Afinitor

Dosage and Administration ( 2.8 , 2.11 ) 6/2026

1 INDICATIONS AND USAGE 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. ( 1.1 ) 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. Limitations of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors. ( 1.2 ) Adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. ( 1.3 ) Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. ( 1.4 ) AFINITOR and AFINITOR DISPERZ 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. ( 1.5 ) AFINITOR DISPERZ 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. ( 1.6 ) 1.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer AFINITOR ® is 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. 1.2 Neuroendocrine Tumors (NET) AFINITOR is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. AFINITOR is indicated for the treatment of adult patients with progressive, well-differentiated, non-functional NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. Limitations of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2)] . 1.3 Renal Cell Carcinoma (RCC) AFINITOR is indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib. 1.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma AFINITOR is indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery. 1.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) AFINITOR and AFINITOR DISPERZ ® are indicated in adult and pediatric patients aged 1 year and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. 1.6 Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures AFINITOR DISPERZ is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

2 DOSAGE AND ADMINISTRATION Do not combine AFINITOR and AFINITOR DISPERZ to achieve the total daily dose. ( 2.1 ) Breast Cancer : 10 mg orally once daily. ( 2.2 ) NET : 10 mg orally once daily. ( 2.3 ) RCC : 10 mg orally once daily. ( 2.4 ) TSC-Associated Renal Angiomyolipoma : 10 mg orally once daily. ( 2.5 ) TSC-Associated SEGA : 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. ( 2.6 , 2.8 ) TSC-Associated Partial-Onset Seizures : 5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. ( 2.7 , 2.8 ) 2.1 Important Dosage Information AFINITOR and AFINITOR DISPERZ are two different dosage forms. Select the recommended dosage form based on the indication [see Indications and Usage (1)] . Do not combine AFINITOR and AFINITOR DISPERZ to achieve the total dose. 2.2 Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for Neuroendocrine Tumors (NET) The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.5 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of AFINITOR/AFINITOR DISPERZ is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)] . 2.7 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures The recommended starting dosage of AFINITOR DISPERZ is 5 mg/m 2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)] . 2.8 Therapeutic Drug Monitoring (TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) and TSC-Associated Partial-Onset Seizures Monitor everolimus whole blood trough concentrations at time points recommended in Table 1. Titrate the dose to attain trough concentrations of 5 ng/mL to 15 ng/mL. Adjust the dose using the following equation: New dose * = current dose x (target concentration divided by current concentration) * The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration. When possible, use the same assay and laboratory for TDM throughout treatment. Table 1: Recommended Timing of Therapeutic Drug Monitoring Abbreviation: P-gp, P-glycoprotein. Event When to Assess Trough Concentrations After Event Initiation of AFINITOR/AFINITOR DISPERZ 1 to 2 weeks Modification of AFINITOR/AFINITOR DISPERZ dose 1 to 2 weeks Switch between AFINITOR and AFINITOR DISPERZ 1 to 2 weeks Initiation or discontinuation of moderate CYP3A inhibitor and P-gp inhibitor 2 weeks Initiation or discontinuation of cannabidiol oral solution 2 weeks Initiation or discontinuation of strong CYP3A inducer and P-gp inducer 2 weeks Change in hepatic function 2 weeks Stable dose with changing body surface area (BSA) Every 3 to 6 months Stable dose with stable BSA Every 6 to 12 months 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of AFINITOR/AFINITOR DISPERZ for the management of adverse reactions. Table 2: Recommended Dosage Modifications for AFINITOR/AFINITOR DISPERZ for Adverse Reactions Adverse Reaction Severity Dosage Modification Non-infectious pneumonitis [see Warnings and Precautions (5.1)] Grade 2 Withhold until improvement to Grade 0 or 1. Res …

