Everolimus

RECENT MAJOR CHANGES SECTION DOSAGE AND ADMINISTRATION ( 2.8 , 2.11 ) 06/2026

1 INDICATIONS AND USAGE Everolimus tablets for oral suspension are kinase inhibitor 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 ) Everolimus tablets for oral suspension are 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 ) 1.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) Everolimus tablets for oral suspension 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 Everolimus tablets for oral suspension are 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 everolimus tablets for oral suspension to achieve the total daily dose. ( 2.1 ) 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 • Do not combine AFINITOR and everolimus tablets for oral suspension to achieve the total dose. 2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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 Event When to Assess Trough Concentrations After Event Initiation of everolimus tablets for oral suspension 1 to 2 weeks Modification of everolimus tablets for oral suspension dose 1 to 2 weeks Switch between AFINITOR and everolimus tablets for oral suspension 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 Abbreviation: P-gp, P-glycoprotein. 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of everolimus tablets for oral suspension for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus Tablets for Oral Suspension 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. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks. Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If toxicity recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. Stomatitis [see Warnings and Precautions (5.5) ] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if t …

3 DOSAGE FORMS AND STRENGTHS Everolimus tablets for oral suspension 2 mg tablets: White to off white, round shaped, flat faced bevelled edged tablets debossed with "E2" on one side and plain on other side and free from physical defects. 3 mg tablets: White to off white, round shaped, flat faced bevelled edged tablets debossed with "E3" on one side and plain on other side and free from physical defects. 5 mg tablets: White to off white, round shaped, flat faced bevelled edged tablets debossed with "E5" on one side and plain on other side and free from physical defects. Everolimus tablets for oral suspension: 2 mg, 3 mg, and 5 mg ( 3 )

4 CONTRAINDICATIONS Everolimus tablets for oral suspension are 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) ] 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 Amneal Pharmaceuticals LLC at 1-877-835-5472 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. TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA) The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of AFINITOR in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were white and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving AFINITOR. The most common adverse reactions reported for AFINITOR (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3 to 4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3 to 4 laboratory abnormality (incidence ≥ 3%) was neutropenia. There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 17. Laboratory abnormalities are presented in Table 18. Table 17: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1 AFINITOR N = 78 Placebo N = 39 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Gastrointestinal Stomatitis a 62 9 f 26 3 f Vomiting 22 1 f 13 0 Diarrhea 17 0 5 0 Constipation 10 0 3 0 Infections Respiratory tract infection b 31 3 23 0 Gastroenteritis c 10 5 3 0 Pharyngitis streptococcal 10 0 3 0 General Pyrexia 23 6 f 18 3 f Fatigue 14 0 3 0 Psychiatric Anxiety, aggression or other behavioral disturbance d 21 5 f 3 0 Skin and subcutaneous tissue Rash e 21 0 8 0 Acne 10 0 5 0 Grading according to NCI CTCAE Version 3.0. a Includes mouth ulceration, stomatitis, and lip ulceration. b Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral. c Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. d Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder. e Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria. f No Grade 4 adverse reactions were reported. Amenorrhea occurred in 17% of AFINITOR-treated fe …

7 DRUG INTERACTIONS Strong CYP3A inhibitor and P-gp inhibitor : Avoid co-administration. ( 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 Everolimus Tablets for Oral Suspension Strong or Moderate CYP3A Inhibitor and P-gp Inhibitor Avoid the co-administration of a strong CYP3A inhibitor and P-gp inhibitor [see Dosage and Administration (2.11) , Clinical Pharmacology (12.3) ] . Reduce the dosage for everolimus tablets for oral suspension with a moderate CYP3A inhibitor and P-gp inhibitor as recommended [see Dosage and Administration (2.11) , Clinical Pharmacology (12.3) ] . Cannabidiol Oral Solution Reduce the dosage of everolimus tablets for oral suspension when co-administered with cannabidiol oral solution [see Dosage and Administration (2.11) ] . Co-administration 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 everolimus tablets for oral suspension with a strong CYP3A inducer and P-gp 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 everolimus tablets for oral suspension may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with everolimus tablets for oral suspension [see Warnings and Precautions (5.4) ] .

8 USE IN SPECIFIC POPULATIONS 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) ] , everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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 everolimus tablets for oral suspension [see Use in Specific Populations (8.1) ] . Contraception Everolimus tablets for oral suspension 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 everolimus tablets for oral suspension and for 8 weeks after the last dose. Males: Advise male patients with female partners of reproductive potent …

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. 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 Everolimus tablets for oral suspension are kinase inhibitor. The chemical name of everolimus USP 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: Everolimus tablets for oral suspension for oral administration contains 2 mg, 3 mg or 5 mg of everolimus, USP and the following inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, mannitol, and microcrystalline cellulose. image-04

16 HOW SUPPLIED/STORAGE AND HANDLING Everolimus tablets for oral suspension 2 mg tablets: White to off white, round shaped, flat faced bevelled edged tablets debossed with "E2" on one side and plain on other side and free from physical defects. HDPE Bottles of 28’s Count ---------------------------------- NDC 70377-090-11 Blisters of 28 tablets (Desiccant Embedded Alu-Alu Blister pack) -- NDC 70377-090-23 Each carton contains 4 blister cards of 7 tablets each 3 mg tablets: White to off white, round shaped, flat faced bevelled edged tablets debossed with "E3" on one side and plain on other side and free from physical defects.: HDPE Bottles of 28’s Count ---------------------------------NDC 70377-091-11 Blisters of 28 tablets (Desiccant Embedded Alu-Alu Blister pack) -- NDC 70377-091-23 Each carton contains 4 blister cards of 7 tablets each 5 mg tablets: White to off white, round shaped, flat faced bevelled edged tablets debossed with "E5" on one side and plain on other side and free from physical defects.: HDPE Bottles of 28’s Count ---------------------------------NDC 70377-092-11 Blisters of 28 tablets (Desiccant Embedded Alu-Alu Blister pack) -- NDC 70377-092-23 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 to 30°C (59°F to 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