Certirobel Tablet 0.5 mg (Everolimus)

Adult dosage

Treatment with this drug should be initiated and maintained only by physicians experienced in immunosuppressive therapy following organ transplantation and able to perform whole-blood concentration monitoring of everolimus. This drug is administered concomitantly with cyclosporine in microemulsion formulation and corticosteroids, or with tacrolimus and corticosteroids. Since the safety of long-term concomitant administration of this drug and cyclosporine has not been established, renal function should be closely monitored when this drug is administered with cyclosporine, and the cyclosporine dose may need to be reduced based on the patient's clinical response. In kidney and heart transplant patients, the initial dose of this drug is 0.75mg orally twice daily (total daily dose 1.5mg), as soon as possible after transplantation. In liver transplant patients, the initial dose is 1.0mg orally twice daily (total daily dose 2.0mg), approximately 4 weeks after transplantation. The total daily dose of this drug should always be administered consistently either with food or on an empty stomach, in 2 divided doses, and concomitantly with cyclosporine in microemulsion formulation or tacrolimus. This drug is for oral use only. It should be swallowed whole with water and should not be crushed before administration. The dose may be adjusted according to the blood concentration in the patient receiving this drug, tolerability, individual patient response, changes in concomitant medications, and clinical circumstances. Dose adjustments may be made at intervals of 4-5 days. Two clinical studies of this drug (everolimus 1.5mg/day, 3mg/day) versus mycophenolate mofetil (MMF) as the control were conducted in kidney transplant patients [Study B201 (N=588); Study B251 (N=583)]. In both studies, at 6 months after transplantation, the efficacy failure rate (biopsy-proven acute rejection, graft loss and death, graft loss, death, and loss to follow-up) in the drug treatment groups (everolimus 1.5mg/day, 3mg/day) was comparable to that in the control drug (mycophenolate mofetil, MMF) group. At 12 months, the rates of graft loss, death, and loss to follow-up in the 3.0mg/day group were comparable to those in the control drug (MMF) group; however, in one clinical study (Study B251), the rates of graft loss, death, and loss to follow-up at 12 months in the 1.5mg/day group were significantly higher than in the control group. In kidney transplant patients, the efficacy benefit of everolimus 3.0mg/day over the 1.5mg/day dose has not been established, and patients receiving everolimus 3.0mg/day had poorer tolerability than patients receiving 1.5mg/day and MMF. In a clinical study (N=634) of this drug (everolimus 1.5mg/day, 3mg/day) in heart transplant patients, with azathioprine (AZA) as the control, the drug treatment groups (everolimus 1.5mg/day, 3mg/day) were shown to be superior to the control drug (azathioprine, AZA) group for the primary efficacy endpoint [biopsy-proven acute rejection of grade 3A or higher at 6 months after transplantation, acute rejection associated with hemodynamic compromise, graft loss, death, and loss to follow-up]. However, results for the efficacy endpoints excluding biopsy-proven acute rejection of grade 3A or higher at 6 months after transplantation [acute rejection associated with hemodynamic compromise, graft loss, death, and loss to follow-up] were similar to those in the control group. In heart transplant patients, the 3.0mg/day dose had an efficacy benefit over the 1.5mg/day dose of everolimus; however, patients receiving everolimus 3.0mg/day had poorer tolerability than patients receiving 1.5mg/day and azathioprine (see Precautions for Use). Elderly patients (65 years and older): Although clinical experience in patients aged 65 years and older is limited, no clear differences in everolimus pharmacokinetics have been observed between patients aged 65-70 years and older and healthy adult patients. Patients with renal impairment: No dose adjustment is required. Patients with hepatic impairment: Whole-blood trough concentrations of everolimus should be closely monitored in patients with hepatic impairment. In patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced to approximately 2/3 of the normal dose. When administering to patients with moderate hepatic impairment (Child-Pugh B), the dose should be reduced to approximately 1/2 of the normal dose, and when administering to patients with severe hepatic impairment (Child-Pugh C), the dose should be reduced to approximately 1/3 of the normal dose. The dose should subsequently be adjusted through therapeutic drug monitoring. When reducing the dose, refer to the table below to ensure that the closest available tablet strength can be used. <Dose reduction of this drug for administration to patients with hepatic impairment> Normal hepatic function Mild hepatic impairment (Child-Pugh A) Moderate hepatic impairment (Child-Pugh B) Severe hepatic