Everolimus

958.232

958.22

1806241-263-5

DTXSID0040599

29349990

205 Ų

1.18±0.1 g/cm3(Predicted)

No melting point

998.7±75.0 °C(Predicted)

2℃

1.548

Soluble in dimethysulfoxide,ethanol and chloroform. Slightly soluble in water.

−20°C

UN 1648 3 / PGII

2

48/25-36-20/21/22-11

45-36/37-26-16

T,Xn,F

Hygroscopic

P210-P305 + P351 + P338

H225-H302 + H332-H319

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including everolimus, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H372 (97.92%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]|P260, P264, P270, P273, P314, and P501|Aggregated GHS information provided by 96 companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H372: Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

Skin protection: Handle with gloves.|Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.|Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.Normal measures for preventive fire protection.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

IDENTIFICATION AND USE: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) kinase, is an antineoplastic agent and macrolide immunosuppressive agent. Everolimus (brand name Afinitor) is used in the treatment of certain types of breast cancers, neuroendocrine tumors of pancreatic origin, renal cell carcinoma, renal angiomyolipoma with tuberous sclerosis complex, and subependymal giant cell astrocytoma with tuberous sclerosis complex. Everolimus (brand name Zortress) is used for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. It is also used for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. HUMAN EXPOSURE AND TOXICITY: Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability. Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including opportunistic infections. Some of these infections have been severe (e.g., resulting in respiratory or hepatic failure) or fatal. Fatal noninfectious pneumonitis also has been reported with everolimus. Increases in serum creatinine concentrations and proteinuria have been reported in clinical trials with everolimus (Afinitor). Cases of renal failure (including acute renal failure), some with a fatal outcome, also have been observed in everolimus-treated patients. ANIMAL STUDIES: Everolimus was not carcinogenic in mice or rats when administered daily by oral gavage for 2 years at doses of 0.9 mg/kg. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses greater than or equal to 0.1 mg/kg (0.6 mg/sq m). In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/sq m. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/sq m), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (approximately 5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. In a 13-week male fertility oral gavage study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count and plasma testosterone concentrations were diminished at 5 mg/kg which caused a decrease in male fertility. There was evidence of reversibility of these findings in animals examined after 13 weeks post-dosing. The 0.5 mg/kg dose in male rats resulted in AUCs in the range of clinical exposures, and the 5 mg/kg dose resulted in AUCs approximately 5 times the AUCs in humans receiving 0.75 mg twice daily. Everolimus did not affect female fertility in nonclinical studies, but everolimus crossed the placenta and was toxic to the conceptus. Everolimus was not mutagenic in the bacterial reverse mutation, the mouse lymphoma thymidine kinase assay, or the chromosome aberration assay using V79 Chinese hamster cells, or in vivo following two daily doses of 500 mg/kg in the mouse micronucleus assay.

Serum enzyme elevations occur in up to a quarter of patients taking everolimus, but the abnormalities are usually mild, asymptomatic and self-limiting, rarely requiring dose modification or discontinuation. Liver test elevations above 5 times ULN occur in only 1% to 2% of treated patients. In contrast, idiosyncratic, clinically apparent acute liver injury has not been linked to everolimus therapy despite its wide scale use in several malignant and non-malignant syndromes. Elevations in serum enzymes and bilirubin and hepatitis are listed as potential adverse events in the product label for everolimun. Thus, acute clinically apparent liver injury with jaundice due to everolimus is probably quite rare, if it occurs at all.

Use of HMG-CoA reductase inhibitors such as lovastatin or simvastatin was strongly discouraged in clinical trials of everolimus with cyclosporine in renal transplant patients because of an interaction between HMG-CoA reductase inhibitors and cyclosporine. The manufacturer of Zortress recommends that patients receiving everolimus and cyclosporine therapy who are concurrently receiving an HMG-CoA reductase inhibitor and/or fibric acid derivative be monitored for the possible development of rhabdomyolysis and other adverse effects, which are described in the prescribing information for these antilipemic agents.|Studies in healthy individuals indicate that there are no clinically important pharmacokinetic interactions between single-dose everolimus and atorvastatin (a CYP3A4 substrate) or pravastatin (a non-CYP3A4 substrate and P-gp substrate); HMG-CoA reductase bioactivity in plasma also was not substantially affected. Therefore, dosage adjustments are not necessary when everolimus and atorvastatin or pravastatin are used concurrently. In a population pharmacokinetic analysis, simvastatin (a CYP3A4 substrate) did not affect clearance of everolimus. The manufacturer of Zortress cautions that these results cannot be extrapolated to other HMG-CoA reductase inhibitors.|Concomitant use of angiotensin-converting enzyme (ACE) inhibitors with everolimus may increase the risk of angioedema. The use of alternative antihypertensive agents should be considered in everolimus-treated patients, if necessary.|If coadministration of a P-gp inhibitor is required in patients with SEGA, everolimus dosage should be reduced by approximately 50% to maintain trough everolimus concentrations of 5-10 ng/mL. If dosage reduction is required in patients receiving 2.5 mg daily, alternate-day dosing should be considered. Subsequent dosing should be individualized based on therapeutic drug monitoring. Trough everolimus concentrations should be assessed approximately 2 weeks after the addition of the P-gp inhibitor. If the P-gp inhibitor is discontinued, the everolimus dosage should be returned to the dosage used prior to initiation of the P-gp inhibitor and the trough everolimus concentration should be reassessed approximately 2 weeks later.|For more Interactions (Complete) data for EVEROLIMUS (23 total), please visit the HSDB record page.

