Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) kinase, is an antineoplastic agent and macrolide immunosuppressive agent.1, 13
Everolimus (Afinitor®) is used in combination with exemestane for the treatment of advanced hormone receptor-positive, human epidermal growth factor receptor type 2 ( HER2 )-negative breast cancer in postmenopausal women following failure of prior therapy with letrozole or anastrozole.1, 22, 32, 33, 41 Efficacy of everolimus for this use is principally supported by results of a randomized, double-blind, placebo-controlled, phase 3 study in which everolimus in combination with exemestane was associated with prolonged progression-free survival compared to exemestane alone.1, 22 Guidelines generally support the use of everolimus in combination with exemestane in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer in the second- or subsequent-line setting following treatment with a non-steroidal aromatase inhibitor.69, 70
The indication for everolimus in breast cancer is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (Breast Cancer Trials of Oral Everolimus-2 [BOLERO-2]) in postmenopausal women with hormone receptor-positive, HER2 -negative advanced or metastatic breast cancer whose disease was refractory to previous letrozole or anastrozole therapy.1, 22 Patients had at least 1 measurable lesion or mainly lytic bone lesions in the absence of measurable disease.22 In addition, patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less.22 In this study, 724 patients were randomized (stratified by documented prior sensitivity to hormonal therapy and the presence of visceral metastasis) in a 2:1 ratio to receive either everolimus (10 mg daily) or placebo in combination with exemestane (25 mg daily).1, 22 Treatment was continued until disease progression, unacceptable toxicity occurred, or withdrawal of patient consent.22 The primary end point of efficacy was progression-free survival (assessed using Response Evaluation Criteria in Solid Tumors [RECIST]) evaluated by local investigators; secondary end points included overall survival, objective response rate, clinical benefit rate, time to deterioration of ECOG performance status, safety, and quality of life.1, 22 The median age of patients enrolled in the study was 62 years (range: 28-93).22 Of the enrolled patients, 56% had visceral involvement, 76% had bone metastasis, and 69% had measurable disease.22 All patients had received prior therapy for breast cancer, including regimens consisting of letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%).22
In the final analysis of progression-free survival, with median follow-up of 17.7 months, patients receiving everolimus in combination with exemestane in the BOLERO-2 study had a longer median progression-free survival than those receiving placebo in combination with exemestane (7.8 and 3.2 months, respectively).1, 65 The results of the progression-free survival analysis based on an independent, blinded, central radiological assessment were consistent with the investigator assessment.1, 65 In addition, patients receiving everolimus in combination with exemestane had a higher objective response rate than those receiving placebo (12.6 versus 1.7%, respectively).1 There were 3 complete responses (0.6%) and 58 partial responses (12%) in patients receiving everolimus in combination with exemestane compared with no complete responses and 4 partial responses (1.7%) in patients receiving placebo in combination with exemestane.1 In the final analysis of overall survival, with median follow-up of 39.3 months, there was no difference in patients receiving everolimus in combination with exemestane compared to those receiving placebo in combination with exemestane.1, 41
In a health-related quality of life analysis of the BOLERO-2 study data, median time to definitive deterioration in global health status was prolonged in patients receiving everolimus in combination with exemestane compared with those receiving placebo in combination with exemestane (8.3 versus 5.8 months, respectively).32
Guidelines from the American Society of Clinical Oncology (ASCO) provide recommendations for treatment of postmenopausal women and men with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.70
ASCO states that aromatase inhibitors should be offered as first-line endocrine therapy in postmenopausal women with hormone receptor-positive, metastatic breast cancer.70 The updated guidelines include unchanged recommendations from the 2016 guideline for endocrine therapy in patients with hormone receptor-positive metastatic breast cancer, which state that exemestane and everolimus may be offered to postmenopausal women with disease progression on prior treatment with non-steroidal aromatase inhibitors.69, 70 The guidelines stipulate that this combination should not be offered in the first-line setting for patients who relapse more than 12 months after prior treatment with a non-steroidal aromatase inhibitor or for patients who are naïve to hormonal therapy, and note that there is more toxicity associated with the combination of exemestane and everolimus than single-agent hormonal therapy options.69, 70
Everolimus (Afinitor®) is used for the treatment of progressive neuroendocrine tumors (NET) of pancreatic origin (PNET) and progressive, well-differentiated, non-functional NET of GI or lung origin in adults with unresectable, locally advanced, or metastatic disease.1, 25, 26, 42, 43, 44 Everolimus has been designated an orphan drug by the FDA for the treatment of these cancers.36 Safety and efficacy of everolimus for these indications are principally supported by the results of 2 randomized, double-blind, placebo-controlled, phase 3 studies (RADIANT-3, PNET; RADIANT-4, non-functional NET of GI or lung origin) in which everolimus was associated with prolonged progression-free survival compared to placebo.25, 43 Guidelines generally support consideration of everolimus among other options for the management of progressive PNET74 and NET of GI71, 72 and lung origin.75
Everolimus is not indicated for use in patients with functional carcinoid tumors.1, 45, 66
Clinical Experience in Neuroendocrine Tumors of Pancreatic Origin
The use of everolimus in patients with advanced PNET was mainly established in a randomized, double-blind, placebo-controlled, multicenter, phase 3 study (RAD001 in Advanced Neuroendocrine Tumors, Third Trial [RADIANT-3]) conducted in 410 adults with advanced, low- or intermediate-grade PNET with radiologic documentation of disease progression within the previous 12 months.1, 25 Patients had measurable disease, as assessed by RECIST, and a World Health Organization (WHO) performance status of 2 or less.25 Patients were randomized in a 1:1 ratio to receive either everolimus (10 mg once daily) or placebo, along with best supportive care (including somatostatin analogues [e.g., octreotide]).1, 25 Treatment was continued until disease progression, unacceptable toxicity, drug interruption for 3 weeks or longer, or withdrawal of consent;25 upon disease progression, patients previously randomized to receive placebo were permitted to cross over to open-label everolimus therapy.1, 25 The primary end point was progression-free survival (assessed using RECIST) evaluated by local investigators; secondary end points included safety, objective response rate, response duration, and overall survival.1, 25 Median duration of treatment was approximately 8.8 months in patients receiving everolimus compared with approximately 3.7 months in those receiving placebo.25
Patients randomized to receive everolimus along with best supportive care in the RADIANT-3 study demonstrated a substantial improvement in progression-free survival (11 months) compared with patients receiving placebo and best supportive care (4.6 months).1, 25 At 18 months, the estimated proportion of patients who were alive and free of disease progression was 34% in patients receiving everolimus compared with 9% in patients receiving placebo.25 Confirmed objective responses (i.e., partial responses) were observed in 5 or 2% of patients receiving everolimus or placebo, respectively; there were no complete responses.25 In the final analysis of overall survival, there was no difference in patients receiving everolimus compared to those receiving placebo.1, 42
Clinical Perspective in Neuroendocrine Tumors of Pancreatic Origin
The North American Neuroendocrine Tumor Society (NANETS) published consensus guidelines on surgical and medical management of PNET in 2020.73, 74 Management of well-differentiated PNET is patient-specific; options in both early and advanced disease settings may include surgery (primary and cytoreductive), liver-directed therapy, systemic therapy, and observation.73, 74 In patients with advanced disease warranting systemic treatment, somatostatin analogues are generally recommended as first-line therapy, but chemotherapy, liver-directed therapy, everolimus, and/or sunitinib are generally considered options in select situations.74 Because there are insufficient data to guide therapeutic sequencing, these options are also generally supported in patients with PNET who experience disease progression.74
Clinical Experience in Neuroendocrine Tumors of Gastrointestinal or Lung Origin
The safety and efficacy of everolimus in patients with advanced NET of GI or lung origin was principally established by a randomized, double-blind, placebo-controlled, multicenter phase 3 trial (RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial [RADIANT-4]).1, 43 This study enrolled 302 adults with unresectable or metastatic, non-functional, well-differentiated neuroendocrine NET of GI or lung origin with evidence of disease progression within the prior 6 months.1 Patients had measurable disease according to modified RECIST criteria and a WHO performance status of 0 or 1.43 Candidates with a history of carcinoid syndrome, PNET, or who had received more than 1 prior line of chemotherapy were excluded.1, 43 Patients were randomized 2:1 to receive everolimus 10 mg once daily or placebo, along with best supportive care (excluding anticancer therapy such as somatostatin analogues).1, 43 Treatment continued until disease progression, initiation of new anticancer therapy, unacceptable toxicity, or withdrawal of consent.43 Crossover after disease progression was not permitted.43 The primary endpoint was centrally-assessed progression-free survival according to modified RECIST criteria.1, 43
The median age of patients enrolled in RADIANT-4 was 63 years.1 Most patients had a WHO performance status of 0; the most common primary tumor sites were the lung, ileum, and rectum.1, 43 Most patients had undergone prior treatment with surgery and/or somatostatin analogues, and large proportions had received prior chemotherapy, radiotherapy, and/or locoregional or ablative therapy.43
Median progression-free survival was substantially longer in the everolimus arm (11 months) than the placebo arm (3.9 months).1 There was no significant difference in overall survival with everolimus versus placebo.1 The best overall response was stable disease in 81% of patients receiving everolimus and 64% of patients receiving placebo; objective responses, all of which were partial responses, were achieved in 2% of patients receiving everolimus and 1% of patients receiving placebo.43
In a pre-specified analysis of health-related quality of life in patients enrolled in RADIANT-4, there was no difference in median time to definitive deterioration in overall quality of life with everolimus compared to placebo (11.27 versus 9.23 months, respectively).44
Everolimus is not indicated for use in patients with functional carcinoid tumors.1 In the randomized, double-blind, placebo-controlled, multicenter phase 3 RAD001 in Advanced Neuroendocrine Tumors, Second Trial (RADIANT-2), 429 adults with unresectable or metastatic, well-differentiated, progressive NET with carcinoid syndrome-associated secretory symptoms received long-acting octreotide and were randomized 1:1 to receive concomitant everolimus 10 mg daily or placebo.1, 45 The study did not meet its primary endpoint of clinically meaningful prolonged progression-free survival with everolimus relative to placebo, and the final analysis of overall survival favored the placebo arm.1, 45, 66
Clinical Perspective in Neuroendocrine Tumors of Gastrointestinal or Lung Origin
Guidelines with recommendations for the management of NET of GI or lung origin include the 2013 NANETS consensus guideline update for general management of NET,71 2017 NANETS consensus guideline update for management of midgut (small bowel and cecum) NET,72 and 2020 NANETS endorsement and update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines for management of lung NET.75
In patients with NET of the stomach, distal colon, or rectum, surgery is recommended for locoregional disease and should be considered in advanced disease.71 Observation is recommended in select cases.71 In patients presenting with newly-diagnosed advanced gastric NET with high tumor volume and those with progressive disease, everolimus, octreotide, and liver-directed therapies may generally be considered; in patients with NET of the distal colon or rectum, everolimus is generally considered among options for use in the setting of progressive disease.71
As with other NETs of GI origin, patients with midgut NET generally undergo surgical resection of locoregional disease.72 In the setting of advanced disease with low tumor burden, observation or initial management with a somatostatin analogue are considered acceptable.72 In patients with progressive disease following somatostatin analogue therapy who have positive somatostatin receptor imaging, peptide receptor radiotherapy is considered appropriate; in those with subsequent disease progression or who are not candidates for peptide receptor radiotherapy, hepatic embolization or everolimus may be considered.72
In patients with NET of lung origin, surgery is also considered by NANETS to be a mainstay of therapy for locoregional disease and appropriate cases with advanced disease.75 Patients unable to undergo surgery may also receive ablative therapy or radiotherapy for local disease control and/or palliation.75 Observation is also considered appropriate in select cases.75 As in other NET types, somatostatin analogues are generally considered to be appropriate first-line systemic agents, and peptide receptor radiotherapy may be considered in patients with positive somatostatin receptor imaging.75 Everolimus is generally recommended in the setting of progressive disease in nonfunctional NET of lung origin; chemotherapy may also be considered.75
