Everolimus Tablets Instructions

Approval Date: 01/22/2013
Revision Date: 04/15/2013 02/13/2014 08/11/2014
February 13, 2015 June 23, 2015 November 13, 2015
         November 29, 2016 February 24, 2017 May 23, 2017
May 26, 2017 June 27, 2017 September 12, 2017
 Instructions for Everolimus tablets
Please read the instructions carefully and use under the guidance of a physician
Drug name]
Generic name: everolimus tablets
Trade name: Fenitrol®, Afinitor®
English Name: Everolimus Tablets
Hanyu Pinyin：Yiweimosi Pian
 Ingredients】The main ingredient of this product is everolimus.
Chemical name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19, 30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxo-4-aza-tricyclo[30.3.1.04,9]-trihexadeca-16,24,26,28-tetraene-2,3,10,14,20-pentylone
Chemical structure formula.
Molecular formula: C53H83NO14
Molecular weight: 958.2
 Properties
This product is a white or slightly yellow tablet.
【Indications】.
Everolimus is indicated for the treatment of patients with
Adult patients with advanced renal cell carcinoma who have failed prior treatment with sunitinib or sorafenib.
Adult patients with unresectable, locally advanced or metastatic, well-differentiated (moderately differentiated or highly differentiated) progressive pancreatic neuroendocrine tumors.
Adult patients with unresectable, locally advanced or metastatic, well-differentiated, progressive non-functional neuroendocrine tumors (NETs) of gastrointestinal or pulmonary origin.
Adult and pediatric patients with tubulointerstitial subventricular giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TSC) who require therapeutic intervention but are not amenable to surgical resection. The effectiveness of this product is demonstrated primarily by sustainable objective remission (i.e., reduction in SEGA tumor volume). Whether patients with tuberous sclerosis-associated subventricular giant cell astrocytoma will achieve disease-related symptom improvement and prolonged overall survival has not been demonstrated.
For the treatment of adult patients with tuberous sclerosis-associated renal vascular smooth muscle lipoma (TSC-AML) who do not require immediate surgical treatment.
 【Specifications】.
(1) 2.5mg; (2) 5mg; (3) 10mg
 Dosage]
This product should be used under the supervision of a physician experienced in the treatment of tumors or tuberous sclerosis.
Advanced renal cell carcinoma, advanced neuroendocrine tumor and renal vascular smooth muscle lipoma associated with tuberous sclerosis
Recommended Dose
The recommended dose of this product is 10 mg once daily.
This product is administered orally once daily, at the same time of day, with or without food (see [Pharmacokinetics]).
The tablets should be delivered whole with a glass of water and should not be chewed or crushed. For patients who are unable to swallow the tablet, place the tablet in a glass of water (approximately 30 ml) before administration and stir gently until completely dissolved (approximately 7 minutes) and take immediately. Wash the glass of water with the same volume of water and take the entire wash solution to ensure that the full dose has been taken.
Treatment should be continued as long as clinical benefit exists or until intolerable toxic reactions occur.
Dose adjustment
Management of Adverse Reactions
Management of serious and/or intolerable adverse reactions may require temporary reduction of the administered dose and/or interruption of treatment with this product. If a dose reduction is required, the recommended dose is approximately half the previously administered dose (see [Precautions]). If the dose is reduced below the lowest available tablet size, consideration should be given to every other day dosing.
Table 1 summarizes the recommendations for dose reduction, interruption, or discontinuation of therapy in the event of an adverse reaction in patients treated with this product, along with recommendations for routine management. Management should be guided by the individual patient’s benefit/risk assessment and the clinical judgment of the treating physician.
Table 1: Recommendations for dose reduction, interruption, or discontinuation of therapy in the event of an adverse reaction in patients treated with this product
Adverse drug reaction severitya Dose adjustment of this productb and recommendations for management Non-infectious pneumonia Grade 1
Asymptomatic, only clinically or diagnostically observed findings; no treatment intervention required No dose adjustment required.
Perform appropriate monitoring. grade 2
Symptomatic, requiring pharmacologic intervention; instrumental ADLc limited Consider interruption of therapy, exclude infection and consider corticosteroid therapy until symptoms resolve to ≤ grade 1.
Restart treatment at a low dose.
Discontinue treatment if no recovery within 4 weeks. grade 3
Severe symptoms; self-care ADLc limited; requires oxygen interruption until symptoms resolve to ≤ grade 1. Rule out infection and consider corticosteroid therapy.
Consider restarting treatment at a low dose.
Consider discontinuing treatment if re-treatment is followed by grade 3 toxicity. grade 4
Development of life-threatening impaired respiratory function; require urgent intervention (e.g., tracheotomy or intubation) to discontinue treatment, rule out infection and consider corticosteroid therapy. Stomatitis grade 1
Asymptomatic or mildly symptomatic, no interventional therapy required no dose adjustment
Rinse mouth with alcohol-free water or saline (0.9%) several times a day. grade 2
Moderate pain; does not interfere with swallowing; requires temporary interruption of treatment with modified food until recovery to ≤ grade 1.
Restart treatment at the same dose.
If grade 2 stomatitis reappears, interrupt treatment until recovery to ≤ grade 1. Restart treatment at a lower dose.
Use topical analgesic oral therapy (e.g., benzocaine, aminobenzyl, bupivacaine hydrochloride, menthol, or phenol) in combination with topical corticosteroids (e.g., trenbolone oral patch) as appropriate. dGrade 3
Severe pain; swallowing impaired Temporary interruption of treatment until recovery to ≤ grade 1.
Restart treatment at a low dose.
Use topical analgesic oral therapy (e.g., benzocaine, aminobenzyl, bupivacaine hydrochloride, menthol, or phenol) in combination with topical corticosteroids (e.g., trenbolone oral patch), as appropriate. d4
Life-threatening consequences; requires urgent intervention to terminate treatment and use appropriate medical therapy Other non-hematologic toxicity (except metabolic events) Grade 1 No dose adjustment required if toxicity is tolerable. Use appropriate medical therapy and monitor. grade 2 No dose adjustment required if toxicity is tolerated. Treat with appropriate medical therapy and monitor.
If toxicity is intolerable, interrupt treatment until return to ≤ grade 1. Restart treatment at the same dose.
If a Grade 2 event occurs again, interrupt treatment until recovery to ≤ Grade 1. Restart treatment at a lower dose. level 3 Temporarily interrupt treatment until recovery to ≤ level 1. Apply appropriate medical therapy and monitor.
Consider restarting treatment at a low dose. Consider discontinuing treatment if a Grade 3 event occurs again. Grade 4 discontinue treatment with appropriate medical therapy. Metabolic events (e.g., hyperglycemia, dyslipidemia) Grade 1 No dose adjustment required. Use appropriate medical therapy and monitor. level 2 No dose adjustment required. Use appropriate medical therapy and monitor. level 3 Temporary interruption of therapy.
Restart treatment at a low dose.
Level 4 discontinue treatment with appropriate medical therapy and monitor. level 4 discontinue treatment with appropriate medical therapy. level 4 discontinue treatment with appropriate medical therapy. level 4 discontinue treatment with appropriate medical therapy. Thrombocytopenia (decreased platelet count) Grade 1 (<LLNe – 75,000/mm3; <LLNe – 75.0 x 109/L) No dose adjustment required. Grade 2
(<75,000 – 50,000/mm3; <75.0 – 50.0 x 109/L) Temporarily interrupt dosing until remission to ≤ Grade 1.
Restart therapy at the same dose. grade 3
(<50,000 – 25,000/mm3; <50.0 – 25.0 x 109/L) or
Grade 4
(<25,000/mm3; <25.0 x 109/L) Temporarily interrupt dosing until remission to ≤ Grade 1.
Restart therapy at a low dose. Neutropenia (decreased neutrophil count) Grade 1
(<LLNe – 1,500/mm3; <LLNe – 1.5 x 109/L) or
Grade 2
(<1,500 – 1,000/mm3; <1.5 – 1.0 x 109/L) No dose adjustment required. grade 3
(<1,000 – 500/mm3; <1.0 – 0.5 x 109/L) Temporarily interrupt dosing until remission to ≤ grade 2.
Restart therapy at the same dose. grade 4
(<500/ mm3; <0.5 x 109/L) Temporarily discontinue dosing until remission to ≤ Grade 2.
Restart therapy at a lower dose. Febrile neutropenia grade 3
ANCf <1,000/mm3 , single measurement of temperature >38.3ºC (101ºF) or prolonged temperature ≥38ºC (100.4ºF) for more than 1 hour Temporarily interrupt dosing until remission to ≤Grade 2.
Restart treatment at a low dose. level 4
Life-threatening consequences; requires urgent intervention to terminate treatment.a Severity grading: Grade 1 = mild symptoms; Grade 2 = moderate symptoms; Grade 3 = severe symptoms; Grade 4 = life-threatening symptoms.
Grading is based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.03
b If a downward dose adjustment is required, the recommended dose is approximately 50% of the previously administered dose.
c Activities of Daily Living (ADL).
d Avoid products containing hydrogen peroxide, iodine, and thyme derivatives in the management of stomatitis, as these ingredients may worsen mouth ulcers.
e Lower limit of normal range (LLN).
f Absolute neutrophil count (ANC).
 
 Impaired renal function
No clinical studies of this product have been conducted in patients with reduced renal function. Impaired renal function is not expected to affect drug exposure, and everolimus dose adjustment is not recommended in patients with impaired renal function (see [Pharmacokinetics]).
Impaired Hepatic Function
Impaired hepatic function increases everolimus exposure (see [Precautions]). Dosing adjustments should be made as follows.
Mild hepatic impairment (Child-Pugh Class A): the recommended dose is 7.5 mg/day; if not well tolerated, the dose may be reduced to 5 mg/day.
Moderate hepatic impairment (Child-Pugh Class B): the recommended dose is 5mg/day; if not well tolerated, the dose may be reduced to 2.5mg/day.
Severe hepatic impairment (Child-Pugh Class C): 2.5 mg/day once if the expected benefit is higher than the risk, but this dose should not be exceeded.
The dose should be adjusted if the patient’s hepatic function (Child-Pugh classification) status changes during treatment.
CYP3A4 and/or P-glycoprotein (PgP) inhibitors
Avoid CYP3A4 potent inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) (see [PRECAUTIONS] and [DRUG INTERACTIONS]).
