Everolimus

Table 1:

Recommended Timing of Therapeutic Drug Monitoring Event When to Assess Trough Concentrations After Event Abbreviation: P-gp, P-glycoprotein. 9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of everolimus tablets/everolimus tablets for oral suspension for the management of adverse reactions.

1) ] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks.

Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If toxicity recurs at Grade 3, permanently discontinue.

Grade 4 Permanently discontinue. 5) ] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.

Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. 9) ] Grade 3 Withhold until improvement to Grade 0, 1, or 2.

Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Other non-hematologic toxicities Grade 2 If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1.

Resume at same dose. If toxicity recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1.

Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. 10) ] Grade 2 Withhold until improvement to Grade 0 or 1.

Resume at same dose. Grade 3 OR Grade 4 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. 10) ] Grade 3 Withhold until improvement to Grade 0, 1, or 2.

Resume at same dose. Grade 4 Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. 10) ] Grade 3 Withhold until improvement to Grade 0, 1, or 2, and no fever.

Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. 6) ] : Table 3: Recommended Dosage Modifications for Patients With Hepatic Impairment Indication Dose Modification for Everolimus Tablets/Everolimus Tablets for Oral Suspension Abbreviations: NET, Neuroendocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex.

5 mg once daily is not tolerated. 5 mg orally once daily if a dose of 5 mg once daily is not tolerated. 5 mg once daily. 5 mg/m 2 orally once daily. 8) ]. 1) ]. Avoid ingesting grapefruit and grapefruit juice. 3) ]. 5 mg once daily. May increase dose to 5 mg once daily if tolerated.

Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures 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. 8) ]. 12 Dosage Modifications for P-gp and CYP3A4 Inducers Avoid concomitant use of St. John's Wort (Hypericum perforatum). 3) ].

Table 5:

Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets/Everolimus Tablets for Oral Suspension With P-gp and Strong CYP3A4 Inducers Indication Dose Modification for Everolimus Tablets/Everolimus Tablets for Oral Suspension Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Avoid coadministration where alternatives exist.

If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days.

TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures 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.

8) ] . Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days. 13 Administration and Preparation Administer everolimus tablets/everolimus tablets for oral suspension at the same time each day.

3) ]. If a dose of everolimus tablets/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/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 Everolimus Tablets should be swallowed whole with a glass of water.

Do not break or crush tablets. 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.

The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred in 2% of patients who received everolimus tablets.

The rate of adverse reactions resulting in permanent discontinuation was 24% for the everolimus tablets arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the everolimus tablets arm. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets vs.

placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. 9 weeks; 33% were exposed to everolimus tablets for a period of ≥ 32 weeks. 0. Gastrointestinal Stomatitis Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration.

67 8 No Grade 4 adverse reactions were reported. 4 Asthenia 13 2 4 0 Infections Infections Includes all reported infections, including but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections.

6 12 0 Dyspnea 21 4 11 1 Epistaxis 17 0 1 0 Pneumonitis Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. 0. Hematology Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

Anemia 68 6 40 1 Leukopenia 58 2 No Grade 4 laboratory abnormalities were reported. 5 mg/5 mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) concurrently with everolimus tablets and exemestane.

No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone mouthwash. The primary objective of this study was to assess the incidence of Grade 2 to 4 stomatitis within 8 weeks. The incidence of Grade 2 to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the BOLERO-2 trial.

The incidence of Grade 1 stomatitis was 19%. No cases of Grade 3 or 4 stomatitis were reported. 2% in the BOLERO-2 trial. Coadministration of everolimus tablets/everolimus tablets for oral suspension and dexamethasone alcohol-free oral solution has not been studied in pediatric patients.

Pancreatic Neuroendocrine Tumors (PNET) In a randomized, controlled trial (RADIANT-3) of everolimus tablets (n = 204) vs. placebo (n = 203) in patients with advanced PNET the median age of patients was 58 years (20 to 87 years), 79% were White, and 55% were male.

