Afinitor

Everolimus.

Afinitor also contains the following excipients: Butylated hydroxytoluene (E321), magnesium stearate, lactose monohydrate, hypromellose, crospovidone and anhydrous lactose.

Pharmacology: Mechanism of Action: Everolimus is a signal transduction inhibitor targeting mammalian target of rapamycin (mTOR), or more specifically, mammalian 'target of rapamycin' complex 1 (mTORC1). mTOR is a key serine-threonine kinase playing a central role in the regulation of cell growth, proliferation and survival. The regulation of mTORC1 signaling is complex, being modulated by mitogens, growth factors, energy and nutrient availability. mTORC1 is an essential regulator of global protein synthesis downstream on the PI3K/AKT pathway, which is dysregulated in the majority of human cancers.
Activation of the mTOR pathway is a key adaptive change driving endocrine resistance in breast cancer. Various signal transduction pathways are activated to escape the effect of endocrine therapy. One pathway is the P13K/Akt/mTOR pathway, which is constitutively activated in aromatase inhibitor (AI)-resistant and long-term estrogen-deprived breast cancer cells. In breast cancer cells, resistance to AIs due to Akt activation can be reversed by co-administration with everolimus.
Pharmacodynamics: Everolimus is a selective mTOR inhibitor, specifically targeting the mTOR-raptor signal transduction complex (mTORC1). mTOR is a key serine-threonine kinase in the P13K/AKT signaling cascade, a pathway known to be dysregulated in the majority of human cancers. Everolimus exerts its activity through high affinity interaction with the intracellular receptor protein FKBP12. The FKBP12/everolimus complex binds to mTORC1, inhibiting its signaling capacity. mTORC1 signaling is effected through modulation of the phosphorylation of downstream effectors, the best characterized of which are the translational regulators S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP). Disruption of S6K1 and 4E-BPI function, as a consequence of mTORC1 inhibition, interferes with the translation of mRNAs encoding pivotal proteins involved in cell cycle regulation, glycolysis and adaptation to low oxygen conditions (hypoxia). This inhibits tumor angiogenic processes [eg, the vascular endothelial growth factor (VEGF)]. Everolimus is a potent inhibitor of the growth and proliferation of tumor cells, endothelial cells, fibroblasts and blood vessel-associated smooth muscle cells. Consistent with the central regulatory role of mTORC1, everolimus has been shown to reduce tumor cell proliferation, glycolysis and angiogenesis in solid tumors in vivo, and thus provides 2 independent mechanisms of inhibiting tumor growth: Direct antitumor cell activity inhibition of the tumor stromal compartment.
Clinical Studies: Hormone Receptor-Positive Advanced Breast Cancer: BOLERO-2 (study CRAD001Y2301) a randomized, double-blind, multicentre phase III study of Afinitor+exemestane versus placebo+exemestane was conducted in postmenopausal women with estrogen receptor-positive, HER 2-neu/non-amplified advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Patients were randomized in a 2:1 ratio to receive either everolimus (10 mg daily) or matching placebo in addition to open-label exemestane (25 mg daily). Randomization was stratified by documented sensitivity to prior hormonal therapy (yes vs no) and by the presence of visceral metastasis (yes vs no). Sensitivity to prior hormonal therapy was defined either (1) documented clinical benefit [complete response (CR), partial response (PR), stable disease ≥24 weeks] to at least 1 prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence.
The primary endpoint for the trial was progression-free survival (PFS) evaluated by Response Evaluation Criteria in Solid Tumors (RECIST), based on the investigators (local radiology) assessment. Supportive PFS analyses were based on an independent central radiology review.
Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR),safety, change in quality of life (QoL) and time to ECOG PS deterioration. Additional endpoints included changes in bone turnover markers at 6 and 12 weeks.
A total of 724 patients were randomized in 2:1 ratio to the combination everolimus (10 mg daily)+exemestane (25 mg daily) (n=485) or placebo+exemestane arm (25 mg daily) (n=239). The 2 treatment groups were generally balanced with respect to the baseline demographics of disease characteristics and history of prior antineoplastic usages. The median age of patients was 61 years (range 28-93) and 75% were Caucasian.
The efficacy results were obtained from an interim analysis after 359 local PFS events and 217 central PFS events were observed. Patients in the placebo+exemestane arm did not crossover to everolimus at the time of progression.
The study demonstrated a statistically significant clinical benefit of everolimus+exemestane over placebo+exemestane by a 2.4-fold prolongation in median PFS (median: 6.93 months vs 2.83 months), resulting in a 57% risk reduction of progression or death (PFS HR 0.43; 95% CI: 0.35, 0.54; one-sided log-rank test p-value <0.0001 per local investigator assessment (see Table 1 and Figure 1).
The analysis of PFS based on independent central radiological assessment was supportive and showed a 2.6-fold prolongation in median progression-free survival (10.58 months vs 4.14 months), resulting in a 64% risk reduction progression or death (PFS HR 0.36; 95% CI: 0.27, 0.47; one-sided log-rank test p-value <0.0001 (see Table 1 and Figure 2) BOLERO-2-Kaplan-Meier progression-free survival curves (independent radiological review).
Objective response as per investigator assessment based on RECIST was observed in 9.5% of patients (95% CI: 7, 12.4) in the everolimus+exemestane arm versus 0.4% (95% CI: 0-2.3) in the placebo+exemestane arm versus 0.4% (95% CI: 0-2.3) in the placebo+exemestane arm (p<0.0001 for comparison between arms). Clinical benefit rate for everolimus+exemestane was 33.4% versus 18% in the control arm; p<0.0001 (see Table 1).

