Important Safety Information

AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis:...

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Indication

AFINITOR® (everolimus) Tablets is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery.

Safety Profile

Adverse Reactions Profile

Adverse Reaction Chart

Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.
Median duration of blinded study treatment was 48 weeks (range: 2-115 weeks) for AFINITOR.1
Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.1
No grade 4 adverse reactions were reported.

  • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis and amenorrhea1
  • Amenorrhea occurred in 15% of AFINITOR® (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%)1
  • The following additional adverse reactions occurred in less than 10% of AFINITOR-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%)
  • 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 stomatitis1
  • The rate of adverse reactions 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 hypophosphatemia1

Grading Scale for Adverse Events

The CTC/CTCAE guidelines, developed by the National Cancer Institute's Cancer Therapy Evaluation Program (CTEP/NCI), define the severity of adverse events using the following grading system.2

Grade
DefinitionClarification
1 Mild adverse event Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated
2 Moderate adverse event Minimal, local, or noninvasive intervention (eg, packing, cautery) indicated; limiting age-appropriate instrumental activites of daily living (ADL)
3 Severe or medically significant, but not immediately life-threatening, adverse event Hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL
4 Life-threatening consequences adverse event 

Consequences; urgent intervention indicated

5 Death related to adverse event 

CTC/CTCAE, Common Toxicity Criteria/Common Terminology Criteria for Adverse Events.

Laboratory Abnormalities

Laboratory Abnormalities

a Grading according to CTCAE Version 3.0.
b No grade 4 laboratory abnormalities were reported.

  • The most common grade 3/4 laboratory abnormality (incidence ≥3%) was hypophosphatemia1

  • Updated safety information from 112 patients treated with AFINITOR 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%)1

 

References:

  1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018.
  2. National Cancer Institute. NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs. National Cancer Institute website. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf. Published September 16, 2013. Accessed November 29, 2018.

IMPORTANT SAFETY INFORMATION

AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: Noninfectious pneumonitis is a class effect of rapamycin derivatives. Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials, some cases 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. Consider a diagnosis of noninfectious pneumonitis in patients presenting with nonspecific 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 AFINITOR without dose alteration in patients who develop radiological changes suggestive of noninfectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis. For grade 2 to 4 noninfectious pneumonitis, withhold or permanently discontinue AFINITOR 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 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, sepsis 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. The incidence of serious infections was reported at a higher frequency in patients <6 years of age. Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue AFINITOR 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 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 for the development of clinically significant hypersensitivity.

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitor with AFINITOR may be at increased risk for angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue AFINITOR for angioedema.

Stomatitis: Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR 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, 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.

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR. 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 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 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 in the perisurgical period.

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

Myelosuppression: Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR. 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, every 6 months for the first year of treatment, and annually thereafter. Withhold or permanently discontinue AFINITOR based on severity.

Risk of Infection or Reduced Immune Response With Vaccinations: The safety of immunization with live vaccines during AFINITOR therapy has not been studied. Due to the potential increased risk of infection and/or reduced immune response to the vaccine, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with AFINITOR. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of live vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

Embryo-Fetal Toxicity: Based on animal studies and the mechanism of action, AFINITOR 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 AFINITOR 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 and for 4 weeks after the last dose.

Adverse Reactions: 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 patients with TSC-associated renal angiomyolipoma, the most common laboratory abnormalities (incidence ≥50%, all grades) were hypercholesterolemia (85%), hypertriglyceridemia (52%), and anemia (61%). 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%).

Please see full Prescribing Information.

Indication

AFINITOR® (everolimus) Tablets is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery.