Everolimus

Uses

Everolimus is used for advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC), Advanced Neuroendocrine Tumors (NET); Advanced Renal Cell Carcinoma (RCC); Renal Angiomyolipoma With Tuberous Sclerosis Complex (TSC); Subependymal Giant Cell Astrocytoma (SEGA) With Tuberous Sclerosis Complex (TSC)

In combination with ciclosporin for microemulsion & corticosteroids for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic renal or cardiac transplant. In combination with tacrolimus & corticosteroids for the prophylaxis of organ rejection in patients receiving hepatic transplant.

Everolimus is also used to associated treatment for these conditions: Heart Transplant Rejection, Kidney Transplant Rejection, Liver Transplant Rejection, Renal angiomyolipoma, tuberous sclerosis complex, Subependymal giant cell astrocytoma, tuberous sclerosis complex, Advanced Carcinoid tumor, Locally advanced gastrointestinal origin Progressive Neuroendocrine Tumors, Locally advanced lung origin Progressive Neuroendocrine Tumors, Metastatic gastrointestinal origin Progressive Neuroendocrine Tumors, Metastatic lung origin Progressive Neuroendocrine Tumors, Pancreatic origin Progressive Neuroendocrine Tumors, Refractory Advanced Renal Cell Carcinoma, Refractory Waldenstrom's Macroglobulinaemia, Refractory, advanced Breast cancer, Unresectable gastrointestinal origin Progressive Neuroendocrine Tumors, Unresectable lung origin Progressive Neuroendocrine Tumors

How Everolimus works

Everolimus is a mTOR inhibitor that binds with high affinity to the FK506 binding protein-12 (FKBP-12), thereby forming a drug complex that inhibits the activation of mTOR. This inhibition reduces the activity of effectors downstream, which leads to a blockage in the progression of cells from G1 into S phase, and subsequently inducing cell growth arrest and apoptosis. Everolimus also inhibits the expression of hypoxia-inducible factor, leading to a decrease in the expression of vascular endothelial growth factor. The result of everolimus inhibition of mTOR is a reduction in cell proliferation, angiogenesis, and glucose uptake.

Dosage

Everolimus dosage

General kidney & heart transplant population: Initially 0.75 mg bd administered as soon as possible after transplantation.

Hepatic transplant: 1 mg bd with initial dose starting 4 wk after transplantation.

Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced NET, Advanced RCC, And Renal Angiomyolipoma With TSC: The recommended dose is 10 mg, to be taken once daily at the same time every day. Administer either consistently with food or consistently without food. Everolimus Tablets should be swallowed whole with a glass of water. Do not break or crush tablets. Continue treatment until disease progression or unacceptable toxicity occurs.

Side Effects

Stomatitis, Constipation, Infections, Asthenia, Fatigue, Cough, Diarrhea, Rash, Anemia, Nausea, Anorexia, Edema, peripheral, Dyspnea, Pyrexia, Vomiting, Headache, Epistaxis, Decreased lymphocytes, Grade 3, Increased glucose, Grade 3, Pneumonitis, Pruritus, Dry skin, Decreased Hgb, Grade 3, Menstrual irregularities, Dysgeusia, Hypertension, Hemorrhage, Tachycardia, CHF

Toxicity

IC50 of 0.63 nM.

Precaution

Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema. Interstitial lung disease/noninfectious pneumonitis; monitor for clinical symptoms or radiological changes; fatal cases have occurred; manage by dose reduction or discontinuation until symptoms resolve, and consider use of corticosteroids; pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event reported

Elicits immunosuppressive effects and may increase risk for infections; some infections have been severe or fatal; monitor for signs and symptoms and treat promptly. Pneumocystis jiroveci pneumonia, some with a fatal outcome, reported; this may be associated with concomitant use of corticosteroids or other immunosuppressive agents

Mouth ulcers, stomatitis, and oral mucositis are common; management includes mouthwashes (without alcohol or peroxide) and topical treatments May delay wound healing and increase wound-related complications (eg, dehiscence, wound infection, incisional hernia, lymphocele, and seroma)

• Cases of renal failure (including acute renal failure), some fatal, have been observed
• May cause angioedema and fluid accumulation
• Decreases Hgb, lymphocytes, ANC, platelets; increases cholesterol, TG, glucose, creatinine
• Elevations of serum creatinine, urinary protein, blood glucose, and lipids may occur;
• decreases in hemoglobin, neutrophils, and platelets may also occur; monitor renal
• function, blood glucose, lipids, and hematologic parameters prior to treatment and periodically thereafter
• May impair male fertility
• Child-Pugh Class C hepatic impairment
• Avoid use of live vaccines during treatment and close contact with live vaccine recipients
• Can cause fetal harm when administered to a pregnant woman; advise female patients of reproductive potential to use highly effective contraception while receiving everolimus and for up to 8 weeks after ending treatment.

Interaction

CYP3A4 inhibitors &/or inducers, CYP2D6 substrates with narrow therapeutic index, PgP inhibitors, rifampicin, ACE inhibitors, grapefruit juice & live vaccines.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the metabolism of everolimus through the CYP3A4 pathway and, therefore, may increase serum levels of everolimus.
• Avoid St. John's Wort. Coadministration of St. John's Wort with everolimus may reduce serum levels of everolimus by inducing CYP3A4 and P-glycoprotein (PGP).
• Take at the same time every day.
• Take with a full glass of water.
• Take with or without food. Take consistently with regard to food as food may reduce the AUC and Cmax of everolimus.

[Moderate] GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered everolimus.

The mechanism is inhibition of CYP450 3A4 and P-glycoprotein activity in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Patients treated with everolimus should avoid consumption of grapefruit and grapefruit juice.

Everolimus Cholesterol interaction

[Moderate] Elevations in cholesterol and triglyceride levels have been reported in patients taking inhibitors of mTOR (mammalian target of rapamycin).

Monitoring of fasting lipid profile is recommended prior to the start of therapy and periodically thereafter.

Clinicians should achieve control of lipid levels before initiating therapy with these agents.

Everolimus Drug Interaction

Unknown: aspirin, aspirin, lorazepam, amoxicillin / clavulanate, sulfamethoxazole / trimethoprim, diphenhydramine, loratadine, loperamide, ferrous sulfate, levetiracetam, atorvastatin, pregabalin, metoprolol, mycophenolic acid, acetaminophen, pantoprazole, acetaminophen, ascorbic acid, cholecalciferol, ondansetron

Everolimus Disease Interaction

Major: liver disease, vaccination, renal diseaseModerate: hematologic abnormalities, blood glucose, cholesterol, Infections, wound complication

Volume of Distribution

The blood-to-plasma ratio of everolimus is 17% to 73%.

Elimination Route

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 between 5 mg and 10 mg. At 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. Dose Proportionality in Patients with SEGA (subependymal giant-cell astrocytomas) and TSC (tuberous sclerosis complex): In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.

Half Life

~30 hours.

Clearance

Following a 3 mg radiolabeled dose of everolimus, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine.

Elimination Route

After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Lactation: Distribution into breast milk is unknown; not recommended

Contraindication

Patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives

Innovators Monograph

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