Certican 0.5 mg (Everolimus)

Adult dosage

Treatment with this drug should be initiated and maintained only by physicians experienced in immunosuppressive therapy after organ transplantation and able to perform whole-blood therapeutic drug monitoring of everolimus. This drug is administered concomitantly with cyclosporine in microemulsion formulation and corticosteroids, or with tacrolimus and corticosteroids. The safety of long-term concomitant administration of this drug and cyclosporine has not been established; therefore, renal function must 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. Adults: In kidney and heart transplant recipients, the initial dose of this drug is 0.75mg twice daily orally (total daily dose 1.5mg), as soon as possible after transplantation. In liver transplant recipients, the initial dose is 1.0mg twice daily orally (total daily dose 2.0mg), approximately 4 weeks after transplantation. The daily dose of this drug should always be administered consistently either with food or on an empty stomach, in 2 divided doses, and in combination 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 blood concentrations, tolerability, individual patient response, changes in concomitant medications, and clinical status. Dose adjustments may be made at intervals of 4-5 days. Two clinical studies of this drug (everolimus 1.5mg/day, 3mg/day), with mycophenolate mofetil (MMF) as the control, were conducted in kidney transplant recipients [Study B201 (N=588); Study B251 (N=583)]. In both studies, at 6 months after transplantation, this drug (everolimus 1.5mg/day, 3mg/day) showed efficacy comparable to that of the control drug (mycophenolate mofetil, MMF) for the efficacy failure rate (biopsy-proven acute rejection, graft loss and death, graft loss, death, and loss to follow-up). At 12 months, the 3.0mg/day group showed an effect comparable to that of the control drug (MMF) for graft loss, death, and loss to follow-up; however, in one clinical study (Study B251), graft loss, death, and loss to follow-up at 12 months were significantly higher in the 1.5mg/day group than in the control group. In kidney transplant recipients, an efficacy benefit of everolimus 3.0mg/day over 1.5mg/day has not been established, and patients receiving everolimus 3.0mg/day had poorer tolerability than patients receiving 1.5mg/day or MMF. In a clinical study (N=634) of this drug (everolimus 1.5mg/day, 3mg/day) in heart transplant recipients, with azathioprine (AZA) as the control, this drug (everolimus 1.5mg/day, 3mg/day) was shown to be superior to the control drug (azathioprine, AZA) for the primary efficacy endpoint [biopsy-proven acute rejection of grade 3A or higher, acute rejection associated with hemodynamic compromise, graft loss, death, and loss to follow-up at 6 months after transplantation]. However, 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], results were similar to those in the control group. In heart transplant recipients, the 3.0mg/day dose provided an efficacy benefit over the 1.5mg/day dose; however, patients receiving everolimus 3.0mg/day had poorer tolerability than patients receiving 1.5mg/day or azathioprine (see Precautions for Use). Elderly patients (65 years and older): Although clinical experience in patients 65 years and older is limited, no apparent differences in everolimus pharmacokinetics have been observed between patients aged 65-70 years and older and healthy adults. Patients with renal impairment: No dose adjustment is required. Patients with hepatic impairment: Whole-blood trough concentrations of everolimus must 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. For patients with moderate hepatic impairment (Child-Pugh B), the dose should be reduced to approximately 1/2 of the normal dose, and for patients with severe hepatic impairment (Child-Pugh C), it should be reduced to approximately 1/3 of the normal dose. Subsequent doses should be adjusted through therapeutic drug monitoring. When reducing the dose, refer to the table below to allow dosing with the tablet strength closest to the required dose. <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 transplant 0.75 mg twice daily 0.5 mg twice daily 0.5 mg twice daily 0.25 mg twice daily Liver transplant 1 mg twice daily 0.75 mg twice daily 0.5 mg twice daily 0.5 mg twice daily Therapeutic drug monitoring: Because this drug has a narrow therapeutic range, the dose may need to be adjusted to maintain therapeutic response. Regular monitoring of therapeutic whole-blood concentrations of everolimus is required. Based on exposure-efficacy and exposure-safety analyses, patients with whole-blood everolimus trough concentrations of 3.0ng/ml or higher were found to have a lower incidence of biopsy-confirmed acute rejection in kidney, heart, and liver transplantation 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 especially important in patients with hepatic impairment during concomitant administration of potent CYP3A4 inducers or inhibitors, and when the prescription for this drug is changed and/or the cyclosporine dose is substantially reduced. Optimal dose adjustment of this drug should be based on trough concentrations obtained 4-5 days or more after the previous dose change. Cyclosporine interacts with everolimus, and consequently everolimus concentrations may decrease when cyclosporine exposure is substantially reduced (e.g., blood 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 account. Recommended cyclosporine dose in kidney transplantation: This drug should not be used long term with full-dose cyclosporine. In kidney transplant recipients receiving this drug, reduced cyclosporine exposure improves renal function. Based on experience from Study A2309, cyclosporine exposure should be reduced immediately after transplantation according to the following recommended whole-blood trough concentration ranges. <Recommended target cyclosporine blood trough concentration range in kidney transplantation> Target cyclosporine blood trough concentration C0(ng/ml) 1 month 2-3 months 4-5 months 6-12 months Patients receiving this drug 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 trough concentrations of 25-50ng/ml after 12 months in kidney transplant recipients are limited. Recommended cyclosporine dose in heart transplantation: To improve renal function, the cyclosporine dose should be reduced in heart transplant recipients 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 recipients, the cyclosporine dose may be based on the cyclosporine blood trough concentration. In clinical studies, serum creatinine levels were significantly higher in the groups receiving this drug than in the azathioprine group at 3, 6, 9, 18, and 24 months: from 1 month after treatment in the 3.0mg/day group and from 3 months after treatment in the 1.5mg/day group. Renal function should be closely monitored regularly in all patients when this drug is administered with full-dose cyclosporine, and cyclosporine dose reduction should be considered in patients with elevated serum creatinine concentrations. Data are limited on the administration of this drug in heart transplant recipients when cyclosporine blood trough concentrations are below 175ng/ml during 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 recipients, the tacrolimus dose should be reduced to minimize calcineurin-associated nephrotoxicity. Starting approximately 3 weeks after initiation of concomitant administration of this drug and tacrolimus, adjust the dose to achieve a tacrolimus trough blood concentration of 3-5ng/ml. There are no controlled clinical studies of this drug administered with the 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 similar efficacy. Currently, efficacy and safety data in Black patients are too limited to support specific recommendations for use of everolimus.