Everolimus (Afinitor®) is used for the treatment of advanced renal cell carcinoma (RCC) in adults following failure of sunitinib and/or sorafenib therapy.1, 2, 16 Efficacy of everolimus for this use is principally supported by the results of a randomized, double-blind, phase 3 study in which use of everolimus was associated with prolonged progression-free survival compared to placebo.1, 2, 16 Guidelines generally support the use of everolimus in combination with lenvatinib† for the treatment of advanced RCC in patients who experience disease progression;76 some experts support the use of everolimus as monotherapy for certain patients with advanced RCC in the second- and subsequent-line treatment setting.77
This indication for everolimus is based principally on the results of a randomized, double-blind, placebo-controlled, multicenter, phase 3 study (RECORD-1) in 416 patients 18 years of age and older with metastatic clear-cell RCC that had progressed during or within 6 months following discontinuation of therapy with sunitinib, sorafenib, or both (given sequentially); patients who previously received aldesleukin, bevacizumab, or interferon alfa also were permitted to enroll in the study.1, 2, 16 Patients were randomized in a 2:1 ratio to receive either everolimus (10 mg daily) or placebo, along with best supportive care.1, 2, 16 Treatment in both groups was continued until disease progression, unacceptable toxicity, death, or discontinuance of therapy for other reasons occurred;2 upon radiographic progression, patients previously randomized to receive placebo were permitted to cross over to open-label everolimus.1, 2, 16
A planned second interim analysis indicated that patients receiving everolimus had longer median progression-free survival compared with those receiving placebo.2 Following these favorable results, the independent data monitoring committee recommended early termination of the trial, and all patients previously randomized to receive placebo crossed over to receive open-label everolimus.2 In a final analysis of the RECORD-1 trial, patients receiving everolimus (following a median duration of treatment of 141 days16 ) had longer median progression-free survival (4.9 months) compared with those receiving placebo (1.9 months); improved progression-free survival was observed across all Memorial Sloan-Kettering Cancer Center (MSKCC) risk categories.1, 16 Objective responses (i.e., partial responses) were observed in 2 or 0% of patients receiving everolimus or placebo, respectively.1, 16 Final overall survival data did not show a substantial difference between the treatment groups; however, planned crossover between treatments at the time of disease progression may have confounded interpretation of the survival data.1
Everolimus was compared to nivolumab in adults with advanced RCC in the randomized, open-label, multicenter, phase 3 CheckMate 025 trial.46 This study enrolled 821 patients with advanced or metastatic clear-cell RCC who had received no more than 3 prior lines of systemic therapy, 1 or 2 of which included anti-angiogenic therapy, and had a Karnofsky performance status of 70 or better.46 Patients were randomized 1:1 to receive nivolumab 3 mg/kg IV every 2 weeks or everolimus 10 mg orally once daily until disease progression without clinical benefit or treatment discontinuation.46 The primary endpoint was overall survival.46
The median age of patients enrolled in CheckMate 025 was 62 years.46 Most patients were male (75%) and white (88%), had a Karnofsky performance status of 90 (34%) or 100 (32%), had MSKCC favorable- (36%) or intermediate-risk disease (49%), and had received 1 prior line of anti-angiogenic therapy (72%).46
Based on a planned interim analysis indicating substantially prolonged survival with nivolumab compared to everolimus, trial accrual was stopped early at the recommendation of an independent data monitoring committee.46 In an updated analysis with median follow-up of 72 months, the overall survival benefit was maintained in the nivolumab arm compared to the everolimus arm (median overall survival, 25.8 versus 19.7 months, respectively).47 Progression-free survival was also substantially prolonged with nivolumab, and patients receiving nivolumab were substantially more likely to achieve objective response by RECIST criteria compared to those receiving everolimus.47
Everolimus was also compared to cabozantinib in adults with advanced RCC in the randomized, open-label, multicenter phase 3 METEOR trial.48 This study enrolled 658 patients with advanced or metastatic clear-cell RCC who had received 1 or more prior lines of systemic treatment, at least 1 of which was a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), and had a Karnofsky performance status of 70 or better.48 Patients were randomized 1:1 to receive oral cabozantinib 60 mg once daily or everolimus 10 mg once daily as long as clinical benefit was observed or until development of unacceptable toxicity.48 The primary endpoint was progression-free survival.48
The median age of patients enrolled in METEOR was 63 years in the cabozantinib arm and 62 years in the everolimus arm.48 Most patients were male and white, had an ECOG performance status of 0, had MSKCC favorable- or intermediate-risk disease, and were previously treated with sunitinib and/or pazopanib.48
A planned interim analysis indicated substantially prolonged progression-free survival in patients receiving cabozantinib compared to those receiving everolimus.48 An updated analysis with median follow-up of 11.4 months in the cabozantinib arm and 11.5 months in the everolimus arm confirmed the substantial progression-free survival benefit with cabozantinib compared to everolimus (7.4 versus 3.9 months, respectively).49 In the updated analysis of overall survival, with median follow-up of 18.7 months in the cabozantinib arm and 18.8 months in the everolimus arm, patients receiving cabozantinib also experienced substantially prolonged overall survival compared to those receiving everolimus (21.4 versus 16.5 months, respectively).49
In an exploratory analysis of health-related quality of life in patients enrolled in METEOR, there was no difference identified between cabozantinib and everolimus in measures of symptom severity, symptom interference in activity, or general perception of health status.50 A post-hoc analysis indicated substantially prolonged time to deterioration (defined as the earlier of death, disease progression, or ≥ 4-point decrease from baseline in 9-item Functional Assessment of Cancer Therapy-Kidney Symptom Index questionnaire) in patients receiving cabozantinib compared to those receiving everolimus (median 5.5 months versus 3.7 months, respectively).50
Everolimus has been studied for the treatment of RCC in combination with lenvatinib † in a randomized, open-label, multicenter phase 2 study (Study 205).51, 52 This study enrolled 153 adults with advanced or metastatic clear-cell RCC who had received 1 or more prior lines of systemic treatment, 1 of which was VEGF-targeted therapy, and had an ECOG performance status of 0 or 1.52 Patients were randomized 1:1:1 to receive oral lenvatinib (18 mg once daily) in combination with everolimus (5 mg once daily), lenvatinib (24 mg once daily) alone, or everolimus (10 mg once daily) alone, until disease progression or unacceptable toxicity.51, 52 The primary endpoint was progression-free survival.51, 52
The median age of patients randomized to receive lenvatinib in combination with everolimus or everolimus alone in Study 205 was 60 years; most patients in these arms were male (72%), white (96%).51, 52 MSKCC favorable, intermediate, and poor risk categories were observed in 24, 37, and 39%, respectively, of patients receiving lenvatinib in combination with everolimus, and 24, 38, and 38%, respectively, of patients receiving everolimus alone.51, 52
Progression-free survival assessed via retrospective independent radiographic review was substantially prolonged in patients receiving the combination of lenvatinib and everolimus compared with those receiving everolimus alone (14.6 versus 5.5 months, respectively).51 In the analysis of overall survival, there was no difference between patients receiving lenvatinib in combination with everolimus and those receiving everolimus alone.51 An objective response was observed in 37% of patients receiving lenvatinib in combination with everolimus compared with 6% of those receiving everolimus monotherapy.51 Based on the results of this study, lenvatinib is FDA-approved for the treatment of advanced RCC following 1 prior anti-angiogenic therapy when used in combination with everolimus.51
Clear-cell histology is the most common subtype of RCC; guidelines published by ASCO in 2022 provide recommendations for the management of metastatic clear-cell RCC.76 In patients with newly-diagnosed metastatic clear-cell RCC who require systemic treatment, dual immune checkpoint inhibitor therapy, an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor, or monotherapy with an agent from either class are generally recommended according to disease risk stratification and comorbidities.76 In the second- and subsequent-line setting, treatment with nivolumab or cabozantinib is recommended in patients who experienced disease progression with VEGFR tyrosine kinase inhibitor monotherapy.76 Otherwise, nivolumab or VEGFR tyrosine kinase inhibitor therapy (including agents not previously utilized in patients with prior VEGFR tyrosine kinase exposure) are generally recommended according to treatment history and patient preferences and comorbidities.76 This includes combination treatment with lenvatinib and everolimus.76
Some experts recommend monotherapy with everolimus or axitinib as second-line treatment in patients with clear-cell RCC when nivolumab, cabozantinib, or combined treatment with lenvatinib and everolimus are not available.77 After second-line treatment, some experts recommend treatment with nivolumab or cabozantinib when they have not previously been utilized.77 If these are not available, everolimus or axitinib are recommended; in patients who have previously received VEGF-targeted therapy and a mammalian target of rapamycin (mTOR) inhibitor for whom nivolumab and cabozantinib are not available, some experts suggest considering use of other tyrosine kinase inhibitors or rechallenge with a tyrosine kinase inhibitor.77
Renal Angiomyolipoma with Tuberous Sclerosis Complex
Everolimus (Afinitor®) is used in adults for the treatment of renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery.1, 29 Everolimus has been designated an orphan drug by the FDA for the treatment of this cancer.36 The efficacy of everolimus in the treatment of TSC-associated renal angiomyolipoma is principally supported by the double-blind, placebo-controlled primary analysis of a phase 3 randomized trial indicating substantially improved likelihood of objective response with everolimus compared to placebo and the results of a 4-year, open-label trial extension indicating durable responses.1, 29, 53 Guidelines generally support the use of everolimus as initial therapy for asymptomatic TSC-associated angiomyolipoma over 3 cm in diameter.78
The indication for everolimus in renal angiomyolipoma with TSC is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (EXIST-2) conducted in 118 adults with renal angiomyolipoma as a feature of TSC or sporadic lymphangioleiomyomatosis.1, 29 Eligibility requirements for the study included at least 1 angiomyolipoma (3 cm or larger in its longest diameter) and no immediate indication for surgery.1, 29 Patients were randomized (stratified by enzyme-inducing anticonvulsant use at randomization and presence of sporadic lymphangioleiomyomatosis) in a 2:1 ratio to receive either everolimus (10 mg daily) or placebo.1, 29 Treatment was continued until disease progression or unacceptable toxicity occurred.1, 29 Patients randomized to placebo were permitted to receive everolimus at the time of disease progression or after the primary analysis was completed as part of an open-label trial extension.1, 53 The primary efficacy end point was the angiomyolipoma response rate based on independent central radiology review (defined as a 50% or greater reduction in angiomyolipoma volume, absence of new angiomyolipoma lesions of 1 cm or greater, absence of kidney volume increase of 20% or greater, and no angiomyolipoma-related bleeding of grade 2 or greater), with primary analysis limited to the blinded treatment period.1, 29
In the EXIST-2 study, the median age of enrolled patients was 31 years (age range: 18-61 years).29 In the primary analysis, the median duration of follow-up was 8.3 months.1 The renal angiomyolipoma response rate was substantially higher in patients receiving everolimus (41.8%) than in those receiving placebo (0%).1, 29 Responses were ongoing at the time of the primary analysis, with a median response duration of at least 5.3 months (range: 2.3-19.6 months).1 Angiomyolipoma progression was documented in 3 patients receiving everolimus and in 8 patients receiving placebo, according to central radiologic review.1, 29 The response rate of skin lesions, assessed by local investigators, also was substantially higher in patients receiving everolimus compared with patients receiving placebo (26 and 0%, respectively); all of the skin responses in the everolimus treatment group were partial responses.1, 29 After completion of the primary analysis, 112 patients received everolimus in the open-label extension, including 79 patients originally assigned to everolimus and 33 patients who switched from placebo to everolimus.1 In the 4-year final analysis of the open-label extension, the median duration of treatment was 3.9 years; 58% of patients experienced an objective response according to central radiologic review, with a median time to response of 2.9 months.1, 53
The International TSC Consensus Group published updated recommendations for the management of TSC in 2021.78 The consensus guidelines generally support the use of mTOR inhibitors as first-line therapy in patients with asymptomatic, growing angiomyolipomas larger than 3 cm in diameter.78 Invasive interventions, including embolization, kidney-sparing resection, or ablative therapy, are generally reserved for patients in whom treatment with an mTOR inhibitor is contraindicated.78
Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis Complex
