These highlights do not include all the information needed to use   AFINITOR safely   and effectively. See full prescribing information for   AFINITOR . AFINITOR ( everol

AFINITOR is indicated for the treatment of patients with advanced RCC after failure of treatment with sunitinib or sorafenib.

AFINITOR is indicated for the treatment of patients with SEGA associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection. 

The effectiveness of AFINITOR is based on an analysis of change in SEGA volume [see Clinical Studies (14.2)]. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been demonstrated.

AFINITOR should be administered orally once daily at the same time every day, either consistently with food or consistently without food [see Clinical Pharmacology (12.3)].

AFINITOR tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed. 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.

The recommended dose of AFINITOR for treatment of advanced RCC is 10 mg, to be taken once daily.

Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.

Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of AFINITOR therapy. If dose reduction is required, the suggested dose is 5 mg daily [see Warnings and Precautions (5.1)].

Hepatic I mpairment  

For patients with moderate hepatic impairment (Child-Pugh class B), reduce the dose to 5 mg daily. AFINITOR has not been eva luated in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this patient population [ se e Warnings and Precautions (5.6 ) and Use in Specific Populations (8.7)].

CYP3A4 and/ or P-glycoprotein ( PgP )   I nhibitors

Avoid the use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [ see Warnings and Precautions (5.5) and Drug   Interactions (7.1) ].

Use caution when co-administered with moderate CYP3A4 and/or PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4 and/or PgP inhibitor, reduce the AFINITOR dose to 2.5 mg daily. The reduced dose of AFINITOR is predicted to adjust the area under the curve (AUC) to the range observed without inhibitors. An AFINITOR dose increase from 2.5 mg to 5 mg may be considered based on patient tolerance. If the moderate inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the AFINITOR dose is increased. If the moderate inhibitor is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4 and/or PgP inhibitor.

Strong CYP3A4 I nducers  

Avoid the use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). If patients require co-administration of a strong CYP3A4 inducer, consider increasing the AFINITOR dose from 10 mg daily up to 20 mg daily (based on pharmacokinetic data), using 5 mg increments. This dose of AFINITOR is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [ see Warnings and Precautions (5.5) and Drug   Interactions (7.2) ] .

Grapefruit, grapefruit juice and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment. St. John’s Wort (Hypericum   perforatum) may decrease everolimus exposure unpredictably and should be avoided.

The recommended starting dose of AFINITOR for treatment of patients with SEGA is according to Table 1:

Patients receiving AFINITOR may require dose adjustments based on everolimus trough blood concentrations achieved, tolerability, individual response, and change in concomitant medications including CYP3A4-inducing antiepileptic drugs [see Warnings and Precautions (5.5) and Drug Interactions ( 7.1, 7.2)]. Dose adjustments can be made at two week intervals [ See Dosage and Administration (2.4 , 2.5 ) ]. 

eva luate SEGA volume approximately 3 months after commencing AFINITOR therapy and periodically thereafter, with subsequent dose adjustments taking into consideration changes in SEGA volume, corresponding trough concentration, and tolerability. Responses have been observed at trough concentrations as low as 3 ng/mL; as such, once acceptable efficacy has been achieved, additional dose increases may not be necessary.

AFINITOR has not been studied in patients with SEGA < 3 years of age or with BSA < 0.58 m. 

The optimal duration of therapy for patients with SEGA is unknown.

Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of AFINITOR therapy [see Warnings and Precautions (5.1)]. If dose reduction is required for patients receiving 2.5 mg daily, consider alternate day dosing.

CYP3A4 and/ or P-glycoprotein ( PgP ) Inhibitors

Avoid the use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [ see Warnings and Precautions (5.5) and Drug   Interactions (7.1) ].

Use caution when co-administered with moderate CYP3A4 and/or PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4 and/or PgP inhibitor, reduce the AFINITOR dose by approximately 50% to maintain trough concentrations of 5 to 10 ng/mL. If dose reduction is required for patients receiving 2.5 mg daily, consider alternate day dosing. Subsequent dosing should be individualized based on therapeutic drug monitoring. Everolimus trough concentrations should be assessed approximately 2 weeks after the addition of a moderate CYP3A4 and/or PgP inhibitor. If the moderate inhibitor is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4 and/or PgP inhibitor and the everolimus trough concentration should be re-assessed approximately 2 weeks later [ see Warnings and Precautions (5.5) and Drug Interactions (7.1) ].

Strong CYP3A4 Inducers  

Avoid the use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). For patients requiring a concomitant strong CYP3A4 inducer, double the AFINITOR dose. Subsequent dosing should be individualized based on therapeutic drug monitoring. If the strong inducer is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer and the everolimus trough concentrations should be assessed approximately 2 weeks later [ see Warnings and Precautions (5.5) and Drug Interactions (7.2) ].

Grapefruit, grapefruit juice and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment. St. John’s Wort (Hypericum   perforatum) may decrease everolimus exposure unpredictably and should be avoided.

Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients using a validated assay. Trough concentrations should be assessed approximately 2 weeks after commencing treatment. Dosing should be titrated to attain trough concentrations of 5 to 10 ng/mL. 

There is limited safety experience with patients having trough concentrations > 10 ng/mL. If concentrations are between 10 to 15 ng/mL, and the patient has demonstrated adequate tolerability and tumor response, no dose reductions are needed. The dose of AFINITOR should be reduced if trough concentrations > 15 ng/mL are observed. 

