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Afinitor

"On Thursday, the U.S. Food and Drug Administration approved Afinitor (everolimus) to treat patients with progressive neuroendocrine tumors located in the pancreas (PNET) that cannot be removed by surgery or that have spread to other parts o"...

Afinitor

Afinitor

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Non-infectious Pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% 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 0.2%, 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 such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis. 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 [see Table 1 in DOSAGE AND ADMINISTRATION].

For cases of Grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to Grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see DOSAGE AND ADMINISTRATION]. If toxicity recurs at Grade 3, consider discontinuation of AFINITOR. For cases of Grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for PJP may be considered. 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, candidiasis, or pneumocystis jiroveci pneumonia (PJP) 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 sepsis, 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.

Pneumocystis jiroveci pneumonia, some with a fatal outcome, has been reported in patients who received everolimus. This 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.

Oral Ulceration

Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of patients [see ADVERSE REACTIONS]. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme- 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].

Impaired Wound Healing

Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the peri-surgical period.

Geriatric Patients

In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, 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 AND ADMINISTRATION, Use In Specific Populations].

Laboratory Tests and Monitoring

Renal Function

Elevations of serum creatinine 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. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.

Blood Glucose and Lipids

Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking AFINITOR [see ADVERSE REACTIONS]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when AFINITOR is co-administered with other drugs that may induce hyperglycemia. 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 patients taking AFINITOR [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/PgP 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/PgP inhibitor [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4/PgP 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 HR+ BC, 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 patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see DOSAGE AND ADMINISTRATION].

Vaccinations

During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

Embryo-fetal Toxicity

Based on the mechanism of action, AFINITOR can cause fetal harm. 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 this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use)

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 sepsis, 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, peroxide, iodine, or thyme [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].

Impaired Wound Healing

Inform patients of the possibility of impaired wound healing or dehiscence while being treated with AFINITOR [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/PgP inhibitors or inducers while on AFINITOR treatment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and 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].

Embryo-fetal Toxicity

Advise female patients of childbearing potential that AFINITOR may cause fetal harm and that a highly effective method of contraception should be used during therapy with AFINITOR and for up to 8 weeks after ending treatment [see WARNINGS AND PRECAUTIONS].

Safe Handling Practices for AFINITOR DISPERZ

Advise patients and their caregivers to read and carefully follow the FDA approved AFINITOR DISPERZ “Instructions for Use”.

Dosing Instructions

Inform patients to take AFINITOR Tablets orally once daily at the same time every day, either consistently with food or consistently without food. Inform patients that AFINITOR Tablets should be swallowed whole with a glass of water.

Inform patients to take AFINITOR DISPERZ orally once daily at the same time every day as a suspension. Refer patients to the “Instructions for Use” pamphlet for additional information regarding these procedures.

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 (AUC0-24h) 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 2 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. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. These doses result in exposures which are within the range of therapeutic exposure (52 ng•hr/mL and 414 ng•hr/mL respectively compared to 560 ng•hr/mL human exposure at 10 mg/day), and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at the AUC0-24h values below that of therapeutic exposure (approximately 10%-81% of the AUC0-24h 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 increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Risk Summary

Based on the mechanism of action, AFINITOR can 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, apprise the patient of the potential hazard to the fetus [see WARNINGS AND PRECAUTIONS].

Animal Data

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 in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m²) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m²), approximately 1.6 times either the 10 mg daily dose or the median 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 the dose of 0.1 mg/kg (0.6 mg/m²), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of 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.

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

Pediatric use of AFINITOR Tablets and AFINITOR DISPERZ is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets and AFINITOR DISPERZ have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA.

The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies]. Improvement in disease-related symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown.

Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see ADVERSE REACTIONS]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see ADVERSE REACTIONS]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see CLINICAL PHARMACOLOGY].The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see DOSAGE AND ADMINISTRATION].

Geriatric Use

In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 years and over. 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 [see WARNINGS AND PRECAUTIONS].

In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 years and over.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see CLINICAL PHARMACOLOGY].

No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Females And Males Of Reproductive Potential

Contraception

Females

AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

Infertility

Females

Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR [see ADVERSE REACTIONSand Nonclinical Toxicology].

Males

AFINITOR treatment may impair fertility in male patients based on animal findings [see Nonclinical Toxicology].

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 HR+ BC, 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 patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 7/14/2014
This monograph has been modified to include the generic and brand name in many instances.

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