ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling:oNon-infectious Pneumonitis [see Warnings and Precautions 5.1 )]. oInfections [see Warnings and Precautions 5.2 )]. oSevere Hypersensitivity Reactions [seeWarnings and Precautions(5.3)].oAngioedema with Concomitant Use of ACE Inhibitors [see Warnings and Precautions 5.4)].oStomatitis [see Warnings and Precautions 5.5)]. oRenal Failure [see Warnings and Precautions 5.6)].oImpaired Wound Healing [see Warnings and Precautions 5.7)]. oMetabolic Disorders [see Warnings and Precautions(5.9)].oMyelosuppression [seeWarnings and Precautions(5.10)].oRadiation Sensitization and Radiation Recall [see Warnings and Precautions (6.2)].. oNon-infectious Pneumonitis [see Warnings and Precautions 5.1 )]. oInfections [see Warnings and Precautions 5.2 )]. oSevere Hypersensitivity Reactions [seeWarnings and Precautions(5.3)].. oAngioedema with Concomitant Use of ACE Inhibitors [see Warnings and Precautions 5.4)].. oStomatitis [see Warnings and Precautions 5.5)]. oRenal Failure [see Warnings and Precautions 5.6)].. oImpaired Wound Healing [see Warnings and Precautions 5.7)]. oMetabolic Disorders [see Warnings and Precautions(5.9)].. oMyelosuppression [seeWarnings and Precautions(5.10)].. oRadiation Sensitization and Radiation Recall [see Warnings and Precautions (6.2)].. oRCC: 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)oTSC-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. oRCC: 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). oTSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence >= 30%) is stomatitis. (6.1). 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 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 to 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 to 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 12. Laboratory abnormalities are presented in Table 13. Table 12: Adverse Reactions Reported in >= 10% of Patients with RCC and at Higher Rate in the Everolimus Arm than in the Placebo Arm in RECORD-1EverolimusN 274PlaceboN 137All GradesGrades 3-4All GradesGrades 3-4%%%%Gastrointestinal StomatitisStomatitis (including aphthous stomatitis), and mouth and tongue ulceration. 44480 Diarrhea302No Grade adverse reactions were reported. 70 Nausea262 190 Vomiting202 120InfectionsIncludes all reported infections including, but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections.3710182General Asthenia334234 Fatigue316 274 Edema peripheral25<1 8<1 Pyrexia20<1 90 Mucosal inflammation192 10Respiratory, Thoracic and Mediastinal Cough30<1 160 Dyspnea248153 Epistaxis18000 PneumonitisIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. 1444 00Skin and Subcutaneous Tissue Rash291 70 Pruritus14< 70 Dry skin13< 50Metabolism and Nutrition Anorexia252 14<1 Nervous System Headache1919<1 Dysgeusia10020Musculoskeletal and connective tissue Pain in extremity101 70Grading 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 13: Selected Laboratory Abnormalities Reported in Patients with RCC at Higher Rate in the Everolimus Arm Than the Placebo Arm in RECORD-1Laboratory ParameterEverolimusN 274PlaceboN 137All GradesGrade 3-4All GradesGrade 3-4%%%%HematologyReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. Anemia9213796 Lymphopenia5118285No Grade laboratory abnormalities were reported. Thrombocytopenia231 2< Neutropenia14< 140Chemistry Hypercholesterolemia774 350 Hypertriglyceridemia73< 340 Hyperglycemia5716252 Increased creatinine increased502 340 Hypophosphatemia376 80 Increased AST25170 Increased ALT211 40 Hyperbilirubinemia3120Grading according to NCI CTCAE Version 3.0.Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The data described below are based on randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of Everolimus in 118 patients with renal angiomyolipoma as 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 to adverse reactions (incidence >= 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence >= 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade to 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 14. Laboratory abnormalities are presented in Table 15.Table 14: Adverse Reactions Reported in >= 10% of Everolimus-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2EverolimusN 79PlaceboN 39All Grades Grade 3-4All Grades Grade 3-4%%%%Gastrointestinal Stomatitis786No Grade adverse reactions were reported 230 Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. Vomiting15050 Diarrhea14050General Peripheral edema13080Infections Upper respiratory tract infection11050Musculoskeletal and connective tissue Arthralgia13050Respiratory, thoracic and mediastinal Cough200130Skin and subcutaneous tissueAcne22050Grading 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 15: Selected Laboratory Abnormalities Reported in Everolimus -Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2EverolimusN 79PlaceboN 39All Grades Grade 3-4All Grades Grade 3-4%%%% Hematology Anemia610490 Leukopenia370210 Neutropenia251260 Lymphopenia201No Grade laboratory abnormalities were reported. 80 Thrombocytopenia19030 Chemistry Hypercholesterolemia851 460 Hypertriglyceridemia520100 Hypophosphatemia495 150 Increased alkaline phosphatase321 100 Increased AST231 80 Increased ALT201 150 Hyperglycemia (fasting)14080Grading according to NCI CTCAE Version 3.0Updated safety information from 112 patients treated with Everolimus for 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%).. 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%). Stomatitis. Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. Vomiting. Diarrhea. Peripheral edema. Upper respiratory tract infection. Arthralgia. Cough. Anemia. Leukopenia. Neutropenia. Lymphopenia. Thrombocytopenia. Hypercholesterolemia. Hypertriglyceridemia. Hypophosphatemia. Increased alkaline phosphatase. Increased AST. Increased ALT. Hyperglycemia (fasting). 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Everolimus. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate frequency or establish causal relationship to drug exposure:oBlood and lymphatic disorders: Thrombotic microangiopathy oCardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as secondary eventoGastrointestinal: Acute pancreatitisoHepatobiliary: Cholecystitis and cholelithiasisoInfections: Sepsis and septic shockoNervous System: Reflex sympathetic dystrophyoVascular: Arterial thrombotic eventsoInjury, poisoning and procedural complications: Radiation Sensitization and Radiation Recall. oBlood and lymphatic disorders: Thrombotic microangiopathy oCardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as secondary event. oGastrointestinal: Acute pancreatitis. oHepatobiliary: Cholecystitis and cholelithiasis. oInfections: Sepsis and septic shock. oNervous System: Reflex sympathetic dystrophy. oVascular: Arterial thrombotic events. oInjury, poisoning and procedural complications: Radiation Sensitization and Radiation Recall.