Everolimus

Do not combine everolimus tablets and everolimus tablets for oral suspension to achieve the total daily dosage. (2.1) RCC:

• 10 mg orally once daily. (2.4) TSC-Associated Renal Angiomyolipoma:
• 10 mg orally once daily. (2.5)

2.1Important Dosage Information

• Everolimus tablets and everolimus tablets for oral suspension are two different dosage forms. Select the recommended dosage form based on the indication [see Indications and Usage (1)]. Do not combine everolimus tablets and everolimus tablets for oral suspension to achieve the total dose. 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) The recommended dosage of Everolimus 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 is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of Everolimus for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus 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 the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9)] Grade 3 Withhold until improvement to Grade 0, 1, or 2. 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 Permanently discontinue. Other non-hematologic toxicities Grade 2 If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1. Resume at same dose. If toxicity 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. If recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. Thrombocytopenia [see Warnings and Precautions (5.10)] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. Grade 3 OR Grade 4 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. Neutropenia [see Warnings and Precautions (5.10)] Grade 3 Withhold until improvement to Grade 0, 1, or 2. Resume at same dose. Grade 4 Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Febrile neutropenia [see Warnings and Precautions (5.10)] Grade 3 Withhold until improvement to Grade 0, 1, or 2, and no fever. 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 Permanently discontinue. 2.10 Dosage Modifications for Hepatic Impairment The recommended dosages of Everolimus for patients with hepatic impairment are described in Table 3 [see Use in Specific Populations (8.6)]: Table 3: Recommended Dosage Modifications for Patients with Hepatic Impairment Indication Dose Modification for Everolimus RCC and TSC-Associated Renal Angiomyolipoma
• Mild hepatic impairment (Child-Pugh class A) - 7.5 mg orally once daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated.
• Moderate hepatic impairment (Child-Pugh class B) - 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated.
• Severe hepatic impairment (Child-Pugh class C) - 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily. Abbreviations: RCC, Renal Cell Carcinoma; TSC, Tuberous Sclerosis Complex. 2.11 Dosage Modifications for Drug Interactions Strong or Moderate CYP3A Inhibitor and P-glycoprotein (P-gp) Inhibitor
• Avoid the coadministration of a strong CYP3A inhibitor and P-gp inhibitor [see Drug Interactions (7.1)].
• Reduce the dosage for everolimus with a moderate CYP3A inhibitor and P-gp as recommended in Table 4 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Table 4: Recommended Dosage Modifications with a Moderate CYP3A Inhibitor and P-gp Inhibitor Indication Dosage Modification for Everolimus RCC and TSC-Associated Renal Angiomyolipoma
• Reduce dose to 2.5 mg once daily.
• May increase dose to 5 mg once daily if tolerated.
• Resume dosage administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. Cannabidiol Oral Solution
• Reduce the dosage of everolimus when coadministered with cannabidiol oral solution as recommended in Table 5 [see Clinical Pharmacology (12.3)]. The effects of other cannabidiol products on everolimus exposure are unknown. Table 5: Recommended Dosage Modifications with Cannabidiol Oral Solution Indication Dosage Modification for Everolimus RCC and TSC-Associated Renal Angiomyolipoma
• Reduce dose to 5 mg once daily.
• May increase dose to 7.5 mg once daily if tolerated.
• Resume dosage administered prior to cannabidiol oral solution initiation, once cannabidiol oral solution is discontinued for 3 days. Strong CYP3A Inducer and P-gp Inducer
• Increase the dosage for everolimus with a strong CYP3A inducer and P-gp inducer as recommended in Table 6 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Table 6: Recommended Dosage Modifications with a Strong CYP3A Inducer and P-gp Inducer Indication Dosage Modification for Everolimus RCC and TSC-Associated Renal Angiomyolipoma
• Avoid coadministration where alternatives exist.
• If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required.
• Resume the dosage administered prior to inducer initiation, once an inducer is discontinued for 5 days. 2.12 Administration and Preparation
• Administer Everolimus at the same time each day.
• Administer Everolimus consistently either with or without food [see Clinical Pharmacology (12.3)].
• If a dose of Everolimus is missed, it can be administered up to 6 hours after the time it is normally administered. After more than 6 hours, the dose should be skipped for that day. The next day, Everolimus should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed.
• Everolimus should be swallowed whole with a glass of water. Do not break or crush tablets.

• Non-Infectious Pneumonitis: Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. (2.9, 5.1)
• Infections: Monitor for signs and symptoms of infection. Withhold or permanently discontinue based on severity. (2.9, 5.2)
• Severe Hypersensitivity Reactions: Permanently discontinue for clinically significant hypersensitivity. (5.3)
• Angioedema: Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. (5.4, 7.2)
• Stomatitis: Initiate dexamethasone alcohol-free mouthwash when starting treatment. (5.5, 6.1)
• Renal Failure: Monitor renal function prior to treatment and periodically thereafter. (5.6)
• 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. (5.7)
• Metabolic Disorders: Monitor serum glucose and lipids prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. (2.9, 5.9)
• Myelosuppression: Monitor hematologic parameters prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. (2.9, 5.10)
• 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. (5.11)
• Radiation Sensitization and Radiation Recall: Severe radiation reactions may occur. (5.12, 6.2)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.13, 8.1, 8.3)

5.1Non-infectious Pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with Everolimus in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Grade 3 and 4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms. Consider opportunistic infections, such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. Continue Everolimus without dose alteration in patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis. For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue Everolimus based on severity [see Dosage and Administration (2.9)]. Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose. 5.2 Infections Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP), and viral infections (e.g., reactivation of hepatitis B virus) have occurred. Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue Everolimus based on severity of infection [see Dosage and Administration (2.9)]. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. 5.3 Severe Hypersensitivity Reactions Hypersensitivity reactions to Everolimus have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications (4)]. The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue Everolimus for the development of clinically significant hypersensitivity. 5.4 Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with Everolimus may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking Everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue Everolimus for angioedema. 5.5 Stomatitis Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with Everolimus at an incidence ranging from 44% to 78% across clinical trials. Grades 3-4 stomatitis was reported in 4% to 9% of patients [see Adverse Reactions (6.1)]. Stomatitis most often occurs within the first 8 weeks of treatment. When starting Everolimus, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis [see Adverse Reactions (6.1)]. If stomatitis does occur, mouthwashes and/or other topical treatments are recommended. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme- containing products, as they may exacerbate the condition. Do not administer antifungal agents, unless fungal infection has been diagnosed. 5.6 Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking Everolimus. Elevations of serum creatinine and proteinuria have been reported in patients taking Everolimus [see Adverse Reactions (6.1)]. The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting Everolimus and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure. 5.7 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, Everolimus has the potential to adversely affect wound healing. Withhold Everolimus 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 upon resolution of wound healing complications has not been established. 5.9 Metabolic Disorders Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking Everolimus at an incidence up to 75%, 86%, and 73%, respectively. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively [see Adverse Reactions (6.1)]. In non-diabetic patients, monitor fasting serum glucose prior to starting Everolimus and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting Everolimus and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting Everolimus. For Grade 3 to 4 metabolic events, withhold or permanently discontinue Everolimus based on severity [see Dosage and Administration (2.9)]. 5.10 Myelosuppression Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking Everolimus. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively [see Adverse Reactions (6.1)]. Monitor complete blood count (CBC) prior to starting Everolimus every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue Everolimus based on severity [see Dosage and Administration (2.9)]. 5.11 Risk of Infection or Reduced Immune Response with Vaccination The safety of immunization with live vaccines during Everolimus therapy has not been studied. Due to the potential increased risk of infection, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with Everolimus. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. 5.12 Radiation Sensitization and Radiation Recall Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) have been reported in patients treated with radiation prior to, during, or subsequent to everolimus treatment [see Adverse Reactions (6.2)]. Monitor patients closely when everolimus is administered during or sequentially with radiation treatment. 5.13 Embryo-Fetal Toxicity Based on animal studies and the mechanism of action, Everolimus can cause fetal harm when administered to a pregnant woman. 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 clinical dose of 10 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with Everolimus and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Everolimus and for 4 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

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)].
• 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) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 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. The data described below reflect exposure to Everolimus (n=274) and placebo (n=137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (27 to 85 years), 88% were white, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving Everolimus. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3 to 4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3 to 4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Everolimus arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the Everolimus group. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during Everolimus treatment were for infections, anemia, and stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus vs. placebo are presented in Table 13. Laboratory abnormalities are presented in Table 14. Table 13: Adverse Reactions Reported in ≥ 10% of Patients with RCC and at a Higher Rate in the Everolimus Arm than in the Placebo Arm in RECORD-1 Everolimus N = 274 Placebo N = 137 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitis Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. 44 4 8 0 Diarrhea 30 2 No Grade 4 adverse reactions were reported. 7 0 Nausea 26 2 19 0 Vomiting 20 2 12 0 Infections Includes all reported infections including, but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections. 37 10 18 2 General Asthenia 33 4 23 4 Fatigue 31 6 27 4 Edema peripheral 25 <1 8 <1 Pyrexia 20 <1 9 0 Mucosal inflammation 19 2 1 0 Respiratory, Thoracic and Mediastinal Cough 30 <1 16 0 Dyspnea 24 8 15 3 Epistaxis 18 0 0 0 Pneumonitis Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. 14 4 4 0 0 Skin and Subcutaneous Tissue Rash 29 1 7 0 Pruritus 14 < 1 7 0 Dry skin 13 < 1 5 0 Metabolism and Nutrition Anorexia 25 2 14 <1 Nervous System Headache 19 1 9 <1 Dysgeusia 10 0 2 0 Musculoskeletal and Connective Tissue Pain in extremity 10 1 7 0 Grading according to NCI CTCAE Version 3.0. Other notable adverse reactions occurring more frequently with Everolimus than with placebo, but with an incidence of <10% include: Gastrointestinal: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General: Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, Thoracic and Mediastinal: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and Subcutaneous Tissue: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (<1%) Metabolism and Nutrition: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric: Insomnia (9%) Nervous System: Dizziness (7%), paresthesia (5%) Ocular: Eyelid edema (4%), conjunctivitis (2%) Vascular: Hypertension (4%), deep vein thrombosis (<1%) Renal and Urinary: Renal failure (3%) Cardiac: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and Connective Tissue: Jaw pain (3%) Hematologic: Hemorrhage (3%) Table 14: Selected Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the Everolimus Arm Than the Placebo Arm in RECORD-1 Laboratory Parameter Everolimus N = 274 Placebo N = 137 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. Anemia 92 13 79 6 Lymphopenia 51 18 28 5 No Grade 4 laboratory abnormalities were reported. Thrombocytopenia 23 1 2 < 1 Neutropenia 14 < 1 4 0 Chemistry Hypercholesterolemia 77 4 35 0 Hypertriglyceridemia 73 < 1 34 0 Hyperglycemia 57 16 25 2 Increased creatinine increased 50 2 34 0 Hypophosphatemia 37 6 8 0 Increased AST 25 1 7 0 Increased ALT 21 1 4 0 Hyperbilirubinemia 3 1 2 0 Grading according to NCI CTCAE Version 3.0. Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of Everolimus in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The median age of patients was 31 years (18 to 61 years), 89% were white, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving Everolimus. The most common adverse reaction reported for Everolimus (incidence ≥ 30%) was stomatitis. The most common Grade 3 to 4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3 to 4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia. The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the Everolimus-treated patients. Adverse reactions leading to permanent discontinuation in the Everolimus arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of Everolimus-treated patients. The most common adverse reaction leading to Everolimus dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus and occurring more frequently with Everolimus than with placebo are presented in Table 15. Laboratory abnormalities are presented in Table 16. Table 15: Adverse Reactions Reported in ≥ 10% of Everolimus-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus N = 79 Placebo N = 39 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Stomatitis Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. 78 6 No Grade 4 adverse reactions were reported. 23 0 Vomiting 15 0 5 0 Diarrhea 14 0 5 0 General Peripheral edema 13 0 8 0 Infections Upper respiratory tract infection 11 0 5 0 Musculoskeletal and Connective Tissue Arthralgia 13 0 5 0 Respiratory, Thoracic and Mediastinal Cough 20 0 13 0 Skin and Subcutaneous Tissue Acne 22 0 5 0 Grading according to NCI CTCAE Version