If concentrations are < 5 ng/mL, the daily dose may be increased by 2.5 mg every 2 weeks, subject to tolerability. Daily dose may be reduced by 2.5 mg every 2 weeks to attain a target of 5 to 10 ng/mL. If dose reduction is required for patients receiving 2.5 mg daily, alternate day dosing should be used. 

Trough concentrations should be assessed approximately 2 weeks after any change in dose, or after an initiation or change in co-administration of CYP3A4 and/or PgP inducers or inhibitors [ see Dosage and Administration (2.4), Warnings and Precautions (5.5), Drug Interactions (7.1 , 7.2 ) ].

2.5 mg tablet

White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other.

5 mg tablet

White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other.

10 mg tablet

White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other.

Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. 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 and other rapamycin derivatives.

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized advanced RCC study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively [see Adverse Reactions (6.1)]. 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.

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.

AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [ see Adverse Reactions (6.1 , 6.2 )]. Localized and systemic infections, including pneumonia, 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.

Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized advanced RCC study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 or 2 [see Adverse Reactions (6.1)]. In the SEGA study, 86% of AFINITOR-treated patients developed stomatitis which was mostly CTCAE grade 1 or 2 [see Adverse Reactions (6.2)]. 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 (7.1)].

Renal F unction

Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions (6.1 , 6.2 )]. 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 (6.1 , 6.2 )]. 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 P arameters

Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1 , 6.2 )]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2 , 2.4 ) and Drug Interactions (7.1)].

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2 , 2.4 ) and Drug Interactions (7.1)] .

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2 , 2.4 ) and Drug Interactions (7.2)].

Exposure of everolimus was increased in patients with moderate hepatic impairment [see Clinical Pharmacology (12.3)].

For advanced RCC patients with moderate hepatic impairment (Child-Pugh class B), a dose reduction is recommended [see Dosage and Administration (2.2 )].

For SEGA patients with moderate hepatic impairment (Child-Pugh class B), adjustment to the starting dose may not be needed. However, subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.5)].

AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population.

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.

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 for advanced RCC and SEGA patients. 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 (8.1)] .

The following serious adverse reactions are discussed in greater detail in another section of the label:

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo.

The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis.

Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include:

     Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)

     General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%)

     Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)

     Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%)

     Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%)

     Psychiatric disorders: Insomnia (9%)

     Nervous system disorders: Dizziness (7%), paresthesia (5%)

     Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

     Vascular disorders: Hypertension (4%)

     Renal and urinary disorders: Renal failure (3%)

     Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%)

     Musculoskeletal and connective tissue disorders: Jaw pain (3%)

     Hematologic disorders: Hemorrhage (3%)

Key treatment-emergent laboratory abnormalities are presented in Table 3.

The data described below reflect exposure to AFINITOR (n=28) in an open-label, single-arm trial for the treatment of patients with SEGA. The reliability of the frequency of adverse reactions and laboratory abnormalities reported in this trial is limited because of the small number of patients. The median age of patients was 11 years (range 3-34), 86% were Caucasian, and 61% were male. In total, 17 of the 28 patients were exposed to AFINITOR for ≥ 21 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, upper respiratory tract infection, sinusitis, otitis media, and pyrexia. The grade 3 adverse reactions were convulsion, infections (single cases of sinusitis, pneumonia, tooth infection, and bronchitis viral), and single cases of stomatitis, aspiration, cyclic neutropenia, sleep apnea syndrome, vomiting, dizziness, white blood cell count decreased, and neutrophil count decreased. A grade 4 convulsion was also reported. 

Table 4 summarizes the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10%. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Other notable adverse reactions occurring with an incidence of < 10% include:

     Gastrointestinal disorders: Gastritis (7%)

     Skin and subcutaneous tissue disorders: Pityriasis rosea (4%)

     Investigations: Chest x-ray abnormal (4%)

     General disorders and administration site conditions: Fatigue (7%), edema peripheral (4%)

     Respiratory, thoracic and mediastinal disorders: Pharyngeal inflammation (7%)

     Nervous system disorders: Somnolence (7%)

     Psychiatric disorders: Anxiety (7%)

     Renal and urinary disorders: Proteinuria (7%)

     Eye disorders: Ocular hyperemia (4%)

     Vascular disorders: Hypertension (4%)

Key Laboratory Abnormalities

Single cases of grade 3 elevated aspartate transaminase (AST) concentrations and low absolute neutrophil count (ANC) were reported. No grade 4 laboratory abnormalities were noted. Laboratory abnormalities observed in > 1 patient (and listed in decreasing order of frequency) included elevations in AST concentrations (89%), total cholesterol (68%), alanine transaminase (ALT) (46%), triglycerides (43%) (hypertriglyceridemia reported as adverse reaction in 11% of patients, blood triglycerides increased reported as adverse reaction in 7% of patients), glucose (25%), and creatinine (11%), and reductions in white blood cell counts (54%) (reported as adverse reaction in 11% of patients), hemoglobin (39%), glucose (32%), and platelet counts (21%). Most of these laboratory abnormalities were mild (grade 1).

Two cases of neutrophil count decreased and blood immunoglobulin G decreased were reported as adverse reactions.

Information from further clinical trials

In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcomes.