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Non-infectious pneumonitis: Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious pneumonitis (including interstitial lung disease) have also been described in patients taking Afinitor (see Adverse Reactions). Some of these have been severe and on rare occasions, a fatal outcome was observed.
A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnea, and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jirovecii pneumonia (PJP) should be ruled out in the differential diagnosis of non-infectious pneumonitis (see Infections as follows).
Patients should be advised to report promptly any new or worsening respiratory symptoms.
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue Afinitor therapy without dose alteration (see Table 6 under Dosage & Administration).
If symptoms are moderate (grade 2), consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Afinitor may be reintroduced at a daily dose approximately 50% lower than the dose previously administered.
For cases of grade 3 non-infectious pneumonitis, interrupt Afinitor until resolution to less than or equal to grade 1. Afinitor may be re-initiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of Afinitor. For cases of grade 4 non-infectious pneumonitis, Afinitor therapy should be discontinued. Corticosteroids may be indicated until clinical symptoms resolve.
For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for pneumocystis jirovecii pneumonia (PJP) may be considered.
The development of pneumonitis has also been reported at a reduced dose (see Table 6 under Dosage & Administration).
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, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jirovecii pneumonia (PJP) and viral infections including reactivation of hepatitis B virus, have been described in patients taking Afinitor. Some of these infections have been severe (e.g. leading to sepsis [including septic shock], respiratory or hepatic failure) and occasionally have had a fatal outcome in adult and pediatric patients (see Adverse Reactions).
Physicians and patients should be aware of the increased risk of infection with Afinitor. Treat pre-existing infections prior to starting treatment with Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor.
If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy.
Cases of pneumocystis jirovecii pneumonia (PJP), some with fatal outcome, have been reported in patients who received everolimus. PJP may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.
Hypersensitivity reactions: Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see Contraindications).
Angioedema with concomitant use of angiotensin-converting enzyme (ACE) inhibitors: Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).
Stomatitis: Stomatitis, including mouth ulceration and oral mucositis, is the most commonly reported adverse drug reaction in patients treated with Afinitor (see Adverse Reactions). Stomatitis mostly occurs within the first 8 weeks of treatment. If stomatitis occurs, topical treatments are recommended, but alcohol-, hydrogen peroxide, iodine-, or thyme-containing products should be avoided as they may exacerbate the condition (see Table 6 under Dosage & Administration). Antifungal agents should not be used unless fungal infection has been diagnosed (see Interactions).
In a single arm study in 92 postmenopausal breast cancer patients, a topical alcohol-free corticosteroid oral solution was administered as a mouthwash during the initial 8 weeks of starting treatment with Afinitor plus exemestane. In this study, a clinically meaningful reduction in the incidence and severity of stomatitis was observed (see Adverse Reactions).
Renal failure events: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Afinitor. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function (see Laboratory tests and monitoring as follows and Adverse Reactions).
Laboratory tests and monitoring: Renal function: Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients taking Afinitor (see Adverse Reactions). Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter.
Blood glucose: Hyperglycemia has been reported in patients taking Afinitor (see Adverse Reactions). Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. More frequent monitoring is recommended when Afinitor is co-administered with other drugs that may induce hyperglycemia. Optimal glycemic control should be achieved before starting a patient on Afinitor.
Blood lipids: Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in patients taking Afinitor. Monitoring of blood cholesterol and triglycerides prior to the start of Afinitor therapy and periodically thereafter as well as management with appropriate medical therapy is recommended.
Hematological parameters: Decreased hemoglobin, lymphocytes, platelets and neutrophils have been reported in patients treated with Afinitor (see Adverse Reactions). Monitoring of complete blood count is recommended prior to the start of Afinitor therapy and periodically thereafter.
Interactions: Co-administration with strong CYP3A4/P-glycoprotein (PgP) inhibitors should be avoided (see Interactions).
Use caution when administered in combination with moderate CYP3A4/PgP inhibitors. If Afinitor must be co-administered with a moderate CYP3A4/PgP inhibitor, the patient should be carefully monitored for undesirable effects and the Afinitor dose reduced if necessary (see Dosage & Administration and Interactions).
Co-administration with strong CYP3A4/PgP inducers should be avoided (see Interactions). If Afinitor must be co-administered with a strong CYP3A4/PgP inducer, the patient should be carefully monitored for clinical response. Consider a dose increase of Afinitor when co-administered with strong CYP3A4/PgP inducers if alternative treatment is not possible (see Dosage & Administration and Interactions).
Exercise caution when Afinitor is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Afinitor is taken with orally administered CYP3A4 substrates with a narrow therapeutic index, the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see Interactions).
Hepatic impairment: Exposure to everolimus was increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment (see Pharmacology under Actions).
Afinitor is not recommended in patients ≥18 years of age with severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk (see Dosage & Administration and Pharmacology under Actions).
Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor (see Interactions).
Wound healing complications: Impaired wound healing is a class effect of rapamycin derivatives, including everolimus. Caution should therefore be exercised with the use of Afinitor in the peri-surgical period.
Radiation therapy complications: Severe radiation reactions (including radiation esophagitis, radiation pneumonitis and radiation skin injury) have been reported when everolimus was used during, or shortly after radiation therapy. Caution should therefore be exercised for patients using everolimus in close temporal relationship with radiation therapy.
Additionally, radiation recall syndrome has been reported in patients on everolimus who have received prior radiotherapy.