3.0Amenorrhea

Occurred in 15% of Everolimus-treated females (8 of 52). Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). The following additional adverse reactions occurred in less than 10% of Everolimus-treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), ovarian cyst (3%), pneumonitis (1%), and angioedema (1%). Table 16: Selected Laboratory Abnormalities Reported in Everolimus-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2 Everolimus N = 79 Placebo N = 39 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Anemia 61 0 49 0 Leukopenia 37 0 21 0 Neutropenia 25 1 26 0 Lymphopenia 20 1 No Grade 4 laboratory abnormalities were reported. 8 0 Thrombocytopenia 19 0 3 0 Chemistry Hypercholesterolemia 85 1 46 0 Hypertriglyceridemia 52 0 10 0 Hypophosphatemia 49 5 15 0 Increased alkaline phosphatase 32 1 10 0 Increased AST 23 1 8 0 Increased ALT 20 1 15 0 Hyperglycemia (fasting) 14 0 8 0 Grading according to NCI CTCAE Version

3.0Updated

Safety information from 112 patients treated with Everolimus for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Everolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure:

• Blood and lymphatic disorders: Thrombotic microangiopathy
• Cardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event
• Gastrointestinal: Acute pancreatitis
• Hepatobiliary: Cholecystitis and cholelithiasis
• Infections: Sepsis and septic shock
• Nervous System: Reflex sympathetic dystrophy
• Vascular: Arterial thrombotic events, lymphedema
• Injury, poisoning and procedural complications: Radiation Sensitization and Radiation Recall

• 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)

7.1Effect of Other Drugs on Everolimus

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 Everolimus 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 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 Everolimus 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 may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with Everolimus [see Warnings and Precautions (5.4)].

• For RCC or TSC-associated renal angiomyolipoma patients with hepatic impairment, reduce the dose. (2.10, 8.6)

8.1Pregnancy Risk Summary

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], Everolimus can cause fetal harm when administered to a pregnant woman. There are limited case reports of Everolimus 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 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 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). 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 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 [see Use in Specific Populations (8.1)]. Contraception Everolimus 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 and for 8 weeks after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Everolimus and for 4 weeks after the last dose. Infertility Females: Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking Everolimus. Based on these findings, Everolimus may impair fertility in female patients [see Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)]. Males: Cases of reversible azoospermia have been reported in male patients taking Everolimus. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of Everolimus 10 mg orally once daily. Based on these findings, Everolimus may impair fertility in male patients [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of Everolimus in pediatric patients have not been established in:

• Renal Cell Carcinoma (RCC)
• TSC-associated renal angiomyolipoma

8.5Geriatric

Use In RECORD-1, 41% of patients with renal cell carcinoma treated with Everolimus were ≥ 65 years of age, while 7% were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients. 8.6 Hepatic Impairment Everolimus exposure may increase in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. For patients with RCC and TSC-associated renal angiomyolipoma who have hepatic impairment, reduce the Everolimus dose as recommended [see Dosage and Administration (2.10)].

Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], Everolimus can cause fetal harm when administered to a pregnant woman. There are limited case reports of Everolimus 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 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 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). 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.

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.

Everolimus Tablets 2.5 mg tablets are supplied as a white to off white, uniform to lightly speckled, capsule-shaped, flat-face, beveled edge tablet with “54 [space] 391” debossed on one side and plain on the other side. NDC 0054-0480-13: Bottle of 30 Tablets NDC 0054-0480-22: Bottle of 90 Tablets NDC 0054-0480-14: Blister Pack of 28 Tablets 5 mg tablets are supplied as a white to off white, uniform to lightly speckled, capsule-shaped, flat-face, beveled edge tablet with “54 [space] 451” debossed on one side and plain on the other side. NDC 0054-0481-13: Bottle of 30 Tablets NDC 0054-0481-22: Bottle of 90 Tablets NDC 0054-0481-14: Blister Pack of 28 Tablets 7.5 mg tablets are supplied as a white to off white, uniform to lightly speckled, capsule-shaped, flat-face, beveled edge tablet with “54 [space] 627” debossed on one side and plain on the other side. NDC 0054-0497-13: Bottle of 30 Tablets NDC 0054-0497-22: Bottle of 90 Tablets NDC 0054-0497-14: Blister Pack of 28 Tablets 10 mg tablets are supplied as a white to off white, uniform to lightly speckled, capsule-shaped, flat-face, beveled edge tablet with “54 [space] 701” debossed on one side and plain on the other side. NDC 0054-0482-13: Bottle of 30 Tablets NDC 0054-0482-22: Bottle of 90 Tablets NDC 0054-0482-14: Blister Pack of 28 Tablets Store at 20° to 25°C (68° to 77°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