3 DOSAGE FORMS AND STRENGTHS AFINITOR Tablets, white to slightly yellow and elongated with a bevelled edge: 2.5 mg: engraved with “LCL” on one side and “NVR” on the other. 5 mg: engraved with “5” on one side and “NVR” on the other. 7.5 mg: engraved with “7P5” on one side and “NVR” on the other. 10 mg: engraved with “UHE” on one side and “NVR” on the other. AFINITOR DISPERZ Tablets for oral suspension, white to slightly yellowish, round, and flat with a bevelled edge: 2 mg: engraved with “D2” on one side and “NVR” on the other. 3 mg: engraved with “D3” on one side and “NVR” on the other. 5 mg: engraved with “D5” on one side and “NVR” on the other. AFINITOR: 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets ( 3 ) AFINITOR DISPERZ: 2 mg, 3 mg, and 5 mg tablets ( 3 )

4 CONTRAINDICATIONS AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives [see Warnings and Precautions (5.3)] . Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Non-Infectious Pneumonitis [see Warnings and Precautions (5.1)] Infections [see Warnings and Precautions (5.2)] Severe Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Angioedema with Concomitant Use of ACE inhibitors [see Warnings and Precautions (5.4)] Stomatitis [see Warnings and Precautions (5.5)] Renal Failure [see Warnings and Precautions (5.6)] Impaired Wound Healing [see Warnings and Precautions (5.7)] Metabolic Disorders [see Warnings and Precautions (5.9)] Myelosuppression [see Warnings and Precautions (5.10)] Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.12)] 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. ( 6.1 ) TSC-Associated Renal Angiomyolipoma : Most common adverse reaction (incidence ≥ 30%) is stomatitis. ( 6.1 ) TSC-Associated SEGA : Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. ( 6.1 ) TSC-Associated Partial-Onset Seizures : Most common adverse reaction (incidence ≥ 30%) is stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Hormone Receptor-Positive, HER2-Negative Breast Cancer The safety of AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 to 93 years), and 75% were white. The median follow-up was approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred in 2% of patients who received AFINITOR. The rate of adverse reactions resulting in permanent discontinuation was 24% for the AFINITOR arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the AFINITOR arm. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo are presented in Table 7. Laboratory abnormalities are presented in Table 8. The median duration of treatment with AFINITOR was 23.9 weeks; 33% were exposed to AFINITOR for a period of ≥ 32 weeks. Table 7: Adverse Reactions Reported in ≥ 10% of Patients With Hormone Receptor-Positive Breast Cancer in BOLERO-2 Grading according to NCI CTCAE Version 3.0. a Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. b Includes all reported infections, including but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections. c Includes pneumonitis, interstitial lung …

7 DRUG INTERACTIONS Strong CYP3A inhibitor and P-gp inhibitor : Avoid coadministration. ( 2.11 , 7.1 ) Moderate CYP3A inhibitor and P-gp inhibitor : Reduce the dosage as recommended. ( 2.11 , 7.1 ) Cannabidiol oral solution : Reduce the dosage as recommended. ( 2.11 , 7.1 ) Strong CYP3A inducer and P-gp inducer : Increase the dosage as recommended. ( 2.11 , 7.1 ) 7.1 Effect of Other Drugs on AFINITOR/AFINITOR DISPERZ Strong or Moderate CYP3A Inhibitor and P-gp Inhibitor Avoid the coadministration of a strong CYP3A inhibitor and P-gp inhibitor [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)] . Reduce the dosage for AFINITOR/AFINITOR DISPERZ with a moderate CYP3A inhibitor and Pg-p inhibitor as recommended [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)] . Cannabidiol Oral Solution Reduce the dosage of AFINITOR/AFINITOR DISPERZ when coadministered with cannabidiol oral solution [see Dosage and Administration (2.11)] . Coadministration with cannabidiol oral solution increases everolimus exposure [see Clinical Pharmacology (12.3)] , which may increase the risk of everolimus adverse reactions. The effects of other cannabidiol products on everolimus exposure are unknown. Strong CYP3A Inducer and P-gp Inducer Increase the dosage for AFINITOR/AFINITOR DISPERZ with a strong CYP3A inducer and Pg-p inducer as recommended [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)] . 7.2 Effects of Combination Use of Angiotensin Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with AFINITOR/AFINITOR DISPERZ [see Warnings and Precautions (5.4)] .

8 USE IN SPECIFIC POPULATIONS For breast cancer, NET, RCC, or TSC-associated renal angiomyolipoma patients with hepatic impairment , reduce the dose. ( 2.10 , 8.6 ) For patients with TSC-associated SEGA or TSC-associated partial-onset seizures and severe hepatic impairment , reduce the starting dose and adjust dose to attain target trough concentrations. ( 2.8 , 2.10 , 8.6 ) 8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)] , AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of AFINITOR 10 mg orally once daily (see Data) . Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Animal Data 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 ≥ 0.1 mg/kg (0.6 mg/m 2 ) with resulting exposures of approximately 4% of the human exposure at the recommended dose of AFINITOR 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m 2 ), approximately 1.6 times the recommended dose of AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), and 1.3 times the median dose administered to patients with TSC-associated partial-onset seizures based on BSA. 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/m 2 ), 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 (~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. 8.2 Lactation Risk Summary There are no data on the presence of everolimus or its metabolites in human milk, the effects of everolimus on the breastfed infant or on milk production. Everolimus and its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because of the potential for serious adverse reactions in breastfed infants from everolimus, advise women not to breastfeed during treatment with AFINITOR/AFINITOR DISPERZ and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to starting AFINITOR/AFINITOR DISPERZ [see Use in Specific Populations (8.1)] . Contraception AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)] . Females: Advise female patients of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose. Mal …

12.1 Mechanism of Action 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. 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 as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death.

11 DESCRIPTION AFINITOR (everolimus) and AFINITOR DISPERZ (everolimus tablets for oral suspension) are kinase inhibitors. The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.0 4,9 ]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. The molecular formula is C 53 H 83 NO 14 and the molecular weight is 958.2 g/mol. The structural formula is: AFINITOR for oral administration contains 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus and the following inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate. AFINITOR DISPERZ for oral administration contains 2 mg, 3 mg, or 5 mg of everolimus and the following inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose. everolimus structural formula

16 HOW SUPPLIED/STORAGE AND HANDLING AFINITOR 2.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “LCL” on one side and “NVR” on the other; available in: Blisters of 28 tablets..........................................................................................NDC 0078-0594-51 Each carton contains 4 blister cards of 7 tablets each 5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “5” on one side and “NVR” on the other; available in: Blisters of 28 tablets..........................................................................................NDC 0078-0566-51 Each carton contains 4 blister cards of 7 tablets each 7.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “7P5” on one side and “NVR” on the other; available in: Blisters of 28 tablets..........................................................................................NDC 0078-0620-51 Each carton contains 4 blister cards of 7 tablets each 10 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “UHE” on one side and “NVR” on the other; available in: Blisters of 28 tablets..........................................................................................NDC 0078-0567-51 Each carton contains 4 blister cards of 7 tablets each AFINITOR DISPERZ 2 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D2” on one side and “NVR” on the other; available in: Blisters of 28 tablets..........................................................................................NDC 0078-0626-51 Each carton contains 4 blister cards of 7 tablets each 3 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D3” on one side and “NVR” on the other; available in: Blisters of 28 tablets..........................................................................................NDC 0078-0627-51 Each carton contains 4 blister cards of 7 tablets each 5 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D5” on one side and “NVR” on the other; available in: Blisters of 28 tablets..........................................................................................NDC 0078-0628-51 Each carton contains 4 blister cards of 7 tablets each Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). See USP Controlled Room Temperature. Store in the original container, protect from light and moisture. Follow special handling and disposal procedures for anti-cancer pharmaceuticals. 1