EVEROLIMUS (Page 3 of 9)

5.3 Severe Hypersensitivity Reactions

Hypersensitivity reactions to everolimus have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications (4)]. The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue everolimus for the development of clinically significant hypersensitivity.

5.4 Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors

Patients taking concomitant ACE inhibitors with everolimus may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus tablets with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue everolimus for angioedema.

5.5 Stomatitis

Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with everolimus at an incidence ranging from 44% to 78% across clinical trials. Grades 3-4 stomatitis was reported in 4% to 9% of patients [see Adverse Reactions (6.1)]. Stomatitis most often occurs within the first 8 weeks of treatment. When starting everolimus, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis [see Adverse Reactions (6.1)]. If stomatitis does occur, mouthwashes and/or other topical treatments are recommended. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme- containing products, as they may exacerbate the condition. Do not administer antifungal agents, unless fungal infection has been diagnosed.

5.6 Renal Failure

Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking everolimus tablets. Elevations of serum creatinine and proteinuria have been reported in patients taking everolimus [see Adverse Reactions (6.1)]. The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting everolimus and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

5.7 Risk of Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, everolimus have the potential to adversely affect wound healing. Withhold everolimus for at least 1 week prior to elective surgery.

Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment upon resolution of wound healing complications has not been established.

5.8 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. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.9), Use in Specific Populations (8.5)].

5.9 Metabolic Disorders

Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking everolimus tablets at an incidence up to 75%, 86%, and 73%, respectively. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively [see Adverse Reactions (6.1)]. In non-diabetic patients, monitor fasting serum glucose prior to starting everolimus tablets and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting everolimus tablets and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting everolimus tablets. For Grade 3 to 4 metabolic events, withhold or permanently discontinue everolimus tablets based on severity [see Dosage and Administration (2.9)].

5.10 Myelosuppression

Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking everolimus. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively [see Adverse Reactions (6.1)]. Monitor complete blood count (CBC) prior to starting everolimus every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue everolimus based on severity [see Dosage and Administration (2.9)].

5.11 Risk of Infection or Reduced Immune Response With Vaccination

The safety of immunization with live vaccines during everolimus tablets 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. 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 tablets are administered during or sequentially with radiation treatment.

5.13 Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action,everolimus can cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the clinical dose of 10 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with everolimus and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with everolimus and for 4 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Hormone Receptor-Positive, HER2-Negative Breast Cancer

The safety of everolimus tablets (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 to 93 years), and 75% were White. The median follow-up was approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred in 2% of patients who received everolimus tablets. The rate of adverse reactions resulting in permanent discontinuation was 24% for the everolimus tablets arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the everolimus tablets arm.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets versus placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with everolimus tablets was 23.9 weeks; 33% were exposed to everolimus tablets for a period of ≥ 32 weeks.

Table 6: Adverse Reactions Reported in ≥ 10% of Patients With Hormone Receptor-Positive Breast Cancer in BOLERO-2
Grading according to NCI CTCAE Version 3.0.a Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration.b Includes all reported infections including, but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections.c Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis.d No Grade 4 adverse reactions were reported.
Everolimus Tablets with Exemestane N = 482 Placebo with Exemestane N = 238
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Gastrointestinal
Stomatitisa 67 8d 11 0.8
Diarrhea 33 2 18 0.8
Nausea 29 0.4 28 1
Vomiting 17 1 12 0.8
Constipation 14 0.4d 13 0.4
Dry mouth 11 0 7 0
General
Fatigue 36 4 27 1d
Edema peripheral 19 1d 6 0.4d
Pyrexia 15 0.2d 7 0.4d
Asthenia 13 2 4 0
Infections
Infectionsb 50 6 25 2d
Investigations
Weight loss 25 1d 6 0
Metabolism and nutrition
Decreased appetite 30 1d 12 0.4d
Hyperglycemia 14 5 2 0.4d
Musculoskeletal and connective tissue
Arthralgia 20 0.8d 17 0
Back pain 14 0.2d 10 0.8d
Pain in extremity 9 0.4d 11 2d
Nervous system
Dysgeusia 22 0.2d 6 0
Headache 21 0.4d 14 0
Psychiatric
Insomnia 13 0.2d 8 0
Respiratory, thoracic and mediastinal
Cough 24 0.6d 12 0
Dyspnea 21 4 11 1
Epistaxis 17 0 1 0
Pneumonitisc 19 4 0.4 0
Skin and subcutaneous tissue
Rash 39 1d 6 0
Pruritus 13 0.2d 5 0
Alopecia 10 0 5 0
Vascular
Hot flush 6 0 14 0
Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients With Hormone Receptor-Positive Breast Cancer in BOLERO-2
Grading according to NCI CTCAE Version 3.0. a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.b No Grade 4 laboratory abnormalities were reported.
Laboratory Parameter Everolimus Tablets with Exemestane N = 482 Placebo with Exemestane N = 238
All Grades Grade 3-4 All Grades Grade 3-4
% % % %
Hematologya
Anemia 68 6 40 1
Leukopenia 58 2b 28 6
Thrombocytopenia 54 3 5 0.4
Lymphopenia 54 12 37 6
Neutropenia 31 2b 11 2
Chemistry
Hypercholesterolemia 70 1 38 2
Hyperglycemia 69 9 44 1
Increased aspartate transaminase (AST) 69 4 45 3
Increased alanine transaminase (ALT) 51 4 29 5b
Hypertriglyceridemia 50 0.8b 26 0
Hypoalbuminemia 33 0.8b 16 0.8b
Hypokalemia 29 4 7 1b
Increased creatinine 24 2 13 0

