellular growth, proliferation, and metabolism.[1] This compound occupies a unique position in modern pharmacotherapy, embodying a dual identity as both a targeted antineoplastic agent and a critical immunosuppressant in the context of solid organ transplantation.[3] Its development and application highlight the therapeutic potential of modulating fundamental cellular signaling pathways. The clinical utility of everolimus spans a diverse range of conditions, from advanced cancers of the breast, kidney, and neuroendocrine system to the prevention of organ rejection and the management of benign tumors in the genetic disorder tuberous sclerosis complex. This monograph provides a comprehensive analysis of its chemical properties, pharmacological profile, clinical efficacy, and safety considerations, offering a detailed perspective on its role in contemporary medicine.

Key Identifiers:

• DrugBank ID: DB01590 [5]
• CAS Number: 159351-69-6 [6]
• Type: Small Molecule [5]
• Molecular Formula: C53​H83​NO14​ [6]
• Molecular Weight: 958.22 g/mol [6]
• Harmonized System (HS) Code: 294190 [7]
• RTECS Number: VE6255000 [9]

Synonyms and Commercial Formulations

To ensure clarity in clinical and research settings, it is essential to recognize the various nomenclatures for everolimus. Its chemical and research synonyms reflect its structure as a rapamycin derivative, while its commercial brand names are deliberately segregated by therapeutic area—a critical strategy to ensure patient safety.

Chemical and Research Synonyms:

The compound is frequently referred to in scientific literature by its research code, RAD001, or by its chemical descriptor, 40-O-(2-Hydroxyethyl)rapamycin. Other synonyms include 42-O-(2-Hydroxy)ethyl Rapamycin, NVP-RAD001, and SDZRAD.6

Commercial Brand Names:

The manufacturer, Novartis, has implemented a sophisticated risk mitigation strategy by marketing everolimus under distinct brand names with different dosage strengths for its oncology and transplant indications. This separation is not a trivial marketing decision but a fundamental safety measure designed to prevent potentially catastrophic medication errors. An accidental substitution of a high-dose oncology tablet for a low-dose transplant tablet could lead to life-threatening over-immunosuppression and toxicity. This approach creates a "firewall" between disparate patient populations and streamlines regulatory and reimbursement pathways for each distinct use case.

• Oncology Formulations:
• Afinitor®: This brand is indicated for the treatment of various cancers.[3] It is supplied as oral tablets in higher strengths suitable for oncologic dosing, including 2.5 mg, 5 mg, 7.5 mg, and 10 mg.[12]
• Afinitor Disperz®: These are tablets for oral suspension, designed for pediatric patients or adults who have difficulty swallowing.[12] They are available in 2 mg, 3 mg, and 5 mg strengths.[12] It is critical to note that Afinitor® and Afinitor Disperz® are not interchangeable on a milligram-for-milligram basis and should not be combined to achieve a dose.[11]
• Votubia®: In the European Union and other regions, this brand name is used specifically for the treatment of tumors associated with Tuberous Sclerosis Complex (TSC).[3]
• Transplantation Formulations:
• Zortress® (United States): This brand is used for the prophylaxis of organ rejection following kidney and liver transplantation.[3] It is available in significantly lower strengths to allow for precise, individualized dosing based on therapeutic drug monitoring: 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg tablets.[12]
• Certican® (European Union and other countries): This is the corresponding international brand name for the transplant indication.[3]

Physicochemical Properties

The physical and chemical characteristics of everolimus are integral to its formulation, handling, and biological activity.

• Source and Appearance: Everolimus is a semi-synthetic macrolide, derived from rapamycin (sirolimus), which is itself a fermentation product of the bacterium Streptomyces hygroscopicus.[9] It presents as a white to off-white solid or powder.[8]
• Purity and Formulation: For research and pharmaceutical use, it is available in high purity, typically ≥98%, and is used as a certified reference and pharmaceutical primary standard.[6] Its classification as a "potentially dangerous good" necessitates special shipping and handling protocols.[7]
• Solubility: Everolimus exhibits poor aqueous solubility, with less than 1 mg/ml dissolving in water at 25°C.[6] In contrast, it is highly soluble in organic solvents such as dimethyl sulfoxide (DMSO) (100 mg/ml), ethanol (100 mg/ml), methanol, and chloroform.[6] This lipophilic nature facilitates its passage across cell membranes but necessitates its formulation into solid oral dosage forms (tablets or dispersible tablets) for clinical use.
• Stability and Storage: The compound is stable for at least four years when stored at -20°C, protected from light and moisture.[9] It is typically shipped at ambient temperature for short durations.[9]

Historical Development and Regulatory Milestones

The trajectory of everolimus from a laboratory compound to a multi-indication therapeutic agent reflects a highly successful drug development strategy by Novartis. It was conceived as an incremental innovation—a derivative of an existing molecule—but evolved to achieve breakthrough applications that surpassed the scope of its parent compound.

• Origins and Rationale: Everolimus was developed as a 40-O-(2-hydroxyethyl) derivative of sirolimus with the specific goal of improving upon the pharmacokinetic (PK) properties of the parent drug, particularly its oral bioavailability and predictability.[3] This improved PK profile likely made it a more manageable and reliable agent for the rigorous demands of large-scale clinical trials, especially in oncology.
• Early Development and Legal Hurdles: Clinical development programs were initiated by Novartis in 1996, with Phase III trials for organ transplant rejection commencing by the end of 1998.[16] The program faced significant legal challenges in 1999 when American Home Products (AHP) filed a patent infringement lawsuit related to the use of sirolimus in transplantation. Novartis successfully defended its position, with key court rulings in its favor in 2000, which allowed the clinical development to proceed unimpeded.[17]
• Chronology of Key FDA Approvals: The following timeline of approvals from the U.S. Food and Drug Administration (FDA) illustrates the progressive expansion of its therapeutic indications, first in transplantation and then more broadly across oncology:
• March 2009: Approved for advanced renal cell carcinoma (RCC).[3]
• April 2010: Approved for the prophylaxis of kidney transplant rejection.[3]
• October 2010: Approved for subependymal giant cell astrocytoma (SEGA) associated with TSC.[3]
• May 2011: Approved for progressive pancreatic neuroendocrine tumors (PNET).[3]
• July 2012: Approved for advanced hormone receptor-positive (HR+), HER2-negative breast cancer.[3]
• February 2013: Approved for the prophylaxis of liver transplant rejection.[3]
• February 2016: Approved for progressive, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin.[3]
• April 2018: Approved for TSC-associated partial-onset seizures.[3]

Comprehensive Pharmacology

The clinical utility of everolimus is rooted in its precise and potent modulation of the mTOR signaling pathway. Its pharmacological profile—encompassing its mechanism of action, pharmacodynamics, and pharmacokinetics—is essential for understanding its therapeutic effects, predicting its adverse reactions, and guiding its safe and effective use.

Mechanism of Action: The mTORC1 Inhibition Cascade

Everolimus is an allosteric inhibitor of mTOR, exerting its effects through a well-defined molecular cascade.[2] Its mechanism is notable for its high specificity for one of the two major mTOR complexes.