Everolimus tablets (Afinitor®) and everolimus tablets for oral suspension (Afinitor® Disperz®) are used in pediatric patients (1 year of age or older) and adults with TSC for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.1, 17, 27 Everolimus has been designated an orphan drug by the FDA for the treatment of this cancer.36 The efficacy of everolimus in the treatment of TSC-associated SEGA is principally supported by the double-blind, placebo-controlled primary analysis of a phase 3 trial indicating substantially improved likelihood of objective response with everolimus, and the results of a 4-year, open-label trial extension indicating durable responses.1, 27, 54 Guidelines generally support the use of everolimus in management of TSC-associated SEGA in patients who do not have an urgent indication for surgery, are not candidates for surgery, or prefer medical treatment.78
The current indication for everolimus in SEGA with TSC is based principally on the results of 2 clinical trials.1, 27 In a double-blind, placebo-controlled phase 3 study (EXIST-1) conducted in 117 pediatric and adult patients with SEGA and TSC, patients were randomized to receive everolimus (Afinitor®) at an initial dosage of 4.5 mg/m2 daily (with subsequent dosage adjustments to achieve and maintain everolimus trough blood concentrations of 5-15 ng/mL as tolerated) or placebo.1, 27 Treatment was continued until disease progression or unacceptable toxicity occurred.1, 27 Patients randomized to placebo were permitted to receive everolimus at the time of disease progression or after the primary analysis was completed as part of an open-label trial extension.1, 54 The primary efficacy endpoint was the proportion of patients with confirmed tumor response based on independent central review (defined as reduction in the total volume of all target SEGAs of 50% or more relative to baseline, in the absence of worsening of non-target SEGAs, new lesions of 1 cm or greater in diameter, and new or worsening hydrocephalus), with primary analysis limited to the blinded treatment period.1, 27
In EXIST-1 the median age of enrolled patients was 9.5 years (range: 0.8--26 years).1 The median duration of treatment was 41.9 weeks (range: 24-78.9 weeks) in patients receiving everolimus and 36.1 weeks (range: 13.9-79.7 weeks) in patients receiving placebo in the blinded treatment period.27 Patients receiving everolimus had a substantially higher SEGA response rate (35%) than patients receiving placebo (0%).1, 27 With a median follow-up of 8.4 months in the primary analysis, SEGA progression was observed in 15.4% of the placebo recipients and in none of the everolimus recipients.1 After completion of the primary analysis, 111 patients received everolimus in the open-label extension, including 78 patients originally assigned to everolimus and 33 patients who switched from placebo to everolimus.1 In the final analysis of the open-label extension, with median follow-up and treatment duration of 3.9 years, 58% experienced objective response according to central radiologic review, with a median time to response of 5.3 months.1, 54
The second trial was an open-label, single-arm, phase 1/2 study conducted in 28 patients 3 years of age and older with SEGA and TSC and serial radiologic evidence of SEGA growth (Study 2485); patients who previously underwent surgical resection of their SEGA lesions were permitted to enroll in the study.1, 17 Patients received everolimus for a core treatment phase of 6 months; after the core phase, patients could continue to receive everolimus as part of an extension treatment phase.1, 17 The primary efficacy endpoint was the reduction in volume of the largest SEGA lesion according to the independent central review, with primary analysis conducted following the initial 6 months of treatment.1
In study 2485, the median age of enrolled patients was 11 years (range 3-34 years).1 In the primary analysis, 32% of patients experienced objective response after 6 months of treatment.1, 17 In the final 5-year analysis of the extension phase, with median treatment duration of 5.7 years, 82% experienced objective response at any time during treatment.28 Development of new SEGA lesions was not observed in any of the patients receiving everolimus.1 At 5 years following enrollment of the last patient, 11% of patients had documented disease progression.1
The 2021 International TSC Consensus Group guidelines for the management of TSC include recommendations for the management of TSC-associated SEGA.78 The consensus guidelines generally recommend use of mTOR inhibitors in patients with TSC-associated asymptomatic growing or large SEGA, patients with mild to moderate symptoms, and patients who are not surgical candidates or prefer medical treatment.78 In select cases, neoadjuvant use of an mTOR inhibitor may be considered to facilitate surgery.78
Tuberous Sclerosis Complex-Associated Partial-Onset Seizures
Everolimus tablets for oral suspension (Afinitor®Disperz®) are used for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.1 Everolimus has been designated an orphan drug by the FDA for this indication.36 The efficacy of everolimus for this use is principally supported by the randomized, double-blind primary analysis of a phase 3 trial indicating substantial reductions in seizure frequency from baseline compared to placebo, and extension and post-extension phases of the trial demonstrating sustained efficacy.1, 55, 56, 57 Guidelines generally support the use of everolimus for TSC-associated seizures alongside other options in this setting.78
The safety and efficacy of everolimus for adjunctive treatment of TSC-associated partial-onset seizures were principally established by a randomized, double-blind, placebo-controlled phase 3 study (EXIST-3).1, 55 This trial enrolled 366 patients aged 2-65 years with TSC-associated treatment-resistant epilepsy who experienced at least 16 seizures in the 8-week period prior to randomization despite ongoing stable dosing of 1-3 antiepileptic drugs.55 Patients were randomized 1:1:1 to receive everolimus titrated to achieve low (3-7 ng/mL) or high (9-15 ng/mL) trough concentrations, or placebo, in addition to continuing their stable antiepileptic drug regimen.55 Treatment continued until the earlier of the end of the initial 18-week primary analysis period, loss of seizure control, an episode of status epilepticus, interruption of 1 or more concomitant antiepileptic drugs for more than 1 week, or unacceptable toxicity.55 Following the primary analysis period, patients were permitted to enroll in a 48-week extension phase and a subsequent post-extension phase, which continued on a per-patient basis until the earlier of an investigator-assessed lack of benefit from everolimus, commercial availability of everolimus for this indication, or the predefined study end date.55, 56, 57 All patients enrolled in the extension and post-extension phases received everolimus titrated to achieve trough concentrations of 3-15 ng/mL.56, 57 The primary efficacy endpoint was the percentage reduction in seizure frequency from baseline in the latter 12 weeks of the 18-week primary analysis period.1
Among EXIST-3 enrollees, median age was 10.1 years (range: 2.2-56 years); the majority of patients were younger than 18 years of age.1 Most patients were male (52%) and white (65%).1 Prior to enrollment, a large proportion of patients had experienced failure of more than 6 antiepileptic drugs (39%) and were receiving 2 or 3 ongoing antiepileptic drugs at the time of randomization (41 and 47%, respectively).55 The median seizure frequency at baseline was 9.4 per week.1
In the primary analysis, patients receiving everolimus experienced a substantially greater reduction in seizure frequency from baseline (median 29.3 and 39.6% lower in the low- and high-exposure groups, respectively) than those receiving placebo (median 14.9% lower).1 After the primary analysis period, 361 patients received everolimus in the extension phase for a median duration of 21 months.56 Among these patients, median reduction in seizure frequency from baseline after 2 years of everolimus exposure was 57%.56 In the post-extension phase, with median duration of exposure throughout the study of 30 months, median reduction in seizure frequency from baseline at the final evaluation among 244 enrollees was 72%.57
The 2021 International TSC Consensus Group guidelines for the management of TSC include recommendations for the management of TSC-associated epilepsy.78 The consensus guidelines generally recommend everolimus among other interventions for TSC-associated epilepsy, noting that comparative effectiveness data for recommending use of specific agents over others in this setting are not available.78
Everolimus (Zortress®) is used in combination with basiliximab induction and concurrently with corticosteroids and reduced dosages of cyclosporine for the prevention of rejection of renal allografts in adults with low to moderate immunologic risk.13, 18 Efficacy of everolimus for this use was principally established by a clinical trial in which a regimen consisting of everolimus, reduced-dose cyclosporine, and corticosteroids was similarly effective compared with a regimen consisting of mycophenolate sodium, cyclosporine, and corticosteroids in preventing acute rejection, graft loss, and death at 12 months following renal transplantation.13, 18 Safety and efficacy of everolimus have not been established in renal transplant recipients with high immunologic risk, recipients of transplanted organs other than kidney and liver, or pediatric patients.13
The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guideline on renal transplantation generally recommends use of everolimus-containing immunosuppressive regimens only in patients unable to receive recommended standard therapy, and recommends against its combined use with a calcineurin inhibitor (CNI).500 A consensus guideline on maintenance immunosuppression in solid organ transplant recipients published in 2022 by the American College of Clinical Pharmacy (ACCP), American Transplantation Society (AST), and International Society for Heart and Lung Transplantation (ISHLT) generally recommends consideration of an mTOR inhibitor alongside or in place of certain immunosuppresants to minimize risk of renal dysfunction or in cases of intolerance of other agents in kidney transplant recipients, and notes that mTOR inhibitor-containing immunosuppression may reduce risks of de novo post-transplant malignancy and cytomegalovirus in this setting.501
The current indication for everolimus in the prevention of renal allograft rejection was principally established by an open-label, randomized, multicenter, controlled study involving 833 patients 18-70 years of age with low to moderate immunologic risk receiving their first renal allograft (Study A2309).13, 18 Low to moderate immunologic risk was defined as an ABO blood type-compatible first organ or tissue transplant recipient with an anti-human leukocyte antigen (HLA) Class I Panel Reactive Antibody (PRA) of less than 20% by a complement-dependent cytotoxicity-based assay, or less than 50% by a flow cytometry or enzyme-linked immunosorbent assay (ELISA), and with a negative T-cell cross-match.13 In this study, patients were randomized 1:1:1 to receive everolimus at doses targeting trough concentrations of 3-8 ng/mL (starting at 1.5 mg per day) or 6-12 ng/mL (starting at 3 mg per day), as part of immunosuppressive regimens that included reduced-exposure cyclosporine and corticosteroids, or mycophenolate sodium in combination with standard-exposure cyclosporine and corticosteroids.13, 18 All patients also received basiliximab induction therapy.13, 18 The primary efficacy end point was the rate of treatment failure, defined as the first occurrence of a treated episode of biopsy-proven acute rejection, death, graft loss, or loss to follow-up for any reason without a prior biopsy-proven acute rejection episode, at 12 months after transplantation.13, 18
Results of study A2309 indicate that everolimus (with corticosteroids and reduced-exposure cyclosporine) was similarly effective compared with mycophenolate sodium (with corticosteroids and standard-exposure cyclosporine) in reducing the incidence of treatment failure at 12 months following transplantation.13, 18 The treatment failure rates at 12 months for everolimus 1.5 mg daily, everolimus 3 mg daily, and mycophenolate sodium (mycophenolic acid 1.44 g daily) were 25, 22, and 24%, respectively.13, 18 Incidence rates of treated biopsy-proven acute rejection, graft loss, and death at 12 months in patients receiving everolimus 1.5 mg daily or mycophenolate sodium (mycophenolic acid 1.44 g daily) were 16.2 or 17%, 4.3 or 3.2%, and 2.5 or 2.2%, respectively.13 Estimated glomerular filtration rates (GFRs) were similar at 12 months in patients receiving everolimus 1.5 mg daily or mycophenolate sodium (mycophenolic acid 1.44 g daily).13, 18
Two earlier randomized, double-blind, multicenter controlled trials compared fixed dosages of everolimus 1.5 or 3 mg daily, without therapeutic drug monitoring, combined with standard exposures of cyclosporine and corticosteroids to mycophenolate mofetil 2 g daily combined with corticosteroids in de novo renal transplant recipients (RAD B201 and B251 studies).13 19, 20 58 In both studies, increased rates of renal impairment (based on calculated GFR) at 12 months were observed in both everolimus groups compared with the mycophenolate mofetil groups.13, 19, 20, 58 Based on the results of the A2309, B201, and B251 studies, reduced-exposure cyclosporine and therapeutic drug monitoring targeting everolimus trough concentrations of 3-8 ng/mL should be used with everolimus regimens for renal allograft recipients to avoid renal dysfunction.13
Everolimus in combination with reduced-exposure CNI was also compared to mycophenolic acid with standard-exposure CNI for prevention of renal allograft rejection in 2037 adults enrolled in an open-label, randomized, multicenter non-inferiority study (TRANSFORM).59 In the primary analysis of TRANSFORM, everolimus in combination with reduced-exposure CNI was found to be non-inferior to mycophenolic acid in combination with standard-exposure CNI for the composite endpoint of treated biopsy-proven acute rejection or estimated GFR <50 mL/min per 1.73m2 at 12 months post-transplant.59 Updated 24-month results were consistent with those of the primary analysis, with treated biopsy-proven acute rejection occurring in 12.8 and 12.1% and estimated GFR <50 mL/min per 1.73m2 occurring in 46.4 and 41.6% of patients in the everolimus with reduced-exposure CNI and mycophenolic acid with standard-exposure CNI arms, respectively.