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), 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 (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 substrate of mTORC1 and phosphorylates the activation domain 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 and (TSC1, TSC2). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, 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.. 12.2 Pharmacodynamics Cardiac ElectrophysiologyIn randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered single oral dose of Everolimus (20 mg and 50 mg) and placebo. Everolimus at single doses up to 50 mg did not prolong the QT/QTc interval. 12.3 Pharmacokinetics AbsorptionAfter administration of Everolimus tablets in patients with advanced solid tumors, peak everolimus concentrations are reached to hours after administration of oral doses ranging from mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional; however, AUC shows dose-proportionality over the mg to 70 mg dose range. Steady-state was achieved within weeks following once-daily dosing.Effect of Food: In healthy subjects, high-fat meal (containing approximately 1000 calories and 55 grams of fat) reduced systemic exposure to Everolimus 10 mg (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light-fat meals (containing approximately 500 calories and 20 grams of fat) reduced AUC by 32% and Cmax by 42%. DistributionThe blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given Everolimus 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.EliminationThe mean elimination half-life of everolimus is approximately 30 hours.Metabolism:Everolimus is substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.Excretion: No specific elimination studies have been undertaken in cancer patients. Following the administration of 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces.Specific PopulationsNo relationship was apparent between oral clearance and age or sex in patients with cancer.Patients with Renal Impairment: No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus.Patients with Hepatic Impairment: Compared to normal subjects, there was 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [seeDosage and Administration (2.10), Use in Specific Populations(8.6)].Race or Ethnicity: Based on cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose. Oral clearance (CL/F) is on average 20% higher in black patients than in white patients. Drug Interaction StudiesEffect of CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus: Everolimus exposure increased when Everolimus was coadministered with:oketoconazole (a P-gp and strong CYP3A4 inhibitor) Cmax and AUC increased by 3.9- and 15-fold, respectively. oerythromycin (a P-gp and moderate CYP3A4 inhibitor) Cmax and AUC increased by 2- and 4.4-fold, respectively. overapamil (a P-gp and moderate CYP3A4 inhibitor) Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Effect of CYP3A4 and P-gp Inducers on Everolimus: The coadministration of Everolimus with rifampin, P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and Cmax by 58% compared to Everolimus alone [see Dosage and Administration (2.12)].Effect of Everolimus on CYP3A4 Substrates: No clinically significant pharmacokinetic interactions were observed between Everolimus and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate).The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with Everolimus resulted in 25% increase in midazolam Cmax and 30% increase in midazolam AUC0-inf.The coadministration of Everolimus with long acting octreotide increased octreotide Cmin by approximately 50%.Effect of Everolimus on Antiepileptic Drugs (AEDs): Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazams metabolite N-desmethylclobazam by about 10%. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.. oketoconazole (a P-gp and strong CYP3A4 inhibitor) Cmax and AUC increased by 3.9- and 15-fold, respectively. oerythromycin (a P-gp and moderate CYP3A4 inhibitor) Cmax and AUC increased by 2- and 4.4-fold, respectively. overapamil (a P-gp and moderate CYP3A4 inhibitor) Cmax and AUC increased by 2.3- and 3.5-fold, respectively.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.3 Renal Cell Carcinoma (RCC). An international, multi-center, randomized, double-blind trial (RECORD-1, NCT00410124) comparing Everolimus 10 mg once daily and placebo, both in conjunction with BSC, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interleukin 2, or interferon- was also permitted. Randomization was stratified according to prognostic score and prior anticancer therapy. The major efficacy outcome measure for the trial was PFS evaluated by RECIST, based on blinded, independent, central radiologic review. After documented radiological progression, patients randomized to placebo could receive open-label Everolimus. Other outcome measures included OS.In total, 416 patients were randomized 2:1 to receive Everolimus (n=277) or placebo (n=139). Demographics were well balanced between the arms (median age 61 years; 77% male, 88% white, 74% received prior sunitinib or sorafenib, and 26% received both sequentially).Everolimus was superior to placebo for PFS (Table 23 and Figure 4). The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib. Final OS results yield hazard ratio of 0.90 (95% CI: 0.71, 1.14), with no statistically significant difference between the arms. Planned cross-over from placebo due to disease progression to open-label Everolimus occurred in 80% of the 139 patients and may have confounded the OS benefit.Table 23: Progression-Free Survival and Objective Response Rate by Central Radiologic Review in RCC in RECORD-1EverolimusN 277PlaceboN 139Hazard Ratio(95% CI)p-valueLog-rank test stratified by prognostic score.Median Progression-free Survival(95% CI)4.9 Months(4.0, 5.5)1.9 Months(1.8, 1.9)0.33(0.25, 0.43)<0.0001Objective Response Rate2%0%n/aNot applicable. n/a Figure 4: Kaplan-Meier Curves for Progression-Free Survival in RCC in RECORD-1 figure4.jpg. 14.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma A randomized (2:1), double-blind, placebo-controlled trial (EXIST-2, NCT00790400) of Everolimus was conducted in 118 patients with renal angiomyolipoma as feature of TSC (n 113) or sporadic lymphangioleiomyomatosis (n 5). The key eligibility requirements for this trial were at least one angiomyolipoma of >= cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age >= 18 years. Patients received Everolimus 10 mg or matching placebo orally once daily until disease progression or unacceptable toxicity. CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation. The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as >= 50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion >= cm, absence of kidney volume increase >= 20%, and no angiomyolipoma related bleeding of >= Grade 2. Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate. The primary analyses of efficacy outcome measures were limited to the blinded treatment period and conducted months after the last patient was randomized. The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no). Of the 118 patients enrolled, 79 were randomized to Everolimus and 39 to placebo. The median age was 31 years (18 to 61 years), 34% were male, and 89% were White. At baseline, 17% of patients were receiving EIAEDs. On central radiology review at baseline, 92% of patients had at least angiomyolipoma of >= cm in longest diameter, 29% had angiomyolipomas >= cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions. The median values for the sum of all target renal angiomyolipoma lesions at baseline were 85 cm3 (9 to 1612 cm3) and 120 cm3 (3 to 4520 cm3) in the Everolimus and placebo arms, respectively. Forty-six (39%) patients had prior renal embolization or nephrectomy. The median duration of follow-up was 8.3 months (0.7 to 24.8 months) at the time of the primary analysis. The renal angiomyolipoma response rate was statistically significantly higher in Everolimus-treated patients (Table 24). The median response duration was 5.3+ months (2.3+ to 19.6+ months). There were patients in the Everolimus arm and patients in the placebo arm with documented angiomyolipoma progression by central radiologic review (defined as >= 25% increase from nadir in the sum of angiomyolipoma target lesion volumes to value greater than baseline, appearance of new angiomyolipoma >= cm in longest diameter, an increase in renal volume >= 20% from nadir for either kidney and to value greater than baseline, or Grade >= angiomyolipoma-related bleeding). The time to angiomyolipoma progression was statistically significantly longer in the Everolimus arm (HR 0.08 [95% CI: 0.02, 0.37]; < 0.0001). Table 24: Angiomyolipoma Response Rate in TSC-Associated Renal Angiomyolipoma in EXIST-2EverolimusN 79PlaceboN 39p-valuePrimary analysisAngiomyolipoma response ratePer independent central radiology review. % 95% CI 41.8(30.8, 53.4)0(0.0, 9.0)<0.0001Skin lesion response rates were assessed by local investigators for 77 patients in the Everolimus arm and 37 patients in the placebo arm who presented with skin lesions at study entry. The skin lesion response rate was statistically significantly higher in the Everolimus arm (26% vs. 0, = 0.0011); all skin lesion responses were partial responses, defined as visual improvement in 50% to 99% of all skin lesions durable for at least weeks (Physicians Global Assessment of Clinical Condition). Patients randomized to placebo were permitted to receive Everolimus at the time of angiomyolipoma progression or after the time of the primary analysis. After the primary analysis, patients treated with Everolimus underwent additional follow-up CT or MRI scans to assess tumor status until discontinuation of treatment or completion of years of follow-up after the last patient was randomized. total of 112 patients (79 randomized to Everolimus and 33 randomized to placebo) received at least one dose of Everolimus. The median duration of Everolimus treatment was 3.9 years (0.5 months to 5.3 years) and the median duration of follow-up was 3.9 years (0.9 months to 5.4 years). During the follow-up period after the primary analysis, 32 patients (in addition to the 33 patients identified at the time of the primary analysis) had an angiomyolipoma response based upon independent central radiology review. Among the 65 responders out of 112 patients, the median time to angiomyolipoma response was 2.9 months (2.6 to 33.8 months). Fourteen percent of the 112 patients treated with Everolimus had angiomyolipoma progression by the end of the follow-up period. No patient underwent nephrectomy for angiomyolipoma progression and one patient underwent renal embolization while treated with Everolimus.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Everolimus is available in tablets for oral 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: o10 mg orally once daily (2.4)TSC-Associated Renal Angiomyolipoma: o10 mg orally once daily. (2.5). o10 mg orally once daily (2.4). o10 mg orally once daily. (2.5). 2.1 Important Dosage Information oModify 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 (2.11, 2.12)].. oModify 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 (2.11, 2.12)].. 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 summarizes recommendations for dosage modifications of Everolimus for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus for Adverse ReactionsAdverse ReactionSeverityDosage Modification Non-infectious pneumonitis [see Warnings and Precautions (5.1)] Grade 2Withhold until improvement to Grade 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 within weeks. Grade 3Withhold until improvement to Grade 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 4Permanently discontinue. Stomatitis [see Warnings and Precautions (5.5)] Grade 2Withhold until improvement to Grade or 1. Resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 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 3Withhold until improvement to Grade 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 4Permanently discontinue. Metabolic events(e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9)] Grade 3Withhold 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 4Permanently discontinue. Other non-hematologic toxicities Grade 2If toxicity becomes intolerable, withhold until improvement to Grade or 1. Resume at same dose.If toxicity recurs at Grade 2, withhold until improvement to Grade 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 3Withhold until improvement to Grade 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 4Permanently discontinue. Thrombocytopenia [see Warnings and Precautions (5.10)] Grade 2Withhold until improvement to Grade or 1. Resume at same dose. Grade OR Grade 4Withhold until improvement to Grade 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 3Withhold until improvement to Grade 0, 1, or 2. Resume at same dose. Grade 4Withhold 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 3Withhold 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 4Permanently discontinue.. 