1. Intracellular Binding and Complex Formation: After oral administration and absorption, everolimus passively diffuses across the cell membrane into the cytoplasm. There, it binds with high affinity to an abundant intracellular protein known as the FK506 Binding Protein-12 (FKBP-12).[9]
2. Selective Inhibition of mTORC1: The formation of the everolimus-FKBP12 complex is the critical first step. This complex then acts as the functional inhibitor, binding to the FRB (FKBP-Rapamycin Binding) domain of the mTOR protein. This interaction occurs specifically when mTOR is part of the multiprotein complex known as mTOR Complex 1 (mTORC1), which also contains the regulatory protein Raptor.[2] This binding allosterically inhibits the kinase activity of mTORC1, preventing it from phosphorylating its downstream targets.[11] Everolimus is considered more selective for mTORC1 than its parent compound, sirolimus, with less impact on the distinct mTOR Complex 2 (mTORC2), which contains the protein Rictor. This selectivity may contribute to a more favorable side effect profile, particularly concerning glucose metabolism, which is more strongly influenced by mTORC2.[2]
3. Downstream Cellular Consequences: The inhibition of mTORC1 kinase activity triggers a cascade of effects that collectively account for the drug's therapeutic actions:

• Inhibition of Protein Synthesis and Cell Cycle Arrest: mTORC1 normally promotes cell growth by phosphorylating two key downstream effectors: p70 ribosomal S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1).[2] By blocking this phosphorylation, everolimus prevents the release of the translation initiation factor eIF-4E from 4E-BP1. This halts the cap-dependent translation of a specific subset of mRNAs that encode proteins essential for cell proliferation and survival, such as cyclins and c-myc. The ultimate outcome is a blockage of cell cycle progression from the G1 phase into the S phase, leading to cytostatic growth arrest and, in some contexts, apoptosis and autophagy.[2]
• Anti-Angiogenic Effects: Everolimus suppresses the translation of hypoxia-inducible factors (HIFs), particularly HIF-1α.[2] HIFs are master regulators of the cellular response to low oxygen levels and drive the expression of pro-angiogenic factors, most notably Vascular Endothelial Growth Factor (VEGF). By reducing HIF and subsequently VEGF expression, everolimus inhibits angiogenesis, the process of forming new blood vessels, which is critical for starving tumors of the blood supply they need to grow and metastasize.[19]
• Immunosuppressive Effects: In lymphocytes, the mTOR pathway is critical for transducing signals from cytokines like Interleukin-2 (IL-2), which drive T-cell activation and proliferation. By blocking this pathway, everolimus prevents the clonal expansion of T-cells in response to alloantigens, which is the foundational mechanism for its use in preventing organ transplant rejection.[12]

Pharmacodynamics: Linking Concentration to Effect

Pharmacodynamics (PD) describes the relationship between drug concentration and its physiological and therapeutic effects. For everolimus, understanding this relationship is crucial for optimizing dosing to achieve a balance between efficacy and toxicity, defining what can be considered its therapeutic window.

• Biomarkers of Target Engagement: In clinical development, the inhibition of S6K1 phosphorylation in peripheral blood mononuclear cells (PBMCs) served as a key surrogate biomarker to confirm that everolimus was engaging its target in humans.[19] Dose-escalation studies demonstrated that oral doses of 20 mg per week or higher were sufficient to inhibit S6K1 activity for at least seven days, providing a rationale for the weekly and daily dosing regimens ultimately selected for clinical use.[23]
• Concentration-Toxicity Relationship: A clear and direct relationship exists between everolimus exposure, typically measured as the trough whole blood concentration (Ctrough​), and the risk of adverse events.
• In renal transplant recipients, dose levels of 10 mg daily were associated with a significantly higher incidence and severity of adverse events, most notably thrombocytopenia, compared to lower doses.[25]
• More recently, a study in patients with metastatic breast cancer (mBC) provided a more precise threshold. It found that the Ctrough​ was significantly higher in patients who developed dose-limiting toxicities (DLTs) such as severe stomatitis. The analysis identified an optimal Ctrough​ cutoff of 17.3 ng/mL for predicting the development of DLTs.[26] This finding suggests a clear upper boundary for safe dosing.
• Concentration-Efficacy Relationship: The link between drug concentration and therapeutic efficacy is more nuanced and indication-specific.
• In transplantation and Tuberous Sclerosis Complex (TSC), where under-dosing can lead to clear negative outcomes (rejection or tumor growth), therapeutic drug monitoring (TDM) is standard practice. The goal is to maintain the everolimus Ctrough​ within a target therapeutic range, generally 3-8 ng/mL for transplant recipients and 5-15 ng/mL for patients with TSC-associated tumors.[13]
• The picture in oncology is more complex and challenges a simple "more is better" assumption. The same mBC study that identified a toxicity threshold of 17.3 ng/mL also observed that the median progression-free survival (PFS) was numerically longer in patients whose steady-state Ctrough​ was maintained below this threshold (327 days vs. 194 days).[26] While this difference was not statistically significant in the small study, it raises a critical clinical question. The toxicities themselves (e.g., severe stomatitis, fatigue) can force dose interruptions or discontinuations, thereby reducing the total time the patient receives effective therapy and ultimately compromising the overall clinical benefit. This suggests that the optimal strategy may be to maintain a dose that provides sufficient, sustained mTOR inhibition while remaining well-tolerated, rather than pushing to the maximum tolerated dose. This makes a compelling case for exploring TDM in the oncology setting to personalize dosing and maximize the duration of benefit.
• Pharmacogenetic Influences: Emerging evidence indicates that a patient's genetic makeup can influence their pharmacodynamic response. Single nucleotide polymorphisms (SNPs) in genes of the PI3K/AKT/mTOR pathway have been linked to variability in treatment-related toxicities and clinical outcomes, suggesting a potential future role for pharmacogenetic testing to predict which patients are at higher risk.[27]

Pharmacokinetics: The Drug's Journey Through the Body

The pharmacokinetic (PK) profile of everolimus—its absorption, distribution, metabolism, and excretion (ADME)—is dominated by its interaction with the CYP3A4 enzyme system. This single characteristic is the organizing principle for its clinical management, dictating its dosing, food effects, and extensive potential for drug interactions.

Table 1: Key Pharmacokinetic Parameters of Everolimus

Parameter	Value / Description	Clinical Implication	Source(s)
Absorption
Oral Bioavailability	~30%	Moderate bioavailability; oral route is viable.	11
Time to Peak (T_max)	1–2 hours	Rapid absorption after oral dose.	11
Food Effect	High-fat meal decreases C_max by up to 60% and AUC by 16%.	Must be taken consistently with or without food to ensure predictable exposure.	11
Distribution
Plasma Protein Binding	~74%	Moderately bound to plasma proteins.	11
Blood-Brain Barrier	Crosses the blood-brain barrier.	Relevant for its efficacy in treating CNS tumors like SEGA.	11
Metabolism
Primary Pathway	Extensively metabolized by hepatic CYP3A4; also a substrate of P-glycoprotein (P-gp).	This is the basis for numerous and significant drug-drug and drug-food interactions.	11
Metabolites	6 main metabolites identified; all are ~100 times less active than the parent drug.	Everolimus itself is the primary active moiety; metabolites do not contribute significantly to effect.	11
Excretion
Primary Route	Feces (~80% as metabolites)	Primarily eliminated via the biliary system.	11
Secondary Route	Urine (~5% as metabolites)	Minimal renal elimination of the drug.	11
Terminal Half-Life (t₁/₂)	~30 hours	Supports once-daily dosing regimens in oncology.	11
Population PK
Hepatic Impairment	Clearance is significantly reduced.	Dose reduction is mandatory in patients with liver dysfunction.	13
Genetic Variation	CYP3A4*22 allele carriers have higher blood concentrations.	Provides a genetic explanation for some inter-patient variability in exposure.	27

The centrality of CYP3A4 and P-gp in the metabolism and efflux of everolimus cannot be overstated. It positions the drug as one that requires a high degree of pharmacological vigilance. Safe and effective prescribing is contingent upon a thorough review of all concomitant medications and comprehensive patient education regarding food interactions, particularly the strict avoidance of grapefruit. This dependency on a single, highly variable metabolic pathway underscores the indispensable role of clinical pharmacists in multidisciplinary teams that manage patients receiving everolimus therapy.

