Everolimus (Afinitor): FDA Approval, Licensing in Türkiye, and Reimbursement Status

Everolimus (Afinitor)

• FDA Approval: Yes (first approval date: March 20, 2009)
• Trade Name: Afinitor
• Active Ingredient: Everolimus
• Administration: Oral tablets
• Class: Signal transduction inhibitor, mTOR inhibitor
• Category: Targeted agent
• Manufacturer: Novartis
• Distribution in Türkiye: Novartis Türkiye
• Cancers for Which It Is Approved: Advanced kidney cancer after sunitinib/sorafenib, PNET, GI/lung NET, TSC-associated renal angiomyolipoma, TSC-SEGA, TSC-associated partial-onset seizures (≥2 years), and HR+ HER2- advanced breast cancer with exemestane

What Is Afinitor (Everolimus) and How Does It Work?

Containing everolimus, Afinitor, used for advanced kidney cancer, pancreatic neuroendocrine tumors (PNET), gastrointestinal and lung neuroendocrine tumors (NET), breast cancer, and certain conditions associated with tuberous sclerosis complex (TSC), is an oral mTOR inhibitor. It aims to slow progression by suppressing cell growth and tumor cell proliferation.

What Is an mTOR Inhibitor?

mTOR (mammalian target of rapamycin) inhibitors target the mTOR signaling pathway, which regulates cell growth, proliferation, and angiogenesis. Overactivation contributes to tumor growth and progression in many cancers. By suppressing this signaling, inhibitors such as everolimus arrest the cell cycle and may trigger apoptosis and inhibit tumor growth.

⚙️ Mechanism of Action

• Everolimus inhibits mTORC1to prevent tumor cell growth and proliferation.
• Slows the cell cycle: Suppresses proliferation.
• Apoptosis (cell death) may be triggered.
• Suppresses angiogenesis: Reduces new blood vessel formation.
• May reduce VEGF production: May restrict tumor nourishment through HIF-1.
• May reduce the activity of growth signals such as ERK and STAT3.

📜 FDA (United States Food and Drug Administration) Approval History

• March 20, 2009: Advanced kidney cancer after sunitinib or sorafenib
• May 30, 2011: Pancreatic neuroendocrine tumors (PNET)
• April 20, 2012: TSC-associated SEGA
• February 26, 2016: TSC-associated renal angiomyolipoma
• July 30, 2019: HR+ HER2- advanced breast cancer, combined with exemestane
• April 10, 2021: TSC-associated partial-onset seizures (≥2 years)

🇹🇷 Licensing in Türkiye

Afinitor's licensed conditions/therapeutic indications in Türkiye are summarized as follows:

• Metastatic renal cell carcinoma progressing during/after VEGF-targeted therapy
• Pancreatic NET progressing by RECIST within the past 12 months, unsuitable for surgery/local treatment, well differentiated with Ki-67 ≤20, after a somatostatin analog and chemotherapy
• Progressive, well-differentiated, nonfunctional NET of GI or lung origin (PS 0–1), after at least 1 treatment line
• Postmenopausal recurrent/metastatic breast cancer that is HER2-negative and strongly HR-positive (≥40%), without symptomatic visceral disease, progressing after 1 chemotherapy regimen + 1 nonsteroidal aromatase inhibitor regimen, only in combination with exemestane

💳 Reimbursement, Price, and Cost per Cycle

SGK: Reimbursed.

Price (March 2026):

• Afinitor 5 mg retail pharmacy price: 24273.97 TL
• Afinitor 10 mg retail pharmacy price: 34883.58 TL

🏛️ Off-Label Uses Permitted Without Additional TİTCK Approval 

• Advanced endometrial cancer, endometrioid type: progression after 3 treatment lines including anthracyclines, taxanes, and hormonal therapy
• Advanced PEComa, recurrent angiomyolipoma, and lymphangioleiomyomatosis: 2nd line and later

🧬 Mechanisms of Resistance

Some cancer cells may gradually reduce everolimus effectiveness and develop resistance. Mechanisms highlighted in the text include:

• Accelerated cell cycle: Increased CDK2/Cyclin A and CDK1/Cyclin B → reduced antiproliferative effects.
• Increased protein synthesis and growth: Aurora kinase A → EIF4E activation → continued growth.
• Alternative signaling pathways: Activation of mTORC2/Akt, ERK, and STAT3 → possible escape mechanisms.

📦 Pharmacokinetics

Absorption: Peaks 1–2 hours after oral administration; high-fat foods may reduce bioavailability by ~20%.

Distribution: Plasma protein binding up to ~75%; steady state after ~2 weeks of once-daily dosing.

Metabolism / Elimination: Metabolized by CYP3A4; mainly eliminated through bile/feces. Renal elimination approximately 5%. Half-life ~30 hours.

💊 Dose Range

Recommended dose for breast cancer, NET, and kidney cancer: 10 mg/day (a single oral dose).

🔄 Drug Interactions

Because everolimus is metabolized by CYP3A4, it may interact with certain medicines:

Note: Avoid grapefruit products because they may increase everolimus levels.

⚠️ Precautions

• Take a single daily dose at the same time, with or without food.
• Do not chew or crush tablets; swallow with a glass of water.
• Moderate liver impairment (Child-Pugh B): The dose may be reduced to 5 mg.
• Severe liver impairment (Child-Pugh C): Must not be used.
• With CYP3A4 inducers, the dose may be adjusted in 5 mg increments, up to 20 mg/day, with essential clinical monitoring.
• Monitor for cough, breathlessness, and fever indicating pneumonitis/pulmonary toxicity.
• Be alert to opportunistic infections, including bacterial and fungal infections.
• Diabetes/hyperglycemia: Monitor blood glucose.
• Monitor lipids (TG/cholesterol) regularly.
• With mouth sores, avoid mouthwashes containing alcohol or peroxide.
• Do not administer live vaccines; avoid close contact with people who have received live vaccines.
• Pregnancy category D; breastfeeding is not recommended.

🤒 Adverse Reactions

Percentages reflect typical ranges reported across different clinical studies/indications.

• Mouth sores (stomatitis) 44% – 70%
• Rash 30% – 50%
• Fatigue 30% – 44%
• Diarrhea 30% – 40%
• Anorexia (loss of appetite) 25% – 35%
• Nausea 20% – 36%
• Cough 20% – 30%
• Infection (particularly respiratory) 20% – 30%
• Hyperglycemia 10% – 50%
• Anemia 30% – 40%
• Elevated triglycerides 20% – 30%
• Increased creatinine 10% – 20%
• Pneumonitis 10% – 20%
• Thrombocytopenia 10% – 20%
• Stomatitis (Grade 3–4) 5% – 10%