2.10 Dosage Modifications for Hepatic Impairment The recommended dosages of Everolimus for patients with hepatic impairment are described in Table [see Use in Specific Populations (8.6)]:Table 3: Recommended Dosage Modifications for Patients with Hepatic ImpairmentIndicationDose Modification for EverolimusRCC and TSC-Associated Renal Angiomyolipoma oMild hepatic impairment (Child-Pugh class A) 7.5 mg orally once daily; decrease the dose to mg orally once daily if dose of 7.5 mg once daily is not tolerated. oModerate hepatic impairment (Child-Pugh class B) 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if dose of mg once daily is not tolerated. oSevere hepatic impairment (Child-Pugh class C) 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed dose of 2.5 mg once daily. Abbreviations: RCC, Renal Cell Carcinoma; TSC, Tuberous Sclerosis Complex. oMild hepatic impairment (Child-Pugh class A) 7.5 mg orally once daily; decrease the dose to mg orally once daily if dose of 7.5 mg once daily is not tolerated. oModerate hepatic impairment (Child-Pugh class B) 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if dose of mg once daily is not tolerated. oSevere hepatic impairment (Child-Pugh class C) 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed dose of 2.5 mg once daily. 2.11 Dosage Modifications for P-gp and CYP3A4 Inhibitors oAvoid the concomitant use of P-gp and strong CYP3A4 inhibitors [seeDrug Interactions (7.1)].oAvoid ingesting grapefruit and grapefruit juice. oReduce the dose for patients taking Everolimus with P-gp and moderate CYP3A4 inhibitor as recommended in Table [seeDrug Interactions (7.1), Clinical Pharmacology (12.3)].Table 4: Recommended Dosage Modifications for Concurrent Use of Everolimus with P-gp and Moderate CYP3A4 InhibitorIndicationDose Modification for EverolimusRCC and TSC-Associated Renal Angiomyolipoma oReduce dose to 2.5 mg once daily.oMay increase dose to mg once daily if tolerated.oResume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for days.. oAvoid the concomitant use of P-gp and strong CYP3A4 inhibitors [seeDrug Interactions (7.1)].. oAvoid ingesting grapefruit and grapefruit juice. oReduce the dose for patients taking Everolimus with P-gp and moderate CYP3A4 inhibitor as recommended in Table [seeDrug Interactions (7.1), Clinical Pharmacology (12.3)].. oReduce dose to 2.5 mg once daily.. oMay increase dose to mg once daily if tolerated.. oResume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for days.. 2.12 Dosage Modifications for P-gp and CYP3A4 Inducers oAvoid concomitant use of St. Johns Wort (Hypericum perforatum).oIncrease the dose for patients taking Everolimus with P-gp and strong CYP3A4 inducer as recommended in Table [seeDrug Interactions (7.1), Clinical Pharmacology (12.3)].Table 5: Recommended Dosage Modifications for Concurrent Use of Everolimus with P-gp and Strong CYP3A4 InducersIndicationDose Modification for EverolimusRCC and TSC-Associated Renal Angiomyolipoma oAvoid coadministration where alternatives exist.oIf coadministration cannot be avoided, double the daily dose using increments of mg or less. Multiple increments may be required. oResume the dose administered prior to inducer initiation, once an inducer is discontinued for days.. oAvoid concomitant use of St. Johns Wort (Hypericum perforatum).. oIncrease the dose for patients taking Everolimus with P-gp and strong CYP3A4 inducer as recommended in Table [seeDrug Interactions (7.1), Clinical Pharmacology (12.3)].. oAvoid coadministration where alternatives exist.. oIf coadministration cannot be avoided, double the daily dose using increments of mg or less. Multiple increments may be required. oResume the dose administered prior to inducer initiation, once an inducer is discontinued for days.. 2.13 Administration and Preparation oAdminister Everolimus at the same time each day.oAdminister Everolimus consistently either with or without food [seeClinical Pharmacology (12.3)].oIf dose of Everolimus is missed, it can be administered up to hours after the time it is normally administered. After more than 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.oEverolimus should be swallowed whole with glass of water. Do not break or crush tablets. oAdminister Everolimus at the same time each day.. oAdminister Everolimus consistently either with or without food [seeClinical Pharmacology (12.3)].. oIf dose of Everolimus is missed, it can be administered up to hours after the time it is normally administered. After more than 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.. oEverolimus should be swallowed whole with glass of water. Do not break or crush tablets.

PATIENT MEDICATION INFORMATION SECTION.

PATIENT INFORMATION Everolimus Tablets (e ver oh li mus)Read this Patient Information leaflet that comes with Everolimus Tablets before you start taking it and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information should know about Everolimus Tablets Everolimus Tablets can cause serious side effects, including: 1.You may develop lung or breathing problems. In some people lung or breathing problems may be severe and can lead to death. Tell your healthcare provider right away if you have any of these symptoms: oNew or worsening cough oShortness of breath oChest pain oDifficulty breathing or wheezing 2.You may be more likely to develop an infection, such as pneumonia, or bacterial, fungal or viral infection. Viral infections may include active hepatitis in people who have had hepatitis in the past (reactivation). In some people (including adults and children) these infections may be severe and can lead to death. You may need to be treated as soon as possible. Tell your healthcare provider right away if you have temperature of 100.5F or above, chills, or do not feel well. Symptoms of hepatitis or infection may include the following:oFever oChills oSkin rash oJoint pain and swelling oTiredness oLoss of appetite oNauseaoPale stools or dark urine oYellowing of the skin oPain in the upper right side of the stomach 3.Severe allergic reactions. Call your healthcare provider or get medical help right away if you get signs and symptoms of severe allergic reaction including: rash, itching, hives, flushing, trouble breathing or swallowing, chest pain or dizziness. 