Clinical Efficacy and Therapeutic Applications

The clinical utility of everolimus is a tale of two distinct strategies, both stemming from its core mechanism of mTOR inhibition. In oncology, it is primarily employed to overcome or delay resistance to other targeted therapies by blocking a critical cellular escape pathway. In transplant medicine, it is valued for its synergistic effect with calcineurin inhibitors (CNIs), enabling a dose-reduction strategy that mitigates the toxicity of the partner drug. This versatility highlights the adaptability of a single molecule to address different clinical challenges.

Application in Oncology (Afinitor® / Afinitor Disperz®): Targeting the mTOR Pathway in Cancer

Everolimus is approved for several cancers where the PI3K/AKT/mTOR pathway is either a primary driver of tumorigenesis or becomes activated as a mechanism of resistance to other treatments.[4]

• Advanced Breast Cancer:
• Indication: Everolimus is indicated for postmenopausal women with advanced hormone receptor-positive (HR+), HER2-negative breast cancer. It is used in combination with the steroidal aromatase inhibitor exemestane following disease progression on a non-steroidal aromatase inhibitor (letrozole or anastrozole).[3]
• Clinical Rationale: In HR+ breast cancer, prolonged endocrine therapy can lead to the development of resistance, often mediated by the upregulation of alternative signaling pathways, including the PI3K/AKT/mTOR cascade. By inhibiting mTOR, everolimus effectively blocks this escape route, restoring sensitivity to endocrine treatment.[27]
• Pivotal Evidence: The approval was based on the landmark BOLERO-2 trial, which demonstrated that the addition of everolimus to exemestane more than doubled the median progression-free survival compared to exemestane alone.[27] Numerous subsequent trials have further explored its use in this setting, often in combination with other endocrine agents like fulvestrant or letrozole.[31]
• Neuroendocrine Tumors (NETs):
• Indication: Everolimus is approved for the treatment of progressive, well-differentiated, non-functional NETs of pancreatic (PNET), gastrointestinal (GI), or lung origin that are unresectable, locally advanced, or metastatic.[3]
• Pivotal Evidence: The RADIANT-3 trial (NCT00510068) established its efficacy in advanced PNET, showing a significant extension in median PFS from 4.6 months with placebo to 11.0 months with everolimus.[30] The RADIANT-4 trial expanded this indication to non-functional GI and lung NETs, demonstrating a 52% reduction in the risk of disease progression and an extension of median PFS to 11.0 months versus 3.9 months for placebo.[30]
• Renal Cell Carcinoma (RCC):
• Indication: It is approved as a second-line therapy for advanced RCC after the failure of treatment with VEGF-targeted agents like sunitinib or sorafenib.[3]
• Pivotal Evidence: The approval was based on a pivotal trial showing that everolimus significantly delayed tumor growth and disease progression compared to placebo in this patient population.[30]
• Tuberous Sclerosis Complex (TSC)-Associated Tumors:
• Clinical Rationale: TSC is a genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes, which are key negative regulators of mTOR. Loss of their function leads to constitutive, unchecked activation of the mTORC1 pathway, driving the formation of benign tumors (hamartomas) in multiple organs. This makes TSC-related tumors exquisitely sensitive to mTOR inhibition.[35]
• Approved Indications:

1. Subependymal Giant Cell Astrocytoma (SEGA): For adult and pediatric patients (aged 1 year and older) with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected.[3] Studies like the EFFECTS trial have confirmed high rates of tumor volume reduction and durable responses.[37]
2. Renal Angiomyolipoma: For adults with TSC-associated renal angiomyolipomas who do not require immediate surgery.[13]
3. Partial-Onset Seizures: As an adjunctive therapy for the treatment of TSC-associated partial-onset seizures in patients aged 2 years and older.[3]

Application in Transplant Medicine (Zortress® / Certican®): A Calcineurin Inhibitor-Sparing Strategy

In transplant medicine, everolimus functions as a proliferation signal inhibitor, providing immunosuppression through a mechanism distinct from that of calcineurin inhibitors (CNIs) like cyclosporine and tacrolimus. This allows for its use in synergistic, CNI-sparing regimens.

• Prophylaxis of Organ Rejection:
• Indication: Everolimus is approved for the prophylaxis of organ rejection in adult patients at low-to-moderate immunologic risk who are recipients of a kidney transplant or a liver transplant.[3]
• Combination Therapy Rationale: The primary goal of using everolimus in transplantation is to enable a reduction in the dose of the co-administered CNI. Standard doses of CNIs are associated with significant and often irreversible nephrotoxicity. The synergistic immunosuppressive effect achieved by combining the two drug classes allows for effective rejection prophylaxis while using lower, less toxic doses of the CNI, thereby preserving long-term kidney function.[12] The standard regimen involves everolimus in combination with reduced-dose cyclosporine (in kidney transplant) or reduced-dose tacrolimus (in liver transplant), along with corticosteroids.[13]
• Specific Considerations and Limitations: The timing of everolimus initiation post-transplant is a critical consideration, reflecting a delicate balance between providing immunosuppression and avoiding interference with surgical healing. The drug's anti-proliferative and anti-angiogenic properties, while beneficial in oncology, can be detrimental to the re-vascularization and healing of a newly implanted organ. This tension has led to specific, indication-dependent protocols.
• Liver Transplant: Initiation of everolimus is explicitly delayed until at least 30 days after transplantation. Earlier administration was associated with an unacceptably high risk of hepatic artery thrombosis, a devastating complication that can lead to graft loss and death.[13] This delay allows for initial anastomotic healing to occur before the anti-proliferative drug is introduced.
• Kidney Transplant: In contrast, everolimus is typically initiated as soon as possible after transplantation.[13] However, this practice is accompanied by a boxed warning for an increased risk of kidney graft thrombosis (both arterial and venous), which occurs most frequently within the first 30 days post-transplant.[12]
• Heart Transplant: Everolimus is not recommended for use in heart transplant recipients. A clinical trial in de novo heart transplant patients showed an increased risk of mortality within the first three months, often related to severe infections.[12]
• High Immunologic Risk: The safety and efficacy of everolimus have not been established in kidney transplant recipients who are at high immunologic risk (e.g., repeat transplant recipients, patients with high panel-reactive antibodies).[13]

Safety Profile and Risk Management

The safety profile of everolimus is complex and directly linked to its mechanism of action. Inhibiting a central cellular pathway like mTOR inevitably leads to a constellation of on-target effects in healthy, rapidly dividing tissues. This results in a predictable set of adverse reactions that require vigilant monitoring and proactive management. The most serious risks are encapsulated in FDA boxed warnings, while a broader range of common and class-effect toxicities necessitates a high degree of clinical awareness.

