Everolimus

Name: Everolimus

Administration

Afinitor tablets

Swallow whole, do not break or crush tablets

Administer consistently with food or consistently without food

Afinitor Disperz

Administer Afinitor Disperz as a PO suspension only

Administer Afinitor Disperz PO qDay at the same time every day

Administer consistently with food or consistently without food

Administer suspension immediately after preparation; discard suspension if not administered within 60 minutes after preparation

Prepare suspension in water only

Zortress

Swallow tablets whole, do not chew, crush, or split

Kidney transplantation

  • Administer as soon as possible after kidney transplantation
  • Routine everolimus and cyclosporine therapeutic drug concentration monitoring is recommended
  • Administer consistently with or without food at the same time as cyclosporine

Liver transplantation

  • Do not administer until at least 30 days post liver transplant (earlier administration associated with hepatic artery thrombosis, graft loss, and death)
  • Use in combination with reduced doses of tacrolimus and with corticosteroids
  • May continue to taper corticosteroid dose on individual basis
  • Routine everolimus and tacrolimus therapeutic drug concentration monitoring is recommended

Description

Zortress (everolimus) is a macrolide immunosuppressant.

The chemical name of everolimus is (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-dioxa-4-aza-tricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2, 3,10,14,20-pentaone.

The molecular formula is C53H83NO14 and the molecular weight is 958.25. The structural formula is:

Zortress is supplied as tablets for oral administration containing 0.25 mg, 0.5 mg, and 0.75 mg of everolimus together with butylated hydroxytoluene, magnesium stearate, lactose monohydrate, hypromellose, crospovidone and lactose anhydrous as inactive ingredients.

Clinical pharmacology

Mechanism Of Action

Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.

In cells, everolimus binds to a cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian Target of Rapamycin (mTOR), a key regulatory kinase. In the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited. Consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited. The everolimus: FKBP-12 complex has no effect on calcineurin activity.

In rats and nonhuman primate models, everolimus effectively reduces kidney allograft rejection resulting in prolonged graft survival.

Pharmacokinetics

Everolimus pharmacokinetics have been characterized after oral administration of single and multiple doses to adult kidney transplant patients, hepatically-impaired patients, and healthy subjects.

Absorption

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 Cmax and AUC are dose proportional in transplant patients at steady-state.

Food Effect

In 24 healthy subjects, a high-fat breakfast (44.5 g fat) reduced everolimus Cmax by 60%, delayed Tmax by 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 [see DOSAGE AND ADMINISTRATION].

Distribution

The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5000 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).

Metabolism

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, 2 hydrolytic 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.

Excretion

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.

Pharmacokinetics In Kidney Transplant Patients

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.

Table 4: Steady-State Pharmacokinetic Parameters (mean +/- SD) Following the Administration of 0.75 mg Twice Daily

Cmax  Tmax  AUC  CL/F1  Vc/F1  Half-life (T½) 
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 Zortress during steady-state cyclosporine treatment was 30 ± 11 hours (range 19 to 53 hours).

Drug-Drug Interactions

Everolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between everolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

Cyclosporine (CYP3A4/P-gp Inhibitor and CYP3A4 Substrate): Zortress should be taken concomitantly with cyclosporine in kidney transplant patients. Everolimus concentrations may decrease when doses of cyclosporine are reduced, unless the Zortress dose is increased [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].

In a single-dose study in healthy subjects, cyclosporine (Neoral) administered at a dose of 175 mg increased everolimus AUC by 168% (range, 46% to 365%) and Cmax by 82% (range, 25% to 158%) when administered with 2 mg Zortress compared with administration of Zortress alone [see DRUG INTERACTIONS].

Ketoconazole and Other Strong CYP3A4 Inhibitors: Multiple-dose administration of 200 mg ketoconazole twice daily for 5 days to 12 healthy volunteers significantly increased everolimus Cmax, AUC, and half-life by 3.9-fold, 15-fold, and 89%, respectively, when coadministered with 2 mg Zortress. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) should not be co-administered with Zortress [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

Erythromycin (Moderate CYP3A4 Inhibitor): Multiple-dose administration of 500 mg erythromycin 3 times daily for 5 days to 16 healthy volunteers significantly increased everolimus Cmax, AUC, and half-life by 2.0-fold, 4.4-fold, and 39%, respectively, when coadministered with 2 mg Zortress. If erythromycin is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [see DRUG INTERACTIONS].

Verapamil (CYP3A4 Inhibitor and P-gp Substrate): Multiple-dose administration of 80 mg verapamil 3 times daily for 5 days to 16 healthy volunteers significantly increased everolimus Cmax and AUC by 2.3-fold and 3.5-fold, respectively, when co-administered with 2 mg Zortress. Everolimus half-life was not changed. If verapamil is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [see DRUG INTERACTIONS].

Atorvastatin (CYP3A4 Substrate) and Pravastatin (P-gp Substrate): Following administration of a single dose of 2 mg Zortress to 12 healthy subjects, the concomitant administration of a single oral dose administration of atorvastatin 20 mg or pravastatin 20 mg only slightly decreased everolimus Cmax and AUC by 9% and 10%, respectively. There was no apparent change in the mean T½ or median Tmax. In the same study, the concomitant Zortress dose slightly increased the mean Cmax of atorvastatin by 11% and slightly decreased the AUC by 7%. The concomitant Zortress dose decreased the mean Cmax and AUC of pravastatin by 10% and 5%, respectively. No dosage adjustments are needed for concomitant administration of Zortress and atorvastatin and pravastatin [see DRUG INTERACTIONS].

Midazolam (CYP3A4/5 Substrate): In 25 healthy male subjects, coadministration of a single dose of midazolam 4 mg oral solution with steady-state everolimus (10 mg daily dose for 5 days) resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC; whereas, the terminal half-life of midazolam and the metabolic AUC-ratio (1-hydroxymidazolam/midazolam) were not affected [see DRUG INTERACTIONS].

Rifampin (Strong CYP3A4 and P-gp Inducer): Pretreatment of 12 healthy subjects with multiple-dose rifampin (600 mg once daily for 8 days) followed by a single dose of 4 mg Zortress increased everolimus clearance nearly 3-fold, and decreased Cmax by 58% and AUC by 63%. Combination with rifampin is not recommended [see DRUG INTERACTIONS].

Specific Populations

Hepatic Impairment

Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC in 6 patients with mild hepatic impairment (Child-Pugh Class A) was 1.6-fold higher following administration of a 10 mg single-dose. In 2 independently studied groups of 8 and 9 patients with moderate hepatic impairment (Child-Pugh Class B) the average AUC was 2.1-fold and 3.3-fold higher following administration of a 2 mg or a 10 mg single-dose, respectively; and in 6 patients with severe hepatic impairment (Child-Pugh Class C) the average AUC was 3.6-fold higher following administration of a 10 mg single-dose. For patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh B or C), the initial daily dose should be reduced to approximately one-half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient's whole blood trough concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL [see DOSAGE AND ADMINISTRATION].

Renal Impairment

No pharmacokinetic studies in patients with renal impairment were conducted. Posttransplant renal function (creatinine clearance range 11 to 107 mL/min) did not affect the pharmacokinetics of everolimus, therefore, no dosage adjustments are needed in patients with renal impairment.

Geriatrics

A limited reduction in everolimus oral CL of 0.33% per year was estimated in adults (age range studied was 16 to 70 years). There is no evidence to suggest that elderly patients will require a different dosage recommendation from younger adult patients.

Race

Based on analysis of population pharmacokinetics, oral clearance (CL/F) is, on average, 20% higher in black transplant patients.

Everolimus Whole Blood Concentrations Observed In Kidney And In Liver Transplant Patients

Everolimus In Kidney Transplantation

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 3.0 ng/mL have been found to have a lower incidence of treated biopsy-proven acute rejection compared with patients whose trough concentrations were below 3.0 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 [see DOSAGE AND ADMINISTRATION].

In the kidney clinical trial [see Clinical Studies], everolimus whole blood trough concentrations were measured at Days 3, 7, and 14 and Months 1, 2, 3, 4, 6, 7, 9, and 12. The proportion of patients receiving 0.75 mg twice daily Zortress treatment regimen who had everolimus whole blood trough concentrations within the protocol specified target range of 3 to 8 ng/mL at Days 3, 7, and 14 were 55%, 71% and 69%, respectively. Approximately 80% of patients had everolimus whole blood trough concentrations within the 3 to 8 ng/mL target range by Month 1 and remained stable within range through Month 12 posttransplant. The median everolimus trough concentration for the 0.75 mg twice daily treatment group was between 3 and 8 ng/mL throughout the study duration.

Everolimus In Liver Transplantation

In the liver clinical trial [see Clinical Studies], Zortress dosing was initiated after 30 days following transplantation. Whole blood trough everolimus concentrations were measured within 5 days after first dose, followed by weekly intervals for 3 to 4 weeks, and then monthly thereafter. Approximately 49%, 37%, and 18% of patients, respectively, were below 3 ng/mL at 1, 2, and 4 weeks after initiation of Zortress dosing. The majority of patients (approximately 80%) had everolimus trough blood concentrations within the target range of 3 to 8 ng/mL from Month 2 through Month 24 posttransplant.

Cyclosporine Concentrations Observed In Kidney Transplant Patients

In the kidney transplant clinical trial [see Clinical Studies], the target cyclosporine whole blood trough concentration for the Zortress treatment arm of 0.75 mg twice daily were 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. Table 5 below provides a summary of the observed cyclosporine whole blood trough concentrations during the study.

Table 5: Cyclosporine Trough Concentrations Over 12 Months Posttransplant - Kidney Study Median Values (ng/mL) with 10th and 90th Percentiles

Treatment group  Visit  Target (ng/mL)  Median  10th Percentile  90th Percentile
Zortress 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

Tacrolimus Concentrations In Liver Transplant

In the liver transplant clinical trial [see Clinical Studies], the target tacrolimus whole blood trough concentrations were greater than or equal to 8 ng/mL in the first 30 days posttransplant. The protocol required that patients had a tacrolimus trough concentration of at least 8 ng/mL in the week prior to initiation of Zortress. Zortress was initiated after 30 days posttransplant. At that time, the target tacrolimus trough concentrations were reduced to 3 to 5 ng/mL. Table 6 below provides a summary of the tacrolimus whole blood trough concentrations observed during the study through Month 24 posttransplant.

Table 6: Tacrolimus Trough Concentrations Over 24 Months Posttransplant-Liver Study Median Values (ng/mL) with 10th and 90th Percentiles

Treatment group Visit N Target (ng/mL) Median 10th Percentile 90th Percentile
Predose group Week 4 234 3-5 9.5 5.8 14.6
Week 5 219 3-5 8.1 4.5 13.8
Month 2  219 3-5 5.6 3.4 10.3
Month 3  218 3-5 5.2 3.1 9.7
Month 4  196 3-5 4.9 2.9 7.7
Month 5  195 3-5 4.8 2.7 7.3
Month 6  200 3-5 4.6 3 7.5
Month 9  186 3-5 4.4 2.9 8
Month 12  175 3-5 4.3 2.6 7.3
Month 24  109 3-5 3.8 2.3 5.5

Clinical Studies

Prevention Of Organ Rejection After Kidney Transplantation

A 24-month, multi-national, open-label, randomized (1:1:1) trial was conducted comparing two concentration-controlled Zortress regimens of 1.5 mg per day starting dose (targeting 3 to 8 ng/mL using an LC/MS/MS assay method and 3.0 mg per day starting dose (targeting 6 to 12 ng/mL using an LC/MS/MS assay method) with reduced exposure cyclosporine and corticosteroids, to 1.44 g per day of mycophenolic acid with standard exposure cyclosporine and corticosteroids. The mean cyclosporine starting dose was 5.2, 5.0 and 5.7 mg/kg body weight/day in the Zortress 1.5 mg, 3.0 mg and in mycophenolic acid groups, respectively. The cyclosporine dose in the Zortress group was then adjusted to the blood trough concentration ranges indicated in Table 5, whereas in the mycophenolic acid group the target ranges were 200 to 300 ng/mL starting Day 5: 200 to 300 ng/mL, and 100 to 250 ng/mL from Month 2 to Month 12.

All patients received basiliximab induction therapy. The study population consisted of 18 to 70 year old male and female low to moderate risk renal transplant recipients undergoing their first transplant. Low-to-moderate immunologic risk was defined in the study as an ABO blood type compatible first organ or tissue transplant recipient with anti-HLA Class I PRA less than 20% by a complement dependent cytotoxicity-based assay, or less than 50% by a flow cytometry or ELISA-based assay, and with a negative T-cell cross match. Eight hundred thirty-three (833) patients were randomized after transplantation; 277 randomized to the Zortress 1.5 mg per day group, 279 to the Zortress 3.0 mg per day group and 277 to the mycophenolic acid 1.44 g per day group. The study was conducted at 79 renal transplant centers across Europe, South Africa, North and South America, and Asia-Pacific. There were no major baseline differences between treatment groups with regard to recipient or donor disease characteristics. The majority of transplant recipients in all groups (70% to 76%) had three or more HLA mismatches; mean percentage of panel reactive antibodies ranged from 1% to 2%. The rate of premature treatment discontinuation at 12 months was 30% and 22% in the Zortress 1.5 mg and control groups, respectively, (p=0.03, Fisher's exact test) and was more prominent between groups among female patients. Results at 12 months indicated that Zortress 1.5 mg per day is comparable to control with respect to efficacy failure, defined as treated biopsy-proven acute rejection*, graft loss, death or loss to follow-up. The percentage of patients experiencing this endpoint and each individual variable in the Zortress and control groups is shown in Table 7.

Table 7: Efficacy Failure by Treatment Group (ITT Population) at 12 Months after Kidney Transplantation

  Zortress (everolimus) 1.5 mg per day With reduced exposure CsA
N=277 n (%)
Mycophenolic Acid 1.44 g per day With standard exposure CsA
N=277 n (%)
Efficacy Endpoints1
Efficacy Failure Endpoint2  70 (25.3)  67 (24.2) 
  Treated Biopsy Proven Acute Rejection  45 (16.2)  47 (17.0) 
  Death  7 (2.5)  6 (2.2) 
  Graft Loss  12 (4.3)  9 (3.2) 
  Loss to Follow-up  12 (4.3)  9 (3.2) 
Graft Loss or Death or Loss to Follow-up3  32 (11.6)  26 (9.4) 
  Graft Loss or Death  18 (6.5)  15 (5.4) 
  Loss to Follow-up3  14 (5.1)  11 (4.0) 
*Treated biopsy-proven acute rejection (tBPAR) was defined as a histologically confirmed acute rejection with a biopsy graded as IA, IB, IIA, IIB, or III according to 1997 Banff criteria that were treated with anti-rejection medication.
1The difference in rates (Zortress-mycophenolic acid) with 95% CI for primary efficacy failure endpoint is 1.1% (-6.1%, 8.3%); and for the graft loss, death or loss to follow-up endpoint is 2.2% (-2.9%, 7.3%).
2Includes treated BPAR, graft loss, death or loss to follow-up by Month 12 where loss to follow-up represents patient who did not experience treated BPAR, graft loss or death and whose last contact date is prior to 12 month visit
3Loss to follow-up (for Graft Loss, Death, or Loss to Follow-up) represents patient who did not experience death or graft loss and whose last contact date is prior to 12 month visit

The estimated mean glomerular filtration rate (using the MDRD equation) for Zortress 1.5 mg (target trough concentrations 3 to 8 ng/mL) and mycophenolic acid groups were comparable at Month 12 in the ITT population (Table 8).

Table 8: Estimated Glomerular Filtration Rates (mL/min/1.73m²) by MDRD at 12 Months after Kidney Transplantation*

Month 12 GFR (MDRD)  Zortress (everolimus) 1.5 mg per day with reduced exposure CsA
 N=276 
Mycophenolic Acid 1.44 g per day with standard exposure CsA 
N=277 
Mean (SD)**  54.6 (21.7)  52.3 (26.5) 
Median (Range)  55.0 (0-140.9)  50.1 (0.0-366.4) 
*Analysis based on using a subject's last observation carried forward for missing data at 12 months due to death or lost to follow-up data, a value of zero is used for subjects who experienced a graft loss.
**SD=standard deviation

Two earlier studies compared fixed doses of Zortress 1.5 mg per day and 3 mg per day, without TDM, combined with standard exposure cyclosporine and corticosteroids to mycophenolate mofetil 2.0 g per day and corticosteroids. Antilymphocyte antibody induction was prohibited in both studies. Both were multicenter, double-blind (for first 12 months), randomized trials (1:1:1) of 588 and 583 de novo renal transplant patients, respectively. The 12-month analysis of GFR showed increased rates of renal impairment in both the Zortress groups compared to the mycophenolate mofetil group in both studies. Therefore, reduced exposure cyclosporine should be used in combination with Zortress in order to avoid renal dysfunction and everolimus trough concentrations should be adjusted using TDM to maintain trough concentrations between 3 to 8 ng/mL [see BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

Prevention Of Organ Rejection After Liver Transplantation

A 24-month, multinational, open-label, randomized (1:1:1) trial was conducted in liver transplant patients starting 30 days posttransplant. During the first 30 days, after transplant and prior to randomization, patients received tacrolimus and corticosteriods, with or without mycophenolate mofetil. No induction antibody was administered. Approximately 70% to 80% of patients received at least one dose of mycophenolate mofetil at a median total daily dose of 1.5 g during the first 30 days. For eligibility, patients had to have a tacrolimus trough concentration of at least 8 ng/mL in the week prior to randomization.

At randomization, mycophenolate mofetil was discontinued and patients were randomized to one of two Zortress treatment groups [initial dose of 1 mg twice per day (2 mg daily) and adjusted to target trough concentrations using an LC/MS/MS assay of 3 to 8 ng/mL] either with reduced exposure of tacrolimus (target trough whole blood concentrations of 3 to 5 ng/mL) or tacrolimus elimination. In the tacrolimus elimination group, at Month 4 posttransplant, once the everolimus trough concentrations were within the target range of 6 to 10 ng/mL, reduced exposure tacrolimus was eliminated. The Zortress with tacrolimus elimination group was discontinued early due to higher incidence of acute rejection. In the control group, patients received standard exposure tacrolimus (target trough whole blood concentrations of 8 to 12 ng/mL tapered to 6 to 10 ng/mL by month 4 posttransplant). All patients received corticosteroids during the trial.

The study population consisted of 18 to 70 year old male and female liver transplant recipients undergoing their first transplant, mean age was approximately 54 years, more than 70% of patients were male, and the majority of patients were Caucasian, with approximately 89% of patients per treatment group completing the study. Key stratification parameters of HCV status (31 to 32% HCV positive across groups) and renal function (mean baseline eGFR range 79 to 83 mL/min/1.73 m²) were also balanced between groups.

A total of 1147 patients were enrolled into the run-in period of this trial. At 30 days posttransplant a total 719 patients, who were eligible according to study inclusion/exclusion criteria, were randomized into 1 of 3 treatment groups: Zortress with reduced exposure tacrolimus; N=245, Zortress with tacrolimus elimination (tacrolimus elimination group); N=231, or standard dose/exposure tacrolimus (tacrolimus control); N=243. The study was conducted at 89 liver transplant centers across Europe, including the United Kingdom and Ireland, North and South America, and Australia.

Key inclusion criteria were recipients 18 to 70 years of age, eGFR greater than or equal to 30 mL/min/1.73 m², tacrolimus trough level of greater than or equal to 8 ng/mL in the week prior to randomization, and the ability to take oral medication.

Key exclusion criteria were recipients of multiple solid organ transplants, history of malignancy (except hepatocellular carcinoma within Milan criteria), human immunodeficiency virus, and any surgical or medical condition which significantly alter the absorption, distribution, metabolism and excretion of study drug.

There were no major baseline differences between treatment groups with regard to recipient or donor disease characteristics. Mean MELD scores at time of transplantation, cold ischemia times (CIT), and ABO matching were similar across groups. Overall the treatment groups were comparable with respect to the key determinants of liver transplantation.

The tacrolimus elimination group was stopped prematurely due to a higher incidence of acute rejection and adverse reactions leading to treatment discontinuation reported during the elimination phase of tacrolimus. Therefore, a treatment regimen of Zortress with tacrolimus elimination is not recommended.

Results up to 24 months are presented indicating that Zortress with reduced exposure tacrolimus is comparable to standard exposure tacrolimus with respect to efficacy failure, defined as treated biopsy-proven acute rejection, graft loss, death or loss to follow-up throughout 12-24 months of treatment. The percentage of patients experiencing this endpoint and each individual variable in the Zortress and control group for each time interval is shown in Table 9.

Table 9: Efficacy Failure by Treatment Group (ITT Population) at 12 and 24 Months after Liver Transplantation

  Zortress (everolimus) With reduced Exposure Tacrolimus
N=245 n (%)
Tacrolimus (standard exposure)
N=243 n (%)
Efficacy Endpoints1 at 12 months
Composite Efficacy Failure Endpoint1,2  22 (9.0)  33 (13.6) 
  Treated Biopsy Proven Acute Rejection*  7 (2.9)  17 (7.0) 
  Death  13 (5.3)  7 (2.9) 
  Graft Loss  6 (2.4)  3 (1.2) 
  Loss to Follow-up2  4 (1.6)  9 (3.7) 
Graft Loss or Death or Loss to Follow-up3  18 (7.3)  18 (7.4) 
  Graft Loss or Death  14 (5.7)  8 (3.3) 
  Loss to Follow-up3  4 (1.6)  10 (4.1) 
Efficacy Endpoints at 24 months 
Composite Efficacy Failure Endpoint2  45 (18.4)  53 (21.8) 
  Treated Biopsy Proven Acute Rejection 11 (4.5)  18 (7.4) 
  Death  17 (6.9)  11 (4.5) 
  Graft loss  9 (3.7)  7 (2.9) 
  Loss to follow-up2  18 (7.3)  23 (9.5) 
Graft loss or Death or Loss to follow-up3  38 (15.5)  39 (16.0) 
  Graft loss or Death  20 (8.2)  15 (6.2) 
  Loss to follow-up3  18 (7.3)  24 (9.9) 
*Treated biopsy-proven acute rejection (tBPAR) was defined as histologically confirmed acute rejection with a rejection activity index (RAI) greater than or equal to RAI score 3 that received antirejection treatment.
1The difference in rates (Zortress - control) at 12 months with 97.5% CI for efficacy failure endpoint based on normal approximation with Yates continuity correction is -4.6% (-11.4%, 2.2%); and for the graft loss, death or loss to follow-up endpoint is -0.1% (-5.4%, 5.3%).
2Loss to follow-up (for treated BPAR, graft loss, death or loss to follow-up) represents patients who did not experience treated BPAR, graft loss or death and whose last contact date is prior to 12- or 24-month visit.
3Loss to follow-up (for graft loss, death, or loss to follow-up) represents patients who did not experience death or graft loss and whose last contact date is prior to 12- or 24- month visit.

At 12 months, the estimated mean glomerular filtration rate eGFR (using the MDRD equation) for the Zortress group was 80.9 mL/min/1.73m² and the tacrolimus control was 70.3 mL/min/1.73 m² in the ITT population. At Month 24, the estimated mean glomerular filtration rate eGFR (using the MDRD equation) for the Zortress group was 74.7 mL/min/1.73m² and the tacrolimus control was 67.8 mL/min/1.73 m² (Table 10).

Table10: Estimated Glomerular Filtration Rates (mL/min/1.73m²) by MDRD at 12 and 24 Months after Liver Transplantation

eGFR (MDRD)  Zortress (everolimus) with reduced exposure Tacrolimus  Tacrolimus (standard exposure) 
Month 12  N=215  N=209 
  Mean (SD)  80.9 (27.3)  70.3 (23.1) 
  Median (Range)  78.3 (28.4-153.1)  66.4 (27.9-155.8) 
Month 24  N=184  N=186 
  Mean (SD)  74.7 (26.1)  67.8 (21.0) 
  Median (Range)  72.9 (20.3-151.6)  65.2 (27.0-148.9) 

Figure 1: Mean and 95% CI of eGFR (MDRD 4) [mL/min/1.73m²] by Visit Window and Treatment after Liver Transplantation (ITT population 24 Month Analysis)*

*Zortress dosing was initiated 30 days after transplantation

Although the initial protocol was designed for 24 months, the study was subsequently extended to 36 months. One hundred six patients (43%) in the Zortress group and 125 patients (51%) in the control group participated in the extension study from Month 24 to Month 36 after transplantation. The results for the Zortress group at 36 months were consistent with the results at 24 months in terms of tBPAR, graft loss, death and eGFR.

Everolimus Interactions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • St. John’s wort 
  • Medicine for: 
          ○  Fungal infections 
          ○  Bacterial infections 
          ○  Tuberculosis
          ○  Seizures 
          ○  HIV-AIDS 
          ○  Heart conditions or high blood pressure
  • Medicines that suppress your immune system

This is not a complete list of everolimus drug interactions. Ask your doctor or pharmacist for more information.

What is the most important information i should know about zortress (zortress)?

This medication guide provides information about the Zortress brand of everolimus. Afinitor is another brand of everolimus used to treat kidney cancer.

You should not use this medication if you are allergic to everolimus or sirolimus (Rapamune), or if you have problems digesting lactose or galactose (sugar).

Taking Zortress may increase your risk of developing other types of cancer such as lymphoma or skin cancer. Ask your doctor about your individual risk.

Before taking everolimus, tell your doctor if you have liver disease, high cholesterol, a blood clotting disorder, a breathing disorder such as asthma or COPD, a history of skin cancer, or if you are pregnant.

It is not known whether Zortress will harm an unborn baby. Use effective birth control while you are using this medication and for at least 8 weeks after your treatment ends.

Serious and sometimes fatal infections may occur during treatment with Zortress. Stop using this medicine and call your doctor right away if you have signs of infection such as fever, chills, body aches, or flu symptoms.

Do not receive a "live" vaccine while taking everolimus. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), oral polio, typhoid, chickenpox (varicella), BCG (Bacillus Calmette and Guérin), and nasal flu vaccine.

There are many other drugs that can interact with everolimus. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

To be sure this medicine is not causing harmful effects, your blood will need to be tested often. Your kidney function may also need to be tested. Visit your doctor regularly.

What is everolimus (Zortress)?

Everolimus lowers your body's immune system. The immune system helps your body fight infections. The immune system can also fight or "reject" a transplanted organ such as a liver or kidney. This is because the immune system treats the new organ as an invader.

The Zortress brand of everolimus is used to prevent organ rejection after a kidney or liver transplant. Zortress is used together with cyclosporine, steroids, and other medications.

This medication guide provides information about the Zortress brand of everolimus. Afinitor is another brand of everolimus used to treat certain types of cancer.

Everolimus may also be used for purposes not listed in this medication guide.

How should I take Zortress?

Zortress is usually taken twice daily (every 12 hours). Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take the medicine with or without food, but take it the same way each time. If you also take cyclosporine or tacrolimus, take both medications at the same time.

Do not stop taking Zortress or change your dose without first talking to your doctor.

Take this medication with a full glass (8 ounces) of water.

Do not crush or chew an everolimus tablet. Swallow the pill whole.

While using Zortress, you will need frequent blood and urine tests at your doctor's office.

Store at room temperature in the original container, away from moisture, heat, and light. Keep each tablet in its blister pack until you are ready to take it.

