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Non-infectious Pneumonitis: Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Grade 3 and 4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions]. Fatal outcomes have been observed.
Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific 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 non-infectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis.
For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue AFINITOR based on severity [see Dosage & Administration]. 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 infections with opportunistic pathogens [see Adverse Reactions]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP), and viral infections (e.g., reactivation of hepatitis B virus) have occurred. Some of these infections have been severe (e.g., 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 [see as follows].
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 [see Dosage & Administration].
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 (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications].
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 maybe at increased risk for angioedema (e.g., 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 clinical trials. Grades 3-4 stomatitis was reported in 4% to 9% of patients [see Adverse Reactions]. 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 [see Adverse Reactions]. 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.
Risk of Impaired Wound Healing: Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, AFINITOR have the potential to adversely affect wound healing.
Withhold AFINITOR 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. The safety of resumption of treatment upon resolution of wound healing complications has not been established.
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 [see Adverse Reactions]. In non-diabetic 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 [see Dosage & Administration].
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 [see Adverse Reactions]. Monitor complete blood count (CBC) prior to starting AFINITOR every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue AFINITOR based on severity [see Dosage & Administration].
Risk of Infection or Reduced Immune Response with Vaccination: 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.
Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of 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 prior to, during, or subsequent to AFINITOR treatment [see Adverse Reactions].
Monitor patients closely when AFINITOR is administered during or sequentially with radiation treatment.
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 [see Use in Pregnancy & Lactation].
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 [see Adverse Reactions]. 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.
Hepatic Impairment: AFINITOR exposure may increase in patients with hepatic impairment [see Pharmacology under Actions].
For patients with breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma who have hepatic impairment, reduce the AFINITOR dose as recommended [see Dosage & Administration].
For patients with TSC-associated SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR as recommended and adjust the dose based on everolimus trough concentrations [see Dosage & Administration].
Use in Children: TSC-Associated SEGA: The safety and effectiveness of AFINITOR have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of AFINITOR for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients [see Adverse Reactions, Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The safety and effectiveness of AFINITOR have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA.
In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 AFINITOR-treated patients < 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients ≥ 6 years. Thirty-five percent of 23 AFINITOR-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-treated patients ≥ 6 years.
Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, AFINITOR did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with AFINITOR for a median duration of 4.1 years.
Other Indications: The safety and effectiveness of AFINITOR in pediatric patients have not been established in: Hormone receptor-positive, HER2-negative breast cancer; Neuroendocrine tumors (NET); Renal cell carcinoma (RCC); TSC-associated renal angiomyolipoma.
Use in the Elderly: In the randomized hormone receptor-positive, HER2-negative breast cancer study (BOLERO-2), 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 to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage & Administration].
In BOLERO-2, 40% of patients with breast cancer treated with AFINITOR were ≥ 65 years of age, while 15% were ≥ 75 years of age. No overall differences in effectiveness were observed between elderly and younger patients. 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 to 2% in patients < 65 years of age.
Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age.
In RECORD-1, 41% of patients with renal cell carcinoma treated with AFINITOR were ≥ 65 years of age, while 7% were ≥ 75 years of age. In RADIANT-3, 30% of patients with PNET treated with AFINITOR were ≥ 65 years of age, while 7% were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.