The KDIGO Transplant Work Group published guidelines for the care of kidney transplant recipients in 2009.500 The working group generally recommends first-line use of tacrolimus with mycophenolate for maintenance immunosuppression following induction.500 Use of mTOR inhibitors is recommended only when the graft is functional and surgical wounds have healed, and combined use of CNIs and mTOR inhibitors should be avoided.500
The ACCP/AST/ISHLT published consensus recommendations for maintenance immunosuppression in solid organ transplant recipients in 2022.501 In kidney transplant recipients, consideration of mTOR inhibitors, including everolimus or sirolimus, is recommended alongside low-dose CNI, mycophenolic acid (MPA), with or without corticosteroids, or as a replacement for CNI or antimetabolites, to minimize risk of kidney dysfunction.501 The expert panel notes that mTOR inhibitors may also protect against cytomegalovirus infection.501 These agents can also be considered in the setting of MPA intolerance, and may be useful in patients with cancer due to reduced risk of de novo and recurrent malignancy post-transplant.501
Everolimus (Zortress®) is used in combination with tacrolimus (in reduced dosages) and corticosteroids for the prevention of rejection of hepatic allografts in adults.13, 30 Everolimus should be administered no earlier than 30 days posttransplantation.13 Efficacy of everolimus for this use were principally established by a clinical trial in which a regimen consisting of everolimus, reduced-exposure tacrolimus, and corticosteroids was similarly effective compared with a regimen consisting of standard-exposure tacrolimus and corticosteroids in preventing acute rejection, graft loss, death, or loss to follow-up at 12 months following transplantation.13, 30 Safety and efficacy of everolimus have not been established in recipients of transplanted organs other than kidney and liver or pediatric patients.13
In liver transplant recipients, the ACCP/AST/ISHLT 2022 guideline for maintenance immunosuppression in solid organ transplant recipients generally recommends consideration of an mTOR inhibitor alongside or in place of certain immunosuppresants to minimize risk of renal dysfunction or in cases of intolerance of other agents, and notes that mTOR inhibitor-containing immunosuppression may reduce risk of de novo post-transplant malignancy in this setting.501
The current indication for everolimus in the prevention of hepatic allograft rejection is based principally on the results of a randomized, open-label, controlled, multicenter study in 719 patients 18-70 years of age undergoing primary liver transplant from a deceased donor (Study H2304).13, 30 Patients were initiated on an immunosuppressive regimen consisting of tacrolimus (trough concentrations of at least 8 ng/mL in the week prior to randomization) and corticosteroids, with or without mycophenolate mofetil.13, 30 No induction antibody was administered.13 At randomization, mycophenolate mofetil was discontinued and patients were randomized 1:1:1 to receive everolimus adjusted to achieve target trough concentrations of 3-8 ng/mL in conjunction with either reduced-exposure tacrolimus or tacrolimus elimination (at month 4 posttransplant, reduced-exposure tacrolimus was eliminated once everolimus trough concentrations were within the target range of 6-10 ng/mL) or standard exposure tacrolimus monotherapy.13, 30 The tacrolimus elimination group was terminated prematurely because of a higher incidence of acute rejection and adverse reactions leading to discontinuance of therapy reported during the elimination phase of tacrolimus;13, 30 therefore, an immunosuppressive regimen of everolimus in conjunction with tacrolimus elimination is not recommended.13 All patients received corticosteroids during the study.13, 30 The primary efficacy end point was the composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up at 12 months posttransplant.13, 30
In study H2304, 488 patients were enrolled in the everolimus with reduced-exposure tacrolimus and standard-exposure tacrolimus monotherapy arms.30 At 12 months, everolimus with reduced-exposure tacrolimus was comparable to standard-exposure tacrolimus with respect to efficacy failure.13, 30 At 24 months in the full study cohort and in 231 patients who enrolled in a 36-month extension study cohort, efficacy failure rates were similarly comparable between regimens.13 The efficacy failure rates in the full study cohort at 24 months for everolimus with reduced-exposure tacrolimus and standard-exposure tacrolimus were 18.4 and 21.8%,13 respectively; in the 231 patients who enrolled in the extension cohort, 36-month efficacy failure rates for those receiving everolimus with reduced-exposure tacrolimus and standard-exposure tacrolimus were 11.5 and 14.6%, respectively. 68 Incidence rates of treated biopsy-proven acute rejection, death, and graft loss in the full study cohort at 24 months were 4.5, 6.9, and 3.7%, respectively, in patients receiving everolimus with reduced-exposure tacrolimus and 7.4, 4.5, and 2.9%, respectively, in those receiving standard-exposure tacrolimus.13, 30 The estimated mean glomerular filtration rate (GFR) was 80.9 mL/min per 1.73 m2 and 74.7 mL/min per 1.73 m2 in patients receiving everolimus with reduced-exposure tacrolimus and 70.3 mL/min per 1.73 m2 and 67.8 mL/min per 1.73 m2 in those receiving standard-exposure tacrolimus at 12 and 24 months, resepctively.13, 30
Everolimus was evaluated in a multicenter, open-label study of similar design to H2304 in which 448 patients undergoing primary liver transplant from a living donor were randomized 1:1 to receive everolimus (adjusted to achieve target trough concentrations of 3-8 ng/mL) in combination with reduced-exposure tacrolimus (study H2307).60 The results of H2307 were combined in a pooled analysis with those of H2304.61 In the pooled analysis which included 772 patients, the efficacy failure rate (comprising treated biopsy-proven acute rejection, graft loss, or death) at 24 months was comparable between the everolimus with reduced-exposure tacrolimus and standard-exposure tacrolimus groups (9.8 and 10.8%, respectively).61 Rates of treated biopsy-proven acute rejection, death, and graft loss at 24 months were 4.2, 2.5, and 5.5%, respectively, in patients receiving everolimus with reduced-exposure tacrolimus and 6.4, 2.3, and 3.9%, respectively, in patients receiving standard-exposure tacrolimus, respectively.61
Everolimus was also evaluated for prevention of liver allograft rejection in the randomized, multicenter, open-label PROTECT trial.62 In this study, 194 patients age 18-70 years undergoing primary liver transplant who received induction immunosuppression with basiliximab and CNI, with or without corticosteroids, were randomized 1:1 at 4 weeks post-transplant to continue on the CNI-based regimen or receive everolimus (adjusted to achieve target trough concentrations of 5-12 ng/mL) and have the CNI dose reduced by 70%, followed by discontinuation of CNI 8 weeks later.62 The primary endpoint of this study was the estimated Cockcroft-Gault GFR at 12 months post-transplant; the primary hypothesis was that the everolimus-containing regimen would produce a superior outcome to continuation of the CNI regimen, defined as a mean difference in GFR of at least 8 mL/min.62
Among 375 patients enrolled in PROTECT, 203 underwent randomization, 9 of whom were excluded from analysis due to missing GFR data.62 At 12 months post-transplant, the least squares mean difference in GFR was 2.9 mL/min, favoring everolimus.62 Rates of death, treated biopsy-proven acute rejection, and graft loss were similar between groups.62 In the 5-year analysis of an extension study of 81 patients enrolled in PROTECT, the month 59 least squares mean difference in GFR, using last observation carried forward data imputation for patients who did not complete follow-up through month 59, was 12.4 mL/min, favoring everolimus.63 Rates of death, treated biopsy-proven acute rejection, and graft loss remained similar between groups.63
Use of everolimus in combination with reduced-exposure tacrolimus was also compared to the combination of tacrolimus and mycophenolate mofetil in the randomized, multicenter, open-label REDUCE trial.64 In this study, 217 adults undergoing primary liver transplant who received induction immunosuppression with an interleukin-2 receptor antagonist, tacrolimus, mycophenolate mofetil, and corticosteroids were randomized at 4 weeks post-transplant to continue immunosuppression with everolimus (adjusted to achieve target trough concentrations of 3-8 ng/mL) with reduced-exposure tacrolimus or mycophenolate mofetil with standard-exposure tacrolimus.64 The primary endpoint was estimated GFR at 12 months post-transplant.64
Among enrollees in REDUCE, at 12 months, there was a substantial difference in mean change in estimated GFR from randomization favoring the everolimus arm.64 The 12-month change in estimated GFR from randomization was a mean increase of 2.6 mL/min per 1.73 m2 in the everolimus with reduced-exposure tacrolimus arm and a mean decrease of 8.8 mL/min per 1.73 m2 in the mycophenolate mofetil with standard-exposure tacrolimus arm.64 Rates of treated biopsy-proven acute rejection, death, and graft loss at 12 months were similar between groups.64
The ACCP/AST/ISHLT published consensus recommendations for maintenance immunosuppression in solid organ transplant recipients in 2022.501 In liver transplant recipients, consideration of mTOR inhibitors, including everolimus or sirolimus, is recommended alongside low-dose CNI, MPA, with or without corticosteroids, or as a replacement for CNI, to minimize risk of kidney dysfunction.501 The expert panel notes that mTOR inhibitors may be useful in patients with cancer due to reduced risk of de novo and recurrent malignancy post-transplant.501
Everolimus has been used for the prevention of heart transplant rejection†.79, 90, 91, 92, 93, 94 The 2022 ACCP/AST/ISHLT consensus guideline for maintenance immunosuppression in solid organ transplant recipients recommends consideration of mTOR inhibitors, including everolimus or sirolimus, alongside low-dose CNI, MPA, with or without corticosteroids, or as a replacement for CNI or antimetabolites, to minimize risk of kidney dysfunction in heart transplant recipients.501 The expert panel notes that mTOR inhibitors may protect against cytomegalovirus infection, may be useful in patients with cancer due to reduced risk of de novo and recurrent malignancy post-transplant, and are associated with prevention and reduced progression of cardiac allograft vasculopathy in heart transplant recipients.501
Everolimus has been used for the prevention of lung transplant rejection†.80, 81, 95, 96, 98 The 2022 ACCP/AST/ISHLT consensus guideline for maintenance immunosuppression in solid organ transplant recipients recommends consideration of mTOR inhibitors, including everolimus or sirolimus, alongside low-dose CNI, MPA, with or without corticosteroids to minimize risk of kidney dysfunction in lung transplant recipients.501 The expert panel notes that mTOR inhibitors may protect against cytomegalovirus infection and that their use in place of antimetabolites may reduce risk of bronchiolitis obliterans syndrome in this setting.501
Everolimus has been used for the prevention of pancreas transplant rejection†.84 The 2022 ACCP/AST/ISHLT consensus guideline for maintenance immunosuppression in solid organ transplant recipients recommends consideration of mTOR inhibitors, including everolimus or sirolimus, as a replacement for CNI to minimize risk of kidney dysfunction in pancreas transplant recipients.501 The expert panel notes that mTOR inhibitors may be useful in the setting of MPA intolerance; in patients with MPA-induced gastrointestinal toxicity, replacement with an mTOR inhibitor may be considered if the mTOR inhibitor is used in combination with tacrolimus with or without corticosteroids to minimize risk of rejection.501
Vascularized Composite Allotransplantation
Everolimus has been used for the prevention of vascularized composite transplant rejection† in a limited number of patients undergoing hand transplantation and uterus transplantation; larger studies are required to define the standard of care in this setting.85, 86, 87, 88, 89
Dispensing and Administration Precautions
Everolimus is administered orally as tablets (Afinitor®, Zortress®) and as tablets for oral suspension (Afinitor® Disperz®).1, 13 Afinitor® Disperz® is recommended for use only for the treatment of subependymal giant cell astrocytoma (SEGA) with tuberous sclerosis complex (TSC) and as adjunctive treatment for partial-onset seizures with TSC in conjunction with therapeutic drug monitoring.1 The different formulations of Afinitor® are not interchangeable, and they should not be combined to achieve the desired dose.1
If a dose of Afinitor® or Afinitor® Disperz® is missed, the dose can be administered up to 6 hours later.1 If more than 6 hours has passed since the missed dose, the dose should be skipped and administered at its usual scheduled time on the following day.1
Store everolimus tablets and tablets for oral suspension protected from light and moisture between 20-25°C; excursions are permitted between 15-30°C.1, 13
Everolimus tablets (Afinitor® and Zortress®) are administered orally once or twice daily.1, 13 Administer the tablets 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 In patients with renal or hepatic allografts, administer everolimus at the same time as cyclosporine or tacrolimus, respectively.13
Swallow everolimus tablets whole with a glass of water; do not break or crush the tablets.1, 13
Everolimus tablets for oral suspension (Afinitor® Disperz®) are administered orally once daily.1 Administer the drug at the same time every day, either consistently with food or consistently without food.1
Everolimus tablets for oral suspension should only be used as a suspension.1 Prepare the oral suspension in water only and administer immediately after preparation; if not administered within 60 minutes of preparation, discard the suspension.1 Wear gloves when preparing suspensions to avoid possible contact with everolimus.1
If the tablets for oral suspension are to be administered using an oral syringe, place the prescribed dose (up to 10 mg) in a 10-mL syrin do not crush or break the tablets.1 Draw approximately 5 mL of water and 4 mL of air into the syringe.1 Then, place the syringe containing the mixture in a container (tip up) for 3 minutes, until the tablets are in suspension.1 Immediately prior to administration, gently invert the syringe 5 times.1 Following administration, refill the syringe with 5 mL of water and 4 mL of air, swirl to suspend remaining particles, and administer the entire contents of the syringe.1 If a dose of more than 10 mg is required, prepare an additional syringe.1
If the tablets for oral suspension are to be administered using a small drinking glass (maximum size 100 mL), place the prescribed dose (up to 10 mg) into a glass containing approximately 25 mL of water; do not crush or break the tablets.1 Suspend the mixture for 3 minutes.1 Immediately prior to administration, gently stir the contents of the drinking glass with a spoon.1 Following administration of the prepared suspension, add 25 mL of water to the glass and stir the mixture with the same spoon to resuspend remaining particles.1 Then, swallow the entire contents of the glass.1 If a dose of more than 10 mg is required, prepare an additional glass.1
The recommended adult dosage of everolimus for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane therapy following failure of letrozole or anastrozole therapy is 10 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 Dosage adjustments may be required based on tolerability or change in concomitant drug therapy.1
The recommended adult dosage of everolimus for the treatment of advanced neuroendocrine tumors (NET) of pancreatic origin is 10 mg once daily.1
The recommended adult dosage of everolimus for the treatment of advanced, well-differentiated, non-functional NET of gastrointestinal or lung origin is 10 mg once daily.1
Continue therapy for NET until disease progression or unacceptable toxicity occurs.1 Dosage adjustments may be required based on tolerability or change in concomitant drug therapy.1
The recommended adult dosage of everolimus for the treatment of advanced renal cell carcinoma following failure of sunitinib or sorafenib therapy is 10 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 Dosage adjustments may be required based on tolerability or change in concomitant drug therapy.1
The recommended adult dosage of everolimus for the treatment of renal angiomyolipoma with TSC is 10 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 Dosage adjustments may be required based on tolerability or change in concomitant drug therapy.1
The recommended initial dosage of everolimus for the treatment of SEGA with TSC in adult patients is 4.5 mg/m2 once daily.1 Guide subsequent dosing by therapeutic drug monitoring.1 Make dosage adjustments at 1-2-week intervals as needed to achieve and maintain everolimus trough concentrations of 5-15 ng/mL.1
Everolimus trough concentrations are correlated with the magnitude of reduction in SEGA volume.1 Continue treatment with everolimus until disease progression or unacceptable toxicity occurs; the optimal duration of therapy is not known.1
Partial-Onset Seizures with TSC
The recommended initial adult dosage of everolimus for the treatment of TSC-associated partial-onset seizures is 5 mg/m2 once daily.1 Guide subsequent dosing by therapeutic drug monitoring.1 Make dosage adjustments at 1-2 week intervals as needed to achieve and maintain everolimus trough concentrations of 5-15 ng/mL.1
Everolimus trough concentrations have been correlated with the magnitude of reduction in absolute seizure frequency.1 Continue treatment with everolimus until disease progression or unacceptable toxicity occurs.1
For the prevention of renal allograft rejection in adults, the usual initial dosage of everolimus is 0.75 mg orally twice daily (1.5 mg/day).13 Everolimus is used in combination with basiliximab induction and concurrently with reduced dosage cyclosporine and corticosteroids, and should be initiated as soon as possible after transplantation.13
Patients receiving everolimus may require dosage adjustments based on everolimus blood concentrations, tolerability, individual response, change in concomitant drug therapy, and the clinical situation.13 Everolimus maintenance dosage should preferably be adjusted based on trough concentrations obtained 4-5 days after a change in dosage of either everolimus or cyclosporine (since reduced cyclosporine exposure may result in decreased everolimus concentrations).13
If the trough concentration of everolimus decreases to less than 3 ng/mL, double the dosage using the available tablet strengths (0.25 mg, 0.5 mg, 0.75 mg, or 1 mg).13 If 2 consecutive trough measurements of everolimus are greater than 8 ng/mL, decrease the dosage of everolimus by 0.25 mg twice daily.13
Administer oral prednisone once oral medications are tolerated.13 Individualize tapering of steroid dosages based on the patient's clinical status and function of the allograft.13
For the prevention of hepatic allograft rejection in adults, the usual initial dosage of everolimus is 1 mg orally twice daily (2 mg/day).13 Everolimus is used in combination with reduced dosage tacrolimus and corticosteroids, and should be initiated at least 30 days following transplantation.13 Individualize tapering of steroid dosages based on the patient's clinical status and function of the allograft.13
Patients receiving everolimus for prevention of hepatic allograft rejection may require dosage adjustment based on everolimus blood concentrations, tolerability, individual response, change in concomitant drug therapy, and the clinical situation.13 Everolimus maintenance dosage should preferably be adjusted based on trough everolimus concentrations obtained 4-5 days after a change in dosage of everolimus.13
If the trough concentration of everolimus decreases to less than 3 ng/mL, double the dosage using the available tablet strengths (0.25 mg, 0.5 mg, 0.75 mg, or 1 mg).13 If 2 consecutive trough measurements of everolimus are greater than 8 ng/mL, decrease the dosage of everolimus by 0.25 mg twice daily.13
For the prevention of heart allograft rejection†, the usual initial dosage of everolimus is 0.75 mg twice daily (1.5 mg/day) in combination with other immunosuppressive agents, with subsequent dosage adjustment based on trough everolimus concentrations when necessary; everolimus is usually initiated at least 1 month after transplantation.90, 91, 92, 93, 94, 501
For the prevention of lung allograft rejection†, the usual initial dosage of everolimus is 0.75 mg twice daily to 1.5 mg twice daily (1.5 mg/day to 3 mg/day) in combination with other immunosuppressive agents, with subsequent dosage adjustment based on trough everolimus concentrations when necessary; everolimus is usually initiated at least 1 month after transplantation.95, 96, 97, 98, 501
The optimal dosage of everolimus for the prevention of pancreas allograft rejection† has not been established; initial dosages of 0.75 mg twice daily (1.5 mg/day) in combination with other immunosuppressive agents, with subsequent dosage adjustment based on trough everolimus concentrations when necessary, have been described.99 Everolimus is usually initiated at least 1 month after transplantation.501
Vascularized Composite Allotransplantation
The optimal dosage of everolimus for the prevention of vascularized composite transplant rejection† has not been established; initial dosages of 0.75 mg twice daily (1.5 mg/day) in combination with other immunosuppressive agents, with subsequent dosage adjustment based on trough everolimus concentrations when necessary, have been described.85, 86, 89
The recommended initial dosage of everolimus for the treatment of SEGA with TSC in pediatric patients 1 year of age or older is 4.5 mg/m2 once daily.1 Guide subsequent dosing by therapeutic drug monitoring.1 Make dosage adjustments at 1-2 week intervals to achieve and maintain everolimus trough concentrations of 5-15 ng/mL.1
Everolimus trough concentrations are correlated with the magnitude of reduction in SEGA volume.1 Continue treatment with everolimus until disease progression or unacceptable toxicity occurs.1
Partial-Onset Seizures wtih TSC
The recommended initial dosage of everolimus for the adjunctive treatment of TSC-associated partial onset seizures in pediatric patients 2 years of age and older is 5 mg/m2 once daily.1 Guide subsequent dosing by therapeutic drug monitoring.1 Make dosage adjustments at 1-2 week intervals as needed to achieve and maintain everolimus trough concentrations of 5-15 ng/mL.1
Everolimus trough concentrations have been correlated with the magnitude of reduction in absolute seizure frequency in patients with TSC-associated partial-onset seizures.1 Continue treatment with everolimus until disease progression or unacceptable toxicity occurs.1
Therapeutic Drug Monitoring and Dosage Adjustment in SEGA with TSC and Partial-Onset Seizures with TSC
Routine monitoring of everolimus whole blood trough drug concentrations is recommended for pediatric and adult patients receiving everolimus for the treatment of SEGA with TSC and partial-onset seizures associated with TSC.1 Use the same assay and laboratory for therapeutic drug monitoring throughout treatment when possible.1 Measure trough concentrations 1-2 weeks after initiation of treatment.1 Trough concentrations also should be measured 1-2 weeks after any change in everolimus dosage or a change in dosage forms between everolimus tablets (Afinitor®) and everolimus tablets for oral suspension (Afinitor® Disperz®).1 Measure trough concentrations 2 weeks after the initiation or discontinuation of potent inducers or moderate inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 and P-glycoprotein or if there is a change in hepatic function.1
Titrate the dosage to attain trough everolimus concentrations of 5-15 ng/mL.1 Higher trough concentrations may be associated with larger reductions in SEGA volume and a greater reduction in absolute seizure frequency.1 In patients with trough concentrations that are not within the goal range, adjust the new dosage in accordance with the following equation:
New dosage = current dosage multiplied by (target trough concentration divided by current trough concentration).1
With each dosage titration, do not increase the dosage increment by more than 5 mg; multiple titrations may be necessary to achieve target trough concentrations.1
Once a stable dosage of everolimus has been 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 everolimus treatment.1
Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus for Renal Allotransplantation
Routine monitoring of trough whole blood everolimus concentrations is recommended for all renal transplant patients.13 The recommended therapeutic range is 3-8 ng/mL.13 In clinical trials, a lower incidence of treated biopsy-proven acute rejection was observed in renal allograft recipients with whole blood trough everolimus concentrations of 3 ng/mL or greater compared with patients whose trough concentrations were less than 3 ng/mL.13 Similar efficacy and an increased incidence of adverse effects were observed in patients with trough everolimus concentrations of 6-12 ng/mL compared with patients with trough concentrations of 3-8 ng/mL.13 Carefully monitor clinical signs and symptoms, tissue biopsies, and laboratory parameters.
The recommended trough concentration range of 3-8 ng/mL for everolimus is based on a liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay method.13 In clinical practice, everolimus whole blood concentrations may be measured by chromatographic or immunoassay methodologies.13 However, the measured concentrations of everolimus in whole blood depend on the type of assay used, and the individual patient sample concentration values from different assay methodologies may not be interchangeable.13 Consideration of assay results should be made with knowledge of the specific assay that was used.13 Therefore, it is essential that communication be maintained with the laboratory performing the everolimus assays.13
Carefully monitor blood everolimus concentrations in patients with hepatic impairment, patients receiving concomitant treatment with 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 and Dosage Adjustment of Cyclosporine for Renal Allotransplantation
Reduce cyclosporine dosages and target concentrations when cyclosporine is used in combination with everolimus to minimize the risk of nephrotoxicity.13 When administered with everolimus, 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 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 Adjust the cyclosporine dosage based on whole blood trough concentrations.13
Data regarding everolimus dosages with reduced cyclosporine trough concentrations of 25-50 ng/mL after 12 months are limited.13 Everolimus has not been evaluated in clinical trials with other formulations of cyclosporine.13 Prior to dosage reduction of cyclosporine, verify steady-state everolimus whole blood trough concentrations of 3 ng/mL or greater.13 Everolimus concentrations may decrease if cyclosporine exposure is reduced.13
Therapeutic Drug Monitoring and Dosage Adjustment of Everolimus for Hepatic Allotransplantation
Routine monitoring of whole blood everolimus concentrations is recommended for all hepatic transplant patients.13 The recommended therapeutic range is 3-8 ng/mL.13 Carefully monitor clinical signs and symptoms, tissue biopsies, and laboratory parameters.13
The recommended trough concentration range of 3-8 ng/mL for everolimus is based on an LC/MS/MS assay method.13 In clinical practice, everolimus whole blood concentrations may be measured by chromatographic or immunoassay methodologies.13 However, the measured concentrations of everolimus in whole blood depend on the type of assay used, and the individual patient sample concentration values from different assay methodologies may not be interchangeable.13 Consideration of assay results should be made with knowledge of the specific assay that was used.13 Therefore, it is essential that communication be maintained with the laboratory performing the everolimus assays.13
Carefully monitor blood everolimus concentrations in patients with hepatic impairment and patients receiving concomitant treatment with inducers or inhibitors of CYP3A4.13
Therapeutic Drug Monitoring and Dosage Adjustment of Tacrolimus for Hepatic Allotransplantation
Reduce tacrolimus dosages and the target concentrations when tacrolimus is used in combination with everolimus to minimize the risk of nephrotoxicity.13 When administered with everolimus, the recommended therapeutic range for whole blood trough tacrolimus concentrations is 3-5 ng/mL by 3 weeks after the first dose of everolimus (approximately month 2 posttransplant) and through month 12 posttransplant.13 Administer tacrolimus as oral capsules twice daily unless administration of IV tacrolimus cannot be avoided.13 Adjust the tacrolimus dosage based on whole blood trough concentrations.13
Data regarding everolimus dosages with reduced tacrolimus trough concentrations of 3-5 ng/mL after 12 months are limited.13 Prior to dosage reduction of tacrolimus, verify steady-state everolimus whole blood trough concentration of 3 ng/mL or greater.13 Tacrolimus does not affect everolimus trough concentrations, and everolimus concentrations do not decrease if tacrolimus exposure is reduced.13
Dosage Modification for Toxicity
Management of severe or intolerable adverse effects in patients receiving everolimus for breast cancer, neuroendocrine tumors of pancreatic, GI, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures may require temporary dosage reduction and/or interruption of everolimus therapy.1
If dosage reduction is required for patients receiving the lowest available strength of everolimus, alternate-day dosing should be used.1
In patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures experiencing grade 2 noninfectious pneumonitis, withhold everolimus therapy temporarily until recovery to grade 1 or less; once recovered, resume everolimus at 50% of previous dose.1 Dosing may be changed to every other day if the reduced dose is lower than the lowest available strength.1 If toxicity does not resolve or improve to grade 1 within 4 weeks, permanently discontinue everolimus.1
In patients with grade 3 noninfectious pneumonitis, withhold everolimus therapy temporarily until improvement to grade 1 or less.1 Once improved, resume everolimus therapy at 50% of the previous dosage.1 If toxicity recurs at grade 3, permanently discontinue everolimus.1
In patients experiencing grade 4 noninfectious pneumonitis, permanently discontinue everolimus therapy.1
In patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures who develop grade 2 stomatitis, everolimus therapy should be temporarily withheld until recovery to grade 1 or less; reinitiate everolimus at the same dosage following recovery.1 If stomatitis recurs at grade 2, therapy should then be temporarily withheld until recovery to grade 1 or less; reinitiate everolimus at 50% of the previous dosage.1
In patients with grade 3 stomatitis, temporarily withhold everolimus therapy until recovery to grade 1 or less; reinitiate everolimus therapy at 50% of the previous dosage.1 In patients with grade 4 stomatitis, permanently discontinue everolimus.1
In patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures who develop grade 2 nonhematologic toxicities that become intolerable, temporarily withhold everolimus therapy until recovery to grade 1 or less; reinitiate everolimus at the same dosage following recovery.1 If grade 2 nonhematologic toxicity recurs, interrupt therapy until recovery to grade 1 or less; reinitiate everolimus at 50% of the previous dosage.1
In patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures who develop grade 3 nonhematologic toxicity, temporarily withhold everolimus therapy until recovery to grade 1 or less; once recovered, consider reinitiation of everolimus therapy at 50% of the previous dosage.1 If grade 3 toxicity recurs, permanently discontinue everolimus.1 In patients with grade 4 nonhematologic toxicity, permanently discontinue everolimus.1
In patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures experiencing grade 3 metabolic events such as hyperglycemia or dyslipidemia, temporarily interrupt everolimus therapy until recovery to grade 2 or less; once recovered, resume everolimus therapy at 50% of the previous dosage. In1 patients experiencing grade 4 metabolic events, permanently discontinue everolimus.1
In patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures who develop grade 2 thrombocytopenia, temporarily withhold everolimus therapy until recovery to grade 1 or less; once recovered, resume everolimus therapy at the same dosage.1 In patients experiencing grade 3 or 4 thrombocytopenia, temporarily withhold everolimus therapy until recovery to grade 1 or less; once recovered, resume everolimus therapy at 50% of the previous dosage.1
In patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures who develop grade 3 neutropenia, temporarily withhold everolimus therapy until improvement to grade 2 or less; once improved, resume everolimus therapy at the same dosage.1 In patients with grade 4 neutropenia, temporarily withhold everolimus until improvement to grade 2 or less; once improved, resume everolimus therapy at 50% of the previous dosage.1
In patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, SEGA, or partial-onset seizures who develop grade 3 febrile neutropenia, temporarily withhold everolimus therapy until improvement to grade 2 or less and resolution of the fever; once improved, resume everolimus therapy at 50% of the previous dosage.1 In patients with grade 4 febrile neutropenia, permanently discontinue everolimus therapy.1
In patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, the manufacturer recommends an everolimus dosage of 7.5 mg daily in patients with mild (Child-Pugh class A) hepatic impairment; the dosage may be further reduced to 5 mg daily based on patient tolerability.1 The manufacturer recommends a dosage of 5 mg daily in patients with moderate (Child-Pugh class B) hepatic impairment; the dosage may be further reduced to 2.5 mg daily based on patient tolerability.1 In patients with severe (Child-Pugh class C) hepatic impairment, the manufacturer recommends a maximum dosage of 2.5 mg daily, if the potential benefit of therapy outweighs the risk.1
In patients who are receiving everolimus for the prevention of renal or liver allograft rejection with mild (Child-Pugh class A) hepatic impairment, the manufacturer recommends that the usual recommended initial daily dosage of everolimus be reduced by approximately 33%.13 The manufacturer recommends that the usual recommended initial daily dosage of everolimus be reduced by approximately 50% in patients with moderate or severe (Child-Pugh class B or C) hepatic impairment.13 Further dosage adjustments should be made if a patient's whole blood trough concentration of everolimus is not within the target therapeutic range of 3-8 ng/mL.13
In patients with SEGA or partial-onset seizures with TSC who have severe (Child-Pugh class C) hepatic impairment, the manufacturer recommends an everolimus dosage of 2.5 mg/m2 daily.1 Subsequent dosage adjustments should be based on therapeutic drug monitoring.1
The manufacturer states that no dosage adjustment is required in patients with renal impairment.1, 13
The manufacturer states that no adjustment of the initial dosage is required in geriatric patients;1, 13 however, close monitoring and appropriate dosage adjustments for adverse effects are recommended for Afinitor® and Afinitor® Disperz®.1
Management of Immunosuppression
A boxed warning regarding the use of everolimus (Zortress®) only by clinicians experienced in immunosuppressive therapy and the management of transplant patients is included in the prescribing information for everolimus (Zortress®).13 Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources, and the clinician responsible for maintenance therapy should have complete information requisite for follow-up of the patient.13 In limited data with the complete elimination of calcineurin inhibitor, there was an increased risk of acute rejection.13
Malignancies and Serious Infections
A boxed warning about the increased susceptibility and the possible development of malignancies from immunosuppression is included in the prescribing information for everolimus (Zortress®).13 Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including opportunistic infections.1, 13 Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal.1, 13 Localized and systemic infections (e.g., including, but not limited to, respiratory tract infections, urinary tract infections and skin infections) have been reported; grade 3 and 4 infections have been reported in 10 and up to 3% of patients, respectively.1 Serious infections occurred more frequently in patients under 6 years of age.1 Viral infections, including reactivation of hepatitis B virus, also have been reported.1 Infections have been reported in 64% of patients receiving a regimen containing everolimus for prevention of rejection of renal allografts.13 Respiratory tract infections have been reported in 31% of patients with subependymal giant cell astrocytoma (SEGA) receiving everolimus.1 The manufacturer of Zortress® states that antimicrobial prophylaxis for Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia (PJP) and cytomegalovirus (CMV) is recommended in transplant recipients.13
The manufacturer of Afinitor® and Afinitor® Disperz® recommends administration of prophylaxis against PJP when concomitant corticosteroids or immunosuppressives are used with everolimus.1 Monitor for signs and symptoms of infection; if infection develops, promptly institute appropriate treatment and consider interruption or permanent discontinuance of everolimus therapy based on infection severity.1 Complete treatment of a preexisting invasive fungal infection prior to initiating everolimus therapy.1 Patients receiving immunosuppressive therapy, including everolimus, are at increased risk of developing malignancies, such as lymphomas and other malignancies, particularly of the skin.13 The risk of malignancy appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific drug.13 In patients with an increased risk for skin cancer, limit exposure to sunlight and ultraviolet light with use of protective clothing and sunscreen with a high protection factor.13
A boxed warning about an increased risk of kidney arterial and venous thrombosis, resulting in graft loss and occurring primarily within the first 30 days posttransplantation, is included in the prescribing information for everolimus (Zortress®).13
A boxed warning about the risk of nephrotoxicity with concurrent calcineurin-inhibitor use is included in the prescribing information for everolimus (Zortress®).13 Increased nephrotoxicity resulting in a lower glomerular filtration rate can occur with the use of standard dosages of cyclosporine concurrently with everolimus (Zortress®) in renal transplant patients.13 Therefore, reduced dosages of cyclosporine should be administered when the drug is used in combination with everolimus, and cyclosporine and everolimus whole blood trough concentrations should be monitored.13 In hepatic transplant recipients, everolimus has not been studied with standard dosages of tacrolimus.13 Reduced dosages of tacrolimus should be used in combination with everolimus to minimize the potential risk of nephrotoxicity with this combination.13 Renal function should be monitored during everolimus therapy in all transplant patients.13 Clinicians should consider switching to other immunosuppressive therapies if renal function does not improve after dosage adjustments or if the renal dysfunction is thought to be drug related.13 An increased risk of proteinuria has been reported in transplant patients receiving everolimus (Zortress®), with a greater risk observed in patients with higher everolimus whole blood trough concentrations.13 Transplant patients receiving everolimus should therefore be monitored for proteinuria.13 Increases in serum creatinine concentrations and proteinuria have been reported in clinical trials with Afinitor® and Afinitor® Disperz®.1 Cases of renal failure (including acute renal failure), some with a fatal outcome, also have been observed in everolimus-treated patients.1 Monitor renal function prior to initating everolimus and annually thereafter.1 In patients with increased risk factors for renal dysfunction, monitor at least every 6 months.1
Increased Mortality in Cardiac Transplantation
A boxed warning about the increased risk of mortality in patients undergoing cardiac transplantation is included in the prescribing information for everolimus (Zortress®).13 In a clinical trial of de novo cardiac transplant patients, everolimus (Zortress®), in an immunosuppressive regimen with or without induction therapy, resulted in increased mortality, often associated with serious infections, in the first 3 months posttransplantation compared with the control regimen (containing mycophenolate mofetil).13, 39 Therefore, use of everolimus in cardiac transplantation is not recommended by the manufacturer.13
Other Warnings and Precautions
Interstitial Lung Disease/Noninfectious Pneumonitis
Noninfectious pneumonitis, which is a class effect of rapamycin derivatives, has been reported in up to 19% of patients receiving everolimus (Afinitor® and Afinitor® Disperz®) in clinical trials, with pulmonary hypertension in some cases reported as a secondary event (including pulmonary arterial hypertension [PAH]), which includes reduced dosages.1 Grade 3 or 4 events were reported to occur in up to 4 or 0.2%, respectively, of patients receiving the drug.1 Fatal noninfectious pneumonitis also has been reported with everolimus.1, 13
Consider a diagnosis of noninfectious pneumonitis in patients presenting with nonspecific respiratory signs and symptoms, as well as the presence of opportunistic infections such as PJP.1 If radiological changes suggestive of noninfectious pneumonitis develop in patients with minimal or no symptoms, continue Afinitor® and Afinitor® Disperz® without dosage alteration.1 If grade 2-4 noninfectious pneumonitis develops, temporarily interrupt or permanently discontinue everolimus therapy and subsequently reduce the dosage.1 Corticosteroids may be indicated until symptoms resolve.1 Prophylaxis for PJP should be given when corticosteroids and other immunosuppressive treatments are required.1 The development of pneumonitis has occurred even at a reduced dose.1
A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom other causes (e.g., infection, cancer, other non-drug causes) have been excluded.13 Some cases of ILD implying pneumonitis and/or noninfectious fibrosis (some with pulmonary hypertension [including PAH] occurring as a secondary event) have occurred with the use of rapamycin derivatives, including Zortress®.1 Most cases of ILD generally resolve following interruption of everolimus therapy with or without glucocorticoid therapy; however, fatal cases have been reported.13
Stomatitis, which includes oral ulcerations and oral mucositis, is a common adverse effect associated with everolimus and other mammalian target of rapamycin (mTOR) inhibitors; such ulcerations usually appear as aphthous-like ulcerations rather than the mucositis typically observed with conventional chemotherapy.1, 35 Mouth ulcers, stomatitis, and oral mucositis have been reported in 44-78% of patients treated with everolimus (Afinitor® and Afinitor® Disperz®) in clinical trials.1 Grade 3-4 stomatitis was reported in 4-9% of patients.1 Stomatitis generally occurs within the first 8 weeks of starting treatment.1
Initiation of dexamethasone 0.1 mg/mL alcohol-free oral solution as a swish and spit solution (10 mL swished for 2 minutes and then spit out, 4 times daily for 8 weeks) when starting everolimus has been shown to reduce the incidence and severity of stomatitis in adult patients.1 Mouthwashes and/or other topicals are recommended if stomatitis does occur, however, alcohol-, peroxide-, iodine-, and thyme-containing products should be avoided because they may exacerbate the condition.1 Because of the high potential for drug interactions, systemic antifungal therapy should not be used unless fungal infection has been diagnosed.1
Mammalian target of rapamycin (mTOR) inhibitors are associated with an increased risk of hepatic artery thrombosis (HAT).13 Most cases of HAT have occurred within the first 30 days posttransplantation and most resulted in graft loss or death.13 Therefore, the manufacturer states that everolimus should not be administered earlier than 30 days following liver transplantation.13
Patients receiving immunosuppressants, including everolimus, are at an increased risk for opportunistic infections, including polyoma virus infections.13 Polyoma virus infections in transplant recipients may have serious, sometimes fatal outcomes.13 These include polyoma virus-associated neuropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multiple leukoencephalopathy (PML).13 PVAN has been reported in patients receiving immunosuppressants, including everolimus, and may lead to deteriorating renal function and renal graft loss.13 Patient monitoring may help detect patients at risk of PVAN.13
Consider decreasing total immunosuppression in patients who develop evidence of PVAN or PML.13 Clinicians should also consider the potential risk that reduced immunosuppression represents to the functioning allograft.13
Risk of Infection or Reduced Immune Response with Immunization
Use of live vaccines (e.g., influenza virus vaccine live intranasal, measles virus vaccine live, mumps virus vaccine live, rubella virus vaccine live, BCG vaccine, yellow fever vaccine, varicella vaccine live, typhoid vaccine live oral) and close contact with individuals who have received live vaccines should be avoided during everolimus therapy.1, 13
Due to the risk of reduced immune response or infection with vaccination, the manufacturer recommends completion of the childhood series of vaccinations according to the US Public Health Service Advisory Committee on Immunization Practices (ACIP) guidelines prior to the initiation of everolimus therapy.1 The manufacturer also states that an accelerated vaccination schedule may be appropriate.1
Severe Hypersensitivity Reactions
Hypersensitivity reactions including anaphylaxis, dyspnea, flushing, chest pain, and/or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been reported with everolimus and other rapamycin derivatives.1, 13, 37 The manufacturer of Afinitor® and Afinitor® Disperz® recommends permanent discontinuation of everolimus if clinically significant hypersensitivity reactions develop.1
