Important Safety Information

AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.

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Advanced HR+, HER2-Negative Breast Cancer
AFINITOR is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.

Advanced Neuroendocrine Tumors of Pancreatic Origin
AFINITOR is indicated for the treatment of adults with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced, or metastatic disease. 

Limitation of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors.

Progressive, Well-Differentiated, Nonfunctional Gl and Lung Neuroendocrine Tumor
AFINITOR is indicated for the treatment of adults with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced, or metastatic disease.

Limitation of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors.

Advanced Renal Cell Carcinoma
AFINITOR is indicated for the treatment of adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Renal Angiomyolipoma With Tuberous Sclerosis Complex
AFINITOR is indicated for the treatment of adults with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery.

SEGA With Tuberous Sclerosis Complex
AFINITOR Tablets and AFINITOR DISPERZ are indicated in adult and pediatric patients aged 1 year and older with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

Seizure With Tuberous Sclerosis Complex
AFINITOR DISPERZ is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with tuberous sclerosis complex (TSC) associated partial-onset seizures. 

Important Safety Information

AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.

Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR/AFINITOR DISPERZ; some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. Monitor for clinical symptoms or radiological changes. Consider opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. For grade 2 to 4 noninfectious pneumonitis, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ 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.

Infections: AFINITOR/AFINITOR DISPERZ has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including those with opportunistic pathogens. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections; invasive fungal infections, such as aspergillosis, candidiasis, or PJP; and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, to sepsis, septic shock, or resulting in multisystem organ failure) or fatal. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity of infection. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

Severe Hypersensitivity Reactions: Hypersensitivity reactions to AFINITOR/AFINITOR DISPERZ have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment). The incidence of grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue AFINITOR/AFINITOR DISPERZ for the development of clinically significant hypersensitivity.

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitor with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema (eg, 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/AFINITOR DISPERZ with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue AFINITOR/AFINITOR DISPERZ for angioedema.

Stomatitis: Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR/AFINITOR DISPERZ at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. Stomatitis most often occurs within the first 8 weeks of treatment. When starting AFINITOR/AFINITOR DISPERZ, 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, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing products should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Co-administration of AFINITOR/AFINITOR DISPERZ and dexamethasone alcohol-free oral solution has not been studied in pediatric patients.

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR/AFINITOR DISPERZ. Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR/AFINITOR DISPERZ. 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 AFINITOR/AFINITOR DISPERZ and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

Impaired Wound Healing: AFINITOR/AFINITOR DISPERZ delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR/AFINITOR DISPERZ in the perisurgical period.

Geriatric Patients: In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared with 2% in patients <65 years of age. Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended.

Metabolic Disorders: Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR/AFINITOR DISPERZ 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 nondiabetic patients, monitor fasting serum glucose prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting AFINITOR/AFINITOR DISPERZ. For grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity.

Myelosuppression: Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR/AFINITOR DISPERZ. The incidence of these grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively. Monitor complete blood count prior to starting AFINITOR/AFINITOR DISPERZ every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity.

For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring.

Risk of Infection or Reduced Immune Response With Vaccinations: The safety of immunization with live vaccines during AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ.

Embryo-Fetal Toxicity: Fetal harm can occur if AFINITOR/AFINITOR DISPERZ is administered to a pregnant woman. 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 AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose.

Adverse Reactions in Advanced Breast Cancer: The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (6%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), asthenia (2%), and diarrhea (2%).

Laboratory Abnormalities in Advanced Breast Cancer: The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST, 69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT, 51%), and hypertriglyceridemia (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (6%), hypokalemia (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%).

Adverse Reactions in Advanced PNET: The most common adverse reactions (incidence ≥30%) were stomatitis (70%), rash (59%), diarrhea (50%), fatigue (45%), edema (39%), abdominal pain (36%), nausea (32%), fever (31%), headache (30%), and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence ≥5%) were stomatitis (7%) and diarrhea (6%). Deaths primarily due to adverse events during the double-blind treatment phase occurred in 7 patients taking AFINITOR.