Caution should be exercised when combining with intermediate-acting inhibitors of CYP3A4 and/or PgP (e.g., amiprenavir, furosemivir, aripitant, erythromycin, fluconazole, verapamil, diltiazem, cyclosporine). If patients require a combination of intermediate-acting CYP3A4 and/or PgP inhibitors, the dose of this product may be reduced to 2.5 mg/day. It is expected that the reduced dose of this product will allow the area under the drug-time curve (AUC) to be adjusted to within the AUC range when no inhibitor is used. An increase in dose from 2.5 mg to 5 mg may be considered based on patient tolerability. if a mid-acting inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the dose is increased. If the intermediate-acting inhibitor is discontinued, the dose of this product should be restored to the dose level prior to the use of the intermediate-acting CYP3A4 and/or PgP inhibitor.
Grapefruit, grapefruit juice and other foods known to inhibit cytochrome P450 and PgP activity should be avoided during treatment.
CYP3A4 potent inducers
Avoid the combination of potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, and phenobarbital). If patients require a combination of potent CYP3A4 inducers, consideration should be given to increasing this product in 5 mg dose increments from 10 mg once daily to 20 mg once daily. Based on pharmacokinetic data, it is expected that the incremental dose of this product will allow the AUC to be adjusted to the range of the AUC without the inducer. However, there are no clinical data on dose adjustment in patients on a potent CYP3A4 inducer. If a potent inducer is discontinued, the dose of this product should be returned to the dose prior to the administration of the potent CYP3A4 inducer (see [Precautions] and [Drug Interactions]).
St. John’s Wort (Goldenseal) may unintentionally reduce everolimus exposure and should be avoided.
Subventricular giant cell astrocytoma associated with tuberous sclerosis
Recommended Dose
The recommended starting dose is 4.5 mg/m2 once daily. It should be administered under the supervision of a specialist experienced in the treatment of tuberous sclerosis and its associated subventricular giant cell astrocytoma.
The dose is individualized by body surface area (BSA, m2), which is calculated using the Dubois formula, where weight (W) is in kilograms (kg) and height (H) is in centimeters (cm).
BSA = (W0.425 × H0.725) × 0.007184
The recommended starting dose is 2.5 mg/m2 once daily for patients with severe hepatic impairment (Child-Pugh Class C) or who require concomitant use of an intermediate-acting CYP3A4 and/or PgP inhibitor (see [Dosage and Administration] “Dose Adjustment”). For patients requiring concomitant use of a potent CPY3A4 inducer, the recommended starting dose is 9 mg/m2 once daily (see [Dosage] “Dose Adjustment”). Please round the calculated dose to the nearest specification for this product.
Therapeutic drug monitoring should be used to guide subsequent dosing (see [Dosage] “Therapeutic Drug Monitoring”). Dose adjustments may be made at 2-week intervals as necessary to achieve trough concentrations of 5-15 ng/ml (see [Dosage and Administration] “Dose Adjustment” and “Therapeutic Drug Monitoring”).
Continue treatment until disease progression or intolerable toxicity occurs. The optimal duration of treatment is not known.
For optimal clinical efficacy, individualized doses are adjusted in increments of 1 to 4 mg to achieve target trough concentrations. Efficacy, safety, combination of drugs and prevailing trough concentrations should be taken into account when planning dose adjustments. Individualized dose adjustments can be based on a simple ratio calculation of
New everolimus dose = current dose × (target concentration/current concentration)
For example, the patient’s current BSA-based dose is 4 mg and the steady-state concentration is 4 ng/mL. To achieve a target concentration of 5 ng/mL above the Cmin limit, e.g., 8 ng/mL, the new everolimus dose can be adjusted to 8 mg (an increase of 4 mg over the current daily dose). This should be followed by an assessment of trough concentrations 1 to 2 weeks after this dose adjustment.
Therapeutic drug monitoring
Routine monitoring of whole blood trough concentrations of everolimus should be performed in all patients. If possible, the same analytical methods and laboratories should be used for therapeutic drug monitoring during treatment.
Valley concentrations should be assessed after initiation of therapy, or after a dose change, after initiation or adjustment of concomitant administration of CYP3A4 and/or PgP inducers or inhibitors, or approximately 1 to 2 weeks after changes in liver function. After reaching a stable dose, trough concentrations should be monitored every 3 to 6 months during treatment for patients with altered body surface area and every 6 to 12 months for patients with stable body surface area.
Adjust the dose to achieve a trough concentration of 5~15ng/ml.
If the trough concentration is less than 5ng/ml, increase the daily dose by a margin of 2.5mg.
If the trough concentration is greater than 15ng/ml, reduce the daily dose by 2.5mg.
If a patient receiving the lowest available specification dose requires a downward dose adjustment, the dose should be administered every other day.
Dose Adjustment
Management of Adverse Reactions
If serious and/or intolerable adverse reactions occur, dose reduction and/or suspension of this product is required (see [Precautions]). Reduce the dose of this product by approximately 50%. If a downward dose adjustment is required for patients receiving the lowest available size dose, administer every other day (see Table 1).
Impaired Renal Function
No clinical studies of this product have been conducted in patients with reduced renal function. Impaired renal function is not expected to affect drug exposure, and everolimus dose adjustment is not recommended in patients with impaired renal function (see [Pharmacokinetics]).
Hepatic Impairment
For patients with subventricular giant cell astrocytoma with severe hepatic impairment (Child-Pugh class C), the starting dose of everolimus should be reduced by approximately 50% (see Dosage and Administration, Recommended Dosage). For patients with mild (Child-Pugh Grade A) or moderate (Child-Pugh Grade B) hepatic impairment in subventricular giant cell astrocytoma, the recommended starting dose may not need to be adjusted, but subsequent dosing should be based on therapeutic drug monitoring.
Everolimus trough concentrations should be assessed after treatment initiation, after a dose change, or approximately 2 weeks after a change in hepatic function (see [Dosage] “Recommended Dose” and “Therapeutic Drug Monitoring”).
CYP3A4 and/or P-glycoprotein (PgP) inhibitors
Concomitant use of potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) should be avoided in patients using this product (see [Precautions] “Drug Interactions” and [Drug Interactions] “Drugs that can increase everolimus blood levels”).
For patients requiring intermediate-acting CYP3A4 and/or PgP inhibitors (e.g., amiprenavir, furosemivir, aripitant, erythromycin, fluconazole, verapamil, diltiazem, cyclosporine).
Reduce the dose of this product by approximately 50%. If a downward dose adjustment is required for patients receiving the lowest available size dose, the dose should be administered every other day (see [DOSAGE AND ADMINISTRATION] “Recommended Dosage”).
Everolimus trough concentrations should be evaluated approximately 1-2 weeks after the dose reduction (see Dosage and Administration, Recommended Dosage and Therapeutic Drug Monitoring).
After 2-3 days of discontinuation of the intermediate-acting inhibitor, the dose should be returned to the dose level prior to initiation of the intermediate-acting CYP3A4 and/or PgP inhibitor, and everolimus trough concentrations should be assessed again in approximately 2 weeks (see [Dosage and Administration] “Recommended Dosage” and “Therapeutic Drug Monitoring”).
Avoid foods or nutritional supplements known to inhibit cytochrome P450 and PgP activity (e.g., grapefruit, grapefruit juice). potent inducers of CYP3A4
Avoid concomitant use of potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available (see [Precautions] “Drug Interactions” and [Drug Interactions] “Drugs that can reduce everolimus blood levels”). For patients requiring a potent CYP3A4 inducer.
Patients with SEGA on concomitant strong CYP3A4 inducers (e.g., the enzyme-inducing antiepileptic drugs carbamazepine, phenobarbital, and phenytoin) may require an increase in the dose of this product at initiation of therapy to achieve trough concentrations of 5 to 15 ng/mL. double the daily dose of this product and assess tolerability. Evaluate everolimus trough concentrations approximately 2 weeks after dose doubling. Further adjust the dose in increments of 1 to 4 mg as necessary to maintain trough concentrations.
For patients with SEGA or epilepsy who are not receiving a strong induction agent at the time of initiation of everolimus therapy, the addition of a strong induction agent may require an increase in the dose of this product. Doubling the daily dose of this product and assessing tolerability. Evaluate everolimus trough concentrations approximately 2 weeks after dose doubling. Adjust the dose further by increases of 1 to 4 mg as necessary to maintain trough concentrations.
Concomitant addition of another potent CYP3A4 inducer may not require additional dose adjustment. Evaluate everolimus trough concentrations approximately 2 weeks after initiation of additional inducers. Adjust the dose further by increments of 1 to 4 mg as necessary to maintain trough concentrations.
If one of the multiple potent CYP3A4 inducers is discontinued, no additional dose adjustment may be required, but everolimus trough concentrations should be assessed approximately 2 weeks after discontinuation of this inducer. If all strong inducers are discontinued, a minimum elution period of 3 to 5 days should be considered before the dose of this product is returned to the dose prior to initiation of the strong CYP3A4 inducer (which is a reasonable time to remove significant enzyme induction) and everolimus trough concentrations should be evaluated approximately 2 weeks later (see [Dosage] “Therapeutic Drug Monitoring”, [Precautions] “Drug Interactions” and [Drug Interactions ]).
Avoid foods or nutritional supplements known to induce cytochrome P450 activity (e.g., St. John’s wort [Hypericum]).
Missed Doses
Missed doses may be made up for up to 6 hours after the normal time of administration of this product. After 6 hours, the dose should be skipped and the product should be taken at the normal time the following day. Do not double the dose to make up for the missed dose.
 
 [Adverse Reactions].
Oncology – Summary of Safety Characteristics
Adverse drug reaction (ADR, i.e., suspected by the investigator to be treatment-related) information is based on combined safety data from patients (N=2672) treated with this product in randomized, double-blind, placebo- or active drug-controlled, phase III and phase II clinical studies related to approved oncology indications.
Of the combined safety data, the most common adverse drug reactions (incidence ≥1/10 and where the investigator suspected that the event was related to study treatment) were (in descending order): stomatitis, rash, fatigue, diarrhea, infection, nausea, decreased appetite, anemia, taste disturbance, non-infectious pneumonia, peripheral edema, hyperglycemia, weakness, pruritus, weight loss, high cholesterol, epistaxis, cough, and headache .
The most common grade 3-4 adverse drug reactions (incidence ≥1/100 and <1/10 and investigator suspected event related to study treatment) were stomatitis, anemia, hyperglycemia, fatigue, infection, noninfectious pneumonia, diarrhea, weakness, thrombocytopenia, neutropenia, dyspnea, lymphopenia, proteinuria, hemorrhage, hypophosphatemia, rash, hypertension, glutathione aminotransferase (AST) elevation, glutamic aminotransferase (ALT) elevation, infectious pneumonia, and diabetes mellitus.