Boxed Warnings: The Most Serious Risks

The U.S. FDA has mandated boxed warnings for everolimus (under the Zortress® brand for transplantation), highlighting risks that can lead to severe morbidity or mortality.[39]

• Malignancies and Serious Infections: As an immunosuppressant, everolimus increases the patient's susceptibility to infections from bacteria, fungi, viruses, and protozoa, including opportunistic pathogens. These infections can be severe and potentially fatal. The immunosuppression also elevates the long-term risk of developing malignancies, particularly lymphoma and skin cancer. Management of patients on everolimus should be conducted by physicians experienced in immunosuppressive therapy in facilities with adequate supportive resources.
• Kidney Graft Thrombosis: There is a heightened risk of arterial and venous thrombosis in the transplanted kidney, which can result in graft loss. This risk is most acute within the first 30 days following transplantation.
• Nephrotoxicity: The concomitant use of everolimus with standard doses of cyclosporine can lead to increased kidney toxicity. It is mandatory to use a reduced dose of cyclosporine in combination with everolimus and to perform therapeutic drug monitoring of both agents to mitigate this risk.
• Mortality in Heart Transplantation: Use of everolimus in de novo heart transplant recipients is not recommended due to an observed increase in mortality, often associated with serious infections, within the first three months post-transplant in a pivotal clinical trial.

Contraindications and Precautions

• Contraindication: The only absolute contraindication to everolimus is a history of a clinically significant hypersensitivity reaction to everolimus itself, to other rapamycin derivatives (sirolimus, temsirolimus), or to any of the excipients in the formulation.[11]
• Key Precautions and Warnings:
• Non-infectious Pneumonitis / Interstitial Lung Disease (ILD): This is a serious and potentially fatal class effect of mTOR inhibitors. Patients may present with non-specific respiratory symptoms such as cough, dyspnea, or hypoxia. A diagnosis of non-infectious pneumonitis should be considered after infectious causes have been ruled out. Patients must be advised to report any new or worsening respiratory symptoms promptly. Management is based on severity and may require dose reduction or permanent discontinuation.[4]
• Impaired Wound Healing: As a proliferation inhibitor, everolimus can delay or impair wound healing. Caution is advised during the peri-surgical period, and patients should be monitored for wound complications like dehiscence or fluid accumulation.[4]
• Angioedema: An increased risk of angioedema (swelling of the face, mouth, and airways) has been observed, particularly in patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril, ramipril). This can be a life-threatening emergency.[12]
• Embryo-Fetal Toxicity: Everolimus can cause harm to a developing fetus. Women of reproductive potential must use effective contraception during treatment and for 8 weeks after the final dose. Male patients with female partners of reproductive potential should also use effective contraception during treatment and for 4 weeks after the final dose.[41]
• Male Infertility: Cases of azoospermia (absence of sperm) and oligospermia (low sperm count) have been reported, which may affect male fertility.[11]
• Vaccinations: The immune response to vaccines may be diminished. The use of live attenuated vaccines should be avoided during everolimus therapy due to the risk of infection from the vaccine strain.[28]

Adverse Drug Reactions

The adverse reactions to everolimus are largely predictable consequences of inhibiting the fundamental mTOR pathway in various tissues. The high rate of cell turnover in the oral mucosa, the role of mTOR in metabolic regulation, and its importance for hematopoietic cell proliferation directly explain the most common toxicities. This understanding shifts the clinical approach from simply reacting to side effects to anticipating and proactively managing them.

Table 2: Common and Serious Adverse Reactions with Incidence Rates

System Organ Class	Adverse Reaction	Incidence Range (%)	Severity / Management Notes	Source(s)
Gastrointestinal	Stomatitis (mouth ulcers, mucositis)	44 - 77	Most common ADR; typically occurs within 8 weeks. Prophylactic steroid mouthwash recommended. Dose modification based on grade.	4
	Diarrhea	30 - 58	Generally manageable with supportive care.	4
	Nausea	26 - 41	Usually well-controlled with antiemetics.	11
Metabolic/Endocrine	Hyperglycemia	12 - 57	Class effect. Requires regular glucose monitoring. May require anti-diabetic agents. Dose hold for Grade 3/4.	11
	Hypercholesterolemia	20 - 77	Class effect. Requires regular lipid monitoring. May require statin therapy.	11
	Hypertriglyceridemia	15 - 73	Class effect. Requires regular lipid monitoring.	11
Respiratory	Non-infectious Pneumonitis / ILD	14 - 19	Potentially fatal class effect. Requires high index of suspicion for new respiratory symptoms. Management is grade-dependent; Grade 3/4 requires permanent discontinuation.	11
	Cough	30	Very common, but must be evaluated to rule out pneumonitis or infection.	11
	Epistaxis (Nosebleed)	12 - 23	Common; usually mild.	25
Dermatologic	Rash	20 - 59	Usually maculopapular; manageable with topical therapies.	42
	Pruritus (Itching)	19 - 39	Common; manageable with supportive care.	42
Hematologic	Anemia	38 - 92	Very common. Requires regular CBC monitoring.	11
	Thrombocytopenia	7 - 34	Dose-limiting toxicity. Requires dose modification for Grade ≥2.	11
	Neutropenia / Leukopenia	3 - 14	Increases infection risk. Dose modification for Grade ≥3.	11
General	Fatigue / Asthenia	31 - 51	Very common and can be dose-limiting.	4
	Peripheral Edema	25 - 42	Common; may require supportive management.	11
Infections	Infections (all types)	37 - 59	Increased risk of bacterial, viral, fungal infections. Pneumonia is common (6%). Reactivation of latent viruses (HBV, BK virus) is a key concern.	11
Renal	Increased Serum Creatinine / Renal Failure	3 - 50	Risk of nephrotoxicity, especially with CNIs. Requires renal function monitoring.	11
	Proteinuria	Common	Monitor urine protein, especially at higher trough concentrations.	41

Management of Toxicities

Successful therapy with everolimus hinges on a proactive management strategy that anticipates, monitors for, and rapidly addresses its common and serious toxicities.

• Stomatitis: This is the most frequent adverse event. Prophylactic use of a dexamethasone-based, alcohol-free oral solution (swish and spit) is recommended to reduce its incidence and severity. Patients should be advised to maintain good oral hygiene and avoid mouthwashes containing alcohol, hydrogen peroxide, iodine, or thyme, as these can exacerbate the condition. For established stomatitis, management is grade-based, involving dose interruption for Grade ≥2 and dose reduction upon recurrence.[13]
• Non-infectious Pneumonitis: Clinicians must maintain a high index of suspicion for any new or worsening respiratory symptoms. Baseline and periodic monitoring of pulmonary function and imaging may be warranted. Management is strictly dictated by the grade of toxicity. Grade 2 pneumonitis requires withholding the drug until symptoms resolve to Grade ≤1, followed by resumption at a 50% reduced dose. If symptoms do not resolve within 4 weeks, or if toxicity recurs at Grade 3, permanent discontinuation is necessary. Grade 4 pneumonitis requires immediate and permanent discontinuation.[13]
• Metabolic Events: Regular monitoring of fasting serum glucose and lipid profiles is mandatory. Hyperglycemia may require the initiation or adjustment of oral hypoglycemic agents or insulin. Hyperlipidemia may necessitate treatment with statins or other lipid-lowering agents. For Grade 3 or 4 metabolic events, everolimus should be withheld until improvement, with consideration for dose reduction upon resumption.[13]
• Hematologic Toxicities: Complete blood counts (CBC) should be monitored regularly. For thrombocytopenia or neutropenia, dose interruption is required for Grade ≥2 or Grade 3, respectively. The dose may be resumed at the same or a reduced level once the counts have recovered to a safe level (e.g., Grade ≤1).[13]

Dosing, Administration, and Therapeutic Monitoring

The dosing of everolimus is highly specific to the indication and the target patient population, reflecting the different therapeutic goals in oncology versus transplantation. Administration guidelines are critical to ensure consistent absorption, and therapeutic drug monitoring (TDM) is a cornerstone of its use in certain settings to optimize the efficacy-to-toxicity ratio.