Laboratory Abnormalities in Advanced PNET: The most common laboratory abnormalities (incidence ≥50%, all grades) were: anemia (86%), hyperglycemia (75%), increased alkaline phosphatase (74%), hypercholesterolemia (66%), decreased bicarbonate (56%), and elevated aspartate transaminase (56%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were: anemia (15%), lymphopenia (16%), hypophosphatemia (10%), hyperglycemia (17%), and increased alkaline phosphatase (8%).

Adverse Reactions in Progressive, Well-Differentiated, Nonfunctional GI and Lung NET: The most common adverse reactions (incidence ≥30%) were stomatitis (63%), infections (58%), diarrhea (41%), peripheral edema (39%), fatigue (37%), and rash (30%). The most common grade 3/4 adverse reactions (incidence ≥5%) were infections (11%), stomatitis (9%), diarrhea (9%), fatigue (5%), and hyperglycemia (5%).

Laboratory Abnormalities in Progressive, Well-Differentiated, Nonfunctional GI and Lung NET: The most common laboratory abnormalities (incidence ≥50%, all grades) were anemia (81%), hypercholesterolemia (71%), lymphopenia (66%), elevated aspartate transaminase (57%), and hyperglycemia (55%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were lymphopenia (16%), hyperglycemia (6%), hypokalemia (6%), elevated alanine transaminase (5%), and anemia (5%).

Adverse Reactions in Advanced RCC: The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The most common grade 3/4 adverse reactions (incidence ≥5%) were infections (10%), dyspnea (8%), and fatigue (6%).

Laboratory Abnormalities in Advanced RCC: The most common laboratory abnormalities (incidence ≥50%, all grades) were: anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%), and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), and hypophosphatemia (6%).

Adverse Reactions in Renal AML-TSC: The most common adverse reaction (incidence ≥30%) was stomatitis (78%). The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis and amenorrhea. Updated safety information from 112 patients treated with AFINITOR for a median duration of 3.9 years identified the following additional adverse reactions: urinary tract infection (31%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%).

Laboratory Abnormalities in Renal AML-TSC: The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (85%), anemia (61%) and hypertriglyceridemia (52%). The most common grade 3/4 laboratory abnormality (incidence ≥3%) was hypophosphatemia (5%). Updated safety information from 112 patients treated with AFINITOR for a median duration of 3.9 years identified the following additional key laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), and proteinuria (18%).

Adverse Reactions in SEGA-TSC: The most common adverse reactions (incidence ≥30%, all grades) in the phase 3 study were stomatitis (62%) and respiratory tract infection (31%). The most common grade 3/4 adverse reactions (incidence ≥2%) in the phase 3 study were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions: decreased appetite (14%), hypertension (11%), urinary tract infection (9%), cellulitis (6%), abdominal pain (5%), and decreased weight (5%).

Laboratory Abnormalities in SEGA-TSC: The most common key laboratory abnormalities (incidence ≥50%, all grades) in the phase 3 study were hypercholesterolemia (81%) and elevated partial thromboplastin time (72%). The most common grade 3/4 laboratory abnormality (incidence ≥3%) in the phase 3 study was neutropenia (9%). Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional key laboratory abnormalities: hyperglycemia (13%), decreased fibrinogen (8%), elevated creatinine (5%), and azoospermia (1%).

Adverse Reactions in TSC-Associated Partial-Onset Seizures: In patients with TSC-associated partial-onset seizures, the most common adverse reaction reported for AFINITOR DISPERZ (incidence ≥30%) was stomatitis (55% low trough, 64% high trough). The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis, pneumonia, and irregular menstruation. Updated safety information from 357 patients treated with AFINITOR DISPERZ for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%).

Laboratory Abnormalities in TSC-Associated Partial-Onset Seizures: In patients with TSC-associated partial-onset seizures, the most common laboratory abnormality (incidence ≥50%) was hypercholesterolemia (86% low trough, 85% high trough). The most common grade 3/4 laboratory abnormality (incidence ≥2%) was neutropenia.

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