impairment (Child-Pugh C) Kidney and heart transplantation 0.75 mg twice daily 0.5 mg twice daily 0.5 mg twice daily 0.25 mg twice daily Liver transplantation 1 mg twice daily 0.75 mg twice daily 0.5 mg twice daily 0.5 mg twice daily Therapeutic drug monitoring: Since this drug has a narrow therapeutic range, the dose may need to be adjusted to maintain the therapeutic response. Regular monitoring of therapeutic everolimus concentrations in whole blood is required. Based on exposure-efficacy and exposure-safety analyses, patients with a whole-blood everolimus trough concentration of 3.0ng/ml or higher were found to have a lower incidence of biopsy-proven acute rejection in kidney, heart, and liver transplants than patients with trough concentrations below 3.0ng/ml. An upper limit of the therapeutic range of 8ng/ml is recommended; concentrations exceeding 12ng/ml have not been studied. The recommended blood concentration range for everolimus is based on a chromatographic method. Monitoring of everolimus blood concentrations is particularly important in patients with hepatic impairment when this drug is changed during concomitant administration of potent CYP3A4 inducers or inhibitors and/or when the cyclosporine dose is substantially reduced. Optimal dose adjustment of this drug should be based on the trough concentration obtained 4-5 days or more after a previous dose change. Cyclosporine interacts with everolimus, and consequently everolimus concentrations may decrease when cyclosporine exposure is substantially reduced (e.g., trough concentration <50ng/ml). Dose adjustment of this drug should not be based solely on therapeutic drug monitoring; clinical symptoms/signs, biopsy findings, and laboratory test results should also be taken into consideration. Recommended dose of cyclosporine in kidney transplantation: This drug should not be used long term with a full dose of cyclosporine. Reduced cyclosporine exposure in kidney transplant patients receiving this drug improves renal function. Based on experience from Study A2309, reduction of cyclosporine exposure should begin immediately after transplantation according to the following recommended whole-blood trough concentration ranges. <Recommended target blood trough concentration ranges for cyclosporine in kidney transplantation> Target cyclosporine blood trough concentration C0 (ng/ml) 1 month 2-3 months 4-5 months 6-12 months This drug treatment group 100-200 75-150 50-100 25-50 Before reducing the cyclosporine dose, confirm that the steady-state whole-blood trough concentration of everolimus is 3ng/ml or higher. Data on administration of this drug with cyclosporine at a trough concentration of 25-50ng/ml beyond 12 months in kidney transplant patients are limited. Recommended dose of cyclosporine in heart transplantation: To improve renal function, the cyclosporine dose should be reduced in heart transplant patients during the maintenance phase. If renal impairment progresses further or calculated creatinine clearance is below 60ml/min, the dose should be adjusted. In heart transplant patients, the cyclosporine dose may be based on the cyclosporine blood trough concentration. In clinical studies, in the everolimus 3.0mg/day group, serum creatinine levels were significantly increased compared with the azathioprine group at 3, 6, 9, 18, and 24 months, starting 1 month after treatment; in the 1.5mg/day group, this increase was significant starting 3 months after treatment. When this drug is administered concomitantly with a full dose of cyclosporine, renal function should be closely and regularly monitored in all patients, and a reduction in the cyclosporine dose should be considered in patients with elevated serum creatinine concentrations. Data are limited regarding administration of this drug in heart transplant patients when cyclosporine blood trough concentrations are below 175ng/ml in the first 3 months, below 135ng/ml at 6 months, and below 100ng/ml after 6 months. Before reducing the cyclosporine dose, confirm that the steady-state whole-blood trough concentration of everolimus is 3ng/ml or higher. Recommended tacrolimus dose in liver transplantation: In liver transplant patients, the tacrolimus dose should be reduced to minimize calcineurin-associated nephrotoxicity. Starting approximately 3 weeks after initiating concomitant treatment with this drug and tacrolimus, the tacrolimus trough blood concentration should be maintained at 3-5ng/ml. There are no controlled clinical studies of this drug administered with a normal dose of tacrolimus. Black patients: In kidney transplantation, the incidence of biopsy-proven acute rejection was significantly higher in Black patients than in non-Black patients. Limited information suggests that Black patients may require higher doses than non-Black patients to achieve efficacy comparable to that in non-Black patients. Currently, efficacy and safety data in Black patients are too limited to allow specific recommendations for the use of everolimus.