Dosing Regimens by Indication

The separation of brand names (Afinitor® vs. Zortress®) corresponds directly to the vastly different dosing regimens required for cancer and transplant patients.

Table 3: Dosing and Administration Summary by Indication

Indication	Brand Name(s)	Starting Dose	Dosing Frequency	Key Administration & Monitoring Notes	Source(s)
ONCOLOGY
Advanced Breast Cancer	Afinitor®	10 mg	Once Daily	Take consistently with or without food. Used with exemestane.	13
Advanced NET (Pancreatic, GI, Lung)	Afinitor®	10 mg	Once Daily	Take consistently with or without food.	13
Advanced Renal Cell Carcinoma (RCC)	Afinitor®	10 mg	Once Daily	Take consistently with or without food.	13
TSC - Renal Angiomyolipoma	Afinitor®	10 mg	Once Daily	Take consistently with or without food.	13
TSC - SEGA	Afinitor®, Afinitor Disperz®	4.5 mg/m²	Once Daily	Dose based on Body Surface Area (BSA). TDM required; target trough 5-15 ng/mL.	13
TSC - Partial-Onset Seizures	Afinitor Disperz®	5 mg/m²	Once Daily	Dose based on BSA. TDM required; target trough 5-15 ng/mL.	13
TRANSPLANTATION
Kidney Transplant Rejection Prophylaxis	Zortress®	0.75 mg	Twice Daily (q12h)	Start ASAP post-transplant. Use with reduced-dose cyclosporine. TDM required; target trough 3-8 ng/mL.	13
Liver Transplant Rejection Prophylaxis	Zortress®	1.0 mg	Twice Daily (q12h)	Delay start until ≥30 days post-transplant. Use with reduced-dose tacrolimus. TDM required; target trough 3-8 ng/mL.	13

Administration Guidelines

Proper administration is crucial for achieving consistent drug exposure and minimizing variability.

• Consistency with Food: Due to the significant effect of high-fat meals on absorption, everolimus must be taken consistently, either always with food or always without food, at the same time each day.[13]
• Tablet Handling:
• Afinitor® / Zortress® Tablets: These tablets must be swallowed whole with a glass of water. They should never be crushed, broken, or chewed. If a tablet is accidentally broken, hands should be washed immediately.[13]
• Afinitor Disperz® (Tablets for Oral Suspension): These tablets must not be swallowed whole. They are to be prepared as a suspension in water immediately prior to administration, using either an oral syringe or a small glass. The suspension should be administered within 60 minutes of preparation. Detailed instructions for mixing and administration are provided in the patient information leaflet and should be followed precisely.[38]
• Missed Doses: If a dose is missed, it can be taken up to 6 hours after the usual time. If more than 6 hours have passed, the missed dose should be skipped, and the next dose should be taken at the regular time. Patients should not take a double dose to make up for a missed one.[38]

Dose Adjustments

Dose modifications are frequently required to manage toxicities or to account for changes in organ function or concomitant medications.

• For Adverse Reactions: Detailed guidelines exist for dose interruption, reduction, or discontinuation based on the grade of toxicity for non-infectious pneumonitis, stomatitis, other non-hematologic toxicities, and hematologic toxicities (thrombocytopenia, neutropenia).[13] In general, Grade 2 toxicities may require a dose hold and resumption at the same or reduced dose, while Grade 3 or 4 toxicities often necessitate a dose hold followed by a 50% dose reduction or permanent discontinuation.
• For Hepatic Impairment: Everolimus clearance is significantly reduced in patients with liver dysfunction. Dose reductions are mandatory.
• For oncology indications (e.g., breast cancer, RCC), the dose is reduced based on the Child-Pugh class: to 7.5 mg daily for mild (Class A), 5 mg daily for moderate (Class B), and 2.5 mg daily for severe (Class C) impairment.[13]
• For transplant indications, the daily dose is reduced by approximately one-third for mild impairment and by one-half for moderate-to-severe impairment.[13]
• For Drug Interactions: Dose adjustments are critical when co-administering with drugs that affect the CYP3A4 enzyme. These are detailed in Section 6.

Therapeutic Drug Monitoring (TDM)

TDM involves measuring whole blood trough concentrations (Ctrough​) of everolimus to guide dosing. This practice is essential for indications where a clear therapeutic window has been established.

• Rationale: TDM helps to individualize therapy, ensuring that drug exposure is sufficient for efficacy while remaining below levels associated with significant toxicity. This is particularly important given the inter-patient variability in everolimus pharmacokinetics.
• Application:
• Transplantation (Kidney and Liver): TDM is standard of care. The goal is to maintain the everolimus Ctrough​ within the target range of 3-8 ng/mL. Dosing adjustments are based on trough levels measured 4-5 days after a dose change.[13]
• TSC-Associated Tumors (SEGA and Seizures): TDM is also required for these indications. Doses are titrated to achieve and maintain a target trough concentration of 5-15 ng/mL. Monitoring is recommended 1-2 weeks after initiation or dose modification, and periodically thereafter.[13]
• Oncology (e.g., Breast Cancer, RCC): TDM is not currently standard practice for these indications, which use a fixed-dose approach. However, given the emerging evidence linking trough concentrations to both toxicity and potentially efficacy, the role of TDM in the broader oncology setting is an area of active investigation and clinical interest.[26]

Drug and Food Interactions

The clinical use of everolimus is profoundly influenced by its potential for numerous and significant interactions with other drugs, supplements, and certain foods. The vast majority of these interactions stem from its primary metabolic pathway: everolimus is a sensitive substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme and the P-glycoprotein (P-gp) efflux transporter.[11] Therefore, any substance that inhibits or induces this system can dramatically alter everolimus concentrations, leading to either increased toxicity or loss of efficacy.

CYP3A4 and P-glycoprotein Interactions

Clinicians must conduct a thorough medication review before initiating everolimus and exercise extreme caution when adding or discontinuing any concomitant medication.

