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 (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Safety Profile

Important Safety Information

  • AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, other rapamycin derivatives, or any excipients.
  • 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 taking AFINITOR, some with fatal outcomes.
  • Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitor therapy may be at increased risk for angioedema.
  • Oral ulceration is the most frequently occurring adverse event and occurred in 44% to 78% of AFINITOR-treated patients across the clinical trial experience. Most of these events were grade 1/2. Grade 3/4 stomatitis was reported in 4% to 9% of patients.
  • Exercise caution with the use of AFINITOR in the perisurgical period, as everolimus 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.
  • Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have also been reported; monitoring of laboratory tests is recommended.
  • 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.

Please see full Prescribing Information.

Adverse Reactions Profile

The majority of adverse reactions were grade 1/21,2

Most common AFINITOR-related adverse reactions

 Common AFINITOR®-related Adverse Events All Grade
Common AFINITOR®-related Adverse Events Grades 3-4
a Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration.
b Includes all preferred terms within the infections and infestations system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%),  sepsis (<1%), and hepatitis C (<1%).
c Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis.

  • Other key adverse reactions of interest include noninfectious pneumonitis* (19% vs <1%; all grades) and hyperglycemia (14% vs 2%; all grades) for the AFINITOR plus exemestane and the placebo plus exemestane arms, respectively1
  • Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared with patients who received placebo plus exemestane (0.4%)1
  • Rates of treatment-emergent adverse reactions resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively1
  • In BOLERO-2, the median time to onset of grade ≥2 stomatitis and related events after treatment initiation was 15 days in the AFINITOR plus exemestane treatment arm3
*

Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis.

 
 Laboratory Abnormalities

Adverse Reactions Management

Recommendations exist to support proactive management of select adverse reactions1,4

Symptom assessment conducted during prompt follow-up visits after therapy initiation may allow for early identification of adverse reactions and intervention1,5,6

  • Management of severe or intolerable adverse reactions may require temporary dose interruption (with or without a dose reduction of AFINITOR therapy) or discontinuation1
  • If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered1
  • The rates of treatment-emergent adverse reactions resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively1
  • Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared with patients who received placebo plus exemestane (0.4%)1
  • Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% vs 14%)1
    • Patients in the AFINITOR plus exemestane arm received a median AFINITOR dose of 8.6 mg/day7

Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.1

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)

Stomatitis Management

Stomatitis

Stomatitis was the most common adverse reaction reported in the BOLERO-2 trial, with the median time to onset of grade ≥2 stomatitis and related events being 15 days after treatment initiation in the AFINITOR plus exemestane treatment arm1,3

  • Mouth ulcers, stomatitis, and oral mucositis have 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 patients1
  • This stomatitis is distinct from conventional chemotherapy-induced mucositis in both its pathophysiology and clinical presentation8,9

AFINITOR® and Stomatitis

© 2009 Oncology Nursing Society. Used with permission.

AFINITOR dose adjustment and management recommendations

AFINITOR® Dosing Adjustment and Management for Stomatitis

a Severity grade description: 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms; 4=life-threatening symptoms.

If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously administered.

  • Avoid using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in the management of stomatitis, as they may worsen the condition
  • Antifungal agents should not be used unless fungal infection has been diagnosed

 

ADL, activities of daily living; 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.

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2016. 2. Data on file. AFINITOR CRAD001Y2301 Clinical Study Report. Novartis Pharmaceuticals Corp; March 2012. 3. Perez A, Rugo HS, Baselga J, et al. Clinical management and resolution of stomatitis in BOLERO-2. Poster presented at: 2013 ASCO Annual Meeting; June 2013; Chicago, IL. 4. Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita M. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Target Oncol. 2009;4(2):135-142. 5. Rugo HS, Gnant M, Geberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Poster presented at: St Gallen International Breast Cancer Conference; March 2013; St Gallen, Switzerland. 6. Moldawer NP, Wood LS. Management of key adverse events associated with everolimus therapy. Kidney Cancer J. 2008;372:51-59. 7. 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. 8. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer. 2010;116(1):210-215. 9. Campistol JM, de Fijter JW, Flechner SM, Langone A, Morelon E, Stockfleth E. mTOR inhibitor-associated dermatologic and mucosal problems. Clin Transplant. 2010;24(2):149-156.

Indication

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

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 was reported in up to 19% of patients treated with AFINITOR; some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Common Terminology Criteria (CTC) 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
  • Opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis
  • Manage noninfectious pneumonitis by dose interruption until symptoms resolve, follow with a dose reduction, and consider the use of corticosteroids. Discontinue AFINITOR if toxicity recurs at grade 3 or for grade 4 cases. For patients who require use of corticosteroids, prophylaxis for PJP may be considered
  • 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, leading to sepsis, respiratory failure, or hepatic failure) or fatal
  • Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR
  • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered
  • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment
  • PJP has been reported in patients who received everolimus, sometimes with a fatal outcome. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents; consider prophylaxis for PJP when concomitant use of these agents is required

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors

  • Patients taking concomitant ACE inhibitor therapy 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

Oral Ulceration

  • Mouth ulcers, stomatitis, and oral mucositis have 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
  • In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes 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 been observed in patients treated with AFINITOR

Impaired Wound Healing

  • Everolimus 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

Laboratory Tests and Monitoring

  • Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function
  • Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR
  • Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Monitoring of complete blood count is recommended prior to treatment and periodically thereafter

Drug-Drug Interactions

  • Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole)
  • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem)
  • Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less

Hepatic Impairment

  • Exposure to everolimus was increased in patients with hepatic impairment
  • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended

Vaccinations

  • The use of live vaccines and close contact with those who have received live vaccines should be avoided 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 of the potential risk to a fetus and to use effective contraception while using AFINITOR and for 8 weeks after ending treatment

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 (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), 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 (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%)

Please see full Prescribing Information.