Summary of the list of adverse drug reactions that occurred in oncology clinical trials
Table 2 presents the frequency classification of adverse drug reactions derived from the safety analysis of the combined data.
Adverse drug reactions are listed by MedDRA system organ classification. Within each system organ classification, the adverse drug reactions are listed in descending order of frequency of occurrence. Within each frequency group, the adverse drug reactions were then listed in descending order of frequency of occurrence. In addition, the corresponding frequency classification for each adverse reaction was as follows (CIOMS III): very common (≥1/10); common (≥1/100 and <1/10); occasional (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000 ).
Table 2: Adverse drug reactions in oncology trials
Infections and infections very common infectionsa Blood and lymphatic disorders very common anemia common thrombocytopenia, neutropenia, leukopenia, lymphocytopenia occasional
Rare whole blood cytopenia
Pure red blood cell aplastic anemia Immune system disorders occasional allergies Metabolic and nutritional disorders very common decreased appetite, hyperglycemia, hypercholesterolemia common hypertriglyceridemia, hypophosphatemia, diabetes mellitus, hyperlipidemia, hypokalemia, dehydration Psychiatric disorders common insomnia Neurological disorders very common taste disorders, headaches occasional loss of taste Cardiac disorders occasional congestive heart failure Vascular disorders common bleedingb Hypertension occasional deep vein thrombosis respiratory, thoracic and mediastinal disorders very common
Non-infectious pneumonia commonc, epistaxis, cough
Respiratory distress occasionally
Rare hemoptysis, pulmonary embolism
Acute respiratory distress syndrome gastrointestinal disorders very common stomatitisd, diarrhea, nausea common vomiting, dry mouth, abdominal pain, mouth pain, dyspepsia, dysphagia skin and subcutaneous tissue disorders very common rash, pruritus common
Rare dry skin, nail disorders, acne, erythema, hand-foot syndromee
angioedema musculoskeletal and connective tissue disorders common arthralgia renal and urinary disorders common proteinuria, renal failure occasional increased daytime urination, acute renal failure genital and breast disorders common
Occasional irregular menstruationf
Amenorrhea f Systemic disease and site of administration abnormalities very common fatigue, weakness, peripheral edema common fever, mucosal inflammation occasional non-cardiogenic chest pain, impaired wound healing examination abnormalities very common weight loss common elevated glutamate transaminase, elevated glutamic transaminase, elevated creatinine a Includes all reactions in the systemic organ classification “Infection and Infection”, including: common: infectious pneumonia, urinary tract infection; not Common: bronchitis, herpes zoster, sepsis, abscesses, and independent cases of opportunistic infections (e.g., Aspergillosis, Candida infection, and hepatitis B); rare: viral myocarditis.
bIncludes different bleeding events at different sites, not listed individually.
cIncludes common: noninfectious pneumonia, interstitial lung disease, and pulmonary infiltrates; rare: alveolitis, alveolar hemorrhage, and pulmonary toxicity.
dIncludes very common: stomatitis; common: stomatitis with mouth sores, mouth and tongue ulcers; uncommon: tongue inflammation, tongue pain.
e reported as palmoplantar erythema sensory abnormalities syndrome.
f
Frequency of occurrence is based on the number of women aged 10 to 55 years in the combined safety data. Clinically significant laboratory abnormalities
The following were newly occurring or exacerbated clinically significant laboratory abnormalities with an incidence of ≥1/10 (very common, in descending order of frequency) in the safety-combined database of the double-blind, phase III trial.
Hematology: hemoglobin reduction, lymphopenia, leukopenia, decreased platelet count, and neutropenia (or collectively, allohemocytopenia)
Clinical biochemistry: elevated fasting glucose, elevated cholesterol, elevated triglycerides, elevated AST, decreased blood phosphorus, elevated ALT, elevated creatinine, decreased blood potassium and decreased albumin.
Most abnormalities observed (≥1/100) are mild (grade 1) or moderate (grade 2). grade 3 or 4 hematologic and biochemical abnormalities include
Hematology: lymphocytopenia, hemoglobin reduction (very common); neutropenia, thrombocytopenia, leukopenia (all common).
Clinical biochemistry: elevated blood glucose (fasting) (very common); decreased blood phosphorus, decreased blood potassium, elevated AST, elevated ALT, elevated creatinine, elevated total cholesterol, elevated triglycerides, and decreased albumin (all common).
There is a lack of safety data for Chinese patients with pancreatic neuroendocrine tumors treated with this product.
TSC-Safety Profile Summary
Adverse drug reaction (ADR) information is based on combined data from three randomized, double-blind, placebo-controlled, phase III studies (including blinded treatment period and open treatment period) and one non-randomized, open, single-arm, phase II study in patients with TSC treated with this product (N= 612, including 409 patients under 18 years of age), as shown in Table 3.
Table 3: Combined safety data from the TSC study of this product
Study name CRAD001C2485aEXIST-1 (M2301)EXIST-2 (M2302)EXIST-3 (M2304)Indication TSC-SEGATSC-SEGATSC-Renal vascular smooth muscle lipoma TSC-EpilepsyTotal number of patients receiving everolimus28111112b361cMedian duration of exposure ( months) (range) 67.8 (4.7 to 83.2) 47.1 (1.9 to 58.3) 46.9 (0.5 to 63.9) 20.8 (0.5 to 37.9) cExposure (patient-years) 146391391603a Open, single-arm trial with no reference or control group.
bTotal number of patients receiving everolimus during the double-blind and open extension periods, including patients who switched from the placebo arm to everolimus treatment.
cTotal number of patients receiving everolimus in the core and extension phases, including patients who switched from the placebo arm to the everolimus treatment arm. In the combined safety database, the most common adverse drug reactions (incidence ≥1/10) were (in descending order) stomatitis, nasopharyngitis, fever, diarrhea, upper respiratory tract infection, vomiting, cough, headache, rash, amenorrhea, acne, irregular menstruation, infectious pneumonia, sinusitis, urinary tract infection, pharyngitis, decreased appetite, fatigue, and hypercholesterolemia.
The most common grade 3-4 adverse drug reactions (incidence ≥1/100 and <1/10) were infectious pneumonia, stomatitis, amenorrhea, neutropenia, fever, irregular menstruation, cellulitis, and hypophosphatemia.
Summary of the list of adverse drug reactions that occurred in the TSC clinical trials
Table 4 presents the incidence of adverse drug reactions based on combined data from the everolimus TSC studies (including double-blind and open studies and extension studies), covering a median exposure duration of 27.4 months (approximately 47 months in the TSC with SEGA and TSC with renal vascular smooth muscle lipoma studies and approximately 21 months in the TSC with epilepsy study). Adverse drug reactions are listed by MedDRA system organ classification. The corresponding frequency classification for each adverse reaction was as follows: very common (≥1/10); common (≥1/100 and <1/10); occasional (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000); unknown (based on available data could not be estimated). In each frequency grouping, adverse drug reactions were ranked in descending order of frequency of occurrence.
Table 4: Adverse drug reactions in TSC clinical trials
Infections and infections very common nasopharyngitis, upper respiratory tract infections, infectious pneumonia, sinusitis, urinary tract infections, pharyngitis common otitis media, cellulitis, streptococcal pharyngitis, viral gastroenteritis, gingivitis occasional herpes zoster, sepsis, viral bronchitis blood and lymphatic system disorders common anemia, neutropenia, leukopenia, thrombocytopenia, lymphopenia immune system disorders Common allergic metabolic and nutritional disorders very common decreased appetite, hypercholesterolemia common hypertriglyceridemia, hyperlipidemia, hypophosphatemia, hypophosphatemia
hyperglycemia psychiatric disorders common insomnia, aggressive behavior, irritability neurological disorders very common headache occasional taste disorders vascular disorders common hypertension, lymphedema respiratory, thoracic, and mediastinal disorders very common cough common epistaxis, noninfectious pneumonia gastrointestinal disorders very common stomatitisa, diarrhea, vomiting common constipation, nausea, abdominal pain, bloating, sore mouth, gastritis skin and subcutaneous tissue disorders very common
Common
Occasional rashb, acne
Dry skin, acneiform dermatitis
Angioedema renal and urinary disorders common proteinuria genital and breast disorders very common
Common amenorrheac, irregular menstruationc
Excessive menstruation, ovarian cysts, vaginal bleeding occasional delayed menstruationc Systemic disease and site of administration abnormalities very common Fever, fatigue examination abnormalities common Elevated blood lactate dehydrogenase, elevated blood luteinizing hormone occasional elevated blood follicle stimulating hormone a including very common: stomatitis, mouth ulcers, aphthous ulcers; common: tongue ulcers, lip ulcers,; occasional: sore gums, tongue inflammation
b Includes very common: rash; common: erythematous rash; occasionally: generalized rash, erythema, maculopapular rash, maculopapular rash.
c
Frequency based on the number of women aged 10 to 55 years during treatment in the combined safety data. Clinically Significant Laboratory Abnormalities
The following new or worsening, clinically significant laboratory abnormalities occurred at a rate of ≥1/10 in the safety combined database of the TSC trial (very common, in descending order of frequency)
Hematology: prolonged partial thromboplastin time, neutropenia, decreased hemoglobin, decreased leukocytes, decreased platelet count, and decreased lymphocytes.
Clinical biochemistry: elevated cholesterol, elevated triglycerides, elevated AST, elevated ALT, decreased phosphorus, elevated alkaline phosphatase and elevated fasting glucose.
Most laboratory abnormalities are mild (grade 1) or moderate (grade 2). grade 3-4 hematologic and biochemical abnormalities include
Hematology: neutropenia, prolonged partial thromboplastin time, decreased hemoglobin (all common), decreased lymphocytes, decreased platelet count, and decreased white blood cells (occasional).
Clinical biochemistry: decreased blood phosphorus, elevated triglycerides, elevated alkaline phosphatase, elevated AST, elevated ALT (all common), elevated cholesterol, and elevated fasting glucose (all occasional).
Safety data are lacking for patients with subventricular giant cell astrocytoma and renal vascular smooth muscle lipoma associated with tuberous sclerosis in China treated with this product.
Description of Selected Adverse Reactions
Serious cases of hepatitis B virus reactivation caused by everolimus have been identified in clinical trials and post-marketing spontaneous reports, including cases of death. Infection reactivation is an expected event during immunosuppression (see [Precautions]).
Everolimus has been found to cause acute renal failure (including cases with fatal outcome) and proteinuria in clinical trials and post-marketing spontaneous reports. Monitoring of renal function is recommended (see [Precautions]).
Everolimus has been found to cause amenorrhea (including secondary amenorrhea) in clinical trials and post-marketing spontaneous reports.
Pneumocystis jirovecii pneumonia has been reported in clinical trials and post-marketing spontaneous reports during everolimus treatment, with some cases having a fatal outcome (see [Precautions]).
Angioedema has been reported in clinical trials and post-marketing spontaneous reports in patients with or without concomitant ACE inhibitors (see [Precautions]).
In a post-marketing, single-arm study (N=92) in hormone receptor-positive, HER 2-negative women with advanced postmenopausal breast cancer, topical dexamethasone 0.5 mg/5 mL, alcohol-free oral solution (gargle with 10 mL for 2 minutes, followed by spitting, repeated daily 4 times a day for 8 weeks) as a mouthwash reduced the incidence and severity of stomatitis. The incidence of grade ≥2 stomatitis at 8 weeks (n=2/85 evaluable patients) was lower than historical data reported in another phase 3 study (BOLERO-2) conducted in this patient population (n=132/482). 18.8% (n=16/85) of grade 1 stomatitis was reported and no grade 3 or 4 stomatitis was reported. ), and no grade 3 or 4 stomatitis was reported. The overall safety profile of the study was consistent with established data on the use of everolimus for oncology and TSC indications, except that the incidence of oral candidiasis was higher in this study (2.2%, n=2/92) than in the BOLERO-2 data (0.2%, n=1/482).
 Special Populations
Pediatric patients (under 18 years of age)
Everolimus is recommended for pediatric patients with TSC-related SEGA who do not require immediate surgery. The safety and efficacy of everolimus in pediatric cancer patients has not been established.
The following two clinical trials demonstrated the safety of this product for use in pediatric patients with TSC-related SEGA.
The overall type, frequency and severity of adverse drug reactions were similar in all age groups, with the exception of infections, which were more frequent and severe in patients younger than 6 years of age. grade 3 or 4 infections occurred in a total of 46 of 137 patients (34%) younger than 6 years of age, compared to 49/272 (18%) in patients younger than 6 to 18 years of age and 49/272 (18%) in patients 18 years of age and older was 24/203 (12%). Two cases of death due to infection were reported in 409 patients under 18 years of age treated with everolimus.
The results of the clinical trials did not show an effect of everolimus on growth and pubertal development.
A trend toward lower dose-normalized (by mg/m2) Cmin was observed in younger patients with TSC-related SEGA. Median Cmin normalized by mg/m2 was lower in the younger patient group, indicating that everolimus clearance (normalized by body surface area) was higher in younger patients.
Older patients (≥65 years)
In the combined oncology safety database, 37% of patients treated with everolimus were ≥65 years of age.
The proportion of oncology patients who experienced an adverse drug reaction leading to discontinuation of treatment with this product was higher in the ≥65-year-old patient group (20% vs. 13%). The most common adverse drug reactions (≥1/100) leading to discontinuation of treatment were non-infectious pneumonia (including interstitial lung disease), stomatitis, fatigue, and dyspnea.
 Contraindications
Contraindicated in patients with hypersensitivity to the active ingredient, other rapamycin derivatives, or any of the excipients in this product. Manifestations of hypersensitivity reactions that have been observed in patients using everolimus and other rapamycin derivatives include, but are not limited to: hypersensitivity, dyspnea, flushing, chest pain, or angioedema (e.g., airway or tongue swelling with or without respiratory insufficiency).
[Caution].
Non-infectious pneumonia
Non-infectious pneumonia is a class effect of rapamycin derivatives (including this product). In clinical trials, non-infectious pneumonia was reported in 19% of patients treated with this product. The incidence of non-infectious pneumonia on Common Criteria for Drug Toxic Reactions (CTC) grade 3 and 4 was 4.0% and 0.2%, respectively (see [Adverse Reactions]). A single case of death has been observed.
The diagnosis of noninfectious pneumonia should be considered in patients with nonspecific respiratory signs and symptoms (e.g., hypoxia, pleural effusion, cough, or dyspnea) and appropriate tests to exclude infection, neoplasia, and other causes. Patients are advised to promptly report any new or worsening respiratory symptoms. In the differential diagnosis of noninfectious pneumonia, opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) should be excluded.
When radiographic changes suggest non-infectious pneumonia but the patient has minimal (or no) symptoms, treatment with this product may be continued without dose adjustment. Imaging appears to overestimate the incidence of clinical pneumonia.
In case of moderate symptoms, consider interrupting therapy until symptoms improve. Corticosteroids may be considered. Treatment may be restarted at approximately half the dose previously used (see [DOSAGE]).
For grade 4 non-infectious pneumonia, discontinue treatment. Corticosteroids may be considered until clinical remission. For grade 3 noninfectious pneumonia, discontinue treatment until remission to ≤ grade 1. Depending on the clinical status of the individual patient, treatment may be restarted at approximately half the dose previously used (see [DOSAGE]). If a Grade 3 event occurs again, discontinuation of therapy should be considered.
Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) may be considered for patients requiring corticosteroids for the treatment of non-infectious pneumonia.
Pneumonia has been reported even at reduced doses.
Infection
Patients are susceptible to bacterial, fungal, viral, or protozoal infections, including those caused by opportunistic pathogens, because of the immunosuppressive nature of this product (see [ADVERSE REACTIONS]). Local and systemic infections (including pneumonia, mycobacterial infections), other bacterial infections and invasive fungal infections (such as Aspergillosis or candidiasis, or Pneumocystis jirovecii pneumonia), viral infections (including hepatitis B virus reactivation) have been reported in patients treated with this product. Rarely, they are severe (e.g., leading to sepsis [including septic shock], respiratory failure, or hepatic failure) and occasionally fatal in adults and pediatric patients (see [ADVERSE REACTIONS]).
Physicians and patients should be aware that treatment with this product increases the risk of infection. Pre-existing invasive fungal infections should be thoroughly treated before initiating treatment with this product. Be alert for signs and symptoms of infection while taking this product; if infection is diagnosed, promptly initiate appropriate therapy and consider discontinuing or stopping treatment with this product. If an invasive systemic fungal infection is diagnosed, discontinue treatment with this product immediately and administer appropriate antifungal therapy.
Cases of Pneumocystis jellies pneumonia have been reported in patients treated with everolimus, with some cases having a fatal outcome. Pneumocystis jellies pneumonia may be associated with concomitant use of corticosteroids or other immunosuppressive agents. If a patient requires concomitant use of corticosteroids or other immunosuppressive agents, prophylaxis for Pneumocystis jirovecii pneumonia should be considered.
Angioedema occurring during concomitant treatment with angiotensin-converting enzyme (ACE) inhibitors
Patients on concomitant angiotensin-converting enzyme inhibitors may be at increased risk of angioedema (e.g., airway or tongue swelling, with or without respiratory compromise).
Stomatitis
Stomatitis includes oral ulcers and oral mucositis. In clinical trials, the incidence ranged from approximately 44% to 86%. Grade 3 or 4 stomatitis was reported in 4% to 9% of patients (see [Adverse Reactions]). The majority of stomatitis occurred within the first 8 weeks of treatment. If stomatitis occurs, topical treatment is recommended, but mouthwashes containing alcohol, peroxide, iodine, or thyme can aggravate the condition and should be avoided (see [Dosage]). Antifungals should not be used unless a fungal infection is diagnosed (see [Drug Interactions]).
In a single-arm study including 92 postmenopausal breast cancer patients, a topical, alcohol-free corticosteroid oral solution was used as a mouthwash during the first 8 weeks of treatment with everolimus in combination with exemestane. A clinically meaningful decrease in the incidence and severity of stomatitis was observed in this study (see [Adverse Reactions]).
Renal Failure Events
Cases of renal failure (including acute renal failure), some of which can result in death, have been observed in patients treated with this product. Renal function should be monitored especially in patients with other risk factors that may further impair renal function (see “Laboratory Tests and Monitoring”).
Laboratory Tests and Monitoring
Renal Function
Increased blood creatinine and proteinuria have been reported in patients treated with this product (see [ADVERSE REACTIONS]). Monitoring of renal function, including blood urea nitrogen (BUN), urine protein, and creatinine, is recommended prior to initiation of treatment with this product and should be reviewed periodically.
Blood Glucose
Hyperglycemia has been reported in patients treated with this product (see [ADVERSE REACTIONS]). It is recommended that fasting blood glucose be checked before starting treatment with this product and periodically after treatment. More frequent checks are recommended if this product is used in combination with other drugs that may cause hyperglycemia. If possible, ideal blood glucose control should be obtained before the patient starts treatment with this product.
Blood lipids
Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in patients treated with this product. Blood cholesterol and triglycerides are recommended to be checked prior to initiation of this product and periodically thereafter, and management with appropriate medical therapy is recommended.
Hematological parameters
Decreases in hemoglobin, lymphocytes, neutrophils and platelets have been reported in patients treated with this product (see [Adverse Reactions]). It is recommended that a complete blood count be checked prior to initiating treatment with this product and that it be reviewed periodically.
Drug Interactions
Potent CYP3A4 inhibitors can significantly increase everolimus exposure and should be avoided in combination (see [Dosage] and [Drug Interactions]).
Dose reduction is recommended when combined with intermediate-acting CYP3A4 and/or PgP inhibitors (see [Dosage] and [Drug Interactions]).
When combined with potent CYP3A4 inducers, an increase in the dose of this product is recommended (see [Dosage] and [Drug Interactions]).
Hepatic Impairment
Everolimus exposure is increased in patients with impaired hepatic function (see [Pharmacokinetics]).
In patients with advanced renal cell carcinoma and advanced pancreatic neuroendocrine tumor with severe hepatic impairment (Child-Pugh class C) and renal vascular smooth muscle lipoma associated with tuberous sclerosis, the dose may be reduced if the expected 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 [Pharmacokinetics]).
For patients with subventricular giant cell astrocytoma with mild or moderate hepatic impairment, the dose of this product should be adjusted based on therapeutic drug monitoring. For patients with severe hepatic impairment of subventricular giant cell astrocytoma, the starting dose should be reduced by approximately 50% and subsequent dosing should be adjusted based on therapeutic drug monitoring (see [Dosage], “Therapeutic Drug Monitoring” and “Dose Adjustment”).
Vaccination
Avoid receiving live vaccines during treatment with this product and avoid close contact with persons who have received live vaccines. Examples of live vaccines: intranasal influenza, measles, mumps, rubella, oral poliomyelitis, BCG, yellow fever, varicella, and TY21a typhoid vaccine.
For pediatric patients with subventricular giant cell astrocytoma who do not require immediate treatment, the recommended sequence of live childhood vaccines should be completed according to the appropriate planned immunization guidelines prior to initiating treatment. A rapid vaccination protocol may be used when appropriate.
Embryo-fetal toxicity
See [Use in Pregnant and Lactating Women].
Affects wound healing
Affecting wound healing is a class effect of rapamycin derivatives including everolimus, which delays wound healing and increases the risk of wound-related complications such as wound dehiscence, wound infection, incisional hernia, lymphatic cysts, and hematomas. These wound-related complications may require surgical intervention. This product should be used with caution in the perioperative period.
For Pregnant and Lactating Women
Pregnancy
There is insufficient information on the use of this product for treatment in pregnant women. The potential risk to humans is not known. Animal studies have shown reproductive toxicity of everolimus, including embryotoxicity and fetal toxicity. This product should not be used in pregnant women unless the potential benefit of everolimus treatment outweighs the potential risk to the fetus.
Animal Data
Female rats receiving everolimus at doses of ≥0.1 mg/kg administered orally (AUC0-24h approximately 4% of patients receiving 10 mg/day) experienced an increased incidence of pre-labour loss. Everolimus can cross the placental barrier and be toxic to fetal litters. In rats, everolimus was found to cause embryo-fetal toxicity at systemic exposure levels below therapeutic levels, as evidenced by death and decreased fetal weight. At doses of 0.3 and 0.9 mg/kg, the incidence of skeletal variation and malformations (e.g., sternal splitting) was increased. In rabbits, embryotoxicity was evident, as evidenced by elevated late absorption at a dose of 0.8 mg/kg (9.6 mg/m2, which is equivalent to 1.6 times the patient’s dose of 10 mg/day or median dose based on body surface area) administered orally. In male rats, there is a lack of evidence of fetal adverse effects associated with everolimus treatment. (See [Pharmacology and Toxicology]).
Human data
There have been reports of everolimus use during pregnancy, partly due to exposure through the mother and partly through the father (i.e., pregnancy in the female spouse of a male patient treated with everolimus). No congenital anomalies have been reported. In some cases, pregnancies progressed well and healthy, normal infants were delivered.
Breastfeeding
It is not known whether everolimus is secreted into human milk. The use of everolimus during lactation has not been reported in humans. However, in animal studies, everolimus and its metabolites were found to be excreted into the milk of lactating rats at concentrations 3.5 times the maternal serum concentration.
Women taking everolimus should not breastfeed during treatment and for 2 weeks after the last dose.
Fertility
Contraception
Women of childbearing potential should be informed that animal studies have been conducted showing that everolimus is harmful to the fetus in the womb. Sexually active women of childbearing potential should use highly effective contraception (i.e., less than 1% annual failure rate when used correctly) during everolimus treatment and for 8 weeks after finishing treatment. Male patients who are using everolimus should not attempt to have children (see [Pharmacologic Toxicology]).
Fertility
Animal data
In animal reproduction studies, fertility was found to be unaffected in females. However, preimplantation loss of embryos was observed. In male rats, testicular morphology was affected at doses ≥0.5 mg/kg; sperm motility, sperm head count and plasma testosterone levels were decreased at doses of 5 mg/kg, all within the therapeutic exposure range (52 ng-hr/mL and 414 ng-hr/mL, respectively, compared to 560 ng-hr/mL in humans at 10 mg/day) , both resulting in decreased male fertility. There is evidence of reversibility. (See [Pharmacology and Toxicology]).
Human Data
Everolimus may have an effect on fertility in either women or men (see [Pharmacologic Toxicology]).
Irregular menstruation, secondary amenorrhea, and associated luteinizing hormone (LH)/follicle stimulating hormone (FSH) imbalance have been observed in female patients treated with everolimus. Increased blood FSH and LH levels, decreased blood testosterone levels and azoospermia have been observed in male patients treated with everolimus.
[Pediatric Dosage].
For advanced renal cell carcinoma and advanced neuroendocrine tumors, there are no data on the use of this product in children.
This product is recommended for pediatric patients ≥1 year of age with tuberous sclerosis-related subventricular giant cell astrocytoma who require therapeutic intervention but cannot be removed by radical surgery. Use under the supervision of an experienced specialist is required.
The efficacy of this product in the treatment of pediatric patients with subventricular giant cell astrocytoma associated with tuberous sclerosis has been demonstrated by the durable objective remission (as judged by reduction in subventricular giant cell astrocytoma tumor volume) observed in two clinical studies (see [Clinical Trials]). The ability of pediatric patients with subventricular giant cell astrocytoma to achieve improvement in disease-related symptoms and prolonged overall survival has not been demonstrated. The long-term effects of this product on growth and pubertal development are not known.
Study 1 was a randomized, double-blind, multicenter study conducted in pediatric and adult patients to compare this product (n=78) with placebo (n=39). The median age of the patients was 9.5 years (range 0.8 to 26 years). At 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 other adverse drug reactions were similar in all age groups except for a higher per capita incidence of the serious adverse event, infection, in the <3-year age group. In the <3-year-old age group, a total of 6 of 13 (46%) patients treated with this product experienced at least one serious adverse event due to infection compared with 2 of 7 (29%) placebo-treated patients. Discontinuation of treatment with this product due to infection was not seen in any age group (see [Adverse Reactions]). Subgroup analysis showed a reduction in the size of subventricular canalicular giant cell astrocytomas in all pediatric age subgroups treated with this product.
Study 2 was an open, single-arm, single-center study in patients ≥3 years of age (N=28); the median age of patients was 11 years (range 3 to 34 years). A total of 16 patients were 3 to <12 years of age, 6 patients were 12 to <18 years of age, and 6 patients were ≥18 years of age. The frequency of adverse reactions was essentially similar between age groups (see [Adverse Reactions]). Subgroup analysis showed a reduction in the volume of subventricular canalicular giant cell astrocytomas in all pediatric age subgroups treated with this product.
Clearance of everolimus, normalized for body surface area, was higher in pediatric patients with subventricular giant cell astrocytoma than in adult patients (see [Pharmacokinetics]). Both adult and pediatric patients with subventricular giant cell astrocytoma require the recommended starting dose followed by therapeutic drug monitoring to achieve and maintain a trough concentration of 5-15 ng/ml (see [Dosage], “Recommended Dosage” and “Therapeutic Drug Monitoring”).
Geriatric Use]
In two randomized studies (advanced renal cell carcinoma and advanced pancreatic neuroendocrine tumor), there was no overall difference in efficacy between elderly patients and relatively young patients. In the randomized study of advanced renal cell carcinoma, 41% of the patients treated with this product were ≥65 years old, of whom 7% were ≥75 years old. In the randomized study of advanced pancreatic neuroendocrine tumors, 30% of patients treated with this product were ≥65 years of age, of whom 7% were ≥75 years of age.
No differences in efficacy between older and relatively younger patients were seen in other clinical trials, but a higher sensitivity in some older individuals cannot be excluded (see [Pharmacokinetics]).
No dose adjustment is required in elderly patients, but close monitoring for adverse effects and appropriate dose adjustments are recommended (see [Pharmacokinetics]).
Drug Interactions]
Everolimus is a substrate of CYP3A4 and a substrate and intermediate inhibitor of the efflux pump PgP of many drugs. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.
Drugs that can elevate everolimus blood levels
CYP3A4 inhibitors and PgP inhibitors
In healthy subjects, exposure to everolimus was significantly increased when this product was combined with the following drugs compared to the use of this product alone.
Ketoconazole (potent CYP3A4 inhibitor and PgP inhibitor) with a 3.9-fold and 15.0-fold increase in Cmax and AUC, respectively.
Erythromycin (intermediate CYP3A4 inhibitor and PgP inhibitor), with a 2.0-fold and 4.4-fold increase in Cmax and AUC, respectively.
Verapamil (intermediate CYP3A4 inhibitor and PgP inhibitor), 2.3-fold and 3.5-fold increase in Cmax and AUC, respectively.
Cyclosporine (CYP3A4 substrate and PgP inhibitor), Cmax and AUC increased 1.8-fold and 2.7-fold, respectively).
It should not be combined with CYP3A4 potent inhibitors (see [Dosage] and [Precautions]).
This product should be used with caution in combination with intermediate-acting CYP3A4 and/or PgP inhibitors. If treatment is not an option, the dose of this product should be reduced (see [Dosage] and [Precautions]).
Drugs that may reduce the blood concentration of everolimus
CYP3A4 inducers
In healthy subjects, everolimus AUC and Cmax were reduced by 63% and 58%, respectively, when combined with rifampin (a potent CYP3A4 inducer) compared to everolimus alone. When this product is combined with CYP3A4 or PgP potent inducers, an increase in the dose of this product should be considered if treatment is not an option. St. John’s wort unintentionally decreases everolimus exposure and should be avoided (see [Dosage]).
Drugs whose blood levels can be altered by everolimus
Studies in healthy subjects have shown no clinically meaningful pharmacokinetic interactions between this product and the carboxymethylglutarate monoacyl coenzyme A (HMG-CoA) reductase inhibitors atorvastatin (CYP3A4 substrate) and pravastatin (non-CYP3A4 substrate), and no effects of simvastatin (CYP3A4 substrate) on the clearance of this product have been detected in population pharmacokinetic analyses .
Results of studies in healthy subjects showed that concomitant oral administration of midazolam (a sensitive CYP3A4 substrate) and everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC0-inf.
Everolimus increased the pre-dose concentrations of the metabolites of the antiepileptic drugs (AEDs) carbamazepine, clobazam, and clobazam, N-desmethylclobazam, by approximately 10%. These elevated pre-dose concentrations of AEDs are unlikely to be clinically significant, and dose adjustments may need to be considered for AEDs with narrow therapeutic indices (e.g., carbamazepine). Everolimus does not affect the pre-dose concentrations of AEDs that are CYP3A4 substrates (clobazam, valium, felbamate, and zonisamide). Everolimus also has no effect on the pre-dose concentrations of other AEDs including valproic acid, topiramate, oxcarbazepine, phenobarbital, phenytoin, and paromidone.
