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Included as part of the PRECAUTIONS section.

Non-infectious Pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 14% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.1%, 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. Imaging appears to overestimate the incidence of clinical pneumonitis.

If symptoms are moderate, consider interrupting 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 where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy. Corticosteroids may be indicated until clinical symptoms resolve. AFINITOR may be re-initiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances. 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, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an 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.

Oral Ulceration

Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-7% of patients [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].

Renal Failure

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Laboratory Tests and Monitoring

Renal Function

Elevations of serum creatinine and proteinuria have been reported in clinical trials [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 andLipids

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.

Hematologic Parameters

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.

Drug-drug Interactions

Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Hepatic Impairment

Exposure to everolimus was increased in patients with hepatic impairment [see CLINICAL PHARMACOLOGY].

For advanced PNET, advanced RCC, and renal angiomyolipoma with TSC 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 [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see DOSAGE AND ADMINISTRATION].

Vaccinations

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.

The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy.

Use in Pregnancy

There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on the 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. 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].

Patient Counseling Information

Non-infectious Pneumonitis

Warn patients of the possibility of developing non-infectious pneumonitis. In clinical studies, some non-infectious pneumonitis cases have been severe and occasionally fatal. Advise patients to report promptly any new or worsening respiratory symptoms [see WARNINGS AND PRECAUTIONS].

Infections

Inform patients that they are more susceptible to infections while being treated with AFINITOR and that cases of hepatitis B reactivation have been associated with AFINITOR treatment. In clinical studies, some of these infections have been severe (e.g., leading to respiratory or hepatic failure) and occasionally fatal. Patients should be aware of the signs and symptoms of infection and should report any such signs or symptoms promptly to their physician [see WARNINGS AND PRECAUTIONS].

Oral Ulceration

Inform patients of the possibility of developing mouth ulcers, stomatitis, and oral mucositis. In such cases, mouthwashes and/or topical treatments are recommended, but these should not contain alcohol or peroxide [see WARNINGS AND PRECAUTIONS].

Renal Failure

Inform patients of the possibility of developing kidney failure. In some cases kidney failure has been severe and occasionally fatal. Inform patients of the need for the healthcare provider to monitor kidney function, especially in patients with risk factors that may impair kidney function [see WARNINGS AND PRECAUTIONS

Laboratory Tests and Monitoring

Inform patients of the need to monitor blood chemistry and hematology prior to the start of AFINITOR therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS].

Drug-drug Interactions

Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements. Inform the patients to avoid concomitant administration of strong CYP3A4 inhibitors or inducers while on AFINITOR treatment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

Vaccinations

Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines [see WARNINGS AND PRECAUTIONS].

Pregnancy

Advise female patients of childbearing potential that AFINITOR may cause fetal harm and that an effective method of contraception should be used during therapy with AFINITOR and for 8 weeks after ending treatment.

Dosing Instructions

Inform patients to take AFINITOR orally once daily at the same time every day, either consistently with food or consistently without food. AFINITOR should be swallowed whole with a glass of water. For patients unable to swallow tablets, AFINITOR tablet(s) should be dispersed completely in a glass of water (containing approximately 30 mL) by gently stirring, immediately prior to drinking. The glass should be rinsed with the same volume of water and the rinse should be completely swallowed to ensure that the entire dose is administered.

Instruct patients that if they miss a dose of AFINITOR, they may still take it up to 6 hours after the time they would normally take it. If more than 6 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take AFINITOR at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding respectively to 3.9 and 0.2 times the estimated clinical exposure (AUC_0-24h) at the 10 mg daily human dose.

Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m²/day, approximately 255-fold the 10 mg daily human dose, and 103-fold the maximum dose administered to patients with SEGA, based on the body surface area), administered as two doses, 24 hours apart.

Based on non-clinical findings, male fertility may be compromised by treatment with AFINITOR. In a 13-week male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm count, and plasma testosterone levels were diminished at 5 mg/kg, which resulted in infertility at 5 mg/kg. Effects on male fertility occurred at the AUC_0-24h values below that of therapeutic exposure (approximately 10%-81% of the AUC_0-24h in patients receiving the 10 mg daily dose). After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60% (12/20 mated females were pregnant).

Oral doses of everolimus in female rats at ≥0.1 mg/kg (approximately 4% the AUC0-24h in patients receiving the 10 mg daily dose) resulted in increases in pre-implantation loss, suggesting that the drug may reduce female fertility. Everolimus crossed the placenta and was toxic to the conceptus [see Use in Specific Populations].

Use In Specific Populations

Pregnancy

Pregnancy Category D [see WARNINGS AND PRECAUTIONS].

There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on the 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. 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 (AUC_0-24h) in patients receiving the 10 mg daily dose. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the 10 mg daily human dose, and 0.7 times the maximum dose administered to SEGA patients 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 10 mg daily human dose, and 4% of the maximum dose administered to SEGA patients, 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).

Nursing Mothers

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.

Pediatric Use

AFINITOR is recommended for use only in patients with SEGA who are aged ≥ 3 years.

A prospective, open-label, single-arm trial was conducted to evaluate the safety and efficacy of AFINITOR in patients with SEGA associated with TSC. In total, 28 patients received treatment with AFINITOR; median age was 11 years (range 3-34). AFINITOR has not been studied in patients with SEGA < 3 years of age.

Geriatric Use

In the randomized advanced RCC study, 41% of AFINITOR-treated patients were ≥ 65 years of age, while 7% 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].

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].

Hepatic Impairment

The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see CLINICAL PHARMACOLOGY].

For advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, 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 [see DOSAGE AND ADMINISTRATION].

For SEGA patients with severe hepatic impairment (Child-Pugh class C), AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however, subsequent dosing should be individualized based on therapeutic drug monitoring [see DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 5/7/2012
This monograph has been modified to include the generic and brand name in many instances.