Everolimus dosing information

Usual Adult Dose for Breast Cancer:

10 mg orally once a day

Comments:
-Dose should be taken at the same time each day.
-Dose should be taken consistently with or without food.
-Afinitor (R) tablets should be swallowed whole with a glass of water and not chewed, broken, or crushed.

Uses:
AFINITOR(R):
1) Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC):
-Treatment of postmenopausal women with advanced hormone receptor positive, HER2 negative breast cancer in combination with exemestane, after treatment with letrozole or anastrozole has failed.
2) Advanced Neuroendocrine Tumors (NET):
-Treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.
-Treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.
3) Advanced Renal Cell Carcinoma (RCC):
-Treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.
4) Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC):
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

Usual Adult Dose for Renal Cell Carcinoma:

10 mg orally once a day

Comments:
-Dose should be taken at the same time each day.
-Dose should be taken consistently with or without food.
-Afinitor (R) tablets should be swallowed whole with a glass of water and not chewed, broken, or crushed.

Uses:
AFINITOR(R):
1) Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC):
-Treatment of postmenopausal women with advanced hormone receptor positive, HER2 negative breast cancer in combination with exemestane, after treatment with letrozole or anastrozole has failed.
2) Advanced Neuroendocrine Tumors (NET):
-Treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.
-Treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.
3) Advanced Renal Cell Carcinoma (RCC):
-Treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.
4) Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC):
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

Usual Adult Dose for Pancreatic Cancer:

10 mg orally once a day

Comments:
-Dose should be taken at the same time each day.
-Dose should be taken consistently with or without food.
-Afinitor (R) tablets should be swallowed whole with a glass of water and not chewed, broken, or crushed.

Uses:
AFINITOR(R):
1) Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC):
-Treatment of postmenopausal women with advanced hormone receptor positive, HER2 negative breast cancer in combination with exemestane, after treatment with letrozole or anastrozole has failed.
2) Advanced Neuroendocrine Tumors (NET):
-Treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.
-Treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.
3) Advanced Renal Cell Carcinoma (RCC):
-Treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.
4) Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC):
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

Usual Adult Dose for Renal Angiomyolipoma:

10 mg orally once a day

Comments:
-Dose should be taken at the same time each day.
-Dose should be taken consistently with or without food.
-Afinitor (R) tablets should be swallowed whole with a glass of water and not chewed, broken, or crushed.

Uses:
AFINITOR(R):
1) Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC):
-Treatment of postmenopausal women with advanced hormone receptor positive, HER2 negative breast cancer in combination with exemestane, after treatment with letrozole or anastrozole has failed.
2) Advanced Neuroendocrine Tumors (NET):
-Treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.
-Treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.
3) Advanced Renal Cell Carcinoma (RCC):
-Treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.
4) Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC):
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

Usual Adult Dose for Neuroendocrine Carcinoma:

10 mg orally once a day

Comments:
-Dose should be taken at the same time each day.
-Dose should be taken consistently with or without food.
-Afinitor (R) tablets should be swallowed whole with a glass of water and not chewed, broken, or crushed.

Uses:
AFINITOR(R):
1) Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC):
-Treatment of postmenopausal women with advanced hormone receptor positive, HER2 negative breast cancer in combination with exemestane, after treatment with letrozole or anastrozole has failed.
2) Advanced Neuroendocrine Tumors (NET):
-Treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.
-Treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.
3) Advanced Renal Cell Carcinoma (RCC):
-Treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.
4) Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC):
-Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

Usual Adult Dose for Brain/Intracranial Tumor:

4.5 mg/m2 orally once a day

Duration of therapy: Continue until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown.

Comments:
-Dose should be taken at the same time each day.
-Dose should be taken consistently with or without food.
-Afinitor (R) tablets should be swallowed whole with a glass of water and not chewed, broken, or crushed.
-Do not combine AFINITOR (R) tablets and AFINITOR DISPERZ (R) to achieve the desired total dose.
-Use therapeutic drug monitoring to guide subsequent dosing.
-Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5 to 15 ng/mL.

Use:
Afinitor(R) and Afinitor Disperz (R):
The treatment of adult and pediatric patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected

Usual Adult Dose for Organ Transplant -- Rejection Prophylaxis:

Kidney transplant: 0.75 mg orally twice a day

Comments:
-This drug should be administered in combination with reduced dose cyclosporine as soon as possible after transplantation.
-Oral prednisone should be initiated once oral medication is tolerated. Doses may be further individualized based on the clinical status of the patient and function of the graft.

Liver transplant: 1 mg orally twice a day

Comments:
-Start therapy at least 30 days after transplant.
-Use this drug in combination with reduced dose tacrolimus.
-Steroid doses may be individualized based on the clinical status of the patient and function of the graft.

Uses:
Zortress(R):
-Prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant and in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids.
-Prophylaxis of allograft rejection in adult patients receiving a liver transplant to be administered no earlier than 30 days post-transplant concurrently with reduced doses of tacrolimus and with corticosteroids.

Usual Pediatric Dose for Brain/Intracranial Tumor:

4.5 mg/m2 orally once a day

Duration of therapy: Continue until disease progression or unacceptable toxicity occurs.

Use:
Afinitor(R) and Afinitor Disperz(R):
The treatment of adult and pediatric patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not candidates for curative surgical resection.

What other drugs will affect Zortress?

Many drugs can interact with Zortress. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

  • cyclosporine or others medicine to prevent organ transplant rejection;

  • St. John's wort;

  • an antibiotic or antifungal medicine;

  • cholesterol medication;

  • heart or blood pressure medicine;

  • HIV/AIDS medication;

  • seizure medicine; or

  • tuberculosis medication.

This list is not complete and many other drugs can interact with Zortress. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Introduction

Antineoplastic and macrolide immunosuppressive agent; inhibitor of mammalian target of rapamycin (mTOR) kinase.1 2 3 4 5 7 8 9 10 11 13

Everolimus Dosage and Administration

General

Therapeutic Drug Monitoring in Patients with SEGA and TSC

  • The manufacturer recommends routine monitoring of whole blood trough everolimus concentrations for all patients.1 Use the same assay and laboratory when possible.1

  • Measure trough concentrations approximately 2 weeks after initiation of everolimus treatment, any change in everolimus dosage, any change in concomitant treatment with inducers or inhibitors of CYP3A4 and/or P-glycoprotein, a change in hepatic function, or a change in dosage form between everolimus tablets (Afinitor) and everolimus tablets for oral suspension (Afinitor Disperz).1

Therapeutic Drug Monitoring in Renal Allotransplantation Patients

  • The manufacturer recommends monitoring of blood everolimus and cyclosporine concentrations for all patients.13 Standard dosages of cyclosporine in combination with everolimus are associated with an increased risk of nephrotoxicity and should not be used.(See Boxed Warning and also see Nephrotoxicity under Cautions).13

  • Carefully monitor clinical signs and symptoms, tissue biopsies, and laboratory parameters.13

