Everolimus

Warnings and Precautions, Radiation Sensitization and Radiation Recall ( 5.12 ) 4/2021 Warnings and Precautions, Radiation Sensitization and Radiation Recall ( 5.12 ) 4/2021

1. INDICATIONS AND USAGE Everolimus tablets are 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: Everolimus tablets are 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 ) Everolimus tablets and everolimus tablets for oral suspension 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 ) Everolimus tablets for oral suspension 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 Everolimus tablets are 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) Everolimus tablets are indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. Everolimus tablets are 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: Everolimus tablets are not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2) ]. 1.3 Renal Cell Carcinoma (RCC) Everolimus tablets are 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 Everolimus tablets are 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) Everolimus tablets and 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 Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4. ( 2.1 ) 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 ) 2.1 Important Dosage Information Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4 [see Dosage and Administration (2.10 , 2.11 , 2.12 )]. 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) The recommended dosage of everolimus tablets 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 everolimus tablets 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 everolimus tablets is 4.5 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) 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 Asses Trough Concentrations After Event Initiation of everolimus tablets 1 to 2 weeks Modification of everolimus tablets dose 1 to 2 weeks Initiation or discontinuation of P-gp and moderate CYP3A4 inducer 2 weeks Initiation or discontinuation of P-gp and strong CYP3A4 inducer 2 weeks Change in hepatic function 2 weeks Stable dose with changing body surface area (BSA) Every 3 to 6 months Abbreviation: P-gp, P-glycoprotein. Every 6 to 12 months 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of everolimus tablets for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus Tablets for Adverse Reactions Adverse Reactions 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. Grade 4 If toxicity recurs at Grade 3, permanently discontinue. 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. Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Metabolic events (e.g., hypergl …

3. DOSAGE FORMS AND STRENGTHS Everolimus Tablets: 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets with no score ( 3 ) Everolimus tablets for oral suspension: 2 mg, 3 mg, and 5 mg tablets ( 3 ) Everolimus Tablets 2.5 mg: White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '2.5' on the other side. 5 mg: White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '5' on the other side. 7.5 mg: White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '7.5' on the other side. 10 mg: White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and 'NAT' on the other side. Everolimus Tablets for Oral Suspension Tablets for oral suspension, white to off white colored, round, flat tablets: 2 mg: debossed with "2" on one side and "E" on other side. 3 mg: debossed with "3" on one side and "E" on other side. 5 mg: debossed with "5" on one side and "E" on other side.

4 CONTRAINDICATIONS Hypersensitivity to everolimus, sirolimus, or to components of the drug product ( 4 ) Hypersensitivity to everolimus, sirolimus, or to components of the drug product ( 4 ) 4.1 Hypersensitivity Reactions Everolimus is contraindicated in patients with known hypersensitivity to everolimus, sirolimus, or to components of the drug product.

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 )]. 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 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 everolimus tablets (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 everolimus tablets. The rate of adverse reactions resulting in permanent discontinuation was 24% for the everolimus tablets arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the everolimus tablets arm. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets vs. placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with everolimus tablets was 23.9 weeks; 33% were exposed to everolimus tablets for a period of ≥ 32 weeks. Table 6: Adverse Reactions Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2 Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2 Topical Prophylaxis for Stomatitis In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning everolimus tablets (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5 mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) co …

7 DRUG INTERACTIONS Strong-moderate CYP3A4 inhibitors (e.g., cyclosporine, ketoconazole, erythromycin, verapamil) and CYP3A4 inducers (e.g., rifampin) may affect everolimus concentrations ( 7.1 ). Consider everolimus tablets dose adjustment ( 5.14 ) Therapeutic drug monitoring and dose reduction for everolimus tablets should be considered when everolimus tablets are coadministered with cannabidiol (5.22, 7.13) 7.1 Interactions With Strong Inhibitors or Inducers of CYP3A4 and P-glycoprotein Everolimus is mainly metabolized by CYP3A4 in the liver and to some extent in the intestinal wall and is a substrate for the multidrug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or P-gp. Concurrent treatment with strong inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and inducers (e.g., rifampin, rifabutin) of CYP3A4 is not recommended. Inhibitors of P-gp (e.g., digoxin, cyclosporine) may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. In vitro , everolimus was a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the concentrations of medicinal products eliminated by these enzymes. Thus, caution should be exercised when coadministering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index [ s ee Dosage and Administration ( 2. 3 ) ] . All in vivo interaction studies were conducted without concomitant cyclosporine. Pharmacokinetic interactions between everolimus and concomitantly administered drugs are discussed below. Drug interaction studies have not been conducted with drugs other than those described below. 7.2 Cyclosporine (CYP3A4/P-gp Inhibitor and CYP3A4 Substrate) The steady-state C max and area under the curve (AUC) estimates of everolimus were significantly increased by coadministration of single dose cyclosporine [ s ee Clinical Pharmaco logy (12. 5 )] . Dose adjustment of everolimus might be needed if the cyclosporine dose is altered [ s ee Dosage and Administration ( 2. 3)] . Everolimus had a clinically minor influence on cyclosporine pharmacokinetics in transplant patients receiving cyclosporine (Neoral). 7.3 Ketoconazole and Other Strong CYP3A4 Inhibitors Multiple-dose ketoconazole administration to healthy volunteers significantly increased single dose estimates of everolimus C max , AUC, and half-life. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) should not be coadministered with everolimus [ s ee Warnings and Precautions ( 5. 1 4 ), Clinical Pharmaco logy (12. 5 )] . 7.4 Erythromycin (Moderate CYP3A4 Inhibitor) Multiple-dose erythromycin administration to healthy volunteers significantly increased single dose estimates of everolimus C max , AUC, and half-life. If erythromycin is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [ s ee Clinical Pharmaco logy (12. 5 )] . 7.5 Verapamil (CYP3A4 and P-gp Substrate) Multiple-dose verapamil administration to healthy volunteers significantly increased single dose estimates of everolimus C max and AUC. Everolimus half-life was not changed. If verapamil is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [ s ee Clinical Pharmaco logy (12. 5 ) ] . 7.6 Atorvastatin (CYP3A4 Substrate) and Pravastatin (P-gp Substrate) Single-dose administration of everolimus with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a clinically relevant extent. However, these results cannot be extrapolated to other HMG …

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) ] , everolimus tablets/everolimus tablets for oral suspension can cause fetal harm when administered to a pregnant woman. There are limited case reports of everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets 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/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/everolimus tablets for oral suspension [see Use in Specific Populations (8.1) ]. Contraception Everolimus tablets/everolimus tablets for oral suspension can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ]. Females: …

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 Everolimus tablets are a macrolide immunosuppressant. 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-{(2R)-1- [(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30 dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[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 958.24 g/mol. The structural formula is: Everolimus tablets are supplied for oral administration containing 0.25 mg, 0.5 mg, 0.75 mg, and 1 mg of everolimus USP together with butylated hydroxytoluene, crospovidone, hypromellose, lactose anhydrous, lactose monohydrate, magnesium stearate and poloxamer 188 as inactive ingredients. Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye). Everolimus structural formula (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[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2, 3,10,14,20-pentaone.

10 OVERDOSAGE Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability. General supportive measures should be followed in all cases of overdose. Everolimus is not considered dialyzable to any relevant degree (less than 10% of everolimus removed within 6 hours of hemodialysis). In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2,000 mg/kg (limit test) in either mice or rats.

16 HOW SUPPLIED/STORAGE AND HANDLING Everolimus Tablets 2.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and debossed with “EVE” on one side and “2.5” on the other; available in: Bottles of 28 tablets......................................NDC 82293-030-10 Blister carton of 28 tablets..............................NDC 82293-030-21 (Each carton contains 4 blister cards of 7 tablets each) Blister carton of 30 tablets..............................NDC 82293-030-31 (Each carton contains aluminum pouch of 3 blister cards of 10 tablets each and silica gel) 5 mg tablets: White to slightly yellow, elongated tablets with bevelled edge and debossed with “EVE” on one side and “5” on the other; available in: Bottles of 28 tablets......................................NDC 82293-031-10 Blister carton of 28 tablets..............................NDC 82293-031-21 (Each carton contains 4 blister cards of 7 tablets each) Blister carton of 30 tablets..............................NDC 82293-031-31 (Each carton contains aluminum pouch of 3 blister cards of 10 tablets each and silica gel) 7.5 mg tablets: White to slightly yellow, elongated tablets with bevelled edge and debossed with “EVE” on one side and “7.5” on the other; available in: Bottles of 28 tablets.......................................NDC 82293-032-10 Blister carton of 28 tablets................................NDC 82293-032-21 (Each carton contains 4 blister cards of 7 tablets each) Blister carton of 30 tablets................................NDC 82293-032-31 (Each carton contains aluminum pouch of 3 blister cards of 10 tablets each and silica gel) 10 mg tablets: White to slightly yellow, elongated tablets with bevelled edge and debossed with “EVE” on one side and “10” on the other; available in: Bottles of 28 tablets ........................................NDC 82293-033-10 Blister carton of 28 tablets .................................NDC 82293-033-21 (Each carton contains 4 blister cards of 7 tablets each) Blister carton of 30 tablets..................................NDC 82293-033-31 (Each carton contains aluminum pouch of 3 blister cards of 10 tablets each and silica gel) 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