4.Possible increased risk for type of allergic reaction called angioedema, in people who take an Angiotensin-Converting Enzyme (ACE) inhibitor medicine during treatment with Everolimus Tablets. Talk with your healthcare provider before taking Everolimus Tablets if you are not sure if you take an ACE inhibitor medicine. Get medical help right away if you have trouble breathing or develop swelling of your tongue, mouth, or throat during treatment with Everolimus Tablets.5.Mouth ulcers and sores. Mouth ulcers and sores are common during treatment with everolimus but can also be severe. When you start treatment with everolimus, your healthcare provider may tell you to also start prescription mouthwash to reduce the likelihood of getting mouth ulcers or sores and to reduce their severity. Follow your healthcare providers instructions on how to use this prescription mouthwash. If you develop pain, discomfort, or open sores in your mouth, tell your healthcare provider. Your healthcare provider may tell you to re-start this mouthwash or to use special mouthwash or mouth gel that does not contain alcohol, peroxide, iodine, or thyme.6.You may develop kidney failure. In some people this may be severe and can lead to death. Your healthcare provider should do tests to check your kidney function before and during your treatment with Everolimus Tablets.If you have any of the serious side effects listed above, you may need to stop taking Everolimus Tablets for while or use lower dose. Follow your healthcare providers instructions.What are Everolimus Tablets Everolimus Tablets are prescription medicine used to treat: oAdults with advanced kidney cancer (renal cell carcinoma or RCC) when certain other medicines have not worked. opeople with the following types of tumors that are seen with genetic condition called tuberous sclerosis complex (TSC): oadults with kidney tumor called angiomyolipoma, when their kidney tumor does not require surgery right away.It is not known if Everolimus Tablets are safe and effective in children to treat:okidney cancer (renal cell carcinoma)oa kidney tumor called angiomyolipoma, that can happen in children with genetic condition called tuberous sclerosis complex (TSC).Do not take Everolimus Tablets if you have had severe allergic reaction to everolimus. Talk to your healthcare provider before taking this medicine if you are allergic to: osirolimus (Rapamune(R)) otemsirolimus (Torisel(R)) Ask your healthcare provider if you do not know. Before taking Everolimus Tablets,tell your healthcare provider about all of your medical conditions, including if you:oHave or have had kidney problems oHave or have had liver problems oHave diabetes or high blood sugar oHave high blood cholesterol levels oHave any infections oPreviously had hepatitis oAre scheduled to receive any vaccinations. You should not receive live vaccine or be around people who have recently received live vaccine during your treatment with Everolimus Tablets. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. oAre pregnant, can become pregnant, or have partner who can become pregnant. Everolimus Tablets can cause harm to your unborn baby. Females who are able to become pregnant: Your healthcare provider will give you pregnancy test before you start treatment with Everolimus Tablets. You should use effective birth control during treatment and for weeks after your last dose of Everolimus Tablets. Males with female partner, you should use effective birth control during treatment and for weeks after your last dose of Everolimus Tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your healthcare provider right away. oAre breastfeeding or plan to breastfeed. It is not known if Everolimus passes into your breast milk. Do not breastfeed during treatment and for weeks after your last dose of Everolimus Tablets. oAre planning to have surgery or if you have had recent surgery. You should stop taking Everolimus Tablets at least week before planned surgery. See Whatare the possible side effects of Everolimus TabletsoHave received radiation therapy or are planning to receive radiation therapy in the future. See What are the possible side effects of Everolimus TabletsTell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Everolimus Tablets may affect the way other medicines work, and other medicines can affect how Everolimus Tablets work. Taking Everolimus Tablets with other medicines can cause serious side effects. Know the medicines you take. Keep list of them and show it to your healthcare provider and pharmacist when you get new medicine. Especially tell your healthcare provider if you take: oSt. Johns Wort (Hypericum perforatum) oMedicine for: oFungal infections oBacterial infections oTuberculosis oSeizures oHIV-AIDS oHeart conditions or high blood pressure oMedicines that weaken your immune system (your bodys ability to fight infections and other problems) Ask your healthcare provider or pharmacist if you are not sure if your medicine is one of those taken for the conditions listed above. If you are taking any medicines for the conditions listed above, your healthcare provider might need to prescribe different medicine or your dose of Everolimus Tablets may need to be changed. You should also tell your healthcare provider before you start taking any new medicine. How should take Everolimus Tablets oYour healthcare provider will prescribe the dose of Everolimus Tablets that is right for you. oTake Everolimus Tablets exactly as your healthcare provider tells you to. oYour healthcare provider may change your dose of Everolimus Tablets or tell you to temporarily interrupt dosing, if needed.oUse scissors to open the blister pack.oTake Everolimus Tablets time each day at about the same time. oTake Everolimus Tablets the same way each time, either with food or without food. oIf you take too much Everolimus Tablets contact your healthcare provider or go to the nearest hospital emergency room right away. Take the bottle or blister pack of Everolimus Tablets with you. oIf you miss dose of Everolimus Tablets, you may take it if it is less than hours after the time you normally take it. If it is more than hours after you normally take your Everolimus Tablets, skip the dose for that day. The next day, take Everolimus Tablets at your usual time. Do not take doses to make up for missed dose. If you are not sure about what to do, call your healthcare provider. oYou should have blood tests before you start Everolimus Tablets and as needed during your treatment. These will include tests to check your blood cell count, kidney and liver function, cholesterol, and blood sugar levels. oSwallow Everolimus Tablets whole with glass of water. Do not take any tablet that is broken or crushed. What should avoid while taking Everolimus Tablets You should not drink grapefruit juice or eat grapefruit during your treatment with Everolimus Tablets. It may make the amount of Everolimus in your blood increase to harmful level. What are the possible side effects of Everolimus Tablets Everolimus Tablets can cause serious side effects. oSee What is the most important information should know about Everolimus Tablets for more information. oRisk of wound healing problems. Wounds may not heal properly during Everolimus Tablets treatment. Tell your healthcare provider if you plan to have any surgery before starting or during treatment with Everolimus Tablets. oYou should stop taking Everolimus Tablets at least week before planned surgery.oYour healthcare provider should tell you when you may start taking Everolimus Tablets again after surgery. oIncreased blood sugar and fat (cholesterol and triglyceride) levels in the blood. Your healthcare provider should do blood tests to check your fasting blood sugar, cholesterol, and triglyceride levels in the blood before you start and during treatment with