Patients on the placebo arm could cross over to open-label everolimus tablets upon disease progression. The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache.

The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST.

The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, anemia, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased AST, hypokalemia, and thrombocytopenia. Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on everolimus tablets.

Causes of death on the everolimus tablets arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. After cross-over to open-label everolimus tablets, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death.

The rate of adverse reactions resulting in permanent discontinuation was 20% for the everolimus tablets group. Dose delay or reduction was necessary in 61% of everolimus tablets patients. Grade 3-4 renal failure occurred in six patients in the everolimus tablets arm.

Thrombotic events included five patients with pulmonary embolus in the everolimus tablets arm as well as three patients with thrombosis in the everolimus tablets arm. Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets vs.

placebo. Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received everolimus tablets was 37 weeks. In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) everolimus tablets-treated females.

0. Gastrointestinal Stomatitis Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. 70 7 No Grade 4 adverse reactions were reported.

20 0 Diarrhea Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. 5 Pneumonitis Includes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease. 0. 5 Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin In a randomized, controlled trial (RADIANT-4) of everolimus tablets (n = 202 treated) vs.

placebo (n = 98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (22-86 years), 76% were White, and 53% were female. 3 months; 64% of patients were treated for ≥ 6 months and 39% were treated for ≥ 12 months.

Everolimus tablets was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of everolimus tablets-treated patients. Serious adverse reactions occurred in 42% of everolimus tablets-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock).

Adverse reactions occurring at an incidence of ≥ 10% and at ≥ 5% absolute incidence over placebo (all Grades) or ≥ 2% higher incidence over placebo (Grade 3 and 4) are presented in Table 10. Laboratory abnormalities are presented in Table 11.

03. Gastrointestinal Stomatitis Includes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation. 63 9 No Grade 4 adverse reactions were reported. 22 0 Diarrhea 41 9 31 2 Nausea 26 3 17 1 Vomiting 15 4 12 2 General Peripheral edema 39 3 6 1 Fatigue 37 5 36 1 Asthenia 23 3 8 0 Pyrexia 23 2 8 0 Infections Infections Urinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis.

58 11 29 2 Investigations Weight loss 22 2 11 1 Metabolism and nutrition Decreased appetite 22 1 17 1 Nervous system Dysgeusia 18 1 4 0 Respiratory, thoracic and mediastinal Cough 27 0 20 0 Dyspnea 20 3 11 2 Pneumonitis Includes pneumonitis and interstitial lung disease.

03. Hematology Anemia 81 5 No Grade 4 laboratory abnormalities were reported. 41 2 Lymphopenia 66 16 32 2 Leukopenia 49 2 17 0 Thrombocytopenia 33 2 11 0 Neutropenia 32 2 15 3 Chemistry Hypercholesterolemia 71 0 37 0 Increased AST 57 2 34 2 Hyperglycemia (fasting) 55 6 36 1 Increased ALT 46 5 39 1 Hypophosphatemia 43 4 15 2 Hypertriglyceridemia 30 3 8 1 Hypokalemia 27 6 12 3 Hypoalbuminemia 18 0 8 0 Renal Cell Carcinoma (RCC) The data described below reflect exposure to everolimus tablets (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib.

The median age of patients was 61 years (27 to 85 years), 88% were White, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving everolimus tablets. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea.

The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine.

The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. 4%) were observed on the everolimus tablets arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the everolimus tablets 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 tablets treatment were for infections, anemia, and stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets vs. placebo are presented in Table 12. Laboratory abnormalities are presented in Table 13. 0. Gastrointestinal Stomatitis Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration.

44 4 8 0 Diarrhea 30 2 No Grade 4 adverse reactions were reported. 7 0 Nausea 26 2 19 0 Vomiting 20 2 12 0 Infections Includes all reported infections, including but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections.

37 10 18 2 General Asthenia 33 4 23 4 Fatigue 31 6 27 4 Edema peripheral 25 <1 8 <1 Pyrexia 20 <1 9 0 Mucosal inflammation 19 2 1 0 Respiratory, thoracic and mediastina l Cough 30 <1 16 0 Dyspnea 24 8 15 3 Epistaxis 18 0 0 0 Pneumonitis Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.

0. Hematology Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. Anemia 92 13 79 6 Lymphopenia 51 18 28 5 No Grade 4 laboratory abnormalities were reported.

Thrombocytopenia 23 1 2 <1 Neutropenia 14 <1 4 0 Chemistry Hypercholesterolemia 77 4 35 0 Hypertriglyceridemia 73 <1 34 0 Hyperglycemia 57 16 25 2 Increased creatinine 50 2 34 0 Hypophosphatemia 37 6 8 0 Increased AST 25 1 7 0 Increased ALT 21 1 4 0 Hyperbilirubinemia 3 1 2 0 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of everolimus tablets in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5).

The median age of patients was 31 years (18 to 61 years), 89% were White, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving everolimus tablets. The most common adverse reaction reported for everolimus tablets (incidence ≥ 30%) was stomatitis.

The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia.

8% in the everolimus tablets-treated patients. Adverse reactions leading to permanent discontinuation in the everolimus tablets arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of everolimus tablets-treated patients.

The most common adverse reaction leading to everolimus tablets dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets and occurring more frequently with everolimus tablets than with placebo are presented in Table 14.

Laboratory abnormalities are presented in Table 15. 0. Gastrointestinal Stomatitis Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. 78 6 No Grade 4 adverse reactions were reported.

23 0 Vomiting 15 0 5 0 Diarrhea 14 0 5 0 General Peripheral edema 13 0 8 0 Infections Upper respiratory tract infection 11 0 5 0 Musculoskeletal and connective tissue Arthralgia 13 0 5 0 Respiratory, thoracic and mediastinal Cough 20 0 13 0 Skin and subcutaneous tissue Acne 22 0 5 0 Amenorrhea occurred in 15% of everolimus tablets-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 tablets-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%).

0. Hematology Anemia 61 0 49 0 Leukopenia 37 0 21 0 Neutropenia 25 1 26 0 Lymphopenia 20 1 No Grade 4 laboratory abnormalities were reported. 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%).

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 everolimus tablets in 117 patients with SEGA and TSC. 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 everolimus tablets. The most common adverse reactions reported for everolimus tablets (incidence ≥ 30%) were stomatitis and respiratory tract infection.

The most common Grade 3-4 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 3-4 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 everolimus tablets-treated patients.

The most common adverse reaction leading to everolimus tablets dose adjustment was stomatitis. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets and occurring more frequently with everolimus tablets than with placebo are reported in Table 16.

Laboratory abnormalities are presented in Table 17. 0. Gastrointestinal Stomatitis Includes mouth ulceration, stomatitis, and lip ulceration. 62 9 No Grade 4 adverse reactions were reported. 26 3 Vomiting 22 1 13 0 Diarrhea 17 0 5 0 Constipation 10 0 3 0 Infections Respiratory tract infection Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral.

31 3 23 0 Gastroenteritis Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. 10 5 3 0 Pharyngitis streptococcal 10 0 3 0 General Pyrexia 23 6 18 3 Fatigue 14 0 3 0 Psychiatric Anxiety, aggression or other behavioral disturbance Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder.

21 5 3 0 Skin and subcutaneous tissue Rash Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria. 21 0 8 0 Acne 10 0 5 0 Amenorrhea occurred in 17% of everolimus tablets-treated females aged 10 to 55 years (3 of 18).

For this same group of everolimus tablets-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 everolimus tablets-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%).

0. Hematology Elevated partial thromboplastin time 72 3 No Grade 4 laboratory abnormalities were reported. 44 5 Neutropenia 46 9 41 3 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 3 0 Updated safety information from 111 patients treated with everolimus tablets 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%).