  • Carefully monitor blood everolimus concentrations in patients with hepatic impairment, patients receiving concomitant inducers or inhibitors of CYP3A4, when switching cyclosporine formulations, and/or when cyclosporine dosages are reduced according to recommended target concentrations.13

Therapeutic Drug Monitoring in Hepatic Allotransplantation Patients

  • The manufacturer recommends monitoring of blood everolimus and tacrolimus concentrations for all patients.13

  • Carefully monitor clinical signs and symptoms, tissue biopsies, and laboratory parameters.13

  • Carefully monitor blood everolimus concentrations in patients with hepatic impairment and/or in patients receiving concomitant inducers or inhibitors of CYP3A4.13

  • Cyclosporine not used in combination with everolimus in patients with hepatic transplant.13

Administration

Oral Administration

Administer everolimus at the same time every day (or approximately 12 hours apart when given twice daily), either consistently with food or consistently without food.1 13

Available as tablets (Afinitor, Zortress) and as tablets for oral suspension (Afinitor Disperz).1 13 Afinitor Disperz is recommended only for treatment of SEGA with TSC.1 Do not combine everolimus tablets (Afinitor) and everolimus tablets for oral suspension (Afinitor Disperz) to achieve the desired dose; use only one dosage form.1

Tablets

Administer everolimus tablets (Afinitor, Zortress) orally once or twice daily.1 2 3 13

In patients with renal or hepatic allografts, administer twice daily at the same time as cyclosporine or tacrolimus, respectively.13

Swallow everolimus tablets whole with a glass of water; do not chew or crush.1 13

Tablets for Oral Suspension

Administer everolimus tablets for oral suspension (Afinitor Disperz) once daily.1

For administration using an oral syringe, place the prescribed dose (≤10 mg) in a 10-mL syringe; do not crush or break tablets.1 Draw approximately 5 mL of water and 4 mL of air into syringe; place syringe containing mixture in a container (tip up) for 3 minutes, until tablets are in suspension.1 Gently invert the syringe 5 times immediately prior to administration.1 Following administration, refill the syringe with 5 mL of water and 4 mL of air, swirl to suspend remaining particles, and administer entire contents of syringe.1 Prepare an additional syringe if a dose of >10 mg is required.1

For administration using a small drinking glass, place the prescribed dose (≤10 mg) in a glass (size ≤100 mL) containing approximately 25 mL of water; do not crush or break tablets.1 Allow mixture to suspend for 3 minutes.1 Gently stir the mixture with a spoon immediately prior to administration.1 Following administration, add 25 mL of water to the glass and stir with the same spoon to resuspend the remaining particles, and swallow entire contents of the glass.1 Prepare an additional glass if a dose of >10 mg is required.1

Dosage

Pediatric Patients

SEGA with TSC Initial Dosage Oral

4.5 mg/m2 once daily.1

Not studied in patients <1 year of age.1

Round dosage to the nearest strength of either everolimus tablets (Afinitor) or everolimus tablets for oral suspension (Afinitor Disperz).1 Subsequent dosing should be guided by therapeutic drug monitoring.1

Continue therapy until disease progression or unacceptable toxicity occurs.1 The optimal duration of therapy is not known.1

Therapeutic Drug Monitoring and Dosage Adjustments in SEGA with TSC Oral

Adjust dosage at 2-week intervals as needed to achieve and maintain trough blood everolimus concentrations of 5–15 ng/mL.1

Higher trough concentrations may be associated with larger reductions in SEGA volume; however, responses have been observed at trough concentrations as low as 5 ng/mL, and additional dosage increases may not be necessary once acceptable efficacy has been achieved.1

Patients with trough concentrations <5 ng/mL: Increase daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).1

Patients with trough concentrations >15 ng/mL: Reduce daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).1

If dosage reduction is required in patients receiving 2.5 mg (as Afinitor) or 2 mg (as Afinitor Disperz) daily, use alternate-day dosing.1

Once a stable dosage is attained, monitor trough concentrations every 3–6 months in patients with changing body surface area and every 6–12 months in patients with stable body surface area for the duration of treatment.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderate inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

Adults

Breast Cancer Oral

10 mg once daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

Neuroendocrine Tumors of Pancreatic Origin Oral

10 mg once daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

Renal Cell Carcinoma Oral

10 mg once daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

Renal Angiomyolipoma with TSC Oral

10 mg once daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderately potent inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein.1 (See Specific Drugs and Foods under Interactions).

SEGA with TSC Initial Dosage Oral

4.5 mg/m2 once daily.1

Round dosage to the nearest strength of either everolimus tablets (Afinitor) or everolimus tablets for oral suspension (Afinitor Disperz).1 Subsequent dosing should be guided by therapeutic drug monitoring.1

Continue therapy until disease progression or unacceptable toxicity occurs.1 The optimal duration of therapy is not known.1

Therapeutic Drug Monitoring and Dosage Adjustments in SEGA with TSC Oral

Adjust dosage at 2-week intervals as needed to achieve and maintain trough blood everolimus concentrations of 5–15 ng/mL.1

Higher trough concentrations may be associated with larger reductions in SEGA volume; however, responses have been observed at trough concentrations as low as 5 ng/mL, and additional dosage increases may not be necessary once acceptable efficacy has been achieved.1

Patients with trough concentrations <5 ng/mL: Increase daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).1

Patients with trough concentrations >15 ng/mL: Reduce daily dosage by 2.5 mg (in patients receiving Afinitor) or 2 mg (in patients receiving Afinitor Disperz).1

If dosage reduction is required in patients receiving 2.5 mg (as Afinitor) or 2 mg (as Afinitor Disperz) daily, use alternate-day dosing.1

Once a stable dosage is attained, monitor trough concentrations every 3–6 months in patients with changing body surface area and every 6–12 months in patients with stable body surface area for the duration of treatment.1

Consider dosage adjustments when used in conjunction with potent inducers of CYP3A4, moderate inhibitors of CYP3A4, and/or inhibitors of P-glycoprotein. (See Specific Drugs and Foods under Interactions).1

Renal Allotransplantation Initial Dosage Oral

Initially, 0.75 mg twice daily, initiated as soon as possible following transplantation; used with basiliximab induction therapy and in combination with reduced-dosage cyclosporine and corticosteroids.13

Administer oral prednisone once oral medications are tolerated.13 May taper corticosteroid dosage on an individualized basis based on patient’s clinical status and allograft function.13

Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus in Renal Allotransplantation Oral

Adjust dosage based on trough blood everolimus concentrations, tolerability, individual response, change in concomitant drug therapy, and clinical situation.13 (See Interactions). May adjust maintenance dosage based on trough everolimus concentrations obtained 4–5 days after a previous dosage change in either everolimus or cyclosporine.13

Titrate dosage to attain therapeutic trough everolimus concentrations of 3–8 ng/mL.13 In clinical trials, whole blood trough concentrations ≥3 ng/mL were associated with a lower incidence of treated biopsy-proven acute rejection.13 Similar efficacy and more adverse effects observed in patients with trough everolimus concentrations of 6–12 ng/mL compared with patients with trough concentrations of 3–8 ng/mL.13

Recommended therapeutic range of 3–8 ng/mL is based on a liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay method.13 May measure concentrations by chromatographic or immunoassay methodologies; however, the measured concentrations depend on the type of assay used, and individual patient sample concentration values from different assay methodologies may not be interchangeable.13 Consider assay results with knowledge of the specific assay used.13 Maintaining communication with the laboratory performing the assay is essential.13

Therapeutic Drug Monitoring and Dosage Adjustment of Cyclosporine with Everolimus in Renal Allotransplantation Oral

Reduce cyclosporine dosage and target therapeutic range when used in combination with everolimus to minimize risk of nephrotoxicity. (See Nephrotoxicity under Cautions.)13

Adjust cyclosporine dosage based on whole blood trough concentrations.13 The recommended therapeutic ranges for cyclosporine are 100–200 ng/mL through month 1 posttransplant, 75–150 ng/mL at months 2 and 3, 50–100 ng/mL at month 4, and 25–50 ng/mL from month 6 through month 12.13

Administer cyclosporine (USP modified) as oral capsules twice daily unless administration of oral solution or IV cyclosporine cannot be avoided.13 Everolimus has not been evaluated in clinical trials with other formulations of cyclosporine.13

Initiate cyclosporine as soon as possible and no later than 48 hours after reperfusion of the graft, and adjust the dosage to target concentrations from day 5 onward.13 Adjust the treatment regimen if progressive impairment of renal function occurs.13

Data regarding everolimus dosages with reduced trough cyclosporine concentrations of 25–50 ng/mL after 12 months are limited.13

Prior to dosage reduction of cyclosporine, verify steady-state whole blood trough everolimus concentrations of ≥3 ng/mL.13 Everolimus concentrations may decrease if cyclosporine exposure is reduced.13

Hepatic Allotransplantation Initial Dosage Oral

Initially, 1 mg twice daily, initiated ≥30 days following transplantation; used in combination with reduced-dosage tacrolimus and corticosteroids.13

May taper corticosteroid dosage on an individualized basis based on patient’s clinical status and allograft function.13

Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus in Hepatic Allotransplantation Oral

Adjust dosage based on trough blood everolimus concentrations, tolerability, individual response, change in concomitant drug therapy, and clinical situation.13 (See Interactions.) May adjust maintenance dosage based on trough everolimus concentrations obtained 4–5 days after a previous dosage change.13

Titrate dosage to attain therapeutic trough everolimus concentrations of 3–8 ng/mL.13 In clinical trials, whole blood trough concentrations ≥3 ng/mL were associated with a lower incidence of treated biopsy-proven acute rejection.13 Similar efficacy and more adverse effects observed in patients with trough everolimus concentrations of 6–12 ng/mL compared with patients with trough concentrations of 3–8 ng/mL.13

Therapeutic Drug Monitoring and Dosage Adjustment of Tacrolimus with Everolimus in Hepatic Allotransplantation Oral

Reduce tacrolimus dosage and target therapeutic range when used in combination with everolimus to minimize risk of nephrotoxicity.13 (See Nephrotoxicity under Cautions.)

Adjust tacrolimus dosage based on whole blood trough concentrations.13 Recommended therapeutic range for tacrolimus is 3–5 ng/mL by 3 weeks after the first dose of everolimus (approximately month 2 posttransplant) through month 12 posttransplant.13

Administer tacrolimus as oral capsules twice daily unless administration of IV tacrolimus cannot be avoided.13

Data regarding everolimus dosages with reduced trough tacrolimus concentrations of 3–5 ng/mL after 12 months are limited.13 Prior to dosage reduction of tacrolimus, verify steady-state whole blood trough everolimus concentrations of ≥3 ng/mL.13

Tacrolimus does not affect everolimus concentrations.13

Dosage Modification for Toxicity

Adjustment of everolimus dosage and/or interruption of therapy may be required according to toxicity.1 The suggested dosage is approximately 50% lower than the previously administered daily dosage, if dosage reduction is required.1

Noninfectious Pneumonitis

In patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.

Table 1. Recommended Dosage Modifications for Noninfectious Pneumonitis with Everolimus1

Toxicity Grade

Number of Appearances

Comments

Grade 1 (asymptomatic, radiographic findings only)

Any appearance

No dosage adjustment necessary; monitor appropriately

Grade 2 (symptomatic, not interfering with activities of daily living)

1st appearance

Consider interrupting therapy until symptoms improve to grade 1 or less and initiating corticosteroids, then resume everolimus at lower daily dosage; discontinue therapy if failure to recover within 4 weeks

Grade 3 (symptomatic, interfering with activities of daily living, oxygen indicated) 

1st appearance

Interrupt therapy until resolved to grade 1 or less, then may resume at lower daily dosage; rule out infection and consider initiating corticosteroids

 

2nd appearance

Consider therapy discontinuance

Grade 4 (life-threatening, ventilatory support indicated)

1st appearance

Discontinue therapy permanently, rule out infection, and consider initiating corticosteroids

Stomatitis

In patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.

Table 2. Recommended Dosage Modifications for Stomatitis with Everolimus1

Toxicity Grade

Number of Appearances

Comments

Grade 1 (minimal symptoms, normal diet)

Any appearance

Continue therapy without dosage adjustment

Grade 2 (symptomatic, can eat and swallow modified diet)

1st appearance

Interrupt therapy until resolved to grade 0–1, then resume at original daily dosage

2nd appearance

Interrupt therapy until resolved to grade 0–1, then resume at lower daily dosage

Grade 3 (symptomatic, unable to adequately aliment or hydrate orally)

1st appearance

Interrupt therapy until resolved to grade 0–1, then resume at lower daily dosage

Grade 4 (symptoms associated with life-threatening consequences)

1st appearance

Discontinue therapy permanently

Other Nonhematologic Toxicity

Excluding metabolic events; in patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.

Table 3. Recommended Dosage Modifications for Nonhematologic Toxicity with Everolimus1

Toxicity Grade

Number of Appearances

Comments

Grade 1 (mild symptoms)

Any appearance

If toxicity is tolerable, continue therapy without dosage adjustment

Grade 2 (moderate symptoms)

1st appearance

If toxicity is tolerable, continue therapy without dosage adjustment. If toxicity is intolerable, interrupt therapy until resolved to grade 0–1, then resume at original dosage

2nd appearance

Interrupt therapy until resolved to grade 0–1, then resume at lower dosage

Grade 3 (severe symptoms)

1st appearance

Interrupt therapy until resolved to grade 0–1, then consider reinitiating therapy at lower dosage

2nd appearance

Consider therapy discontinuance

Grade 4 (life-threatening symptoms)

1st appearance

Discontinue therapy permanently

Metabolic Events

Metabolic events include hyperglycemia and dyslipidemia; in patients with breast cancer, PNET, renal cell carcinoma, or renal angiomyolipoma.