Everolimus Tablets.oDecreased blood cell counts. Everolimus Tablets can cause you to have decreased red blood cells, white blood cells, and platelets. Your healthcare provider should do blood tests to check your blood cell counts before you start and during treatment with Everolimus Tablets.oWorsening side effects from radiation treatment, that can sometimes be severe. Tell your healthcare provider if you have had or are planning to receive radiation therapy. The most common side effects of Everolimus Tablets in people with advanced kidney cancer include: oInfectionsoRashoFeeling weak or tiredoDiarrheaoSwelling of arms, hands, feet, ankles, face, or other parts of the bodyoStomach-area (abdominal) painoNausea oFever oCoughoHeadacheoDecreased appetiteThe most common side effects of Everolimus Tablets in people who have renal angiomyolipoma with TSC include respiratory tract infections.Other side effects that may occur with Everolimus Tablets: oAbsence of menstrual periods (menstruation). You may miss or more menstrual periods. Tell your healthcare provider if this happens. oEverolimus Tablets may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is concern for you. oEverolimus Tablets may affect fertility in males and may affect your ability to father child. Talk to your healthcare provider if this is concern for you.Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of Everolimus Tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store Everolimus Tablets oStore Everolimus Tablets at room temperature, between 68 to 77F (20 to 25C). oKeep Everolimus Tablets in the container it comes in. oOpen the blister pack just before taking Everolimus Tablets.oKeep Everolimus Tablets dry and away from light. oDo not use Everolimus Tablets that is out of date or no longer needed. Keep Everolimus Tablets and all medicines out of the reach of children. General information about the safe and effective use of Everolimus Tablets.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Everolimus Tablets for condition for which it was not prescribed. Do not give Everolimus Tablets to other people, even if they have the same problem you have. It may harm them. This leaflet summarizes the most important information about Everolimus Tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information written for healthcare professionals. For more information, please call 1-800-962-8364. What are the ingredients in Everolimus Tablets Active ingredient: everolimus. Inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, and magnesium stearate. This Patient Information has been approved by the U.S. Food and Drug Administration. The brands listed are the trademarks or register marks of their respective owners and are not trademarks or register marks of Hikma Pharmaceuticals USA Inc. Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922C50001080/01Revised May 2021. 1.You may develop lung or breathing problems. In some people lung or breathing problems may be severe and can lead to death. Tell your healthcare provider right away if you have any of these symptoms: oNew or worsening cough oShortness of breath oChest pain oDifficulty breathing or wheezing 2.You may be more likely to develop an infection, such as pneumonia, or bacterial, fungal or viral infection. Viral infections may include active hepatitis in people who have had hepatitis in the past (reactivation). In some people (including adults and children) these infections may be severe and can lead to death. You may need to be treated as soon as possible. oFever oChills oSkin rash oJoint pain and swelling oTiredness oLoss of appetite oNausea. oPale stools or dark urine oYellowing of the skin oPain in the upper right side of the stomach 3.Severe allergic reactions. Call your healthcare provider or get medical help right away if you get signs and symptoms of severe allergic reaction including: rash, itching, hives, flushing, trouble breathing or swallowing, chest pain or dizziness. 4.Possible increased risk for type of allergic reaction called angioedema, in people who take an Angiotensin-Converting Enzyme (ACE) inhibitor medicine during treatment with Everolimus Tablets. Talk with your healthcare provider before taking Everolimus Tablets if you are not sure if you take an ACE inhibitor medicine. Get medical help right away if you have trouble breathing or develop swelling of your tongue, mouth, or throat during treatment with Everolimus Tablets.. 5.Mouth ulcers and sores. Mouth ulcers and sores are common during treatment with everolimus but can also be severe. When you start treatment with everolimus, your healthcare provider may tell you to also start prescription mouthwash to reduce the likelihood of getting mouth ulcers or sores and to reduce their severity. Follow your healthcare providers instructions on how to use this prescription mouthwash. If you develop pain, discomfort, or open sores in your mouth, tell your healthcare provider. Your healthcare provider may tell you to re-start this mouthwash or to use special mouthwash or mouth gel that does not contain alcohol, peroxide, iodine, or thyme.. 6.You may develop kidney failure. In some people this may be severe and can lead to death. Your healthcare provider should do tests to check your kidney function before and during your treatment with Everolimus Tablets.. oAdults with advanced kidney cancer (renal cell carcinoma or RCC) when certain other medicines have not worked. opeople with the following types of tumors that are seen with genetic condition called tuberous sclerosis complex (TSC): oadults with kidney tumor called angiomyolipoma, when their kidney tumor does not require surgery right away.. oadults with kidney tumor called angiomyolipoma, when their kidney tumor does not require surgery right away.. okidney cancer (renal cell carcinoma). oa kidney tumor called angiomyolipoma, that can happen in children with genetic condition called tuberous sclerosis complex (TSC).. osirolimus (Rapamune(R)) otemsirolimus (Torisel(R)) oHave or have had kidney problems oHave or have had liver problems oHave diabetes or high blood sugar oHave high blood cholesterol levels oHave any infections oPreviously had hepatitis . oAre scheduled to receive any vaccinations. You should not receive live vaccine or be around people who have recently received live vaccine during your treatment with Everolimus Tablets. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. oAre pregnant, can become pregnant, or have partner who can become pregnant. Everolimus Tablets can cause harm to your unborn baby. Females who are able to become pregnant:. Your healthcare provider will give you pregnancy test before you start treatment with Everolimus Tablets.. You should use effective birth control during treatment and for weeks after your last dose of Everolimus Tablets.. Males with female partner, you should use effective birth control during treatment and for weeks after your last dose of Everolimus Tablets.. Talk to your healthcare provider about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your healthcare provider right away. oAre breastfeeding or plan to breastfeed. It is not known if Everolimus passes into your breast milk. Do not breastfeed during treatment and for weeks after your last dose of Everolimus Tablets. oAre planning to have surgery or if you have had recent surgery. You should stop taking Everolimus Tablets at least week before planned surgery. See Whatare the possible side effects of Everolimus Tablets. oHave received radiation therapy or are planning to receive radiation therapy in the future. See What are the possible side effects of Everolimus Tablets. oSt. Johns Wort (Hypericum perforatum) oMedicine for: oFungal infections oBacterial infections oTuberculosis oSeizures oHIV-AIDS oHeart conditions or high blood pressure oMedicines that weaken your immune system (your bodys ability to fight infections and other problems) oYour healthcare provider will prescribe the dose of Everolimus Tablets that is right for you. oTake Everolimus Tablets exactly as your healthcare provider tells you to. oYour healthcare provider may change your dose of Everolimus Tablets or tell you to temporarily interrupt dosing, if needed.. oUse scissors to open the blister pack.. oTake Everolimus Tablets time each day at about the same time. oTake Everolimus Tablets the same way each time, either with food or without food. oIf you take too much Everolimus Tablets contact your healthcare provider or go to the nearest hospital emergency room right away. Take the bottle or blister pack of Everolimus Tablets with you. oIf you miss dose of Everolimus Tablets, you may take it if it is less than hours after the time you normally take it. If it is more than hours after you normally take your Everolimus Tablets, skip the dose for that day. The next day, take Everolimus Tablets at your usual time. Do not take doses to make up for missed dose. If you are not sure about what to do, call your healthcare provider. oYou should have blood tests before you start Everolimus Tablets and as needed during your treatment. These will include tests to check your blood cell count, kidney and liver function, cholesterol, and blood sugar levels. oSwallow Everolimus Tablets whole with glass of water. Do not take any tablet that is broken or crushed. oSee What is the most important information should know about Everolimus Tablets for more information. oRisk of wound healing problems. Wounds may not heal properly during Everolimus Tablets treatment. Tell your healthcare provider if you plan to have any surgery before starting or during treatment with Everolimus Tablets. oYou should stop taking Everolimus Tablets at least week before planned surgery.oYour healthcare provider should tell you when you may start taking Everolimus Tablets again after surgery. oYou should stop taking Everolimus Tablets at least week before planned surgery.. oYour healthcare provider should tell you when you may start taking Everolimus Tablets again after surgery.. oIncreased blood sugar and fat (cholesterol and triglyceride) levels in the blood. Your healthcare provider should do blood tests to check your fasting blood sugar, cholesterol, and triglyceride levels in the blood before you start and during treatment with Everolimus Tablets.. oDecreased blood cell counts. Everolimus Tablets can cause you to have decreased red blood cells, white blood cells, and platelets. Your healthcare provider should do blood tests to check your blood cell counts before you start and during treatment with Everolimus Tablets.. oWorsening side effects from radiation treatment, that can sometimes be severe. Tell your healthcare provider if you have had or are planning to receive radiation therapy. oInfections. oRash. oFeeling weak or tired. oDiarrhea. oSwelling of arms, hands, feet, ankles, face, or other parts of the body. oStomach-area (abdominal) pain. oNausea oFever oCough. oHeadache. oDecreased appetite. oAbsence of menstrual periods (menstruation). You may miss or more menstrual periods. Tell your healthcare provider if this happens. oEverolimus Tablets may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is concern for you. oEverolimus Tablets may affect fertility in males and may affect your ability to father child. Talk to your healthcare provider if this is concern for you.. oStore Everolimus Tablets at room temperature, between 68 to 77F (20 to 25C). oKeep Everolimus Tablets in the container it comes in. oOpen the blister pack just before taking Everolimus Tablets.. oKeep Everolimus Tablets dry and away from light. oDo not use Everolimus Tablets that is out of date or no longer needed.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics AbsorptionAfter administration of Everolimus tablets in patients with advanced solid tumors, peak everolimus concentrations are reached to hours after administration of oral doses ranging from mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional; however, AUC shows dose-proportionality over the mg to 70 mg dose range. Steady-state was achieved within weeks following once-daily dosing.Effect of Food: In healthy subjects, high-fat meal (containing approximately 1000 calories and 55 grams of fat) reduced systemic exposure to Everolimus 10 mg (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light-fat meals (containing approximately 500 calories and 20 grams of fat) reduced AUC by 32% and Cmax by 42%. DistributionThe blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given Everolimus 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.EliminationThe mean elimination half-life of everolimus is approximately 30 hours.Metabolism:Everolimus is substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.Excretion: No specific elimination studies have been undertaken in cancer patients. Following the administration of 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces.Specific PopulationsNo relationship was apparent between oral clearance and age or sex in patients with cancer.Patients with Renal Impairment: No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus.Patients with Hepatic Impairment: Compared to normal subjects, there was 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [seeDosage and Administration (2.10), Use in Specific Populations(8.6)].Race or Ethnicity: Based on cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose. Oral clearance (CL/F) is on average 20% higher in black patients than in white patients. Drug Interaction StudiesEffect of CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus: Everolimus exposure increased when Everolimus was coadministered with:oketoconazole (a P-gp and