Everolimus

Everolimus tablets for oral suspension are kinase inhibitor indicated for the treatment of adult and pediatric patients aged 1 year and older with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

1.5Tuberous Sclerosis Complex

(TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) Everolimus tablets for oral suspension are indicated in adult and pediatric patients aged 1 year and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected.

Do not combine AFINITOR and everolimus tablets for oral suspension to achieve the total daily dose. Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4. TSC-Associated SEGA: 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5 ng/mL to 15 ng/mL. ( 2.6 , 2.8 )

2.1Important Dosage Information Do

not combine AFINITOR and everolimus tablets for oral suspension to achieve the total dose. Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4 .

2.6Recommended Dosage for Tuberous Sclerosis Complex

(TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of everolimus tablets for oral suspension is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity .

2.8Therapeutic Drug Monitoring

(TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) Monitor everolimus whole blood trough concentrations at time points recommended in Table 1. Titrate the dose to attain trough concentrations of 5 ng/mL to 15 ng/mL. Adjust the dose using the following equation: New dose * = current dose x (target concentration divided by current concentration) * The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration.

When possible, use the same assay and laboratory for TDM throughout treatment. Table 1: Recommended Timing of Therapeutic Drug Monitoring Event When to Assess Trough Concentrations After Event Initiation of everolimus tablets for oral suspension 1 to 2 weeks Modification of everolimus tablets for oral suspension dose 1 to 2 weeks Switch between AFINITOR and everolimus tablets for oral suspension 1 to 2 weeks Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor 2 weeks Initiation or discontinuation of P-gp and strong CYP3A4 inducer 2 weeks Change in hepatic function 2 weeks Stable dose with changing body surface area (BSA) Every 3 to 6 months Stable dose with stable BSA Every 6 to 12 months Abbreviation: P-gp, P-glycoprotein.

2.9Dosage Modifications for Adverse Reactions Table

2 summarizes recommendations for dosage modifications of everolimus tablets for oral suspension for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus Tablets for Oral Suspension for Adverse Reactions Adverse Reaction Severity Dosage Modification Non-infectious pneumonitis 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 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) 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 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 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 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.

2.10Dosage Modifications for Hepatic Impairment The

recommended dosages of everolimus tablets for oral suspension for patients with hepatic impairment are described in Table 3 : Table 3: Recommended Dosage Modifications for Patients With Hepatic Impairment Indication Dose Modification for E verolimus Tablets for Oral Suspension TSC-Associated SEGA Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m 2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended . Abbreviations: SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex.

2.11Dosage Modifications for P-gp and CYP3A4 Inhibitors

Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors . Avoid ingesting grapefruit and grapefruit juice. Reduce the dose for patients taking everolimus tablets for oral suspension with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4 . Table 4: Recommended Dosage Modifications for Concurrent Use of E verolimus Tablets for Oral Suspension With a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for Everolimus Tablets for Oral Suspension TSC-Associated SEGA Reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days.

Assess trough concentrations when initiating and discontinuing the inhibitor .

2.12Dosage Modifications for P-gp and CYP3A4 Inducers

Avoid concomitant use of St. John’s Wort (Hypericum perforatum) . Increase the dose for patients taking everolimus tablets for oral suspension with a P-gp and strong CYP3A4 inducer as recommended in Table 5 . Table 5: Recommended Dosage Modifications for Concurrent Use of E verolimus Tablets for Oral Suspension With P-gp and Strong CYP3A4 Inducers Indication Dose Modification for E verolimus Tablets for Oral Suspension TSC-Associated SEGA Double the daily dose using increments of 5 mg or less. Multiple increments may be required.

Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification. Assess trough concentrations when initiating and discontinuing the inducer . Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days.

2.13Administration and Preparation Administer

everolimus tablets for oral suspension at the same time each day. Administer everolimus tablets for oral suspension consistently either with or without food . If a dose of everolimus tablets for oral suspension 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 tablets for oral suspension should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed. Everolimus Tablets for Oral Suspension Wear gloves to avoid possible contact with everolimus when preparing suspensions of everolimus tablets for oral suspension for another person.