TSC-Associated Partial-Onset Seizures The data described below are based on the 18-week Core phase of a randomized, double-blind, multicenter, three-arm trial (EXIST-3) comparing two everolimus trough levels (3-7 ng/mL and 9-15 ng/mL) to placebo as adjunctive antiepileptic therapy in patients with TSC-associated partial-onset seizures.

A total of 366 patients were randomized to everolimus tablets for oral suspension low trough (LT) (n = 117), everolimus tablets for oral suspension high trough (HT) (n = 130), or placebo (n = 119). 2 to 56 years; 28% were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years), 65% were white, and 52% were male.

Patients received between one and three concomitant antiepileptic drugs. The most common adverse reaction reported for everolimus tablets for oral suspension in both arms (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pneumonia, and irregular menstruation.

The most common laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 2%) was neutropenia. Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the LT and HT arms, respectively.

The most common adverse reaction (incidence ≥ 1%) leading to discontinuation was stomatitis. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the LT and HT arms, respectively.

The most common adverse reactions (incidence ≥ 3%) leading to dose adjustments in the everolimus tablets for oral suspension arms were stomatitis, pneumonia, and pyrexia. Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets for oral suspension are presented in Table 18.

Laboratory abnormalities are presented in Table 19. 03. Gastrointestinal Stomatitis Includes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain. 55 3 No Grade 4 adverse reactions were reported.

8%). 03. Hematology Neutropenia 25 4 No Grade 4 laboratory abnormalities were reported. 3%). 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of everolimus tablets/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

1 Non-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/everolimus tablets for oral suspension in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event.

1) ]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms. Consider opportunistic infections, such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis.

Advise patients to report promptly any new or worsening respiratory symptoms. Continue everolimus tablets/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. 9) ]. Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

The development of pneumonitis has been reported even at a reduced dose. 1) ]. , reactivation of hepatitis B virus) have occurred. , 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.

4) ]. Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. 9) ]. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

, swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications (4) ]. The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue everolimus tablets/everolimus tablets for oral suspension for the development of clinically significant hypersensitivity.

, swelling of the airways or tongue, with or without respiratory impairment). 3% in the control arm with an ACE inhibitor. Permanently discontinue everolimus tablets/everolimus tablets for oral suspension for angioedema. 5 Stomatitis Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with everolimus tablets/everolimus tablets for oral suspension at an incidence ranging from 44% to 78% across clinical trials.

1) ]. Stomatitis most often occurs within the first 8 weeks of treatment. 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. 6 Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking everolimus tablets.

1) ]. The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. 5%, respectively. Monitor renal function prior to starting everolimus tablets/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. 7 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway.

Therefore, everolimus tablets/everolimus tablets for oral suspension have the potential to adversely affect wound healing. Withhold everolimus tablets/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. 8 Geriatric Patients In the randomized hormone receptor-positive, HER2-negative breast cancer study (BOLERO-2), the incidence of deaths due to any cause within 28 days of the last everolimus tablets dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age.

Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. 5) ] . 9 Metabolic Disorders Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking everolimus tablets/everolimus tablets for oral suspension at an incidence up to 75%, 86%, and 73%, respectively.

1) ]. In non-diabetic patients, monitor fasting serum glucose prior to starting everolimus tablets/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/everolimus tablets for oral suspension and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting everolimus tablets/everolimus tablets for oral suspension.

9) ]. 10 Myelosuppression Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking everolimus tablets/everolimus tablets for oral suspension. 1) ]. Monitor complete blood count (CBC) prior to starting everolimus tablets/everolimus tablets for oral suspension every 6 months for the first year of treatment and annually thereafter.

9) ]. 11 Risk of Infection or Reduced Immune Response With Vaccination The safety of immunization with live vaccines during everolimus tablets/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/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. 2) ]. Monitor patients closely when everolimus tablets/everolimus tablets for oral suspension are administered during or sequentially with radiation treatment. 13 Embryo-Fetal Toxicity Based on animal studies and the mechanism of action, everolimus tablets/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/everolimus tablets for oral suspension and for 8 weeks after the last dose. 3) ].