Everolimus Prescribing Information
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Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe everolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient. In limited data with the complete elimination of calcineurin inhibition (CNI), there was an increased risk of acute rejection.
Patients receiving immunosuppressants, including everolimus, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.
As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Patients receiving immunosuppressants, including everolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections
Antimicrobial prophylaxis for
An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, usually within the first 30 days posttransplantation
Both cyclosporine doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with everolimus tablets, in order to minimize the risk of nephrotoxicity
The recommended cyclosporine therapeutic ranges when administered with everolimus tablets are 100 to 200 ng/mL through Month 1 posttransplant, 75 to 150 ng/mL at Months 2 and 3 posttransplant, 50 to 100 ng/mL at Month 4 posttransplant, and 25 to 50 ng/mL from Month 6 through Month 12 posttransplant. The median trough concentrations observed in the clinical trial ranged between 161 to 185 ng/mL through Month 1 posttransplant and between 111 to 140 ng/mL at Months 2 and 3 posttransplant. The median trough concentration was 99 ng/mL at Month 4 posttransplant and ranged between 46 to 75 ng/mL from Months 6 through Month 12 posttransplant
Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or intravenous administration of cyclosporine cannot be avoided. Cyclosporine, USP Modified should be initiated as soon as possible, and no later than 48 hours after reperfusion of the graft and dose adjusted to target concentrations from Day 5 onwards.
If impairment of renal function is progressive, the treatment regimen should be adjusted. In renal transplant patients, the cyclosporine dose should be based on cyclosporine whole blood trough concentrations
In renal transplantation, there are limited data regarding dosing everolimus tablets with reduced cyclosporine trough concentrations of 25 to 50 ng/mL after 12 months. Everolimus tablets has not been evaluated in clinical trials with other formulations of cyclosporine. Prior to dose reduction of cyclosporine, it should be ascertained that steady-state everolimus tablets whole blood trough concentration is at least 3 ng/mL. There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced
Both tacrolimus doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with everolimus tablets, in order to minimize the potential risk of nephrotoxicity [
The recommended tacrolimus therapeutic range when administered with everolimus tablets are whole blood trough (C-0h) concentrations of 3 to 5 ng/mL by three weeks after the first dose of everolimus tablets (approximately Month 2) and through Month 12 posttransplant.
The median tacrolimus trough concentrations observed in the clinical trial ranged between 8.6 to 9.5 ng/mL at Weeks 2 and 4 posttransplant (prior to initiation of everolimus). The median tacrolimus trough concentrations ranged between 7 to 8.1 ng/mL at Weeks 5 and 6 posttransplant, between 5.2 to 5.6 ng/mL at Months 2 and 3 posttransplant, and between 4.3 to 4.9 ng/mL between Months 4 and 12 posttransplant
Tacrolimus is to be administered as oral capsules twice daily unless intravenous administration of tacrolimus cannot be avoided.
In liver transplant patients, the tacrolimus dose should be based on tacrolimus whole blood trough concentrations
In liver transplantation, there are limited data regarding dosing everolimus tablets with reduced tacrolimus trough concentrations of 3 to 5 ng/mL after 12 months. Prior to dose reduction of tacrolimus, it should be ascertained that the steady-state everolimus tablets whole blood trough concentration is at least 3 ng/mL. Unlike the interaction between cyclosporine and everolimus, tacrolimus does not affect everolimus trough concentrations, and consequently, everolimus concentrations do not decrease if the tacrolimus exposure is reduced.
In kidney transplant recipients, everolimus with standard dose cyclosporine increases the risk of nephrotoxicity resulting in a lower glomerular filtration rate. Reduced doses of cyclosporine are required for use in combination with everolimus in order to reduce renal dysfunction [
In liver transplant recipients, everolimus has not been studied with standard dose tacrolimus. Reduced doses of tacrolimus should be used in combination with everolimus in order to minimize the potential risk of nephrotoxicity [
Renal function should be monitored during the administration of everolimus. Consider switching to other immunosuppressive therapies if renal function does not improve after dose adjustments or if the dysfunction is thought to be drug related. Caution should be exercised when using other drugs which are known to impair renal function.
Based on exposure-efficacy and exposure-safety analyses of clinical trials and using an LC/MS/MS assay method, kidney transplant patients achieving everolimus whole blood trough concentrations greater than or equal to 3 ng/mL have been found to have a lower incidence of treated biopsy-proven acute rejection compared with patients whose trough concentrations were below 3 ng/mL. Patients who attained everolimus trough concentrations within the range of 6 to 12 ng/mL had similar efficacy and more adverse reactions than patients who attained lower trough concentrations between 3 to 8 ng/mL
In the kidney clinical trial
In the liver clinical trial
In the kidney transplant clinical trial [
Treatment Group | Visit | N | Target (ng/mL) | Median | 10 thpercentile | 90 thpercentile |
| Everolimus Tablets 0.75 mg twice daily | Day 3 | 242 | 100-200 | 172 | 46 | 388 |
| Day 7 | 265 | 100-200 | 185 | 75 | 337 | |
| Day 14 | 243 | 100-200 | 182 | 97 | 309 | |
| Month 1 | 245 | 100-200 | 161 | 85 | 274 | |
| Month 2 | 232 | 75-150 | 140 | 84 | 213 | |
| Month 3 | 220 | 75-150 | 111 | 68 | 187 | |
| Month 4 | 208 | 50-100 | 99 | 56 | 156 | |
| Month 6 | 200 | 25-50 | 75 | 43 | 142 | |
| Month 7 | 199 | 25-50 | 59 | 36 | 117 | |
| Month 9 | 194 | 25-50 | 49 | 28 | 91 | |
| Month 12 | 186 | 25-50 | 46 | 25 | 100 |
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In a clinical trial of de novo heart transplant patients, everolimus in an immunosuppressive regimen, with or without induction therapy, resulted in an increased mortality often associated with serious infections within the first three months posttransplantation compared to the control regimen. Use of everolimus in heart transplantation is not recommended.
Warnings and Precautions, Cannabidiol Drug Interactions (
When cannabidiol and everolimus are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of everolimus should be considered as needed when everolimus is coadministered with cannabidiol
Everolimus tablets are a mTOR inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients:
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Everolimus tablets are indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunologic risk receiving a kidney transplant
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Everolimus tablets are indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Everolimus tablets are to be administered no earlier than 30 days posttransplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids [
Mammalian target of rapamycin (mTOR) inhibitors are associated with an increase in hepatic artery thrombosis (HAT). Reported cases mostly have occurred within the first 30 days posttransplant and most also lead to graft loss or death. Therefore, everolimus should not be administered earlier than 30 days after liver transplant.
Safety and efficacy have not been established in the following:
• Kidney transplant patients at high immunologic risk (
The safety and efficacy of everolimus tablets has not been established in the following populations:
• Kidney transplant patients at high immunologic risk.
• Recipients of transplanted organs other than kidney and liver
• Pediatric patients (less than18 years).
• Recipients of transplanted organs other than kidney or liver (
The safety and efficacy of everolimus tablets has not been established in the following populations:
• Kidney transplant patients at high immunologic risk.
• Recipients of transplanted organs other than kidney and liver
• Pediatric patients (less than18 years).
In a clinical trial of de novo heart transplant patients, everolimus in an immunosuppressive regimen, with or without induction therapy, resulted in an increased mortality often associated with serious infections within the first three months posttransplantation compared to the control regimen. Use of everolimus in heart transplantation is not recommended.
• Pediatric patients (less than 18 years) (
The safety and efficacy of everolimus tablets has not been established in the following populations:
• Kidney transplant patients at high immunologic risk.
• Recipients of transplanted organs other than kidney and liver
• Pediatric patients (less than18 years).
Patients receiving everolimus tablets may require dose adjustments based on everolimus tablets blood concentrations achieved, tolerability, individual response, change in concomitant medications and the clinical situation. Optimally, dose adjustments of everolimus tablets should be based on trough concentrations obtained 4 or 5 days after a previous dosing change. Dose adjustment is required if the trough concentration is below 3 ng/mL. The total daily dose of everolimus tablets should be doubled using the available tablet strengths (0.25 mg, 0.5 mg, 0.75 mg, or 1 mg). Dose adjustment is also required if the trough concentration is greater than 8 ng/mL on 2 consecutive measures; the dose of everolimus tablets should be decreased by 0.25 mg twice daily
Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients. The recommended everolimus therapeutic range is 3 to 8 ng/mL
There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced. There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and thus, everolimus concentrations do not decrease if the tacrolimus exposure is reduced
The everolimus recommended therapeutic range of 3 to 8 ng/mL is based on an LC/MS/MS assay method. Currently in clinical practice, everolimus whole blood trough concentrations may be measured by chromatographic or immunoassay methodologies. Because the measured everolimus whole blood trough concentrations depend on the assay used, individual patient sample concentration values from different assays may not be interchangeable. Consideration of assay results must be made with knowledge of the specific assay used. Therefore, communication should be maintained with the laboratory performing the assay.
Everolimus pharmacokinetics have been characterized after oral administration of single and multiple doses to adult kidney transplant patients, hepatically-impaired patients, and healthy subjects.
After oral dosing, peak everolimus concentrations occur 1 to 2 hours post dose. Over the dose range of 0.5 mg to 2 mg twice daily, everolimus Cmaxand AUC are dose proportional in transplant patients at steady-state.
In 24 healthy subjects, a high-fat breakfast (44.5 g fat) reduced everolimus Cmaxby 60%, delayed Tmaxby a median 1.3 hours, and reduced AUC by 16% compared with a fasting administration. To minimize variability, everolimus should be taken consistently with or without food [
The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5,000 ng/mL. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume associated with the terminal phase (Vz/F) from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range: 128 to 589 L).
Elimination
Everolimus is a substrate of CYP3A4 and P-gp. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including 3monohydroxylated metabolites, 2hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies and showed approximately 100 times less activity than everolimus itself.
After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine. Parent drug was not detected in urine and feces.
Steady-state is reached by Day 4 with an accumulation in blood concentrations of 2- to 3-fold compared with the exposure after the first dose. Table 4 below provides a summary of the steady-state pharmacokinetic parameters.
C max | T max | AUC | CL/F1 | Vc/F1 | Half-life (T1/2) |
| 11.1 + 4.6 ng/mL | 1-2 h | 75 + 31 ng•h/mL | 8.8 L/h | 110 L | 30 ± 11h |
1Population pharmacokinetic analysis.
The half-life estimates from 12 maintenance renal transplant patients who received single doses of everolimus capsules at
0.75 mg or 2.5 mg with their maintenance cyclosporine regimen indicate that the pharmacokinetics of everolimus are linear over the clinically-relevant dose range. Results indicate the half-life of everolimus in maintenance renal transplant patients receiving single doses of 0.75 mg or 2.5 mg everolimus during steady-state cyclosporine treatment was 30 ± 11 hours (range: 19 to 53 hours).
Everolimus tablets are available as 0.25 mg, 0.5 mg, 0.75 mg and 1 mg tablets.
Dosage Strength | 0.25 mg | 0.5 mg | 0.75 mg | 1 mg |
Appearance | White to off white round shaped tablets debossed with "EVR" on one side and "25" on other side. | White to off white round shaped tablets debossed with "EVR" on one side and "50" on other side. | White to off white round shaped tablets debossed with "EVR" on one side and "75" on other side. | White to off white round shaped tablets debossed with "EVR" on one side and "100" on other side. |
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Based on animal studies and the mechanism of action [
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Everolimus crossed the placenta and was toxic to the conceptus.
Everolimus administered daily to pregnant rats by oral gavage at 0.1 mg/kg (approximately one tenth the exposure in humans administered the lowest starting dose of 0.75 mg twice daily), from before mating through organogenesis, resulted in increased preimplantation loss and embryonic resorptions. These effects occurred in the absence of maternal toxicities.
Everolimus administered daily by oral gavage to pregnant rabbits during organogenesis resulted in abortions, maternal toxicity and lethality, and increased fetal resorptions. At these doses, exposure to everolimus (AUC) was approximately one-tenth-, one-half-, and one-and one-half- fold the exposures in humans administered the starting clinical dose, respectively.
In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At a dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction) and in survival of offspring (~5%). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.
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There is no data regarding the presence of everolimus in human milk, the effects on breastfed infants, or the effects on milk production. Everolimus and/or its metabolites are readily transferred into milk of lactating rats at a concentration 3.5 times higher than in maternal rat serum. In pre-post-natal and juvenile studies in rats, exposure to everolimus during the postnatal period caused developmental toxicity [
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Based on animal studies and the mechanism of action [
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Everolimus crossed the placenta and was toxic to the conceptus.
Everolimus administered daily to pregnant rats by oral gavage at 0.1 mg/kg (approximately one tenth the exposure in humans administered the lowest starting dose of 0.75 mg twice daily), from before mating through organogenesis, resulted in increased preimplantation loss and embryonic resorptions. These effects occurred in the absence of maternal toxicities.
Everolimus administered daily by oral gavage to pregnant rabbits during organogenesis resulted in abortions, maternal toxicity and lethality, and increased fetal resorptions. At these doses, exposure to everolimus (AUC) was approximately one-tenth-, one-half-, and one-and one-half- fold the exposures in humans administered the starting clinical dose, respectively.
In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At a dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction) and in survival of offspring (~5%). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.
Females should not be pregnant or become pregnant while receiving everolimus tablets. Advise females of reproductive potential that animal studies have been performed showing everolimus to be harmful to the mother and developing fetus
Amenorrhea occurred in female patients taking everolimus [
Female fertility may be compromised by treatment with everolimus.
Everolimus treatment may impair fertility in males based on human [
Everolimus was not carcinogenic in mice or rats when administered daily by oral gavage for 2 years at doses up to 0.9 mg/kg, the highest dose tested. In these studies, AUCs in mice were higher (at least 20 times) than those in humans receiving 0.75 mg twice daily, and AUCs in rats were in the same range as those in humans receiving 0.75 mg twice daily.
Everolimus was not mutagenic in the bacterial reverse mutation, the mouse lymphoma thymidine kinase assay, or the chromosome aberration assay using V79 Chinese hamster cells, or
In a 13-week male fertility oral gavage study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count and plasma testosterone concentrations were diminished at 5 mg/kg which caused a decrease in male fertility. There was evidence of reversibility of these findings in animals examined after 13 weeks post- dosing. The 0.5 mg/kg dose in male rats resulted in AUCs in the range of clinical exposures, and the 5 mg/kg dose resulted in AUCs approximately 5 times the AUCs in humans receiving 0.75 mg twice daily.
Oral doses of everolimus in female rats greater or equal to 0.1 mg/kg (approximately 0.13-fold the estimated AUC 0-24h in patients receiving the starting dose 0.75mg twice daily) resulted in increased incidence of pre-implantation loss.