Administer as a suspension only. Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation. Prepare suspension in water only. Using an Oral Syringe to Prepare Oral Suspension: Place the prescribed dose into a 10-mL syringe.

Do not exceed a total of 10 mg per syringe. If higher doses are required, prepare an additional syringe. Do not break or crush tablets. Draw approximately 5 mL of water and 4 mL of air into the syringe. Place the filled syringe into a container (tip up) for 3 minutes, until the tablets are in suspension.

Gently invert the syringe 5 times immediately prior to administration. After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same syringe and swirl the contents to suspend remaining particles. Administer the entire contents of the syringe.

Using a Small Drinking Glass to Prepare Oral Suspension: Place the prescribed dose into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg per glass. If higher doses are required, prepare an additional glass. Do not break or crush tablets.

Allow 3 minutes for suspension to occur. Stir the contents gently with a spoon, immediately prior to drinking. After administration of the prepared suspension, add 25 mL of water and stir with the same spoon to re-suspend remaining particles. Administer the entire contents of the glass.

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. 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. Renal Failure: Monitor renal function prior to treatment and periodically thereafter. 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. 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. 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 tablets for oral suspension 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 . 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 tablets for oral suspension 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 tablets for oral suspension based on severity . 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.

5.2Infections Everolimus

tablets for oral suspension have immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens . 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.

The incidence of serious infections was reported at a higher frequency in patients < 6 years of age . Complete treatment of pre-existing invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue everolimus tablets for oral suspension based on severity of infection . Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

5.3Severe Hypersensitivity Reactions Hypersensitivity

reactions to everolimus tablets for oral suspension 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) . The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue everolimus tablets for oral suspension for the development of clinically significant hypersensitivity.

5.4Angioedema with Concomitant Use of Angiotensin-Converting Enzyme

(ACE) Inhibitors Patients taking concomitant ACE inhibitors with everolimus tablets for oral suspension may be at increased risk for angioedema (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 AFINITOR with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue everolimus tablets for oral suspension for angioedema.

5.5Stomatitis Stomatitis,

including mouth ulcers and oral mucositis, has occurred in patients treated with everolimus tablets for oral suspension at an incidence ranging from 44% to 78% across clinical trials. Grades 3 to 4 stomatitis was reported in 4% to 9% of patients. Stomatitis most often occurs within the first 8 weeks of treatment.

When starting everolimus tablets for oral suspension, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis. 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.

5.6Renal Failure Cases of

renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking everolimus tablets for oral suspension . 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 tablets for oral suspension and annually thereafter.

Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

5.7Risk of Impaired Wound Healing Impaired

wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, everolimus tablets for oral suspension have the potential to adversely affect wound healing. Withhold everolimus tablets for oral suspension 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.

5.9Metabolic Disorders Hyperglycemia,

hypercholesterolemia and hypertriglyceridemia have been reported in patients taking everolimus tablets for oral suspension 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 . In non-diabetic patients, monitor fasting serum glucose prior to starting everolimus tablets for oral suspension and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated.

Monitor lipid profile prior to starting everolimus tablets for oral suspension and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting everolimus tablets for oral suspension. For Grade 3 to 4 metabolic events, withhold or permanently discontinue everolimus tablets for oral suspension based on severity .

5.10Myelosuppression Anemia,

lymphopenia, neutropenia and thrombocytopenia have been reported in patients taking everolimus tablets for oral suspension. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively . Monitor complete blood count (CBC) prior to starting everolimus tablets for oral suspension every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue everolimus tablets for oral suspension based on severity .

5.11Risk of Infection or Reduced Immune Response

With Vaccination The safety of immunization with live vaccines during everolimus tablets for oral suspension 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 tablets for oral suspension. 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.

5.12Radiation 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 tablets for oral suspension treatment . Monitor patients closely when everolimus tablets for oral suspension are administered during or sequentially with radiation treatment.