Table 4: Clinically Significant Drug Interactions and Management Strategies

Interacting Drug/Class	Mechanism	Effect on Everolimus / Patient	Recommended Management	Source(s)
STRONG CYP3A4/P-gp INHIBITORS
Azole Antifungals (e.g., ketoconazole, itraconazole, posaconazole)	Strong CYP3A4/P-gp Inhibition	Dramatically increases everolimus concentration and risk of toxicity. Co-administration with ketoconazole increased everolimus AUC by 15-fold.	Avoid concomitant use.	28
Protease Inhibitors (e.g., ritonavir, atazanavir, indinavir)	Strong CYP3A4/P-gp Inhibition	Dramatically increases everolimus concentration and risk of toxicity.	Avoid concomitant use.	28
Certain Antibiotics (e.g., clarithromycin, telithromycin)	Strong CYP3A4/P-gp Inhibition	Dramatically increases everolimus concentration and risk of toxicity.	Avoid concomitant use.	28
MODERATE CYP3A4/P-gp INHIBITORS
Calcium Channel Blockers (e.g., verapamil, diltiazem)	Moderate CYP3A4/P-gp Inhibition	Increases everolimus concentration.	Reduce everolimus dose. For 10 mg daily indications, reduce to 2.5 mg daily. Monitor trough levels if applicable.	13
Certain Antibiotics (e.g., erythromycin)	Moderate CYP3A4/P-gp Inhibition	Increases everolimus concentration.	Reduce everolimus dose. For 10 mg daily indications, reduce to 2.5 mg daily.	13
Other (e.g., cyclosporine, fluconazole, aprepitant)	Moderate CYP3A4/P-gp Inhibition	Increases everolimus concentration.	Reduce everolimus dose and monitor closely.	28
STRONG CYP3A4/P-gp INDUCERS
Anticonvulsants (e.g., carbamazepine, phenytoin, phenobarbital)	Strong CYP3A4/P-gp Induction	Dramatically decreases everolimus concentration, risking loss of efficacy (e.g., tumor progression, organ rejection).	Avoid if possible. If unavoidable, double the everolimus daily dose (may require multiple increments). Monitor trough levels closely.	13
Rifampin, Rifabutin	Strong CYP3A4/P-gp Induction	Dramatically decreases everolimus concentration.	Avoid concomitant use.	28
St. John's Wort (Herbal Supplement)	Strong CYP3A4/P-gp Induction	Dramatically decreases everolimus concentration.	Concomitant use is contraindicated. Patients must be specifically counseled against using this supplement.	28
OTHER INTERACTIONS
Angiotensin-Converting Enzyme (ACE) Inhibitors (e.g., lisinopril, ramipril)	Pharmacodynamic Interaction	Increased risk of angioedema.	Monitor closely for signs of angioedema (swelling of face, lips, tongue, airways).	12
Live Vaccines (e.g., MMR, varicella, yellow fever)	Pharmacodynamic Interaction	Everolimus is an immunosuppressant. Live vaccines can cause disseminated infection.	Live vaccines are contraindicated during treatment.	28
Benzodiazepines (e.g., midazolam, alprazolam)	CYP3A4 Inhibition by Everolimus	Everolimus can inhibit the metabolism of certain benzodiazepines, increasing their concentration and risk of sedation.	Use with caution; may require dose reduction of the benzodiazepine.	28
Statins (e.g., atorvastatin, simvastatin)	CYP3A4 Inhibition by Everolimus	Everolimus may increase concentrations of statins metabolized by CYP3A4, increasing the risk of muscle-related side effects like rhabdomyolysis.	Use with caution and monitor for muscle toxicity.	28

Food Interactions

• Grapefruit and Grapefruit Juice: This is the most critical food interaction. Grapefruit is a potent inhibitor of intestinal CYP3A4. Consuming grapefruit or its juice can dramatically increase the absorption and bioavailability of everolimus, leading to unpredictable and dangerously high drug levels and an increased risk of severe toxicity. Patients must be explicitly and repeatedly counseled to avoid all grapefruit products for the duration of their treatment.[13]
• High-Fat Meals: As noted in the pharmacokinetics section, high-fat meals can significantly decrease the absorption of everolimus. To ensure consistent drug exposure, patients should be instructed to take their medication at the same time each day and to be consistent with regard to food intake (i.e., always with food or always without food).[11]

Comparative Analysis and Future Directions

Everolimus belongs to the class of mTOR inhibitors, which also includes its parent compound, sirolimus, and the prodrug, temsirolimus. Understanding the distinctions between these agents is crucial for clinical decision-making. Furthermore, the therapeutic landscape for everolimus continues to evolve, with numerous ongoing clinical trials exploring its potential in new combinations and indications.

Comparison with Other mTOR Inhibitors

While all three agents target the mTOR pathway, they have distinct pharmacokinetic profiles, routes of administration, and approved clinical indications.

• Everolimus vs. Sirolimus:
• Structure and PK: Everolimus is the 40-O-(2-hydroxyethyl) derivative of sirolimus, a structural modification designed to improve its pharmacokinetic profile.[3] Everolimus has a shorter half-life (~30 hours) compared to sirolimus (~62-78 hours), allowing it to reach steady-state concentrations faster and be eliminated more quickly after discontinuation.[36] It also has greater oral bioavailability, as sirolimus is more susceptible to intestinal efflux.[36]
• Indications: This is the most significant differentiator. While both are used for transplant rejection prophylaxis (sirolimus primarily for kidney), everolimus has a much broader portfolio of approved oncology indications, including breast cancer, RCC, and various NETs, for which sirolimus is not approved.[3] In the context of TSC, everolimus holds FDA approvals for SEGA and renal angiomyolipoma, whereas sirolimus, despite being studied, does not.[35]
• Formulations: Both are available as oral tablets. However, the relative hydrophobicity of sirolimus allows it to be compounded into topical formulations for treating TSC-related facial angiofibromas, an application for which everolimus is not used.[36]
• Everolimus vs. Temsirolimus:
• Structure and Administration: Temsirolimus is an ester analog of sirolimus and functions as a prodrug.[55] It is administered intravenously (IV), whereas everolimus is an orally active drug.[3] Temsirolimus is converted in the body to its active metabolite, which is sirolimus itself.[56]
• Pharmacokinetics: Temsirolimus has a shorter half-life (~17 hours) than its active metabolite, sirolimus (~55 hours).[57]
• Indications: Temsirolimus is approved primarily for the treatment of advanced renal cell carcinoma.[55] Its range of approved indications is much narrower than that of everolimus.

Ongoing Research and Clinical Trials

The clinical development of everolimus is far from over. It is being actively investigated in numerous clinical trials, reflecting its established role as a valuable combination partner for other targeted agents and chemotherapies.

• New Combinations in Oncology: Many ongoing trials are exploring everolimus in combination with other novel agents.
• Breast Cancer: Trials are combining everolimus with CDK4/6 inhibitors (e.g., ribociclib, abemaciclib), PI3K inhibitors (e.g., alpelisib), and other targeted therapies (e.g., belzutifan, elacestrant) in patients with HR+ breast cancer, often after progression on initial therapies (NCT06105632).[60] This strategy aims to block multiple resistance pathways simultaneously.
• Renal Cell Carcinoma: Studies are evaluating everolimus in combination or sequence with other tyrosine kinase inhibitors like lenvatinib and cabozantinib.[61]
• Neuroendocrine Tumors: A trial is directly comparing the novel agent zanzalintinib against everolimus in patients with advanced NETs, positioning everolimus as the standard-of-care comparator.[61]
• Other Cancers: Everolimus is being tested in combination regimens for T-cell lymphoblastic leukemia/lymphoma, glioblastoma, and various solid tumors with specific genetic mutations (e.g., KRAS p.G12C).[33]
• Exploring New Indications and Uses:
• Central Nervous System (CNS) Metastases: A completed Phase 1b/2 trial (NCT01783756) investigated everolimus in a triplet combination with lapatinib and capecitabine for HER2-positive breast cancer that has metastasized to the brain, leveraging its ability to cross the blood-brain barrier.[62]
• Supportive Care: A terminated Phase 0 trial (NCT03578432) explored the potential of everolimus to restore salivary gland function in head and neck cancer patients with radiation-induced dry mouth, a novel application based on its effects on cell proliferation and regeneration.[63]

Future Perspectives

The future role of everolimus in medicine will likely be defined by its integration into more personalized and combination-oriented treatment paradigms. In oncology, as the understanding of tumor biology deepens, everolimus will continue to be a rational partner for agents that target parallel or upstream pathways (e.g., PI3K, CDK4/6). The development of predictive biomarkers beyond simple pathway activation will be key to identifying the patients most likely to benefit. Furthermore, the potential application of TDM in the oncology setting could refine dosing, potentially improving the duration of therapy and overall outcomes by minimizing dose-limiting toxicities. In transplantation, its role as a CNI-sparing agent is well-established, but future research may focus on further optimizing regimens and expanding its use to other organ types or higher-risk patient populations, if safety can be demonstrated.

Conclusion and Expert Recommendations

Everolimus (DB01590) stands as a paradigm of modern drug development, a molecule that has successfully transitioned from a second-generation derivative to a cornerstone therapy in two distinct and demanding fields: oncology and transplant medicine. Its potent and selective inhibition of the mTORC1 signaling pathway provides a robust mechanism for its cytostatic, anti-angiogenic, and immunosuppressive effects. This dual identity is managed through a sophisticated and necessary strategy of separate branding, formulations, and dosing regimens (Afinitor® for oncology; Zortress®/Certican® for transplantation), which is critical for preventing medication errors and ensuring patient safety.

The pharmacological profile of everolimus is fundamentally defined by its role as a sensitive substrate for the CYP3A4 enzyme and P-glycoprotein. This characteristic, while making it susceptible to a vast array of drug-drug and drug-food interactions, also provides a clear framework for its clinical management. Safe and effective use of everolimus is not possible without a high degree of pharmacological vigilance, including meticulous medication reconciliation and comprehensive patient counseling, particularly regarding the avoidance of grapefruit and certain herbal supplements like St. John's Wort.

In clinical practice, everolimus has demonstrated unequivocal efficacy. In oncology, it serves as a vital tool to overcome or delay therapeutic resistance in advanced breast cancer, renal cell carcinoma, and a range of neuroendocrine tumors. In transplant medicine, it is a key component of calcineurin inhibitor-sparing regimens, enabling effective immunosuppression while mitigating the long-term nephrotoxicity associated with standard CNI therapy.

However, this efficacy is balanced by a complex and predictable safety profile. The majority of its adverse effects—including stomatitis, metabolic disturbances (hyperglycemia, hyperlipidemia), myelosuppression, and non-infectious pneumonitis—are direct, on-target consequences of inhibiting the fundamental mTOR pathway. This reality underscores that "targeted therapy" is not synonymous with "non-toxic therapy" and necessitates a proactive approach to management. Clinical success with everolimus depends on anticipating these toxicities, educating patients on early symptom reporting, and implementing timely, grade-based interventions to maintain patients on therapy safely.

Expert Recommendations for Optimal Use:

1. Emphasize Multidisciplinary Management: Due to its complex profile, the management of patients on everolimus should be a collaborative effort involving the prescribing physician, a clinical pharmacist to manage interactions, and specialized nurses for patient education and toxicity monitoring.
2. Prioritize Proactive Toxicity Management: Clinicians should implement proactive strategies, such as prescribing prophylactic steroid mouthwash to mitigate stomatitis and establishing regular monitoring schedules for blood counts, lipids, and glucose from the outset of therapy.
3. Consider Therapeutic Drug Monitoring (TDM) in Oncology: While not yet standard of care, the emerging evidence linking everolimus trough concentrations to both toxicity and efficacy in oncology warrants consideration. For patients experiencing borderline toxicity or suboptimal response, TDM could be a valuable tool to personalize dosing and potentially improve outcomes.
4. Adhere Strictly to Transplant-Specific Protocols: The timing of initiation in transplant recipients is critical. The mandated 30-day delay in liver transplantation to avoid hepatic artery thrombosis must be strictly followed. Vigilant monitoring for graft thrombosis in the early post-operative period is essential for all transplant patients.

In summary, everolimus is a powerful and versatile therapeutic agent whose benefits, when used appropriately, are substantial. Its successful application requires a deep understanding of its pharmacology, a respect for its safety profile, and a commitment to a proactive, vigilant, and patient-centered approach to care. Its ongoing study in novel combinations promises to further expand its role in the treatment of cancer and other proliferative diseases.