Children's dosage

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

Since this drug suppresses the immune system, the risk of acute rejection may vary when used in conjunction with other immunosuppressants. Careful management is necessary, especially when using or discontinuing this drug with calcineurin inhibitors (cyclosporine or tacrolimus). Additionally, there may be an increased risk of infection when used with certain immunosuppressants such as thymoglobulin. Careful monitoring for infection symptoms is advised as there is an increased risk of bacterial, fungal, and viral opportunistic infections during the use of this drug. Co-administration with drugs that strongly inhibit or induce the CYP3A4 enzyme involved in this drug's metabolism can alter its effects or side effects, so such combinations should be avoided or serum levels monitored. Patients taking this drug may have an increased risk of developing malignancies such as lymphoma or skin cancer, so regular skin checks and sun protection are important. There may also be a risk of vascular edema, particularly when taken with ACE inhibitors. Because kidney function may decline, kidney and heart transplant patients should regularly monitor kidney function and adjust doses of other medications as necessary. This drug may increase proteinuria, so patients with proteinuria need regular testing. The risk of thromboembolism may increase in kidney transplant patients during the first 30 days post-transplant, necessitating caution. Wound healing after surgery may be prolonged, and there is a risk of wound infection or complications at the incision site, so postoperative care is important. Blood-related abnormalities such as thrombotic microangiopathy may occur, requiring blood tests to monitor the condition. Interstitial lung disease can occur due to inflammation or fibrosis in the lungs, so if respiratory symptoms persist, immediate consultation with healthcare professionals is necessary. Patients with hypersensitivity to this drug or certain genetic conditions such as lactose intolerance should not take it. During treatment, regular monitoring of liver function, blood lipids, blood glucose, and metabolic status is essential, and appropriate treatment is needed if abnormalities occur. In men, this drug may cause temporary infertility, so counseling is recommended for long-term use. The effects on driving or operating machinery are unclear, but caution should be exercised if dizziness or drowsiness occurs. This drug may pose risks to the fetus during pregnancy; therefore, women of childbearing age should avoid its use, and nursing mothers should refrain from taking it as well. Effective contraception should be used during and for a period after treatment and discontinuation of this drug. In case of overdose, there is no specific antidote, so appropriate supportive treatment is necessary based on symptoms. This drug should be taken in tablet form and should not be crushed or divided before consumption.

Acute rejection reaction, severe infection, fatal infection, sepsis, BK virus-associated nephropathy, JC virus-associated progressive multifocal leukoencephalopathy, Pneumocystis pneumonia, cytomegalovirus infection, elevated serum creatinine, lymphoma, malignant skin tumors, lymphoproliferative disorders, anemia, erythropenia, leukopenia, thrombocytopenia, pancytopenia, thrombotic microangiopathy, male hypogonadism, hyperlipidemia, new-onset diabetes, hypokalemia, insomnia, anxiety, headache, pericardial effusion, tachycardia, hypertension, venous thromboembolism, epistaxis, lymphorrhea, tissue thrombosis, pleural effusion, cough, dyspnea, interstitial lung disease, diarrhea, nausea, vomiting, abdominal pain, oropharyngeal pain, pancreatitis, gastritis, oral ulceration, non-infectious hepatitis, jaundice, acne, angioedema, rash, myalgia, arthralgia, proteinuria, renal tubular necrosis, erectile dysfunction, pain, fever, peripheral edema, healing failure, incision hernia, liver enzyme abnormalities, leukocyte destructive vasculitis, alveolar proteinosis, erythema, ovarian cysts, pyelonephritis, hydronephrosis, osteoporosis, gastroenteritis, colitis, pruritus, dyspepsia, osteopenia, dizziness, chest pain, stomatitis, urticaria, peripheral arterial occlusive disease, limb pain, menorrhagia, tremor, runny nose, increased serum parathyroid hormone, chest discomfort, hepatic steatosis, sensory abnormalities, sensory loss, subarachnoid hemorrhage, acute pyelonephritis, muscle calcification, muscle weakness, folliculitis, cystitis, pollakiuria, halitosis, systemic lupus erythematosus, boil, anal abscess

This drug is sensitive to air and light, so it should be stored in a tightly sealed container. Additionally, it should be kept in a cool place below 30 degrees Celsius, ensuring it is protected from moisture.

Appearance

A white to yellow, round, flat tablet with a beveled edge, engraved with "CH" on one side and "NVR" on the other side.

Package unit

60 tablets (10 tabs/PTP x 6)