5.13Embryo-Fetal Toxicity Based on

animal studies and the mechanism of action, everolimus tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension and for 4 weeks after the last dose .

Everolimus tablets for oral suspension are contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives . Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.

8.1Pregnancy Risk Summary Based on

animal studies and the mechanism of action , everolimus tablets for oral suspension can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of AFINITOR 10 mg orally once daily . Advise pregnant women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities.

Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m 2 ) with resulting exposures of approximately 4% of the human exposure at the recommended dose of AFINITOR 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m 2 ), approximately 1.6 times the recommended dose of AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA). 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.

8.3Females and Males of Reproductive Potential Pregnancy

Testing Verify the pregnancy status of females of reproductive potential prior to starting everolimus tablets for oral suspension . Contraception Everolimus tablets for oral suspension can cause fetal harm when administered to pregnant women . Females: Advise female patients of reproductive potential to use effective contraception during treatment with everolimus tablets for oral suspension and for 8 weeks after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with everolimus tablets for oral suspension 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 tablets for oral suspension.

Based on these findings, everolimus tablets for oral suspension may impair fertility in female patients . Males: Cases of reversible azoospermia have been reported in male patients taking AFINITOR. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of AFINITOR 10 mg orally once daily. Based on these findings, everolimus tablets for oral suspension may impair fertility in male patients .

The following serious adverse reactions are described elsewhere in the labeling: Non-Infectious Pneumonitis Infections Severe Hypersensitivity Reactions Angioedema with Concomitant Use of ACE inhibitors Stomatitis Renal Failure Impaired Wound Healing Metabolic Disorders Myelosuppression Radiation Sensitization and Radiation Recall TSC-Associated SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA) The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of AFINITOR in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were white and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving AFINITOR. The most common adverse reactions reported for AFINITOR (incidence ≥ 30%) were stomatitis and respiratory tract infection.

The most common Grade 3 to 4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3 to 4 laboratory abnormality (incidence ≥ 3%) was neutropenia.

There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 16.

Laboratory abnormalities are presented in Table 17. Table 16: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1 AFINITOR N = 78 Placebo N = 39 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Gastrointestinal Stomatitis a 62 9 f 26 3 f Vomiting 22 1 f 13 0 Diarrhea 17 0 5 0 Constipation 10 0 3 0 Infections Respiratory tract infection b 31 3 23 0 Gastroenteritis c 10 5 3 0 Pharyngitis streptococcal 10 0 3 0 General Pyrexia 23 6 f 18 3 f Fatigue 14 0 3 0 Psychiatric Anxiety, aggression or other behavioral disturbance d 21 5 f 3 0 Skin and subcutaneous tissue Rash e 21 0 8 0 Acne 10 0 5 0 Grading according to NCI CTCAE Version 3.0. a Includes mouth ulceration, stomatitis, and lip ulceration. b Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral. c Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. d Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder. e Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria. f No Grade 4 adverse reactions were reported. Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18).

For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%) and unspecified menstrual irregularity (6%). The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%), and pneumonitis (1%). Table 17: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1 AFINITOR N = 78 Placebo N = 39 All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Hematology Elevated partial thromboplastin time 72 3 a 44 5 a Neutropenia 46 9 a 41 3 a Anemia 41 0 21 0 Chemistry Hypercholesterolemia 81 0 39 0 Elevated AST 33 0 0 0 Hypertriglyceridemia 27 0 15 0 Elevated ALT 18 0 3 0 Hypophosphatemia 9 1 a 3 0 Grading according to NCI CTCAE Version 3.0. a No Grade 4 laboratory abnormalities were reported.

Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions and selected laboratory abnormalities: decreased appetite (14%), hyperglycemia (13%), hypertension (11%), urinary tract infection (9%), decreased fibrinogen (8%), cellulitis (6%), abdominal pain (5%), decreased weight (5%), elevated creatinine (5%) and azoospermia (1%).

6.2Post-marketing Experience The

following adverse reactions have been identified during post-approval use of everolimus tablets for oral suspension. 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