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AFINITOR® (everolimus) Tablets and AFINITOR DISPERZ® (everolimus tablets for oral suspension) are contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

 

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, 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. Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. 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.

Coadministration 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.

 

Risk of Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, AFINITOR/AFINITOR DISPERZ has the potential to adversely affect wound healing. Withhold AFINITOR/AFINITOR DISPERZ 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 occurs. The safety of resuming treatment upon resolution of wound healing complications has not been established.

 

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% of 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 or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR 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.

 

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 before, during, or after AFINITOR/AFINITOR DISPERZ treatment. Monitor patients closely when administering AFINITOR/AFINITOR DISPERZ during, or sequentially with, radiation treatment.

 

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 while using 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%), and fatigue (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%), increased 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

In patients with TSC-associated renal angiomyolipoma, the most common adverse reaction (incidence ≥30%, all grades) 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

In patients with TSC-associated renal angiomyolipoma, the most common laboratory abnormalities (incidence ≥50%, all grades) 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

In patients with TSC-associated SEGA, the most common adverse reactions (incidence ≥30%, all grades) were stomatitis (62%) and respiratory tract infection (31%). The most common grade 3/4 adverse reactions (incidence ≥2%) 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

In patients with TSC-associated SEGA, the most common key laboratory abnormalities (incidence ≥50%, all grades) were hypercholesterolemia (81%) and elevated partial thromboplastin time (72%). The most common grade 3/4 laboratory abnormality (incidence ≥3%) 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%, all grades) 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%, all grades) was hypercholesterolemia (86% low trough, 85% high trough). The most common grade 3/4 laboratory abnormality (incidence ≥2%) was neutropenia.

 

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