Works cited

1. go.drugbank.com, accessed July 16, 2025, https://go.drugbank.com/drugs/DB01590#:~:text=Everolimus%20is%20a%20mammalian%20target,treat%20various%20types%20of%20malignancies.&text=Everolimus%20is%20a%20derivative%20of,mammalian%20target%20of%20rapamycin)%20inhibitor.%2520inhibitor.&sa=D&source=editors&ust=1752663668955497&usg=AOvVaw2xkwB77S_WpuhDjOAc602k)
2. Biomarker Development for the Clinical Activity of the mTOR Inhibitor Everolimus (RAD001): Processes, Limitations, and Further Proposals, accessed July 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2847314/
3. Everolimus - Wikipedia, accessed July 16, 2025, https://en.wikipedia.org/wiki/Everolimus
4. Everolimus: Understanding the Differences Between Afinitor and Zortress - QuickRx, accessed July 16, 2025, https://quickrxspecialty.pharmacy/everolimus-understanding-the-differences-between-afinitor-and-zortress/
5. Everolimus: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 16, 2025, https://go.drugbank.com/drugs/DB01590
6. Everolimus | CAS 159351-69-6 | SCBT - Santa Cruz Biotechnology, accessed July 16, 2025, https://www.scbt.com/p/everolimus-159351-69-6
7. [Everolimus (300 mg)] - CAS [159351-69-6] - USP Store, accessed July 16, 2025, https://store.usp.org/product/1268976
8. CAS 159351-69-6 - Sigma-Aldrich, accessed July 16, 2025, https://www.sigmaaldrich.com/US/en/search/159351-69-6?focus=products&page=1&perpage=30&sort=relevance&term=159351-69-6&type=cas_number
9. Everolimus | CAS 159351-69-6 - Order from Adipogen Life Sciences, accessed July 16, 2025, https://adipogen.com/ag-cn2-0520-everolimus.html
10. Everolimus (RAD001, CAS Number: 159351-69-6) | Cayman Chemical, accessed July 16, 2025, https://www.caymanchem.com/product/11597/everolimus
11. DRUG NAME: Everolimus - BC Cancer, accessed July 16, 2025, http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Everolimus_monograph.pdf
12. Everolimus: Uses, Dosage, Side Effects, Warnings - Drugs.com, accessed July 16, 2025, https://www.drugs.com/everolimus.html
13. Afinitor, Zortress (everolimus) dosing, indications, interactions, adverse effects, and more, accessed July 16, 2025, https://reference.medscape.com/drug/afinitor-zortress-everolimus-999101
14. Everolimus (Afinitor & Zortress): Uses & Side Effects - Cleveland Clinic, accessed July 16, 2025, https://my.clevelandclinic.org/health/drugs/20760-everolimus-tablets
15. Clinical pharmacokinetics of everolimus - PubMed, accessed July 16, 2025, https://pubmed.ncbi.nlm.nih.gov/14748618/
16. Development of everolimus, a novel oral mTOR inhibitor, across a ..., accessed July 16, 2025, https://pubmed.ncbi.nlm.nih.gov/23659703/
17. Everolimus Novartis | Request PDF - ResearchGate, accessed July 16, 2025, https://www.researchgate.net/publication/11637246_Everolimus_Novartis
18. everolimus | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed July 16, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=5889
19. Everolimus: An Review on the Mechanism of Action and Clinical Data - ChemicalBook, accessed July 16, 2025, https://www.chemicalbook.com/article/everolimus-an-review-on-the-mechanism-of-action-and-clinical-data.htm
20. Sirolimus | Vidium Animal Health, accessed July 16, 2025, https://vidiumah.com/wp-content/uploads/2022/03/Sirolimus-Monograph.pdf
21. Biomarker Development for the Clinical Activity of the mTOR ..., accessed July 16, 2025, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847314/
22. What is the mechanism of Everolimus? - Patsnap Synapse, accessed July 16, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-everolimus
23. Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral ..., accessed July 16, 2025, https://ascopubs.org/doi/10.1200/JCO.2007.14.0988
24. Everolimus (Afinitor®) | OncoLink, accessed July 16, 2025, https://www.oncolink.org/cancer-treatment/oncolink-rx/everolimus-afinitor-R
25. Tolerability and steady-state pharmacokinetics of everolimus in maintenance renal transplant patients - Oxford Academic, accessed July 16, 2025, https://academic.oup.com/ndt/article/19/10/2606/1925553
26. Real-world pharmacokinetics and pharmacodynamics of everolimus in metastatic breast cancer - PubMed, accessed July 16, 2025, https://pubmed.ncbi.nlm.nih.gov/34041638/
27. Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer - Our journal portfolio - PLOS, accessed July 16, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180192
28. Review of Pharmacology: Drug Interactions - Everolimus (Afinitor) - NCBI Bookshelf, accessed July 16, 2025, https://www.ncbi.nlm.nih.gov/books/NBK525613/
29. Everolimus - NCI, accessed July 16, 2025, https://www.cancer.gov/about-cancer/treatment/drugs/everolimus
30. Afinitor | European Medicines Agency (EMA), accessed July 16, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/afinitor
31. Everolimus Completed Phase 2 Trials for Breast Cancer Treatment | DrugBank Online, accessed July 16, 2025, https://go.drugbank.com/drugs/DB01590/clinical_trials?conditions=DBCOND0028036&phase=2&purpose=treatment&status=completed
32. Everolimus Completed Phase 2 Trials for Advanced Breast Cancer Treatment - DrugBank, accessed July 16, 2025, https://go.drugbank.com/drugs/DB01590/clinical_trials?conditions=DBCOND0031019&phase=2&purpose=treatment&status=completed
33. Search for: "Everolimus" | Card Results - ClinicalTrials.gov, accessed July 16, 2025, https://www.clinicaltrials.gov/search?intr=%22Everolimus%22&viewType=Table
34. Novartis drug Afinitor® significantly improves progression-free survival in advanced nonfunctional gastrointestinal and lung NET, accessed July 16, 2025, https://www.novartis.com/news/media-releases/novartis-drug-afinitor-significantly-improves-progression-free-survival-advanced-nonfunctional-gastrointestinal-and-lung-net
35. Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex - ResearchGate, accessed July 16, 2025, https://www.researchgate.net/publication/281171702_Differentiating_the_mTOR_inhibitors_everolimus_and_sirolimus_in_the_treatment_of_tuberous_sclerosis_complex
36. Differentiating the mTOR inhibitors everolimus and sirolimus in the ..., accessed July 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4633932/
37. Everolimus (Afinitor) - CancerIndex, accessed July 16, 2025, http://www.cancerindex.org/Everolimus
38. Everolimus (oral route) - Mayo Clinic, accessed July 16, 2025, https://www.mayoclinic.org/drugs-supplements/everolimus-oral-route/description/drg-20072842
39. HIGHLIGHTS OF PRESCRIBING INFORMATION These ... - Novartis, accessed July 16, 2025, https://www.novartis.com/us-en/sites/novartis_us/files/zortress.pdf
40. Everolimus Monograph for Professionals - Drugs.com, accessed July 16, 2025, https://www.drugs.com/monograph/everolimus.html
41. Label: EVEROLIMUS tablet - DailyMed, accessed July 16, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=59cb86d5-8706-4619-b074-af253d3e0b68
42. Afinitor, INN-everolimus - EMA, accessed July 16, 2025, https://www.ema.europa.eu/en/documents/product-information/afinitor-epar-product-information_en.pdf
43. Everolimus: side effect profile and management of toxicities in breast cancer - PubMed, accessed July 16, 2025, https://pubmed.ncbi.nlm.nih.gov/23907751/
44. Everolimus (Afinitor) | Cancer information - Cancer Research UK, accessed July 16, 2025, https://www.cancerresearchuk.org/about-cancer/treatment/drugs/everolimus
45. Afinitor and Interactions: Other Drugs, Supplements, and More, accessed July 16, 2025, https://www.healthline.com/health/drugs/afinitor-interactions
46. Everolimus - Macmillan Cancer Support, accessed July 16, 2025, https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/everolimus
47. Afinitor (Everolimus Tablets): Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed July 16, 2025, https://www.rxlist.com/afinitor-drug.htm
48. Everolimus Food, Alcohol, Supplements and Drug Interactions - ScriptSave WellRx, accessed July 16, 2025, https://www.wellrx.com/everolimus/lifestyle-interactions/
49. Drug Monograph: Sirolimus (Rapamune) - EBM Consult, accessed July 16, 2025, https://www.ebmconsult.com/articles/monograph-sirolimus-rapamune
50. Afinitor interactions: Alcohol, medications, and other factors, accessed July 16, 2025, https://www.medicalnewstoday.com/articles/drugs-afinitor-interactions
51. Everolimus Patient Handout - BC Cancer, accessed July 16, 2025, http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Everolimus_handout.pdf
52. www.oralchemoedsheets.com, accessed July 16, 2025, https://www.oralchemoedsheets.com/sheets/Everolimus_Patient_Education.pdf
53. Everolimus vs Sirolimus Comparison - Drugs.com, accessed July 16, 2025, https://www.drugs.com/compare/everolimus-vs-sirolimus
54. Sirolimus Monograph for Professionals - Drugs.com, accessed July 16, 2025, https://www.drugs.com/monograph/sirolimus.html
55. Definition of Temsirolimus - NCI Drug Dictionary, accessed July 16, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/temsirolimus
56. Temsirolimus - Wikipedia, accessed July 16, 2025, https://en.wikipedia.org/wiki/Temsirolimus
57. temsirolimus - Cancer Care Ontario, accessed July 16, 2025, https://www.cancercareontario.ca/en/drugformulary/drugs/monograph/44241
58. DRUG NAME: Temsirolimus - BC Cancer, accessed July 16, 2025, http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Temsirolimus_monograph.pdf
59. Label: TEMSIROLIMUS- temsirolimus injection kit - DailyMed, accessed July 16, 2025, https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a1f129ff-c0a4-ede7-ae9c-7a3cfa01fe12
60. Everolimus Active Not Recruiting Phase 2 Trials for Advanced or Metastatic Breast Cancer Treatment - DrugBank, accessed July 16, 2025, https://go.drugbank.com/drugs/DB01590/clinical_trials?conditions=DBCOND0041978&phase=2&purpose=treatment&status=active_not_recruiting
61. Clinical Trials Using Everolimus - NCI, accessed July 16, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/everolimus?pn=1
62. CNS Metastases Completed Phase 1 / 2 Trials for Everolimus (DB01590) | DrugBank Online, accessed July 16, 2025, https://go.drugbank.com/indications/DBCOND0050898/clinical_trials/DB01590?phase=1%2C2&status=completed
63. Everolimus Terminated Phase 0 Trials for Dry Mouth / Head And Neck Cancer / salivary gland dysfunction Supportive Care - DrugBank, accessed July 16, 2025, https://go.drugbank.com/drugs/DB01590/clinical_trials?conditions=DBCOND0038951%2CDBCOND0042625%2CDBCOND0102757&phase=0&purpose=supportive_care&status=terminated