Afinitor is a kinase inhibitor indicated for the treatment of: Postmenopausal women with advanced hormone receptor-positive, HER2- negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. Adults with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. ... Read more Afinitor is a kinase inhibitor indicated for the treatment of: Postmenopausal women with advanced hormone receptor-positive, HER2- negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. Adults with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Afinitor are kinase inhibitors indicated for the treatment of adult and pediatric patients aged 1 year and older with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. Afinitor is a kinase inhibitor indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC- associated partial-onset seizures.
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 and in tuberous sclerosis complex (TSC). 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.
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Everolimus are two different dosage forms. Select the recommended dosage form based on the indication. Do not combine Everolimus to achieve the total dose. Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P glycoprotein (P-gp) and CYP3A4. Hormone Receptor-Positive, HER2-Negative Breast Cancer : The recommended dosage of Everolimus is 10 mg orally once daily until disease progression or unacceptable toxicity. Neuroendocrine Tumors (NET) : The recommended dosage of Everolimus is 10 mg orally once daily until disease progression or unacceptable toxicity. Renal Cell Carcinoma (RCC) : The recommended dosage of Everolimus is 10 mg orally once daily until disease progression or unacceptable toxicity. Tuberous Sclerosis Complex (TSC): Associated Renal Angiomyolipoma : The recommended dosage of Everolimus is 10 mg orally once daily until disease progression or unacceptable toxicity. Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) : The recommended starting dosage of Everolimus is 4.5 mg/m2 orally once daily until disease progression or unacceptable toxicity. Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures : The recommended starting dosage of Everolimus is 5 mg/m2 orally once daily until disease progression or unacceptable toxicity.
Breast cancer, NET, RCC : Most common adverse reactions (incidence ≥30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, and decreased appetite. TSC-Associated Renal Angiomyolipoma : Most common adverse reaction (incidence ≥ 30%) is stomatitis. TSC-Associated SEGA : Most common adverse reactions (incidence ≥30%) are stomatitis and respiratory tract infection. TSC-Associated Partial-Onset Seizures : Most common adverse reaction (incidence ≥30%) is stomatitis.
Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.
P-gp and strong CYP3A4 inhibitors: Avoid concomitant use. P-gp and moderate CYP3A4 inhibitors: Reduce the dose as recommended. P-gp and strong CYP3A4 inducers: Increase the dose as recommended.
Non-Infectious Pneumonitis : Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. Infections : Monitor for signs and symptoms of infection. Withhold or permanently discontinue based on severity. Severe Hypersensitivity Reactions : Permanently discontinue for clinically significant hypersensitivity. Angioedema : Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. Stomatitis : Initiate dexamethasone alcohol-free mouthwash when starting treatment. Renal Failure : Monitor renal function prior to treatment and periodically thereafter. Risk of Impaired Wound Healing : Withhold for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment after resolution of wound healing complications has not been established. Geriatric Patients : Monitor and adjust dose for adverse reactions. Metabolic Disorders : Monitor serum glucose and lipids prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. Myelosuppression : Monitor hematologic parameters prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. Risk of Infection or Reduced Immune Response with Vaccination : Avoid live vaccines and close contact with those who have received live vaccines. Complete recommended childhood vaccinations prior to starting treatment. Radiation Sensitization and Radiation Recall : Severe radiation reactions may occur. Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.