Important Safety Information

There have been reports of noninfectious pneumonitis (including some with pulmonary hypertension as a secondary event), infections, and renal failure (including acute renal failure) in patients...

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Indication AFINITOR® (everolimus) Tablets 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.

Safety Profile

Important Safety Information

  • AFINITOR is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives
  • There have been reports of noninfectious pneumonitis (including some with pulmonary hypertension as a secondary event) and infections in patients taking AFINITOR. Withhold or permanently discontinue based on severity
  • Hypersensitivity reactions have been observed in patients taking AFINITOR and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment). Permanently discontinue AFINITOR for the development of clinically significant hypersensitivity
  • Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitor may be at increased risk for angioedema. Permanently discontinue AFINITOR for angioedema
  • Stomatitis, including mouth ulcers and oral mucositis, is the most frequently occurring adverse event and occurred in 44% to 78% of patients taking AFINITOR across the clinical trial experience. When starting AFINITOR, initiation of topical treatment with dexamethasone mouthwash reduces the incidence and severity of stomatitis. Stomatitis most often occurs within the first 8 weeks of treatment
  • Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. 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
  • Exercise caution with the use of AFINITOR in the perisurgical period, as AFINITOR delays wound healing and increases the occurrence of wound-related complications
  • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared with patients <65 years of age
  • Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR. 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 annually 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
  • Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR. 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
  • The use of live vaccines and close contact with those who have received live vaccines should be avoided
  • AFINITOR can cause fetal harm when administered to a pregnant woman. Advise  patients of reproductive potential to avoid becoming pregnant and to use effective contraception

Please see full Prescribing Information.

Adverse Reactions Profile

AFINITOR has a well-characterized safety profile1

AFINITOR® (everolimus) Tablets has a well-characterized safety profile—serious adverse reactions and risks can occur with AFINITOR including, but not limited to, noninfectious pneumonitis (including some with pulmonary hypertension as a secondary event), infections, severe hypersensitivity reactions, angioedema, stomatitis, renal failure (including acute renal failure), impaired wound healing, geriatric patients, metabolic disorders, myelosuppression, risk of infection or reduced immune response with vaccinations, and embryo-fetal toxicity.


Time to onset and resolution for select AEs from an 18-month follow-up evaluation of BOLERO-2*:

  • Stomatitis: More than one-third of events occurred within first 2 weeks; 97% of patients (n=39) experienced resolution from grade ≥3 to grade ≤1 after a median of 3.1 weeks2
  • Noninfectious pneumonitis: Approximately one-fourth of events occurred within the first 12 weeks; 80% of patients (n=20) experienced resolution from grade ≥3 to grade ≤1 after a median of 3.8 weeks2
  • Fatigue: More than one-third of events occurred within the first 6 weeks; 72% of patients (n=32) experienced resolution from grade ≥3 to grade ≤1 after a median of 8.0 weeks2

The BOLERO-2 trial safety population comprised 720 patients (AFINITOR + exemestane, 482; placebo + exemestane, 238). The median follow-up was 18 months (at baseline and every 6 weeks thereafter). The incidence of associated select class-effect toxicities, including stomatitis, noninfectious pneumonitis, and hyperglycemia, were evaluated by their time course of onset and resolution, as well as the incidences of dose reductions, delays, and discontinuations. Resolution typically followed dose interruption/reduction.2

Complete resolution of grade ≥3 noninfectious pneumonitis was reported in 75% of patients, after a median of 5.4 weeks.2

Complete resolution was reported in 56% of AFINITOR + exemestane-treated patients after a median of 18.7 weeks.2

 
 Laboratory Abnormalities

 

Adverse Reactions Management

Recommendations exist to support proactive management of select adverse reactions1,3

Sign and symptom assessment conducted during prompt follow-up visits after therapy initiation may allow for early identification of adverse reactions and intervention. Refer to the full Prescribing Information for potential risks associated with AFINITOR and recommendations for managing adverse reactions.

  • The rate of adverse reactions resulting in permanent discontinuation was 24% for the AFINITOR arm1
  • Fatal adverse reactions occurred in 2% of patients who received AFINITOR 1
  • Dose adjustments (interruptions or reductions) occurred in 63% of patients in the AFINITOR arm1
    • Patients in the AFINITOR plus exemestane arm received a median AFINITOR dose of 8.6 mg/day3

Select an adverse reaction to review its dose adjustment and management recommendations:

 
 Noninfectious pneumonitis
 Infections
 Other nonhematologic toxicities (excluding metabolic events)
 Metabolic events (eg, hyperglycemia, dyslipidemia)

SWISH Trial

Reduce incidence and severity of stomatitis with a prophylactic strategy in the FDA-approved label1,4
Incidence of stomatitis in SWISH (Week 8) with prophylactic use of alcohol-free dexamethasone-based mouthwash1,4

 

79% of patients experienced no stomatitis

 

  • The primary objective of this study was to assess the incidence of grade ≥2 stomatitis within 8 weeks (56 days)
  • In the SWISH trial, postmenopausal women with HR+, HER2-negative metastatic breast cancer were prophylactically treated with alcohol-free dexamethasone-based mouthwash when prescribed AFINITOR plus exemestane (N=92)1
  • The incidence of Grade 2 to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the overall results of BOLERO-2 trial
  • Oral candidiasis was reported in 2% of patients in this study compared with .2% in the BOLERO-2 trial

Using alcohol-free dexamethasone-based mouthwash per SWISH protocol1

*Patients could continue dexamethasone-based mouthwash regimen for an additional 8 weeks by clinician discretion.4

Dexamethasone-based mouthwash prescription

Click to download a PDF with more information about the SWISH trial.

Download SWISH voucher

Download SWISH voucher for free 8-week supply of alcohol-free dexamethasone oral solution

For your patients taking AFINITOR, Novartis offers a free 8-week supply of the alcohol-free dexamethasone oral solution with a valid prescription from you. Click or go to www.RxMouthwash.com to get more information and download the voucher for your patients.

SWISH Trial Video

Play the video below and discover how this prophylactic strategy can help you to reduce the incidence and severity of stomatitis in your patients.

This video will take you through the results of the SWISH study—a phase 2, single-arm study that evaluated the use of an alcohol-free dexamethasone-based mouthwash to reduce the incidence and severity of stomatitis associated with AFINITOR plus exemestane treatment in postmenopausal women with HR+, HER2-negative breast cancer.

AE, adverse event; BOLERO-2, Breast Cancer Trials of Oral Everolimus-2; CTCAE, Common Terminology Criteria for Adverse Events; HR+ BC, hormone receptor-positive breast cancer; SWISH, dexamethaSone mouthWash for everolImus-related stomatitiS prevention in HR+ MBC.

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 2. Rugo HS, Pritchard KI, Gnant M, et al. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol. 2014;25(4):808-815. 3. Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR+ breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870-884. 4. Rugo HS, Senevirantne L, Beck JT, et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single arm, phase 2 trial. Lancet Oncol. 2017;18(5):654-662.

Indication

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.

Important Safety Information

AFINITOR 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; 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% 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. Withhold or permanently discontinue based on severity. Corticosteroids may be indicated until clinical symptoms resolve
  • For grade 2 to 4 noninfectious pneumonitis, withhold or permanently discontinue 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, 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 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 inhibitors 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 of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking AFINITOR 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

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 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 annually 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/AFINITOR DISPERZ 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/AFINITOR DISPERZ 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, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with AFINITOR

Embryo-Fetal Toxicity

  • Fetal harm can occur if AFINITOR 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 and for 8 weeks after the last dose

Adverse Reactions

  • 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

  • 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%)

Please see full Prescribing Information.