Everolimus and other mTOR inhibitors are associated with the development of angioedema.13, 37 The concomitant use of everolimus with other drugs known to cause angioedema such as angiotensin-converting enzyme (ACE) inhibitors may increase the risk of developing angioedema.1, 13, 37 In a pooled analysis of clinical studies in oncology patients, rates of angioedema in patients receiving an ACE inhibitor and everolimus were 6.8% versus 1.3% for those patients only taking an ACE inhibitor.1 Monitor patients receiving everolimus for possible symptoms of angioedema; if angioedema occurs, prompt treatment is necessary.13 The manufacturer recommends permanent discontinuation of Afinitor® and Afinitor® Disperz® if angioedema occurs.1
Wound Healing and Fluid Accumulation
Everolimus increases the risk of delayed wound healing and increases the incidence of wound-related complications, including wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma.13 Surgical intervention may be required to treat these wound-related complications.13 Generalized fluid accumulation, including peripheral edema (e.g., lymphedema), and other types of localized fluid accumulation, such as pericardial and pleural effusions and ascites, also have been reported.13
Monitor patients receiving everolimus for possible symptoms of delayed wound healing and fluid accumulation, and treat the conditions promptly to minimize potential complications.13
The manufacturer of Afinitor® and Afinitor® Disperz® recommends withholding everolimus for at least 1 week prior to elective surgery, and for at least 2 weeks after completion of the procedure until adequate wound healing has been established.1 The safety of resuming everolimus following the resolution of wound healing complications is not known.1
Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in up to 75, 86, and 73% of patients taking Afinitor® and Afinitor® Disperz®, respectively.1 Hyperlipidemia (e.g., hypercholesterolemia, hypertriglyceridemia) has also been reported in patients receiving Zortress® and may require treatment.13 Risk of hyperlipidemia is increased in patients with higher whole blood trough everolimus concentrations.13
An increased risk of developing new-onset diabetes mellitus has been observed with everolimus (Zortress®) therapy following transplantation.13
Monitor lipid profile prior to and periodically during everolimus (Afinitor® and Zortress®) therapy (annually for patients receiving Afinitor® and Afinitor® Disperz®).1, 13 When possible, optimal lipid control should be achieved prior to initiation of everolimus therapy.1 Patients who develop hyperlipidemia while receiving everolimus (Zortress®) should be treated according to current standards of care.13 Normalization of serum lipids with antihyperlipidemic agents may not be possible in patients receiving everolimus.13 Consider the risk/benefit of everolimus therapy prior to initiating therapy in patients with baseline hyperlipidemia and reevaluate in patients who develop severe refractory hyperlipidemia while receiving the drug.13 Safety and efficacy of everolimus in patients with baseline cholesterol concentrations above 350 mg/dL have not been evaluated.13
Closely monitor glucose concentrations in patients receiving everolimus following renal and hepatic allotransplantation.13 Monitor fasting glucose concentrations prior to and annually during everolimus (Afinitor® and Afinitor®Disperz®) therapy in non-diabetic patients; when possible, achieve optimal glycemic control prior to initiation of everolimus therapy.1 Monitor fasting serum glucose concentrations in diabetic patients more frequently as clinically indicated.1 Depending on severity, interruption of Afinitor® or Afinitor® Disperz® therapy, dosage reduction, and/or drug discontinuance may be required.1
Patients with Hereditary Disorders
Everolimus may cause diarrhea and malabsorption in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption; everolimus should not be used in such patients.13
Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported with everolimus (Afinitor® and Afinitor®Disperz®) therapy.1, 2, 6 Monitor complete blood count (CBC) prior to starting everolimus and then every 6 months during the first year of treatment.1 Thereafter, the CBC can be monitored annually in patients on everolimus.1 Withhold or permanently discontinue everolimus based on the severity of the hematologic toxicity.1
Thrombotic Microangiopathy/Thrombotic Purpura/Hemolytic Uremic Syndrome
Concurrent use of everolimus and cyclosporine may increase the risk of thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS).13 Monitor hematologic parameters in patients concurrently receiving everolimus and cyclosporine.13
Radiation Sensitization and Recall
Radiation sensitization and recall involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis), including some severe cases, have been reported in patients receiving radiation prior to, during, and after initiation of everolimus (Afinitor® and Afinitor® Disperz®).1 Monitor patients closely if everolimus is administered during or in sequence with radiation therapy.1
Interaction with Potent Inhibitors and Inducers of Cytochrome P-450 Isoenzyme 3A4
Concomitant use of everolimus with strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4; e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir) and strong inducers of CYP3A4 (e.g., rifampin, rifabutin) is not recommended or requires close monitoring of whole blood trough everolimus concentrations and/or adjustment of everolimus dosage.1, 13
Fetal/Neonatal Morbidity and Mortality
Everolimus can cause fetal harm; teratogenicity and embryolethality have been demonstrated in animals.1 There are no adequate and well-controlled studies in humans.1, 13 Advise females of childbearing potential to use an effective method of contraception during and for up to 8 weeks following discontinuation of everolimus.1, 13 Advise male partners of such females to use effective contraception during everolimus treatment, and for 4 weeks after discontinuance of the drug.1 If everolimus is used during pregnancy or if the patient becomes pregnant while receiving the drug, apprise the patient of the potential hazard to the fetus.1
Male infertility may be observed with mTOR inhibitors, including everolimus.13 Everolimus may impair male fertility (decreased fertility was observed in male rats) through its effects on rapidly dividing cells (e.g., germ cells); azoospermia or oligospermia may be observed.1, 13 Azoospermia cases have been reversible in male patients taking everolimus.1
Closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity when cannabidiol is administered concurrently with everolimus (Zortress®).13 A dose reduction of everolimus (Zortress®) should be considered as needed when coadministration occurs.13
Grapefruit and grapefruit juice inhibit cytochrome CYP3A4 and P-gp activity and should therefore be avoided with concomitant use of everolimus.1, 13
Based on animal studies and the mechanism of action of everolimus, administration of everolimus during pregnancy may result in fetal harm.1 Reproductive studies in animals have shown that administration of everolimus during pregnancy is maternally toxic and has caused embryofetal toxicities, even at exposures near or lower than comparable human exposures.1, 13 Verify pregnancy status of females of reproductive potential prior to initiation of everolimus.1 Advise females of childbearing potential to use an effective method of contraception during and for up to 8 weeks following the discontinuation of everolimus.1, 13 Advise male partners of such females to use effective contraception during everolimus treatment, and for 4 weeks after discontinuing the drug.1 Advise pregnant patients of the potential for risk to the fetus.1
The National Transplantation Pregnancy Registry (NTPR) is a pregnancy registry for pregnant women receiving immunosuppressants following any solid organ transplantation; the NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant patients by telephone at 877-955-6877 or via their website: [Web].34
Everolimus and/or its metabolites readily distribute into milk in lactating rats at a concentration 3.5 times higher than in maternal serum.1, 13 It is not known whether everolimus is distributed into human milk.1, 13 The effects of the drug on the breast-fed infant or on the production of milk are not known.1, 13 In animal studies, exposure to everolimus during the postnatal period resulted in developmental toxicity.13 In patients taking everolimus for breast cancer, neuroendocrine tumors (NET) of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, SEGA, or partial-onset seizures, it is recommended to avoid breast-feeding during everolimus treatment and for 2 weeks following the last dose due to the potential for serious adverse reactions in infants exposed to everolimus.1 In transplant patients, it is recommended to avoid breast-feeding.13
Females and Males of Reproductive Potential
Male infertility may be observed with mTOR inhibitors, including everolimus.13 Everolimus may impair male fertility (decreased fertility was observed in male rats) through its effects on rapidly dividing cells (e.g., germ cells); azoospermia or oligospermia may be observed.1, 13 Azoospermia cases have been reversible in male patients taking everolimus.1 Fertility may also be impaired in female patients taking everolimus.1 Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone and follicle stimulating hormone have been observed in female patients taking everolimus.1
Safety and efficacy of everolimus for the treatment of SEGA associated with TSC have been evaluated in pediatric patients 1 year of age and older.1 Safety and efficacy have not been established in pediatric patients younger than 1 year of age with SEGA.1 Although a determination remains inconclusive based on available data, the use of everolimus did not appear to adversely affect growth and pubertal development in 115 pediatric patients with TSC-associated SEGA treated with everolimus over a median duration of 4.1 years.1
Safety and efficacy of everolimus for the adjunctive treatment of partial-onset seizures associated with TSC have been evaluated in pediatric patients 2 years of age and older.1 Safety and efficacy as an adjunctive treatment have not been established in pediatric patients younger than 2 years of age with TSC-associated partial-onset seizures.1
The incidence of infections, including serious infections, in pediatric patients under 6 years of age receiving everolimus treatment have been reported at a higher frequency in comparison to patients 6 years of age and older.1
Safety and efficacy of everolimus for the treatment of renal angiomyolipoma with TSC in the absence of SEGA, hormone-receptor positive, HER2-negative breast cancer, NET, and renal cell carcinoma (RCC) have not been established in pediatric patients.1
Clearance of everolimus normalized to body surface area was higher in pediatric patients with SEGA and TSC-associated partial-onset seizures compared with adults.1
Safety and efficacy of everolimus for the prevention of renal or hepatic allograft rejection have not been established in pediatric patients younger than 18 years of age.13
In a randomized clinical study evaluating everolimus in patients with advanced breast cancer, 40% of patients receiving everolimus were 65 years of age or older, and 15% were 75 years of age or older.1 No overall differences in efficacy relative to younger adults were observed.1 The incidence of deaths due to any cause within 28 days of the last everolimus dose in patients younger than 65 years of age was 2% compared with 6% in patients 65 years of age or older.1 Adverse effects leading to permanent treatment discontinuance occurred in 33% of patients aged 65 or older compared with 17% of patients younger than 65 years of age.1
In 2 other randomized clinical studies in patients with advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin, 41 and 30% of patients receiving everolimus were 65 years of age or older, respectively, and 7% were 75 years of age or older in both studies.1 No overall differences in safety and efficacy relative to younger adults were observed in these studies.1
Clinical experience with the use of everolimus (Zortress®) following transplantation in patients 65 years of age or older is limited to date.13
Following administration of a single oral dose of everolimus, exposure (i.e., average area under the plasma concentration-time curve [AUC]) was increased by 1.8-, 3.2-, or 3.6-fold in patients with mild (Child Pugh A), moderate (Child Pugh B), or severe hepatic impairment (Child Pugh C), respectively, compared with individuals with normal hepatic function.1 In another study, the average AUC of everolimus in individuals with moderate hepatic impairment reportedly was twice that observed in those with normal hepatic function.1, 13
In patients with mild, moderate, or severe (Child-Pugh class A, B, or C) hepatic impairment with breast cancer, NET, RCC, TSC-associated renal angiomyolipoma, or who have received a renal or hepatic allotransplant, everolimus dosage reduction is recommended.1, 13 In patients with severe hepatic impairment (Child-Pugh class C) with TSC-associated SEGA or TSC-associated partial-onset seizures, a reduction in the initial dosage is recommended and subsequent dosage adjustment should be based on therapeutic drug monitoring.1
In patients with renal impairment, no significant correlation has been demonstrated between creatinine clearance (range: 25-178 mL/minute) and everolimus clearance.1 In renal transplant patients, creatinine clearance (range: 11-107 mL/minute) did not affect the pharmacokinetics of everolimus.13 Because renal impairment is not expected to influence drug exposure, the manufacturer states that no dosage adjustment is necessary in patients with renal impairment.1, 13
Adverse effects reported in 30% or more of patients receiving everolimus for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer, progressive neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, or advanced renal cell carcinoma, and more frequently with the drug than with placebo include stomatitis (including mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration), infections (including urinary tract infections, upper and lower respiratory tract infections, skin, and gastrointestinal tract infections), rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, and decreased appetite.1
Adverse effects reported in 30% or more of patients receiving everolimus for the treatment of renal angiomyolipoma with tuberous sclerosis complex (TSC) and more frequently with the drug than with placebo include stomatitis (including mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and stomatitis).1
Adverse effects reported in 30% or more of patients receiving everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) with TSC include stomatitis (including mouth and lip ulceration, and stomatitis) and respiratory tract infections (including respiratory tract infection, upper respiratory tract infection, and viral respiratory tract infection).1
Adverse effects reported in 30% or more of patients receiving everolimus for the adjunctive treatment of partial-onset seizures with TSC include stomatitis (including stomatitis, mouth ulceration, apththous ulcer, lip and tongue ulceration, mucosal inflammation, and gingival pain).1
Adverse effects reported in 20% or more of patients receiving everolimus in combination with reduced-exposure cyclosporine for prevention of organ rejection after renal transplantation include peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection, and hyperlipidemia.13
Adverse effects reported in more than 10% of patients receiving everolimus in combination with reduced-exposure tacrolimus for prevention of organ rejection after hepatic transplantation include diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, leukopenia, and hypercholesterolemia.