The combined administration of everolimus and exemestane increased the Cmin and C2h of exemestane by 45% and 71%, respectively. However, no difference was seen in the corresponding steady-state (at 4 weeks) estradiol levels between the two groups. No elevated adverse events associated with exemestane were seen in hormone receptor-positive patients with advanced breast cancer who received the combination of the two drugs. Elevated levels of exemestane are unlikely to have an effect on efficacy or safety.
When everolimus was combined with long-acting octreotide, octreotide Cmin was elevated by approximately 50%. This elevation had no clinically significant effect on the efficacy response to everolimus in patients with advanced neuroendocrine tumors.
[Drug overdose].
In animal studies, everolimus has a low potential for acute toxicity. No lethality or serious toxicity was observed in mice or rats at a single oral dose level of 2000 mg/kg (limited trials).
Reported human drug overdose experience is very limited. Single doses have been administered up to 70 mg with acceptable acute tolerability. The acute toxicity profile observed at the 70 mg dose level was consistent with that observed at the 10 mg dose level.
Systemic supportive therapy should be used in all cases of drug overdose.
[Clinical Trials].
Advanced renal cell carcinoma
Results of foreign clinical studies
An international multicenter, randomized, double-blind trial comparing this product 10 mg once daily plus best supportive care to placebo plus best supportive care in patients with metastatic renal cell carcinoma previously treated with sunitinib, sorafenib, or sequentially with both drugs and experiencing disease progression. Prior treatment with bevacizumab, interleukin 2, or alpha interferon was also allowed. Randomization was stratified according to prognostic score and prior antitumor therapy.
Progression-free survival (PFS) was assessed by blinded, independent-center radiologic review according to the Criteria for Evaluation of Efficacy in Solid Tumors (RECIST version 1.0). After radiological documentation of disease progression, investigators could perform patient unblinding: patients randomized to placebo were open to treatment with this product 10 mg once daily.
In total, 416 patients were randomized to this product (n=277) or placebo (n=139) in a 2:1 ratio. Demographics were well balanced between the two treatment groups (median age 61 years; 77% male; 88% Caucasian; 74% prior use of sunitinib or sorafenib and 26% sequential use of both drugs).
PFS was better in the group with this product than in the placebo group (see Table 5 and Figure 1). Treatment effects were similar between prognostic scores and stratification of prior use of sorafenib and/or sunitinib. The final overall survival (OS) outcome yielded a risk ratio of 0.90 (95% CI: 0.71 to 1.14), with no statistically significant differences seen between the two treatment groups. This was due to the fact that 79.9% (111/139) of patients were switched from the placebo arm to the open native arm due to disease progression according to the regimen, which may have influenced the assessment of OS benefit.
Table 5: Effectiveness results of radiological assessments at independent centers
 Everolimus tablets
N=277 Placebo
N=139 Risk ratio
(95% CI) p-valuea Median progression-free survival 4.9 months 1.9 months 0.33<0.0001 (95% CI) (4.0-5.5) (1.8-1.9) (0.25-0.43) Objective remission rate 2% 0% n/abn/aba Stratified by prognostic score with log-anecdotal test.
b Not applicable
 Figure 1: Kaplan-Meier progression-free survival curve
 Results of clinical studies in China
In a multicenter, open, uncontrolled clinical trial conducted in China, 64 patients with metastatic renal cell carcinoma that had progressed after previous application of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy (sunitinib, sorafenib, or both) were enrolled, with a median age of 51.5 years (range, 19 to 75 years). Patients who had previously used bevacizumab and alpha interferon were allowed to be enrolled in this study. The overall remission and disease control rates were 4.7% and 65.6%, respectively. The median progression-free survival was 6.93 months, and the overall survival rate at 12 months was 55.6%.
Advanced neuroendocrine tumors
Locally advanced or metastatic pancreatic neuroendocrine tumors
A randomized, double-blind, multicenter trial comparing this product in combination with best supportive care (BSC) versus placebo in combination with best supportive care was conducted in patients with locally advanced or metastatic progressive pancreatic neuroendocrine tumors whose disease had progressed within the previous 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes/no) and WHO stamina status (0 vs. 1 and 2). Growth inhibitor analogs were allowed as part of the best supportive therapy. The primary endpoint of the trial was progression-free survival (PFS) as evaluated by the Criteria for Evaluation of Efficacy in Solid Tumors (RECIST version 1.0). After radiographic documentation of disease progression, investigators may unblind subjects; those randomized to the placebo arm are subsequently open to the product. Other endpoints include safety, objective effectiveness (ORR (complete remission (CR) or partial remission (PR)), duration of efficacy, and overall survival.
Patients were randomized 1:1 to everolimus 10 mg/day (n=207) or placebo (n=203). Demographic characteristics were well balanced (median age 58 years, 55% male, 79% Caucasian). 73% (148/203) of patients crossed over from the placebo group to open treatment with this product.
The trial demonstrated a statistically significant improvement in PFS (median 11.0 months versus 4.6 months), with a 65% risk reduction (HR 0.35; 95% CI: 0.27 to 0.45; p<0.001) in terms of investigator-judged PFS (see Table 6 and Figure 2). Improved PFS was observed in all patient subgroups, regardless of prior use of growth inhibitor analogs. See Table 6 for investigator radiologically assessed PFS results, independent center radiologically assessed PFS results, and adjudicated radiologically assessed PFS results.
 
 Table 6: Progression-free survival results
 Everolimus tablets
N=207 Placebo
N=203 Risk ratio
(95% CI) p-value Median progression-free survival
(months) (95% CI) Investigator radiographic assessment 11.0
(8.4-13.9) 4.6
(3.1-5.4) 0.35
(0.27-0.45)<0.001 Independent center radiological assessment13.7
(11.2-18.8) 5.7
(5.4-8.3) 0.38
(0.28-0.51)<0.001 Adjudicated radiological assessmenta11.4
(10.8-14.8) 5.4
(4.3-5.6) 0.34
(0.26-0.44)<0.001a Including adjudicated differences in evaluation between investigator radiology readings and center radiology readings
 Figure 2: Investigator-determined Kaplan-Meier curves for progression-free survival
The investigator-identified remission rate in the everolimus group was low (4.8%) and there was no complete remission. Overall survival outcomes were not completed and there were no statistically significant treatment-related differences in OS (HR=1.05 (95% CI: 0.71 to 1.55)).
 Locally advanced or metastatic neuroendocrine tumors of gastrointestinal or pulmonary origin　
A randomized, double-blind, multicenter trial comparing everolimus plus best supportive care (BSC) and placebo plus best supportive care groups was conducted in patients with unresectable lesions of gastrointestinal (excluding pancreatic) or pulmonary origin, locally advanced or metastatic nonfunctional neuroendocrine tumors (NETs) with good differentiation. Patients were required to have well-differentiated (low- or intermediate-grade) histology, no previous or current carcinoid symptoms, and evidence of disease progression within 6 months prior to randomization. Patients were randomized (2:1) to receive everolimus 10 mg/day or placebo and were stratified according to the presence or absence of prior growth inhibitor analogs (SSA), tumor origin, and WHO physical status score. The primary efficacy outcome measure was progression-free survival (PFS) according to RECIST criteria, independently assessed radiologically, and other additional efficacy outcome measures were overall survival and overall remission rate.
A total of 302 patients were randomized, 205 to the everolimus group and 97 to the placebo group . The median age was 63 years (range 22 to 86 years); 47% were male; 76% were white; 74% had a WHO body status (PS) score of 0 and 26% had a PS of 1. The most common tumor primary locations were lung (30%), ileum (24%), and rectum (13%).
The trial demonstrated: statistically significant improvement in PFS according to independent radiological assessment (see Table 7 and Figure 3). There was no statistically significant difference in overall survival in the planned midterm analysis.
Table 7: Efficacy results
Analysis of everolimus placebo N = 205N = 97 Progression-free survival Number of events 113 (55%) 65 (67%) Disease progression 104 (51%) 60 (62%) Death 9 (4%) 5 (5%) Median PFS (months) (95% CI ) 11.0 (9.2, 13.3) 3.9 (3.6, 7.4) Risk ratio (95% CI) 10.48 (0.35, 0.67) p-value2<0.001 Total remission rate 2% 1%1 Risk ratios are from a stratified Cox proportional risk model.
2 P-values are from stratified Log-rank test.
Figure 3: Kaplan-Meier curves for progression-free survival
 
 
 
 
 
 
 
 
 
 
 Subventricular giant cell astrocytoma associated with tuberous sclerosis
Study 1 was a randomized (2:1), double-blind, placebo-controlled study of this product in 117 pediatric and adult patients with tuberous sclerosis-associated subventricular giant cell astrocytoma. Patients enrolled in the study were required to have at least one subventricular giant cell astrocytoma lesion ≥1.0 cm in longest diameter (using MRI, based on local radiologic assessment) that met one or more of the following criteria: serial radiologic evidence of subventricular giant cell astrocytoma growth, the presence of a new subventricular giant cell astrocytoma lesion ≥1.0 cm in longest diameter, or the presence of new or worsening of hydrocephalus. Patients randomly assigned to the treatment arm received this product at a starting dose of 4.5 mg/m2 daily, after which the dose was adjusted as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/ml, depending on patient tolerability. treatment with this product/matching placebo was continued until disease progression or intolerable toxicity developed. MRI scans were performed at baseline and at weeks 12, 24, and 48 to view disease progression, and annually thereafter.
The primary efficacy endpoint is the rate of remission of subventricular giant cell astrocytoma, based on independent central radiological assessment. Remission of subventricular giant cell astrocytoma was defined as ≥50% reduction in total volume compared with baseline, no definite worsening of non-target lesions of subventricular giant cell astrocytoma, ≥1.0 cm of new lesions, and new or worsening hydrocephalus. Analysis of remission rates for subventricular giant cell astrocytoma was limited to the blinded treatment period, which ended 6 months after the last patient completed randomization. Analysis of remission rates for subventricular giant cell astrocytoma was stratified according to whether enzyme-inducing antiepileptic drugs (EIAED) were used at randomization (yes/no).
