Adverse Reactions Profiles
EXIST-3
ADVERSE REACTIONS REPORTED IN ≥10% OF PATIENTS TREATED WITH AFINITOR DISPERZ OR PLACEBO + AED THERAPY1,a
a Placebo or AFINITOR DISPERZ was added to patients’ concomitant AED therapy.
b Includes reports of stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain.
c No Grade 4 adverse reactions were reported.
Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
- The following additional adverse reactions occurred in <10% of AFINITOR DISPERZ-treated patients (% AFINITOR DISPERZ 3-7 ng/mL, % AFINITOR DISPERZ 9-15 ng/mL): decreased appetite (9%, 7%), pneumonia (2%, 4%), aggression (2%, 0.8%), proteinuria (0%, 2%), menorrhagia (0.9%, 0.8%), and pneumonitis (0%, 0.8%)
- The most common adverse reaction reported for AFINITOR DISPERZ in both groups (incidence ≥30%) was stomatitis. The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis, pneumonia, and irregular menstruation
- Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the AFINITOR DISPERZ 3-7 ng/mL and 9-15 ng/mL groups, respectively
- The most common adverse reaction (incidence ≥1%) leading to AFINITOR DISPERZ discontinuation was stomatitis
- Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the AFINITOR DISPERZ 3-7 ng/mL and 9-15 ng/mL groups, respectively. The most common adverse reactions (incidence ≥3%) leading to dose adjustments in the AFINITOR DISPERZ 3-7 ng/mL and 9-15 ng/mL groups were stomatitis, pneumonia, and pyrexia
EXIST-3 Extension Trial
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.
DEFINITIONS OF TERMS2
| Grade |
Definition | Clarification |
|---|---|---|
| 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 activities 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: EXIST-3
LABORATORY ABNORMALITIES REPORTED IN ≥10% OF PATIENTS TREATED WITH AFINITOR DISPERZ OR PLACEBO + AED THERAPY1,a
a Placebo or AFINITOR DISPERZ was added to patients’ concomitant AED therapy.
b No Grade 4 lab abnormalities were reported.
Grading according to CTCAE version 4.03
- The most common laboratory abnormality (incidence ≥50%) was hypercholesterolemia. The most common grade 3/4 key laboratory abnormality (incidence ≥2%) was neutropenia
- 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%)
Stomatitis Management
Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR® (everolimus) Tablets or AFINITOR DISPERZ at an incidence ranging from 44% to 78% across clinical trials.1 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 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. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme-containing products, as they may exacerbate the condition. Do not administer antifungal agents, unless fungal infection has been diagnosed.
©2009 Oncology Nursing Society. Used with permission.
- Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme-containing products, as they may exacerbate the condition
- Do not administer antifungal agents, unless fungal infection has been diagnosed
Data show prophylactic treatment with dexamethasone-based mouthwash reduces the incidence and severity of stomatitis.1,3 Coadministration of AFINITOR or AFINITOR DISPERZ and dexamethasone alcohol‑free oral solution has not been studied in pediatric patients.
RECOMMENDATIONS FOR STOMATITIS1
If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered.
a Severity grade description: 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms; 4=life-threatening symptoms.
Additional Stomatitis Management Strategies
Data from the SWISH* trial in patients taking AFINITOR show prophylactic treatment with dexamethasone-based mouthwash reduces the incidence and severity of stomatitis. When treating a patient with AFINITOR DISPERZ, prescribing dexamethasone alcohol-free oral solution as a swish-and-spit mouthwash may be an effective stomatitis management strategy.1,3
*The dexamethasone alcohol-free oral solution was studied in a single-arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer.
Alcohol-free dexamethasone-based mouthwash1
- 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution
- Commercially available: NDC 00054-3177-63 (500 mL) or NDC 00054-3177-57 (240 mL)
Patients could continue dexamethasone mouthwash regimen for an additional 8 weeks at clinician's discretion.3
References:
1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.
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.
3. Rugo HS, Seneviratne 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.
IMPORTANT SAFETY INFORMATION
AFINITOR DISPERZ® (everolimus tablets for oral suspension) 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.
Indication
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 DISPERZ® (everolimus tablets for oral suspension) 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 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. 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 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. 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 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 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 DISPERZ for the development of clinically significant hypersensitivity.
Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors
Patients taking concomitant ACE inhibitors with 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, 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 DISPERZ for angioedema.
Stomatitis
Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR or 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 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.
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 or 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 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 DISPERZ has the potential to adversely affect wound healing. Withhold 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.
Metabolic Disorders
Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR or 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 DISPERZ and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting AFINITOR DISPERZ and once yearly thereafter. When possible, achieve optimal glucose and lipid control prior to starting AFINITOR DISPERZ. For grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR DISPERZ based on severity.
Myelosuppression
Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR or 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 DISPERZ, every 6 months for the first year of treatment, and annually thereafter. Withhold or permanently discontinue AFINITOR DISPERZ based on severity.
Risk of Infection or Reduced Immune Response With Vaccinations
The safety of immunization with live vaccines during AFINITOR DISPERZ 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 DISPERZ. 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.
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 DISPERZ treatment. Monitor patients closely when administering AFINITOR DISPERZ during, or sequentially with, radiation treatment.
Embryo-Fetal Toxicity
Based on animal studies and the mechanism of action, AFINITOR DISPERZ 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 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 DISPERZ and for 4 weeks after the last dose.
Adverse Reactions
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
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.