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Overall survival data (OS) data were not mature at the time of the interim analysis for PFS. Eighty-three (83) deaths were reported at the interim analysis, representing 10.6% and 13% of patient-deaths reported in the everolimus+exemestane and placebo+exemestane arms, respectively.

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Nine (9)-month PFS rates were 40% of patients receiving everolimus+exemestane compared with 15% in the placebo+exemestane arm at a median follow-up of 7.6 months.

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The estimated PFS treatment effect was supported by planned subgroup analysis of PFS per investigator assessment. For all analyzed subgroups, a positive treatment effect was seen with everolimus+exemestane with an estimated hazard ratio versus placebo+exemestane ranging from 0.25-0.60 (see Table 2, Figures 3 and 4). Subgroup analyses demonstrated a homogeneous and consistent treatment effect irrespective of sensitivity to prior hormonal therapy and presence of visceral metastasis, and across major demographic and prognostic subgroups.

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Tumor reduction was also evident from the corresponding waterfall plot. Results indicate that 68.1% of patients in the everolimus+exemestane arm experienced tumor shrinkage versus 28% for placebo+exemestane (see Figure 5).

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Clinically or statistically significant differences were not observed between the 2 treatment arms in terms of time to deterioration of ECOG PS (≥1 point) and median times to deterioration (≥5%) of QLQ-C30 domain scores.
Effects on Bone: There are no long-term data on the effect of everolimus on bone. Comparative data from BOLERO-2 showed marked improvement in serum bone-turnover markers during the first 12 weeks of therapy, suggesting a favorable effect on bone turnover.
Advanced Neuroendocrine Tumors of Gastrointestinal, Lung or Pancreatic Origin: RADIANT-3 (study CRAD001C2324), a randomized, double-blind, multicentre phase III study of Afinitor plus best supportive care (BSC) versus placebo plus BSC in patients with advanced pancreatic neuroendocrine tumors (pNET), demonstrated a statistically significant clinical benefit of Afinitor over placebo by a 2.4-fold prolongation in median progression-free survival PFS (11.04 months vs 4.6 months), resulting in a 65% risk reduction in PFS (HR 0.35; 95% CI: 0.27; 0.45; p<0.0001) (see Table 3 and Figure 6).
RADIANT-3 enrolled patients with advanced pNET whose disease had progressed within the prior 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes/no) and by WHO performance status (0 vs 1 and 2). Treatment with somatostatin analogs was allowed as part of BSC.
The primary endpoint for the trial was PFS evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). After documented radiological progression, patients could be unblinded by the investigator: Those randomized to placebo were then able to receive open-label Afinitor.
Secondary endpoints include safety, objective response rate (ORR) [complete response (CR) or partial response (PR)], response duration and overall survival OS.
In total, 410 patients were randomized 1:1 to receive either Afinitor 10 mg/day (n=207) or placebo (n=203). Demographics were well balanced (median age 58 years, 55% male, 78.5% Caucasian).

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Eighteen (18)-month PFS rates were 34.2% for Afinitor therapy compared to 8.9% for placebo.
The overall survival results are not yet mature and no statistically significant difference in OS was noted [HR=0.99 (95% CI: 0.68-1.43)]. Crossover of 72.9% (148/203) of patients from placebo to open-label Afinitor following disease progression likely confounded the detection of any treatment-related difference in OS.
RADIANT-2 (study CRAD001C2325), a randomized, double-blind, multicentre phase III study of Afinitor plus octreotide depot (Sandostatin LAR) versus placebo plus octreotide depot in patients with advanced neuroendocrine tumors (carcinoid tumor) primarily of gastrointestinal or lung origin showed evidence of clinical benefit of Afinitor over placebo by a 5.1-month prolongation in median PFS (16.43 months vs 11.33 months; HR 0.77; 95% CI: 0.59-1; p=0.026), resulting in a 23% risk reduction in primary PFS (see Table 4 and Figure 7). Although statistical significance was not reached for the primary analysis (boundary for statistical significance was p=0.0246), analyses which adjusted for informative censoring and imbalances in the 2 treatment arms showed a treatment effect in favor of everolimus.
RADIANT-2 enrolled patients with advanced neuroendocrine tumors (carcinoid tumor) primarily of gastrointestinal or lung origin whose disease had progressed within the prior 12 months and had a history of secretory symptoms. Eighty point one percent (80.1%) of the patients in the Afinitor group received somatostatin analog therapy prior to study entry compared to 77.9% in the placebo group.
The primary endpoint is PFS evaluated by RECIST. After documented radiological progression, patients could be unblinded by the investigator: Those randomized to placebo were then able to receive open-label Afinitor.
Secondary endpoints include safety, vest overall response, response duration and overall survival.
In total, 429 patients were randomized 1:1 to receive either Afinitor 10 mg/day (n=216) or placebo (n=213), in addition to octreotide depot (Sandostatin LAR, administered IM) 30 mg every 28 days. Notable imbalances were evident for several important baseline prognostic factors, mainly in favor of the placebo group.