Everolimus is a substrate of cytochrome P-450 (CYP) isoenzyme 3A4; the drug is a competitive inhibitor of CYP3A4 and CYP2D6 in vitro.1, 13 Everolimus also is a substrate of the efflux transporter P-glycoprotein (P-gp).1, 13
Inhibitors or Inducers of CYP3A4 and P-glycoprotein
Increased exposure to everolimus (increased peak plasma concentrations and AUC) has been observed during concomitant use with strong CYP3A4 (e.g., clarithromycin, erythromycin, itraconazole, ketoconazole, verapamil, or voriconazole) and P-gp inhibitors (e.g., cyclosporine, digoxin).1, 13 Avoid concomitant use of P-gp and strong CYP3A4 inhibitors with everolimus.1 In drug interaction studies, the use of ketoconazole (a P-gp and strong CYP3A4 inhibitor) increased the peak plasma concentrations and AUC of everolimus by 3.9- and 15-fold, respectively.1
Reduce the dosage of everolimus if used concurrently with P-gp and moderate inhibitors of CYP3A4 (e.g., amprenavir, diltiazem, erythromycin, fluconazole, nelfinavir, nicardipine, verapamil).1
If erythromycin or verapamil is used concurrently with everolimus in transplant patients, monitor blood everolimus concentrations and adjust the dosage of everolimus accordingly.13
If coadministration of a P-gp and moderate CYP3A4 inhibitor is required in patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, advanced renal cell carcinoma, or tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the everolimus dosage to 2.5 mg daily.1 An increase in everolimus dosage from 2.5 mg to 5 mg daily may be considered based on patient tolerance.1 If the P-gp and moderate CYP3A4 inhibitor is discontinued, return the everolimus dosage to the dosage used prior to initiation of the P-gp and moderate CYP3A4 inhibitor 3 days after discontinuance of the P-gp and CYP inhibitor.1
If coadministration of a P-gp and moderate CYP3A4 inhibitor is required in patients with TSC-associated subependymal giant cell astrocytoma (SEGA) or partial-onset seizures, reduce the initial recommended daily dosage by 50%.1 If dosage reduction is required in patients receiving the lowest available strength, change to alternate-day dosing.1 Individualize subsequent dosing based on therapeutic drug monitoring.1 Trough everolimus concentrations should be assessed 2 weeks after dosage reduction.1 If the P-gp and moderate CYP3A4 inhibitor is discontinued, return the everolimus dosage to the dosage used prior to initiation of the P-gp and moderate CYP3A4 inhibitor 3 days after discontinuance of the P-gp and CYP inhibitor; trough everolimus concentration should be reassessed 2 weeks later.1
In patients taking P-gp and CYP3A4 inhibitors, grapefruit and grapefruit juice should not be consumed.1
Pharmacokinetic interactions have been observed during concomitant use with rifampin (decreased peak plasma concentrations and AUC of everolimus).1, 13 Avoid concomitant use with P-gp and strong CYP3A4 inducers (e.g., rifabutin, rifampin) if alternative therapy is available.1, 13
If concomitant use with a P-gp and strong CYP3A4 inducer cannot be avoided in patients with breast cancer, neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin, renal cell carcinoma, or TSC-associated renal angiomyolipoma, double the daily everolimus dosage (from 10 mg daily up to 20 mg daily, titrated in ≤5-mg increments).1 If the P-gp and strong CYP3A4 inducer is discontinued, return the everolimus dosage to the dosage used prior to initiation of the P-gp and potent CYP3A4 inducer 5 days after discontinuance of the P-gp and strong CYP3A4 inducer.1
If concomitant use with a P-gp and strong CYP3A4 inducer cannot be avoided in patients with TSC-associated SEGA or partial-onset seizures, double the daily dosage of everolimus, titrated in ≤5-mg increments.1 Assess trough everolimus concentrations 2 weeks after doubling the dosage, and adjust the dosage if necessary to maintain a trough concentration of 5-15 ng/mL.1 If a second strong CYP3A4 inducer is added to the existing regimen that includes a strong CYP3A4 inducer, and the dosage has already been adjusted, additional dosage modification may not be necessary.1 If the P-gp and strong CYP3A4 inducer is discontinued, reduce the dosage of everolimus to the dosage used prior to initiation of the P-gp and strong CYP3A4 inducer 5 days after discontinuance of the P-gp and strong CYP3A4 inducer, and reassess everolimus trough concentrations 2 weeks later.1
Substrates of CYP3A4 and CYP2D6
Everolimus is unlikely to affect the metabolism of CYP3A4 or CYP2D6 substrates.13 However, everolimus increased concentrations of these substrates in vitro.13 Everolimus should therefore be used with caution with CYP3A4 or CYP2D6 substrates.13
Angiotensin-converting Enzyme Inhibitors
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors with everolimus may increase the risk of angioedema.1, 13 Avoid using ACE inhibitors in patients on everolimus therapy.1
The use of everolimus with carbamazepine, clobazam, oxcarbazepine, and the metabolite of clobazam, N-desmethylclobazam resulted in increased pre-dose concentrations of the antiepileptic drugs by approximately 10%.1 The use of everolimus had no impact on pre-dose concentrations of CYP3A4 substrates clonazepam and zonisamide, or other antiepileptic agents such as valproic acid, topiramate, phenobarbital, and phenytoin.1
Studies in healthy individuals indicate that there are no clinically important pharmacokinetic interactions between single-dose everolimus and atorvastatin (a CYP3A4 substrate), simvastatin (a CYP3A4 substrate), or pravastatin (a non-CYP3A4 substrate and P-gp substrate); HMG-CoA reductase activity of atorvastatin and pravastatin in plasma also was not substantially affected.1, 13 Therefore, dosage adjustments are not necessary when everolimus and atorvastatin or pravastatin are used concurrently.13 The manufacturer of Zortress® cautions that these results cannot be extrapolated to other HMG-CoA reductase inhibitors.13
Use of HMG-CoA reductase inhibitors such as lovastatin or simvastatin was strongly discouraged in clinical trials of everolimus with cyclosporine in renal transplant patients because of an interaction between HMG-CoA reductase inhibitors and cyclosporine.13 The manufacturer of Zortress® recommends that patients receiving everolimus and cyclosporine therapy who are concurrently receiving an HMG-CoA reductase inhibitor and/or fibric acid derivative be monitored for the possible development of rhabdomyolysis and other adverse effects, which are described in the prescribing information for these antilipemic agents.13
Administration of a single dose of cyclosporine resulted in increased steady-state peak plasma concentrations and AUC of everolimus.13 Use of standard-dose cyclosporine therapy with everolimus results in increased risk of nephrotoxicity and decreased glomerular filtration rate.13 Renal transplant patients receiving everolimus should receive reduced-dose cyclosporine therapy, and renal function should be monitored.13 Adjustment of everolimus dosage may be required if cyclosporine dosage is altered.13 Consider switching to alternative immunosuppressive therapies if renal function does not improve after dosage adjustments or if renal dysfunction is thought to be drug-related.13
Concomitant use of everolimus and cyclosporine may increase the risk of thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome.13 Monitor hematologic parameters in patients receiving everolimus and cyclosporine concurrently.13
Concomitant use of everolimus and exemestane increased exemestane trough plasma concentrations by 45% and plasma concentrations at 2 hours by 64%.1 However, corresponding estradiol concentrations at steady state (4 weeks) were not different in patients receiving exemestane and everolimus compared with patients receiving exemestane and placebo.1 In addition, no increase in adverse effects related to exemestane was observed in patients with hormone receptor-positive, HER2 -negative advanced breast cancer who received combined everolimus and exemestane therapy.1
Caution is recommended when other immunosuppressive agents are used with everolimus because of the risk of increased immunosuppression and increased risk of lymphoma, other malignancies, and infection.13
Concurrent administration of single-dose midazolam (4 mg as oral solution), a CYP3A4/5 substrate, with steady-state everolimus (10 mg daily for 5 days) in healthy males increased peak plasma concentrations and AUC of midazolam by 25 and 30%, respectively.1, 13, 38 The elimination half-life of midazolam and the metabolic AUC ratio (i.e., the ratio of 1-hydroxymidazolam AUC to midazolam AUC) were not altered.13, 38 Dosage adjustment of midazolam or other CYP3A4/5 substrates is not necessary when used concomitantly with everolimus.13
Caution is recommended when other nephrotoxic agents are used with everolimus because of the risk of increased nephrotoxicity.13
Concurrent use of everolimus and the long-acting parenteral formulation of octreotide acetate increased trough plasma concentrations of octreotide by approximately 50%.1
Avoid the use of St. John's wort ( Hypericum perforatum ) in patients receiving everolimus concomitantly with P-gp and potent CYP3A4 inducers.1
There is little to no pharmacokinetic effect of tacrolimus on everolimus; therefore, dosage adjustment of everolimus is generally not necessary when used concomitantly with tacrolimus.13
In hepatic transplant recipients, everolimus has not been studied with standard-dose tacrolimus.13 Use reduced dosages of tacrolimus in combination with everolimus to minimize the potential risk of nephrotoxicity with this combination.13 Monitor renal function during combined therapy, and consider switching to other immunosuppressive therapies if renal function does not improve after dosage adjustments or if the renal dysfunction is thought to be drug related.13
Due to a lack of safety data on the use of live vaccines during everolimus therapy and the potential for increased risk of infection, it is recommended to avoid live vaccines and close contact with people who have received live vaccines during everolimus therapy.1
The manufacturer states that live vaccines (including influenza virus vaccine live intranasal, measles virus vaccine live, mumps virus vaccine live, rubella virus vaccine live, poliovirus vaccine live oral [OPV; no longer commercially available in the US], BCG vaccine, yellow fever vaccine, varicella virus vaccine live, typhoid vaccine live oral) should be avoided in patients receiving everolimus therapy.1, 13
Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is an antineoplastic agent and macrolide immunosuppressive agent.1, 2 4, 5, 7, 8, 9, 10, 11, 13 Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.13 Serine/threonine kinases, such as mTOR, are involved in various cascades of intracellular signaling events that regulate cell growth and proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis).1, 2, 4, 5, 9 Everolimus binds with high affinity to the intracellular protein FK506 binding protein-12 (FKBP-12), forming a drug-protein complex with mTOR complex 1 (mTORC1 or everolimus:FKBP-12) that binds to and inhibits the activation of mTOR.1, 2, 5, 6, 9, 10, 13 This disruption of mTOR reduces the activity of downstream effectors (i.e., S6 ribosomal protein kinase [S6K1], eukaryotic elongation factor 4E-binding protein [4E-BP1]), thereby blocking progression of cells from G1 into S phase and, subsequently, inducing cell growth arrest and apoptosis.4, 6, 9, 10, 11, 13 S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor, resulting in ligand-independent activation of the receptor.1 The everolimus:FKBP-12 complex has no effect on calcineurin activity.13 Everolimus also inhibits expression of hypoxia-inducible factor (e.g., HIF-1α), thereby reducing the expression of vascular endothelial growth factor (VEGF).1, 7, 9 Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in vitro and/or in vivo .1, 5, 10
Constitutive activation of the phosphoinositide 3-kinase inhibitor (PI3K)/Akt/mTOR pathway can lead to endocrine resistance in breast cancer.1 Estrogen-dependent and HER2 -positive breast cancer cells are sensitive to the inhibitory effects of everolimus in vitro.1 Concomitant use of everolimus with Akt, HER2 , or aromatase inhibitors (e.g., anastrozole, exemestane, letrozole) enhances the anti-tumor activity of everolimus in a synergistic manner.1
Loss or inactivation of tuberin-sclerosis complexes 1 and 2 ( TSC1 and TSC2 ), oncogene suppressors that are two of the regulators of mTORC1 signaling, leads to activation of downstream signaling.1 In the genetic disorder tuberous sclerosis, inactivating mutations in the TSC1 or TSC2 gene leads to hematoma formation throughout the body; subependymal giant cell astrocytomas (SEGA) may develop in patients with tuberous sclerosis.1, 17
Following oral administration of doses ranging from 5-70 mg in patients with advanced solid tumors, peak everolimus concentrations are attained within 1-2 hours.1 Steady-state concentrations are achieved within 2 weeks of once-daily dosing in patients with advanced solid tumors.1 In patients with SEGA, intrapatient steady-state trough everolimus concentrations were dose-proportional at daily dosages of 1.35-14.4 mg/m2.1 In renal allograft patients, steady-state peak plasma concentrations and area under the concentration-time curve (AUC) values were dose-proportional at dosages of 0.5-2 mg twice daily; steady-state concentrations were achieved by day 4, with an accumulation in blood concentrations of twofold to threefold compared with exposure following the first dose.13 In healthy individuals, administration of 10-mg tablets with a high-fat meal reduces peak plasma concentrations and AUC of everolimus by 54 and 22%, respectively; administration with a light-fat meal reduces peak plasma concentration and AUC by 42 and 32%, respectively.1 In healthy individuals, administration of 9-mg tablets for oral suspension with a high-fat meal reduced everolimus peak plasma concentrations and AUC by 60 and 12%, respectively; administration with a low-fat meal reduced peak plasma concentrations and AUC by 50 and 30%, respectively.1 However, food has no effect on the post-absorption phase concentration-time profile of everolimus.1 In healthy individuals and in those with moderate hepatic impairment, everolimus is approximately 74% bound to plasma proteins.1, 13 The drug has been shown to cross the placenta and distribute into milk in rats.1, 13 Everolimus is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by isoenzyme 3A4.1 13 Six metabolites of everolimus have been detected in human blood and have been shown in animal studies to exhibit 100-times less activity than everolimus.1, 13 The mean elimination half-life of everolimus is approximately 30 hours.1, 13 Following administration of a single 3-mg dose in patients receiving concomitant cyclosporine, approximately 80 and 5% of the dose is excreted in feces and urine, respectively, as inactive metabolites.1 13
The AUC of everolimus tablets for oral suspension (Afinitor® Disperz®) was equivalent to the AUC of everolimus tablets (Afinitor®); peak plasma concentrations were 20-36% lower for everolimus tablets for oral suspension compared with everolimus tablets.1 Following daily administration, predicted steady-state trough concentrations were similar in patients receiving everolimus tablets for oral suspension and everolimus tablets.1
A cross-study comparison of pharmacokinetic data reported higher exposure to everolimus among Japanese patients compared with non-Japanese patients.1 Data from a population pharmacokinetic analysis indicate that clearance of everolimus is 20% higher in black patients than in Caucasian patients.1, 13 The relevance of these differences to the safety and efficacy of everolimus in Japanese or black patients has not been established.1 In patients with cancer, no apparent relationship has been observed between oral clearance and age or sex.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at http://www.ahfsdruginformation.com.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 0.25 mg* | Everolimus Tablets | |
0.5 mg* | Everolimus Tablets | |||
Zortress® | Novartis | |||
0.75 mg* | Everolimus Tablets | |||
Zortress® | Novartis | |||
1 mg* | Everolimus Tablets | |||
Zortress® | ||||
2.5 mg* | Novartis | |||
Everolimus Tablets | ||||
5 mg* | Afinitor® | Novartis | ||
Everolimus Tablets | ||||
7.5 mg* | Afinitor® | Novartis | ||
Everolimus Tablets | ||||
10 mg* | Afinitor® | Novartis | ||
Everolimus Tablets | ||||
Tablets for oral suspension | 2 mg* | Afinitor® Disperz® | Novartis | |
Everolimus Tablets for Oral Suspension | ||||
3 mg* | Afinitor® Disperz® | Novartis | ||
Everolimus Tablets for Oral Suspension | ||||
5 mg* | Afinitor® Disperz® | Novartis | ||
Everolimus Tablets for Oral Suspension |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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