Table 4. Recommended Dosage Modifications for Metabolic Events with Everolimus1

Toxicity Grade

Number of Appearances

Comments

Grade 1 (mild symptoms)

Any appearance

Continue therapy without dosage adjustment

Grade 2 (moderate symptoms)

Any appearance

Continue therapy without dosage adjustment

Grade 3 (severe symptoms)

1st appearance

Interrupt therapy temporarily, then resume at lower dosage

Grade 4 (life-threatening symptoms)

1st appearance

Discontinue therapy permanently

Special Populations

Hepatic Impairment

Breast Cancer, Neuroendocrine Tumors of Pancreatic Origin, Renal Cell Carcinoma, or Renal Angiomyolipoma with TSC Oral

Mild (Child-Pugh class A) hepatic impairment: 7.5 mg daily; may decrease dosage to 5 mg daily if not well tolerated.1

Moderate (Child-Pugh class B) hepatic impairment: 5 mg daily; may decrease dosage to 2.5 mg daily if not well tolerated.1

Severe (Child-Pugh class C) hepatic impairment: If potential benefit outweighs risk, may use maximum dosage of 2.5 mg daily.1

If hepatic status changes during treatment, adjust dosage accordingly.1

SEGA with TSC Oral

Mild or moderate (Child-Pugh class A or B) hepatic impairment: Adjustment of initial dosage may not be necessary; base subsequent dosage on therapeutic drug monitoring.1

Severe (Child-Pugh class C) hepatic impairment: Decrease initial dosage by approximately 50%; base subsequent dosage on therapeutic drug monitoring.1

Renal or Hepatic Allotransplantation Oral

Mild (Child-Pugh class A) hepatic impairment: Decrease initial dosage by approximately 33%; adjust subsequent dosage to attain trough concentrations of 3–8 ng/mL.13

Moderate or severe (Child-Pugh class B or C) hepatic impairment: Decrease initial dosage by approximately 50%; adjust subsequent dosage to attain trough concentrations of 3–8 ng/mL.13

Renal Impairment

Dosage adjustment not required.1 13

Geriatric Patients

Dosage adjustment not required.1 13 Close monitoring and appropriate dosage adjustments for adverse effects are recommended for Afinitor and Afinitor Disperz.1

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Everolimus

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.25 mg

Zortress

Novartis

0.5 mg

Zortress

Novartis

0.75 mg

Zortress

Novartis

2.5 mg

Afinitor

Novartis

5 mg

Afinitor

Novartis

7.5 mg

Afinitor

Novartis

10 mg

Afinitor

Novartis

Tablets for oral suspension

2 mg

Afinitor Disperz

Novartis

3 mg

Afinitor Disperz

Novartis

5 mg

Afinitor Disperz

Novartis

Commonly used brand name(s)

In the U.S.

  • Afinitor
  • Afinitor Disperz
  • Zortress

Available Dosage Forms:

  • Tablet for Suspension
  • Tablet

Therapeutic Class: Antineoplastic Agent

everolimus Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Bloating or swelling of the face, arms, hands, lower legs, or feet
  • bloody nose
  • chest pain or tightness
  • cough or hoarseness
  • decreased weight
  • diarrhea
  • difficult or labored breathing
  • difficulty with swallowing
  • fever or chills
  • general feeling of discomfort or illness
  • lower back or side pain
  • painful or difficult urination
  • rapid weight gain
  • sores, ulcers, or white spots on the lips, tongue, or inside the mouth
  • tingling of the hands or feet
Less common
  • Bleeding gums
  • bloody urine
  • blurred vision
  • burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
  • coughing up blood
  • extreme fatigue
  • fast, pounding, or irregular heartbeat or pulse
  • increased thirst or urination
  • irregular breathing
  • loss of appetite
  • nausea or vomiting
  • nervousness
  • nosebleeds
  • prolonged bleeding from cuts
  • red or black, tarry stools
  • red or dark brown urine
  • slow heartbeat
  • stomachache
  • sweating
  • unusual tiredness or weakness
Incidence not known
  • Agitation
  • confusion
  • depression
  • dizziness
  • hostility or irritability
  • lethargy
  • muscle twitching
  • seizures
  • stupor

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Abdominal or stomach pain
  • change in taste
  • dry skin
  • itching skin or rash
  • lack or loss of strength
  • loss of taste
  • pain in the arms or legs
  • unable to sleep
Less common
  • Back pain
  • blistering, peeling, redness, or swelling of the palms, hands, or bottoms of the feet
  • bumps on the skin
  • burning, dry, or itching eyes
  • discoloration of the fingernails or toenails
  • flushing or redness of the skin
  • full feeling
  • jaw pain
  • numbness, pain, tingling, or unusual sensations in the palms of the hands or bottoms of the feet
  • passing gas
  • redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
  • sleepiness or unusual drowsiness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Contraindications

Hypersensitivity to everolimus, sirolimus, other rapamycin derivatives, or any component of the formulation.

Monitoring Parameters

CBC with differential (baseline and periodic); liver function (baseline and periodic); serum creatinine (baseline and periodic), urinary protein (baseline and periodic), and BUN (baseline and periodic); fasting serum glucose, HbA1c, and lipid profile (baseline and periodic); monitor for signs and symptoms of infection, noninfectious pneumonitis, or malignancy

Solid organ transplantation: Monitor everolimus whole blood trough concentrations (based on an LC/MS/MS assay method), especially in patients with hepatic impairment, with concomitant CYP3A4 inhibitors and inducers, and when cyclosporine or tacrolimus formulations or doses are changed; dosage adjustments should be made on trough concentrations obtained 4 to 5 days after a previous dosage adjustment; monitor cyclosporine or tacrolimus concentrations; monitor for proteinuria

SEGA: Monitor everolimus whole blood trough concentrations ~2 weeks after treatment initiation or with dosage modifications, initiation or changes to concurrent CYP3A4/P-glycoprotein (P-gp) inhibitor/inducer therapy, changes in hepatic function and when changing dosage forms between Afinitor tablets and Afinitor Disperz. Maintain trough concentrations between 5 and 15 ng/mL; once stable dose is attained and if BSA is stable throughout treatment, monitor trough concentrations every 6 to 12 months (monitor every 3 to 6 months if BSA is changing).

Pregnancy Risk Factor C (Zortress) Pregnancy Considerations

Adverse events were observed in animal reproduction studies with exposures lower than expected with human doses. Based on the mechanism of action, may cause fetal harm if administered during pregnancy. Women of reproductive potential should be advised to avoid pregnancy and use highly effective birth control during treatment and for up to 8 weeks after everolimus discontinuation.

Everolimus may cause infertility. In females, menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone and follicle-stimulating hormone have occurred. Azoospermia and oligospermia have been observed in males. Females of reproductive potential should consider family planning options prior to therapy.

The National Transplantation Pregnancy Registry (NTPR) is a registry which follows pregnancies which occur in maternal transplant recipients or those fathered by male transplant recipients. The NTPR encourages reporting of pregnancies following solid organ transplant by contacting them at 877-955-6877 or NTPR@giftoflifeinstitute.org.

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