SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in another section of the label [see WARNINGS AND PRECAUTIONS]:

• Non-infectious pneumonitis [see WARNINGS AND PRECAUTIONS].
• Infections [see WARNINGS AND PRECAUTIONS].
• Oral ulcers [see WARNINGS AND PRECAUTIONS].
• Renal failure [see WARNINGS AND PRECAUTIONS].

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.

Clinical Study Experience in Advanced Hormone-Receptor-Positive, HER2-Negative Breast Cancer

The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of 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 AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%).

Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC*

Key observed laboratory abnormalities are presented in Table 4.

Table 4: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC

Clinical Study Experience in Advanced Pancreatic Neuroendocrine Tumors

In a randomized, controlled trial of AFINITOR (n=204) versus placebo (n=203) in patients with advanced PNET the median age of patients was 58 years (range 20-87), 79% were Caucasian, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR 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 decreased hemoglobin, hyperglycemia, alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST). The most common grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia. Deaths during double-blind treatment where an adverse event was the primary cause occurred in 7 patients on AFINITOR and 1 patient on placebo. Causes of death on the AFINITOR 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. There was 1 death due to pulmonary embolism on the placebo arm. After cross-over to open-label AFINITOR, there were 3 additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to MI with CHF, and the other due to sudden death. The rates of treatment-emergent adverse events resulting in permanent discontinuation were 20% and 6% for the AFINITOR and placebo treatment groups, respectively. Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. grade 3-4 renal failure occurred in 6 patients in the everolimus arm and 3 patients in the placebo arm. Thrombotic events included 5 patients with pulmonary embolus in the everolimus arm and 1 in the placebo arm as well as 3 patients with thrombosis in the everolimus arm and 2 in the placebo arm.

Table 5 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 5: Adverse Reactions Reported ≥ 10% of Patients with Advanced PNET

Key observed laboratory abnormalities are presented in Table 6.

Table 6: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced PNET

Clinical Study Experience in Advanced Renal Cell Carcinoma

The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo.

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. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) 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 AFINITOR treatment were for infections, anemia, and stomatitis.

Table 7 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Table 7: Adverse Reactions Reported in at least 10% of Patients with RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include:

Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)

General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing ( < 1%)

Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)

Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%)

Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus ( < 1%)

Psychiatric disorders: Insomnia (9%)

Nervous system disorders: Dizziness (7%), paresthesia (5%)

Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%), deep vein thrombosis ( < 1%)

Renal and urinary disorders: Renal failure (3%)

Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%)

Musculoskeletal and connective tissue disorders: Jaw pain (3%)

Hematologic disorders: Hemorrhage (3%)

Key laboratory abnormalities are presented in Table 8.

Table 8: Key Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm than the Placebo Arm

Clinical Study Experience in Renal Angiomyolipoma with Tuberous Sclerosis Complex

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial of AFINITOR 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 (range 18 to 61 years), 89% were Caucasian, and 34% were male. The median duration of blinded study treatment was 48 weeks (range 2 to 115 weeks) for patients receiving AFINITOR and 45 weeks (range 9 to 115 weeks) for those receiving placebo.

The most common adverse reaction reported for AFINITOR (incidence ≥ 30%) was stomatitis. The most common grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, amenorrhea, and convulsion. 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 treatment-emergent adverse events resulting in permanent discontinuation was 3.8% in the AFINITOR- treated patients. Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.

Table 9 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 10.

Table 9: Treatment-emergent Adverse Reactions Reported in ≥ 10% of AFINITOR-treated Patients with Renal Angiomyolipoma

Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52) and 4% (1 of 26) of females in the placebo group. Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%).

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include:

Immune system disorders: Hypersensitivity (3%)

Infections and infestations: Otitis media (6%), sinusitis (6%), pustular rash (5%)

Metabolism and nutrition disorders: Decreased appetite (6%)

Nervous system disorders: Convulsions (5%), migraine (5%), dysgeusia (4%), ageusia (1%)

Psychiatric disorders: Depression (5%)

Respiratory, thoracic and mediastinal disorders: Epistaxis (9%), pneumonitis (1%)

Skin and subcutaneous tissue disorders: Dry skin (9%), dermatitis acneiform (8%), papule (5%)

Vascular disorders: Hypertensive crisis (1%)

Table 10: Key Laboratory Abnormalities Reported in AFINITOR-treated Patients with Renal Angiomyolipoma

Clinical Study Experience in Subependymal Giant Cell Astrocytoma

The data described below reflect exposure to AFINITOR (n=28) in an open-label, single-arm trial for the treatment of patients with SEGA. The reliability of the frequency of adverse reactions and laboratory abnormalities reported in this trial is limited because of the small number of patients. The median age of patients was 11 years (range 3-34), 86% were Caucasian, and 61% were male. In total, 17 of the 28 patients were exposed to AFINITOR for ≥ 21 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, upper respiratory tract infection, sinusitis, otitis media, and pyrexia. The grade 3 adverse reactions were convulsion, infections (single cases of sinusitis, pneumonia, tooth infection, and bronchitis viral), and single cases of stomatitis, aspiration, cyclic neutropenia, sleep apnea syndrome, vomiting, dizziness, white blood cell count decreased, and neutrophil count decreased. A grade 4 convulsion was also reported.

Table 11 summarizes the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10%. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Table 11: Adverse Reactions Reported in at least 10% of Patients with SEGA

Other notable adverse reactions occurring with an incidence of < 10% include:

Gastrointestinal disorders: Gastritis (7%)

Skin and subcutaneous tissue disorders: Pityriasis rosea (4%)

Investigations: Chest x-ray abnormal (4%)

General disorders and administration site conditions: Fatigue (7%), edema peripheral (4%)

Respiratory, thoracic and mediastinal disorders: Pharyngeal inflammation (7%)

Nervous system disorders: Somnolence (7%)

Psychiatric disorders: Anxiety (7%)

Renal and urinary disorders: Proteinuria (7%)

Eye disorders: Ocular hyperemia (4%)

Vascular disorders: Hypertension (4%)

Key Laboratory Abnormalities

Single cases of grade 3 elevated aspartate transaminase (AST) concentrations and low absolute neutrophil count (ANC) were reported. No grade 4 laboratory abnormalities were noted. Laboratory abnormalities observed in > 1 patient (and listed in decreasing order of frequency) included elevations in AST concentrations (89%), total cholesterol (68%), alanine transaminase (ALT) (46%), triglycerides (43%) (hypertriglyceridemia reported as adverse reaction in 11% of patients, blood triglycerides increased reported as adverse reaction in 7% of patients), glucose (25%), and creatinine (11%), and reductions in white blood cell counts (54%) (reported as adverse reaction in 11% of patients), hemoglobin (39%), glucose (32%), and platelet counts (21%). Most of these laboratory abnormalities were mild (grade 1).

Two cases of neutrophil count decreased and blood immunoglobulin G decreased were reported as adverse reactions.

Read the entire FDA prescribing information for Afinitor (Everolimus Tablets) »