WARNINGS AND PRECAUTIONS
Non-infectious P neumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%, 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 such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients 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. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at 5 mg daily.
For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.
AFINITOR has immunosuppressive properties and may predispose patients to infections, especially infections with opportunistic pathogens [see Adverse Reactions]. Localized and systemic infections, including pneumonia, other bacterial infections and invasive fungal infections, such as aspergillosis or candidiasis, have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR, be vigilant for signs and symptoms of infection and institute appropriate treatment promptly. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.
5.3 Oral U lceration
Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions].
5.4 Laboratory T ests and M onitoring
Renal F unction
Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.
Blood Glucose and L ipids
Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.
Hematological P arameters
Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.
5.5 Drug-drug I nteractions
Due to significant increases in exposure of everolimus, co-administration with strong or moderate inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, voriconazole, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil or diltiazem) or P-glycoprotein (PgP) should be avoided [see Drug Interactions].
An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) [see Dosage and Administration and Drug Interactions (7.2) ].
5.6 Hepatic I mpairment
The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended.
AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see Dosage and Administration and Use in Specific Populations] .
The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR . Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
5.8 Use in Pregnancy
Pregnancy Category D
There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations] .
USE IN SPECIFIC POPULATIONS
Pregnancy Category D [s ee Warnings and Precautions]
There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.
In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.
In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.
Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2).
It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness in pediatric patients have not been established.
In the randomized study, 41% of AFINITOR-treated patients were ≥ 65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology].
No dosage adjustment is required in elderly patients [see Clinical Pharmacology].
8.6 Renal Impairment
No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology].
7 Hepatic Impairment
For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily [see Dosage and Administration Warnings and Precautions and Clinical Pharmacology (12.3) ].
The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in this patient population is not recommended [see Warnings and Precautions (5.6) ].