Everolimus may cause diarrhea and malabsorption in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption; everolimus should not be used in such patients.

Everolimus is an inhibitor of cell proliferation and immunosuppressive agent that is used alone or in combination with calcineurin inhibitors to prevent cellular rejection after organ transplantation, and in combination with other anticancer agents as treatment of advanced renal cell and other cancers. Everolimus therapy can be associated with mild serum enzyme elevations, but has yet to be linked to instances of clinically apparent liver injury with jaundice.

Antineoplastic Agents; Transplant Agents

Immunosuppressive Agents|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health(NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Everolimus is included in the database.|Afinitor is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. /Included in US product label/|Afinitor Tablets and Afinitor Disperz are indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. /Included in US product label/c|For more Therapeutic Uses (Complete) data for EVEROLIMUS (9 total), please visit the HSDB record page.

/BOXED WARNING/ WARNING: MALIGNANCIES AND SERIOUS INFECTIONS. Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Increased susceptibility to infection and the possible development of malignancies such as lymphoma and skin cancer may result from immunosuppression.|/BOXED WARNING/ WARNING: KIDNEY GRAFT THROMBOSIS. An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, was reported, mostly within the first 30 days post-transplantation.|/BOXED WARNING/ WARNING: NEPHROTOXICITY. Increased nephrotoxicity can occur with use of standard doses of cyclosporine in combination with Zortress. Therefore reduced doses of cyclosporine should be used in combination with Zortress in order to reduce renal dysfunction. It is important to monitor the cyclosporine and everolimus whole blood trough concentrations.|/BOXED WARNING/ WARNING: MORTALITY IN HEART TRANSPLANTATION. Increased mortality, often associated with serious infections, within the first three months post-transplantation was observed in a clinical trial of de novo heart transplant patients receiving immunosuppressive regimens with or without induction therapy. Use in heart transplantation is not recommended.|For more Drug Warnings (Complete) data for EVEROLIMUS (32 total), please visit the HSDB record page.

The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5000 ng/mL. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume associated with the terminal phase (Vz/F) from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range 128 to 589 L).|The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given Afinitor 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.|After administration of Afinitor tablets in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.|No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours.|For more Absorption, Distribution and Excretion (Complete) data for EVEROLIMUS (7 total), please visit the HSDB record page.

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.

The mean elimination half-life of everolimus is approximately 30 hours.

Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that functions via two multiprotein complexes, namely mTORC1 and mTORC2, each characterized by different binding partners that confer separate functions. mTORC1 function is tightly regulated by PI3-K/Akt and is sensitive to rapamycin. mTORC2 is sensitive to growth factors, not nutrients, and is associated with rapamycin-insensitivity. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is thought to modulate growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases such as Akt and SGK. Recent evidence has suggested that mTORC2 may play an important role in maintenance of normal as well as cancer cells by virtue of its association with ribosomes, which may be involved in metabolic regulation of the cell. Rapamycin (sirolimus) and its analogs known as rapalogues, such as RAD001 (everolimus) and CCI-779 (temsirolimus), suppress mTOR activity through an allosteric mechanism that acts at a distance from the ATP-catalytic binding site, and are considered incomplete inhibitors. Moreover, these compounds suppress mTORC1-mediated S6K activation, thereby blocking a negative feedback loop, leading to activation of mitogenic pathways promoting cell survival and growth. Consequently, mTOR is a suitable target of therapy in cancer treatments. However, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. In recent years, new pharmacologic agents have been developed which can inhibit these complexes via ATP-binding mechanism, or dual inhibition of the canonical PI3-K/Akt/mTOR signaling pathway. These compounds include WYE-354, KU-003679, PI-103, Torin1, and Torin2, which can target both complexes or serve as a dual inhibitor for PI3-K/mTOR. This investigation describes the mechanism of action of pharmacological agents that effectively target mTORC1 and mTORC2 resulting in suppression of growth, proliferation, and migration of tumor and cancer stem cells.|Mammalian target of rapamycin (mTOR) inhibitors have anti-tumor effects against renal cell carcinoma, pancreatic neuroendocrine cancer and breast cancer. In this study, we analyzed the antitumor effects of mTOR inhibitors in small cell lung cancer (SCLC) cells and sought to clarify the mechanism of resistance to mTOR inhibitors. We analyzed the antitumor effects of three mTOR inhibitors including everolimus in 7 SCLC cell lines by MTS assay. Gene-chip analysis, receptor tyrosine kinases (RTK) array and Western blotting analysis were performed to identify molecules associated with resistance to everolimus. Only SBC5 cells showed sensitivity to everolimus by MTS assay. We established two everolimus resistant-SBC5 cell lines (SBC5 R1 and SBC5 R10) by continuous exposure to increasing concentrations of everolimus stepwise. SPP1 and MYC were overexpressed in both SBC5 R1 and SBC5 R10 by gene-chip analysis. High expression levels of eukaryotic translation initiation factor 4E (eIF4E) were observed in 5 everolimus-resistant SCLC cells and SBC5 R10 cells by Western blotting. MYC siRNA reduced eIF4E phosphorylation in SBC5 cells, suggesting that MYC directly activates eIF4E by an mTOR-independent bypass pathway. Importantly, after reduction of MYC or eIF4E by siRNAs, the SBC5 parent and two SBC5-resistant cells displayed increased sensitivity to everolimus relative to the siRNA controls. These findings suggest that eIF4E has been shown to be an important factor in the resistance to everolimus in SCLC cells. Furthermore, a link between MYC and mTOR-independent eIF4E contribute to the resistance to everolimus in SCLC cells. Control of the MYC-eIF4E axis may be a novel therapeutic strategy for everolimus action in SCLC.|Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes. In cells, everolimus binds to a cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. In the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited. Consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited. The everolimus: FKBP-12 complex has no effect on calcineurin activity. In rats and nonhuman primate models, everolimus effectively reduces kidney allograft rejection resulting in prolonged graft survival.|Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body.

/SIGNS AND SYMPTOMS/ Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability.|/SIGNS AND SYMPTOMS/ Increases in serum creatinine concentrations and proteinuria have been reported in clinical trials with everolimus (Afinitor). Cases of renal failure (including acute renal failure), some with a fatal outcome, also have been observed in everolimus-treated patients.|/CASE REPORTS/ A 67-year-old man who had been heart transplanted ten years before was admitted to our hospital because of diarrhea. During his stay he developed a severe lingual and facial angioedema. After excluding hereditary angioedema caused by a deficiency in functional C1 esterase inhibitor we focused on adverse effects of his drugs. The medication was composed of Aspirin, Enalapril, Diltiazem, Everolimus, Mycophenolate Mofetil, Bisoprolol, Pravastatin, Esomeprazol and Allopurinol. The angioedema disappeared with anti-allergic treatment. The administration of the suspected trigger enalapril was stopped. However weeks later the patient was admitted again with angioedema. Due to missing urticaria Aspirin was unlikely the causer. The only new drug the patient had been medicated with was Everolimus for 30 days. We assumed a link between the angioedema and Everolimus. Consequently we changed the immunosuppressive regime. After stopping Everolimus no angioedema occurred. Everolimus is a potential trigger of angioedema.|/CASE REPORTS/ Everolimus has recently received approval for immunosuppressive therapy in heart transplant recipients in Austria and Germany. At our heart center we have treated 114 patients with everolimus since January 2004. Here we describe 6 cases of lingual angioedema (corresponding to 5.3% of the patients). Symptoms occurred within 2 to 41 days after initiation of therapy. In 5 out of the 6 patients, lingual angioedema disappeared with anti-allergic treatment alone. However, in one patient, two severe recurrent episodes of lingual angioedema occurred so that therapy had to be discontinued. We conclude that the potentially life-threatening condition of lingual angioedema should be considered a severe drug reaction after initiation of everolimus therapy in heart transplant recipients.|For more Human Toxicity Excerpts (Complete) data for EVEROLIMUS (12 total), please visit the HSDB record page.

Table: Everolimus Preparations [Table#8251]

Whole blood determination by LC/MS.