Of the 117 patients enrolled, 78 received this product and 39 received placebo. The median age of the patients was 9.5 years (range 0.8 to 26 years; 69% were 3 to <18 years old and 17% were <3 years old at enrollment), 57% were male, and 93% were Caucasian. At baseline, 18% of patients received EIAED. based on central radiological evaluation at baseline, 98% of patients had at least one subventricular giant cell astrocytoma lesion ≥1.0 cm in longest diameter, 79% had bilateral subventricular giant cell astrocytoma lesions, 43% had ≥2 subventricular giant cell astrocytoma target lesions, 26% had lesions extending into the subventricular layer, and Evidence of lesion growth beyond the subventricular tissue adjacent to the ventricles was present in 9%, and radiographic evidence of hydrocephalus was present in 7%. At baseline, the median total volume of all subventricular giant cell astrocytoma target lesions was 1.63 cm3 (range 0.18-25.15 cm3) and 1.30 cm3 (range 0.32-9.75 cm3) in the product and placebo groups, respectively. 8 (7%) patients had previous surgery related to subventricular giant cell astrocytoma. The median follow-up period was 8.4 months (range 4.6 to 17.2 months).
The remission rate for subventricular giant cell astrocytoma was higher and statistically significant in patients treated with this product. Twenty-seven (35%) of the patients in the group achieved remission of subventricular giant cell astrocytoma, whereas no remission was seen in the placebo group. The results are shown in Table 8. At the time of final analysis, all subventricular giant cell astrocytoma remissions were ongoing, with a median duration of remission of 5.3 months (range 2.1 to 8.4 months). No patient in either treatment group required surgical intervention during the course of Study 1.
 Table 8: Remission of subventricular canalicular giant cell astrocytoma
 This product
N=78 Placebo
N=39p value Final analysis Subventricular giant cell astrocytoma remission rate a- (%) 350<0.000195% CI24, 460, 9 a based on independent central radiological assessment.
 Progression of subventricular giant cell astrocytoma was found in 6 of 39 patients (15.4%) randomized to placebo during a median follow-up period of 8.4 months, whereas no progression of subventricular giant cell astrocytoma occurred in 78 patients randomized to this product.
Study 2 was an open, single-arm trial evaluating the safety and efficacy of this product in the treatment of patients with subventricular giant cell astrocytoma associated with tuberous sclerosis. Participants in the trial were required to have a range of radiographic evidence of subventricular giant cell astrocytoma growth. Radiological review by an independent center to evaluate subventricular giant cell astrocytoma volume changes at the end of the 6-month core treatment phase. A total of 28 patients were treated with this product: median age was 11 years (range 3 to 34 years), 61% were male, and 86% were Caucasian. 4 patients had surgically resected lesions that subsequently regrowth prior to treatment with this product. After the core treatment phase, patients were allowed to continue with this product as part of an extended treatment phase, with subventricular giant cell astrocytoma volume evaluated every 6 months. The median duration of treatment was 34.2 months (range 4.7 to 47.1 months).
At 6 months, 9 of 28 patients (32%, 95% CI: 16% to 52%) had ≥50% reduction in tumor volume of the largest subventricular giant cell astrocytoma lesion. The median duration of remission for these 9 patients was 11.8 months (range 3.2 to 39.1 months). By the cut-off date, 7 of the 9 patients still had ≥50% tumor volume reduction.
Of the 4 patients with prior surgery, 3 patients had ≥50% tumor volume reduction in the largest subventricular giant cell astrocytoma lesion. One of these 3 patients was in remission at 6 months. No patient developed new lesions.
Renal vascular smooth muscle lipoma associated with tuberous sclerosis
A randomized (2:1), double-blind, placebo-controlled study was conducted in 118 patients with tuberous sclerosis (n=113) or sporadic lymphangioleiomyosarcoma (n=5) who had renal vascular smooth muscle lipoma presentation.
The primary inclusion criteria for the study were at least one vascular smooth muscle lipoma ≥3 cm in longest diameter (by CT or MRI, as assessed by local radiology), not requiring immediate surgical treatment, and aged ≥18 years. Patients received oral doses of 10 mg of this product or matching placebo once daily until the onset of disease progression or intolerable toxicity. Disease progression was assessed at baseline and by CT or MRI scan at weeks 12, 24, 48, and annually thereafter. Clinical and imaging assessments of skin lesions were performed at baseline and every 12 weeks thereafter until treatment termination. The primary efficacy assessment metric was the remission rate of vascular smooth muscle lipoma (based on independent central radiological evaluation), defined as ≥50% reduction of vascular smooth muscle lipoma, no new vascular smooth muscle lipoma ≥1 cm, no ≥20% increase in renal volume, and no grade ≥2 bleeding due to vascular smooth muscle lipoma. The primary supportive indicators of efficacy outcomes were time to vascular smooth muscle lipoma progression and rate of skin lesion remission. Analysis of efficacy outcomes was limited to the blinded treatment period, which ended 6 months after the last patient was randomized. Comparative analysis of vascular smooth muscle lipoma remission rates was stratified according to whether enzyme-induced antiepileptic drugs (EIAED) were used at the time of randomization.
Of the 118 patients enrolled, 79 were randomized to the product group and 39 were randomized to the placebo group. The median age of the patients was 31 years (range 18 to 61 years), 34% were male, and 89% were Caucasian. At baseline, 17% of patients received EIAED (application of enzyme-induced antiepileptic drugs). At central radiological evaluation at baseline, 92% of patients had at least one vascular smooth muscle lipoma ≥3 cm in longest diameter, 29% had ≥8 cm vascular smooth muscle lipoma, 78% had bilateral vascular smooth muscle lipoma, and 97% had cutaneous lesions. The median sum of all renal vascular smooth muscle lipoma target lesions at baseline was 85 cm3 (range 9 to 1612 cm3) in the product group and 120 cm3 (range 3 to 4520 cm3) in the placebo group. 46 (39%) patients had previous nephroembolization therapy or nephrectomy. The median follow-up period was 8.3 months (range 0.7 to 24.8 months).
The remission rate of renal vascular smooth muscle lipoma was significantly higher in the product group than in the placebo group and the difference was statistically significant; 33 (41.8%) patients in the product group had remission of vascular smooth muscle lipoma, whereas no patients in the placebo group had remission. The median duration of remission was 5.3+ months (range 2.3+ to 19.6+ months).
Table 9: Remission rate of vascular smooth muscle lipoma
 Everolimus tablets
N=79 Placebo
N=39P value Primary analysis Vascular smooth muscle lipoma remission ratea – %41.80<0.000195% CI (30.8, 53.4) (0.0, 9.0) a Based on independent central radiological evaluation
 Based on central radiologic evaluation, 3 patients in the product group and 8 patients in the placebo group had confirmed vascular smooth muscle lipoma progression (defined as total vascular smooth muscle lipoma target lesions ≥ 25% greater than nadir and above baseline values, neointimal lipoma appearance ≥ 1.0 cm in longest diameter, ≥ 20% greater than nadir and above baseline values in either kidney, or with ≥ grade 2 (vascular smooth muscle lipoma-associated bleeding). The time to vascular smooth muscle lipoma progression was significantly later in the product group, with a statistically significant difference, risk ratio of 0.08 (95% CI: 0.02, 0.37), p<0.0001.
At study entry, the local investigators evaluated the rate of remission of skin lesions in 77 patients in the present product group and 37 patients in the placebo group. The rate of remission of skin lesions was significantly higher in the everolimus group, with a statistically significant difference (26% vs. 0, p=0.0011); remission of all skin lesions was partial remission, defined as visual improvement in 50-99% of all skin lesions with a duration of improvement of at least 8 weeks (physician’s global assessment of clinical condition).
Patients in the placebo group were allowed to switch to everolimus after progression of vascular smooth muscle lipoma was detected or after the time of the primary analysis. Following the primary analysis, patients treated with this product received additional follow-up CT or MRI examinations to assess tumor status until treatment discontinuation or the end of the 4-year follow-up period after enrollment of the last patient. A total of 112 patients (79 randomized to everolimus and 33 randomized to placebo) received at least one dose of everolimus. The median duration of treatment with this product was 3.9 years (range: 0.5 months to 5.3 years) and the median duration of follow-up was 3.9 years (range: 0.9 months to 5.4 years). During the follow-up period following the primary analysis, 32 additional patients (33 patients found to be in remission in the primary analysis) experienced remission of vascular smooth muscle lipoma based on independent central radiological assessment. The median time to vascular smooth muscle lipoma remission was 2.9 months (range: 2.6 months to 33.8 months) in 65 of 112 patients who were in remission. By the end of the follow-up period, 16 of the 112 patients on this product had vascular smooth muscle lipoma progression. No patient underwent nephrectomy for vascular smooth muscle lipoma progression, and one patient underwent embolization while on this product.
No clinical studies have been registered in Chinese patients with pancreatic neuroendocrine tumors and subventricular giant cell astrocytomas associated with tuberous sclerosis and renal vascular smooth muscle lipomas.
 Pharmacology and Toxicology
Pharmacological effects
Everolimus is a selective inhibitor of mTOR, a key serine-threonine kinase whose activity is upregulated in some human tumors. Inhibition of the mTOR signaling pathway leads to reduced activity of the transcriptional regulator S6 ribosomal protein kinase (S6K1) and the eukaryotic elongation factor 4E-binding protein (4E-BP), which interfere with cell cycle, angiogenesis, glycolysis, and other related proteins. translation and synthesis of related proteins. Everolimus decreases the expression of vascular endothelial growth factor (VEGF). Everolimus is a potent inhibitor of the growth and proliferation of tumor cells, endothelial cells, fibroblasts, and vascular smooth muscle cells, and inhibits glycolysis in solid tumors in vitro and in vivo.
Toxicological studies
General toxicity: The non-clinical safety of everolimus was evaluated in mice, rats, minipigs, monkeys and rabbits. The major target organs and toxicity manifestations were: degeneration of testicular vas deferens, decreased sperm content in the epididymis and uterine atrophy in the reproductive systems of males and females in some animal species; increased alveolar macrophage counts in rats and mice; degranulation and vacuolization of pancreatic secretory cells in monkeys and minipigs and degeneration of islet cells in monkeys; and clouding of the anterior slit of the lens in rat eyes. Age-related increased lipofuscin deposition in tubular epithelial cells and minor renal changes with increased hydronephrosis were observed in rats, and minor renal changes with increased injury were observed in mice.
Exacerbation of spontaneous physiological disorders such as chronic myocarditis in rats, plasma and cardiac coxsackievirus infection in monkeys, gastrointestinal coccidia infection in minipigs, and skin lesions in mice and monkeys occurred with everolimus, and these reactions can usually occur when systemic exposure levels are within or beyond the therapeutic exposure range. Only in rats, because of high tissue distribution, reactions can occur at levels below therapeutic exposure.