strong CYP3A4 inhibitor) Cmax and AUC increased by 3.9- and 15-fold, respectively. oerythromycin (a P-gp and moderate CYP3A4 inhibitor) Cmax and AUC increased by 2- and 4.4-fold, respectively. overapamil (a P-gp and moderate CYP3A4 inhibitor) Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Effect of CYP3A4 and P-gp Inducers on Everolimus: The coadministration of Everolimus with rifampin, P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and Cmax by 58% compared to Everolimus alone [see Dosage and Administration (2.12)].Effect of Everolimus on CYP3A4 Substrates: No clinically significant pharmacokinetic interactions were observed between Everolimus and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate).The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with Everolimus resulted in 25% increase in midazolam Cmax and 30% increase in midazolam AUC0-inf.The coadministration of Everolimus with long acting octreotide increased octreotide Cmin by approximately 50%.Effect of Everolimus on Antiepileptic Drugs (AEDs): Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazams metabolite N-desmethylclobazam by about 10%. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.. oketoconazole (a P-gp and strong CYP3A4 inhibitor) Cmax and AUC increased by 3.9- and 15-fold, respectively. oerythromycin (a P-gp and moderate CYP3A4 inhibitor) Cmax and AUC increased by 2- and 4.4-fold, respectively. overapamil (a P-gp and moderate CYP3A4 inhibitor) Cmax and AUC increased by 2.3- and 3.5-fold, respectively.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oFor RCC or TSC-associated renal angiomyolipoma patients with hepatic impairment, reduce the dose. (2.10, 8.6). oFor RCC or TSC-associated renal angiomyolipoma patients with hepatic impairment, reduce the dose. (2.10, 8.6). 8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], Everolimus can cause fetal harm when administered to 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/m2) 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/m2). The effect in rabbits occurred in the presence of maternal toxicities. In 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/m2), 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 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 weeks after the last dose.. 8.3 Females and Males of Reproductive Potential Pregnancy TestingVerify 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 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 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:oRenal Cell Carcinoma (RCC)oTSC-associated renal angiomyolipoma. oRenal Cell Carcinoma (RCC). oTSC-associated renal angiomyolipoma. 8.5 Geriatric 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oNon-infectious Pneumonitis: Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. (2.9, 5.1)oInfections: Monitor for signs and symptoms of infection. Withhold or permanently discontinue based on severity. (2.9, 5.2)oSevere Hypersensitivity Reactions: Permanently discontinue for clinically significant hypersensitivity. (5.3)oAngioedema: Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. (5.4, 7.2)oStomatitis: Initiate dexamethasone alcohol-free mouthwash when starting treatment. (5.5, 6.1)oRenal Failure: Monitor renal function prior to treatment and periodically thereafter. (5.6)oRisk of Impaired Wound Healing: Withhold for at least week prior to elective surgery. Do not administer for at least 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)oMetabolic Disorders: Monitor serum glucose and lipids prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. (2.9, 5.9)oMyelosuppression: Monitor hematologic parameters prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. (2.9, 5.10) oRisk 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)oRadiation Sensitization and Radiation Recall: Severe radiation reactions may occur. (5.12, 6.2)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. (5.13, 8.1, 8.3). oNon-infectious Pneumonitis: Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. (2.9, 5.1). oInfections: Monitor for signs and symptoms of infection. Withhold or permanently discontinue based on severity. (2.9, 5.2). oSevere Hypersensitivity Reactions: Permanently discontinue for clinically significant hypersensitivity. (5.3). oAngioedema: Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. (5.4, 7.2). oStomatitis: Initiate dexamethasone alcohol-free mouthwash when starting treatment. (5.5, 6.1). oRenal Failure: Monitor renal function prior to treatment and periodically thereafter. (5.6). oRisk of Impaired Wound Healing: Withhold for at least week prior to elective surgery. Do not administer for at least 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). oMetabolic Disorders: Monitor serum glucose and lipids prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. (2.9, 5.9). oMyelosuppression: Monitor hematologic parameters prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. (2.9, 5.10) oRisk 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). oRadiation Sensitization and Radiation Recall: Severe radiation reactions may occur. (5.12, 6.2). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. (5.13, 8.1, 8.3). 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is 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 secondary event. The incidence of Grade and non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions 6.1 )]. Fatal outcomes have been observed. Consider 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 to 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 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 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 and 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 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 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 weeks of treatment. When starting Everolimus, initiating dexamethasone alcohol-free oral solution as 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 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 and elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade and 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 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 week prior to elective surgery. Do not administer for at least 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 and 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 to 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 and 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 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 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 fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with Everolimus and for weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Everolimus and for weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].