Children's dosage

Children under 18 years of age: The safety and efficacy of this medicine have not been established in children under 18 years of age.

This drug is an immunosuppressant and may increase the risk of infection when used in combination with other immunosuppressants. Caution is needed when used with calcineurin inhibitors as it may affect kidney function. Patients receiving this medication are at risk for severe infections and opportunistic infections, so they should immediately consult healthcare professionals if any signs of infection appear. Additionally, as this drug is metabolized in the liver, patients with impaired liver function should carefully monitor drug levels. Blood lipid levels may increase, so patients with hyperlipidemia should have regular blood tests and may need to take lipid-lowering medications if necessary. This drug can elevate blood sugar levels, leading to the potential onset of new diabetes, so blood sugar management is essential. In males, this drug may cause reversible infertility, so consultation is required if planning for pregnancy. During treatment with this drug, there may be an increased risk of malignant tumors such as skin cancer, hence the use of sunscreen and skin check-ups is recommended. Wound healing may be delayed, so surgical post-care should be attended to carefully, and there is also a risk of complications related to thrombosis, so caution is needed if any unusual symptoms occur. This drug may interact with other medications that inhibit or induce certain enzymes, so it is essential to inform healthcare providers about any other medications being taken. Grapefruit and grapefruit juice can affect the efficacy of this medication, therefore, they should be avoided. Women who are pregnant or breastfeeding are advised not to take this drug, and effective contraception should be used during and for a certain period after treatment. In case of overdose, immediate consultation with healthcare professionals is required for appropriate treatment, and the tablets should be taken whole without crushing.

Acute rejection reaction, severe infection, sepsis, BK virus-associated nephropathy, JC virus-associated progressive multifocal leukoencephalopathy, Pneumocystis pneumonia, cytomegalovirus infection, angioedema, renal dysfunction, proteinuria, renal artery and vein thrombosis, wound infection, wound dehiscence, incisional hernia, seroma, fluid retention, lymphocele, pericardial effusion, pleural effusion, thrombotic microangiopathy, thrombocytopenia, hemolytic uremic syndrome, interstitial lung disease, non-infectious pneumonia, infection, pneumonia, upper respiratory infection, urinary tract infection, sepsis, wound infection, malignant tumor, skin malignancy, lymphoma, lymphoproliferative disorder, anemia, erythrocytopenia, leukopenia, thrombocytopenia, pancytopenia, thrombotic microangiopathy, male hypogonadism, hyperlipidemia, new-onset diabetes, hypokalemia, insomnia, anxiety, headache, pericardial effusion, tachycardia, hypertension, venous thromboembolism, bleeding, lymphorrhea, tissue thrombosis, pleural effusion, cough, shortness of breath, interstitial lung disease, diarrhea, nausea, vomiting, abdominal pain, oropharyngeal pain, pancreatitis, gastritis, oral ulceration, non-infectious hepatitis, jaundice, acne, rash, myalgia, arthralgia, proteinuria, renal tubular necrosis, erectile dysfunction, pain, fever, peripheral edema, healing failure, incisional hernia, liver enzyme abnormalities, leukotoxic vasculitis, alveolar proteinosis, erythema multiforme, ovarian cyst, constipation, pruritus, dyspepsia, osteoporosis, acute pyelonephritis, osteopenia, dizziness, chest pain, stomatitis, urticaria, peripheral arterial occlusive disease, limb pain, menorrhagia, tremors, rhinorrhea, increased serum parathyroid hormone, chest discomfort, hepatic steatosis, sensory abnormalities, sensory loss, subarachnoid hemorrhage, acute pyelonephritis, ear infection, muscle calcification, muscle weakness, folliculitis, cystitis, frequency of urination, fetor, renal necrosis, systemic lupus erythematosus, furuncle, anal abscess, increased serum creatinine, transplant rejection, pneumonia, urinary tract infection, lymphorrhea, acute pyelonephritis, gastroenteritis, influenza, bronchopneumonia, transplant loss, infectious colitis, subarachnoid hemorrhage, osteonecrosis, seizures, airway infection, cerebral infarction, femoral neck fracture, palpitations, headache, fever, anemia, upper gastrointestinal bleeding, renal tubular injury, renal necrosis, compression fracture, gastritis, pharyngitis, carbon monoxide poisoning, seroma, bleeding, prolonged bleeding time, Clostridium difficile colitis, Pneumocystis pneumonia, Staphylococcus wound infection, oliguria, lower gastrointestinal bleeding, anal abscess, laryngitis, aspiration pneumonia

This drug is sensitive to air and moisture, so it should be stored in a sealed container. It is also recommended to keep it in a cool place below 30 degrees Celsius and to avoid direct sunlight.

Appearance

White to yellow round tablet

Package unit

60 tablets (10 tablets/PTP X 6)