Results of toxicity tests in young rats showed that developmental marker dose-related delays, including delayed eye opening, slow development, and prolonged latency to learning and memory phases, were observed at doses as low as 0.15 mg/kg/day.
Genotoxicity: The results of the everolimus Ames test, the L5178Y mouse lymphocytoma mutation test, and the V79 Chinese hamster cell chromosome aberration test were all negative. In an in vivo bone marrow micronucleus assay in mice, the results were negative when administered twice daily at doses up to 500 mg/kg/day (1500 mg/m2/day), which is approximately 255 times the human dose of 10 mg/day based on body surface area and 103 times the maximum dose administered to SEGA patients.
Reproductive toxicity: In a 13-week male fertility test in rats, testicular morphological changes were observed at doses ≥0.5 mg/kg; reduced sperm motility, sperm count and plasma testosterone levels were observed at a dose of 5 mg/kg. The in vivo exposure of animals at these doses was lower than the therapeutic exposure of humans at 10 mg/kg (52 ng-hr/mL and 414 ng-hr/mL, respectively, compared to 560 ng-hr/mL at 10 mg/day), and the dose that caused sterility in rats was 5 mg/kg. The effect on fertility in male rats occurred at doses lower than the therapeutic exposure (approximately 10% to 81% of the exposure at the clinical dose of 10 mg/day). After 10-13 weeks of discontinuation, the fertility index increased from 0 (sterility) to 60% (12/20 pregnancies in mated females). An increased incidence of preimplantation loss was seen in female rats given everolimus orally at doses ≥0.1 mg/kg (approximately 4% of exposure at the clinical dose of 10 mg/day).
Oral administration of everolimus to female rats prior to mating and during organogenesis produced embryo-fetal toxicity, including increased embryo uptake, pre- and post-implantation loss, reduced number of live fetuses, malformations (e.g., sternal clefts), and delayed skeletal development. None of these effects were accompanied by maternal toxicity. Embryo-fetal toxicity in rats occurs at everolimus doses ≥0.1 mg/kg (0.6 mg/m2), which is approximately 4% of the exposure at a clinical dose of 10 mg/day. Increased embryonic uptake was seen in rabbits at everolimus doses of 0.8 mg/kg (9.6 mg/m2), with significant embryotoxicity. Based on the body surface area dose, this was approximately 1.6 times the exposure at a clinical dose of 10 mg/day. Embryotoxicity in rabbits was accompanied by maternal toxicity.
In a perinatal developmental toxicity assay in rats, no adverse effects on delivery and lactation were observed at a dose of 0.1 mg/kg (0.6 mg/m2) when administered continuously from implantation to lactation, and no maternal toxicity was observed; offspring showed reduced body weight (9% reduction compared to control) and reduced survival (~5% death or abortion). No drug-related effects were seen in offspring developmental indicators (morphological development, motor activity, learning or fertility assessment).
Carcinogenicity: No carcinogenicity was observed in mice and rats given everolimus for up to 2 years at doses equivalent to 3.9 and 0.2 times the clinically estimated exposure, respectively.
 Pharmacokinetics]
Absorption
In patients with advanced solid tumors, peak concentrations were reached 1~2 hours after oral administration of 5mg to 70mg of this product. After a single dose, the Cmax between 5mg and 10mg is proportional to the dose. At doses of 20 mg and higher, the increase in Cmax was less than the proportional increase in dose, but the AUC was proportional to the dose in the range of 5 mg to 70 mg. Steady state was reached within two weeks after once-daily dosing.
Dose proportionality in patients with tuberous sclerosis-associated subventricular giant cell astrocytoma: In patients with tuberous sclerosis-associated subventricular giant cell astrocytoma, everolimus Cmin was approximately dose proportional over the dose range of 1.35 mg/m2 to 14.4 mg/m2.
Food effects
In healthy subjects, high-fat meals reduced systemic exposure (AUC) of the 10 mg tablet of this product by 22% and reduced Cmax by 54%. Low-fat meals reduced AUC by 32% and Cmax by 42%. However, food had no significant effect on the drug-time profile in the post-absorption phase.
Distribution
The blood-plasma concentration ratio (concentration-dependent in the range of 5-5000 ng/ml) of everolimus ranged from 17% to 73%. In cancer patients given 10 mg/day once, the plasma concentration of everolimus tested was approximately 20% of the whole blood concentration. Plasma protein binding was approximately 74% in both healthy subjects and patients with moderately impaired hepatic function.
Metabolism
Everolimus is a CYP3A4 and PgP substrate. After oral administration, everolimus is the major component in the human blood circulation. Six major metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolysis ring-opening products, and an everolimus phosphatidylcholine conjugate. These metabolites were also found in animal species used for toxicological studies and showed metabolite activity approximately 100-fold lower than everolimus activity.
In in vitro assays, everolimus competitively inhibited the metabolic activity of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. after a single oral dose of 10 mg/day, the mean steady-state Cmax was more than 12-fold lower than the in vitro inhibitory Ki value. Therefore, everolimus is unlikely to affect the metabolism of CYP3A4 and CYP2D6 substrates.
Excretion
No specific excretion studies have been performed in cancer patients. Following a single oral dose of 3 mg of radiolabeled everolimus in transplant patients treated with cyclosporine, 80% of the radioactive material was excreted in the feces and 5% was excreted in the urine. No parent drug was detected in either urine or feces. The mean elimination half-life of everolimus is approximately 30 hours.
Steady-state pharmacokinetics
After daily or weekly application of everolimus in patients with advanced solid tumors, steady-state AUC0-τ was proportional to the dose in the range of 5 to 10 mg administered daily and 5 to 70 mg administered weekly. Steady-state was achieved within two weeks in the daily dosing regimen. Cmax was dose proportional between the 5mg and 10mg dosing ranges in the daily and weekly dosing regimens. At dose levels of 20 mg/week and higher, Cmax increased less than dose proportionally. The tmax was reached 1 to 2 h after dosing. there was a significant correlation between AUC0-τ and pre-dose trough concentrations when daily dosing reached steady state. The mean elimination half-life of everolimus is approximately 30 hours.
Patients with impaired renal function
After administration of [14C]-labeled everolimus 3 mg, approximately 5% of the total radioactive material was excreted via urine. In a population pharmacokinetic analysis of 170 patients with advanced cancer, creatinine clearance (25 to 178 ml/min) did not significantly affect the apparent clearance (CL/F) of everolimus (see [DOSAGE]).
Patients with impaired hepatic function
The safety, tolerability and pharmacokinetics of a single oral dose of this product were evaluated in a study involving subjects with impaired liver function as well as normal liver function and found that mild (Child-Pugh class A, n=6), moderate (Child-Pugh class B, n=9) and severe (Child-Pugh class C, n=6) compared to normal subjects (n=13) Everolimus exposure (i.e., AUC) increased 1.8, 3.2, and 3.6-fold in patients with impaired liver function, respectively. In another study, the mean AUC of everolimus was found to be twice as high in eight subjects with moderate hepatic impairment (Child-Pugh class B) as in eight subjects with normal liver function.
In patients with advanced renal cell carcinoma with severe hepatic impairment, the product may be reduced in dose if the expected benefit exceeds the risk. For patients with mild or moderate hepatic impairment, a dose reduction is recommended (see [Dosage]).
For patients with subventricular giant cell astrocytoma with mild or moderate hepatic impairment, the dose of this product should be adjusted based on therapeutic drug monitoring. For patients with subventricular giant cell astrocytoma with severe hepatic impairment, the starting dose should be reduced by approximately 50% and subsequent dose adjustments should be based on therapeutic drug monitoring (see [Dosage] “Therapeutic Drug Monitoring” and “Dose Adjustment”).
Effect of age and gender
Pharmacokinetic evaluation of the cancer patient population showed no significant relationship between apparent clearance and patient age or gender.
In patients with subventricular giant cell astrocytoma, geometric mean Cmin values normalized by mg/m2 dose were 54% and 40% lower in patients aged <10 years and 10 to <18 years, respectively, than in adult patients (>18 years), indicating that comparative results of everolimus clearance normalized by body surface area were higher in pediatric patients than in adult patients.
Race
Based on crossover study comparisons, mean exposure was higher in Japanese patients (n=6) than in non-Japanese patients at the same dose applied.
Based on population pharmacokinetic analysis, oral clearance (CL/F) was on average 20% higher in black patients than in whites.
The significance of these differences in the safety and efficacy of everolimus in Japanese or black patients has not been determined.
Relationship between exposure and effect
There was a moderate correlation between decreased phosphorylation of 4E-BP1 (P4E-BP1) in tumor tissue and steady-state mean Cmin of everolimus in blood after 5 or 10 mg of this product administered once daily. Additional data suggest that phosphorylation inhibition of S6 kinase is very sensitive to mTOR inhibition by everolimus. All Cmin values after daily 10 mg dose administration showed complete inhibition of eIF-4G phosphorylation.
Pharmacokinetic Data in the Chinese Population
A phase I trial investigated the pharmacokinetics of everolimus administered at 5 mg/day and 10 mg/day in Chinese patients (n=24) with solid tumors. The mean oral clearance (CL/F) of everolimus was 15.8 L/hour and 17.0 L/hour in the 5 mg/day and 10 mg/day dosing groups, respectively. The oral clearance of the drug in Chinese patients was comparable to that of Japanese tumor patients (18.9 L/hour in the 5 mg/day dosing group and 19.1 L/hour in the 10 mg/day dosing group) and Caucasian tumor patients (15.4 L/hour in the 10 mg/day dosing group). The pharmacokinetics of everolimus was generally linear in the 5 mg/day and 10 mg/day dosing ranges, and the peak blood concentration (Cmax), trough concentration (Cmin) and area under the drug-time curve (AUC0-24h) at steady state increased proportionally to the dose.
Storage
Store below 30℃. Keep away from light and moisture.
Avoid misuse by children.
Packaging
PA/AL/PVC aluminum blister package. 30 tablets/box
Expiration date
36 months
Execution Standard
Imported drug registration standard JX20170029
【Approval Number】
Imported drug registration certificate number
2.5mg: H20150093
5mg：H20171145
10mg: H20171146
【Manufacturing Company
Company name: Novartis Pharma Schweiz AG
Production plant: Novartis Pharma Stein AG
Production Address: Schaffhauserstrasse, 4332 Stein, Switzerland
Contact address: No. 31 Yong’an Road, Changping District, Beijing, China
Postal code: 102200
Telephone number: 400 818 0600 / 800 990 0016
Fax number: 010 6505 7099
Website: www.novartis.com.cn