Topical Prophylaxis for Stomatitis

In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning everolimus tablets (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5mL 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. Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO-2 trial.

Coadministration of everolimus and dexamethasone alcohol-free oral solution has not been studied in pediatric patients.

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) orsporadic 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.

The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the everolimus tablets -treated patients. Adverse reactions leading to permanent discontinuation in the Everolimus tablets arm werehypersensitivity/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.

Table 14: Adverse Reactions Reported in ≥ 10% of Everolimus tablets -Treated Patients With TSC Associated Renal Angiomyolipoma in EXIST-2

Everolimus tablets N = 79 Placebo N = 39
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Gastrointestinal
Stomatitisa 78 6b 23 0
Vomiting 15 0 5 0
Diarrhea 14 0 5 0
General
Peripheral Edema 13 0 8 0
Infections
Upper respiratorytract infection 11 0 5 0
Musculoskeletal and connective tissue
Arthralgia 13 0 5 0
Respiratory, thoracic and mediastinal
Cough 20 0 13 0
Skin and subcutaneous tissue
Acne 22 0 5 0
Grading according to NCI CTCAE Version 3.0.a Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.b No Grade 4 adverse reactions were reported.

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%).

Table 15: Selected Laboratory Abnormalities Reported in Everolimus tablets -Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2

Everolimus tablets N = 79 Placebo N = 39
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematology
Anemia 61 0 49 0
Leukopenia 37 0 21 0
Neutropenia 25 1 26 0
Lymphopenia 20 1a 8 0
Thrombocytopenia 19 0 3 0
Chemistry
Hypercholesterolemia 85 1a 46 0
Hypertriglyceridemia 52 0 10 0
Hypophosphatemia 49 5a 15 0
Increased alkaline phosphatase 32 1a 10 0
Increased AST 23 1a 8 0
Increased ALT 20 1a 15 0
Hyperglycemia (fasting) 14 0 8 0
Grading according to NCI CTCAE Version 3.0.a No Grade 4 laboratory abnormalities were reported.

Updated safety information from 112 patients treated with everolimus tablets for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%),abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%).

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. 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 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.

Table 16: Adverse Reactions Reported in ≥ 10% of Everolimus Tablets -Treated Patients With TSC Associated SEGA in EXIST-1

All Grades % Grade 3-4 % All Grades % Grade 3-4 %
*
Includes mouth ulceration, stomatitis, and lip ulceration.
No Grade 4 adverse reactions were reported.
Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral.
§
Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection.
Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder.
#
Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticarial.
Everolimus Tablets N = 78 Placebo N = 39
Gastrointestinal
Stomatitis * 62 9 26 3
Vomiting 22 1 13 0
Diarrhea 17 0 5 0
Constipation 10 0 3 0
Infections
Respiratory tract infection 31 3 23 0
Gastroenteritis § 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 behavioural disturbance 21 5 3 0
Skin and subcutaneous tissue
Rash # 21 0 8 0
Acne 10 0 5 0
Grading according to NCI CTCAE Version 3.0.

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%).

Table 17: Selected Laboratory Abnormalities Reported in Everolimus Tablets-Treated Patients With TSC-Associated SEGA in EXIST-1

*
No Grade 4 laboratory abnormalities were reported.
Everolimus Tablets N = 78 Placebo N = 39
All Grades % Grade 3-4 % All Grades % Grade 3-4 %
Hematology
Elevated partial thromboplastin time 72 3* 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
Grading according to NCI CTCAE Version 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%).

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