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Additional analyses for independent radiological review which is adjusted for informative censoring and imbalances in the 2 treatment arms showed a treatment effect in favor of everolimus. Results of an additional adjusted multivariate analysis which corrected for imbalances between treatment arms yielded a HR of 0.73 (95% CI: 0.56-0.97). A cox model with Inverse Probability of Censoring Weights (IPCW) was used to address and correct for informative censoring and imbalances in baseline characteristics between the 2 study arms. The estimated HR (95% CI) from the IPCW weighted analysis was 0.60 (0.44-0.84), with 1-sided p-value=0.0014 in favor of everolimus.

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Eighteen (18)-month PFS rates were 47.2% for everolimus therapy plus octreotide depot (Sandostatin LAR) compared with 37.4% for placebo plus octreotide depot (Sandostatin LAR).
The overall survival results are not yet mature and no statistically significant difference in OS was noted [HR for pre-specified adjusted analysis=1 (95% CI: 0.76-1.133)]. Crossover of 58.2% (124/213) of patients from placebo to open-label Afinitor following disease progression likely confounded the detection of any treatment-related difference in OS.
Advanced Renal Cell Carcinoma: RECORD-1 (CRAD001C2240), a phase III, international, multicentre, randomized, double-blind study comparing Afinitor 10 mg/day and placebo, both in conjunction with best supportive care, was conducted in patients with metastatic renal cell carcinoma whose disease had progressed despite prior treatment with VEGFR-TK1 (vascular endothelial growth factor receptor tyrosine kinase inhibitor) therapy (sunitinib, sorafenib or both sunitinib and sorafenib). Prior therapy with bevacizumab and interferon-α was also permitted. Patients were stratified according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic score (favourable-vs intermediate-vs poor-risk groups) and prior anticancer therapy (1 vs 2 prior VEGFR-TKIs).
Progression-free survival, documented using RECIST (Response Evaluation Criteria in Solid Tumors) and assessed via a blinded, independent central review, was the primary endpoint. Secondary endpoints included safety, objective tumor response rate, overall survival, disease-related symptoms and quality of life. After documented radiological progression, patients could be unblinded by the investigator: Those randomized to placebo were then able to receive open-label Afinitor 10 mg/day. The Independent Data Monitoring Committee (IDMC) recommended termination of this trial at the time of the 2nd interim analysis as the primary endpoint had been met.
In total, 416 patients were randomized 2:1 to receive Afinitor (n=277) or placebo (n=139). Demographics were well balanced [pooled median age 61 years (range 27-85), 77% male, 88% Caucasian, 74% one prior VEGFR-TK1 therapy].
Results from a planned interim analysis showed that Afinitor was superior to placebo for the primary endpoint of progression-free survival, with a statistically significant 67% reduction in the risk of progression or death (see Table 5 and Figure 8).

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Six (6)-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo.
Confirmed objective tumor responses were observed in 5 patients (2%) receiving Afinitor while none were observed in patients receiving placebo. The progression-free survival advantage, therefore, primarily reflects the population with disease stabilization (corresponding to 67% of the Afinitor treatment group).
No statistically significant treatment-related difference in overall survival was noted, although there was a trend in favour of Afinitor (HR 0.82; 95% CI: 0.57-1.17; p=0.137). Crossover to open-label Afinitor following disease progression for patients allocated to placebo confounded the detection of any treatment-related difference in overall survival.
A strong trend is evident supporting better quality of life among patients receiving Afinitor as measured by disease-related symptoms (HR 075; 95% CI: 0.53-1.06; p=0.053).
Pharmacokinetics: Absorption: In patients with advanced solid tumor, peak everolimus concentrations are reached 1-2 hrs after administration of an oral dose of everolimus 5-70 mg under fasting conditions or with a light fat-free snack. C_max is dose-proportional between 5-10 mg in the daily and weekly regimens. At doses of ≥20 mg/week, the increase in C_max is less than dose-proportional, however, AUC shows dose-proportionality over the 5-70 mg dose range.
Food Effect: In healthy subjects, high-fat meals reduced systemic exposure to Afinitor 10 mg (as measured by AUC) by 22% and the peak plasma concentration C_max by 54%. Light fat meals reduced AUC by 32% and C_max by 42%. Food, however, had no apparent effect on the post-absorption phase concentration-time profile.
Distribution: The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5-5000 ng/mL, is 17-73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given Afinitor 10 mg/day. Plasma protein-binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.
Following IV administration in a rat model, everolimus was shown to cross the blood-brain barrier in a non-linear dose-dependent manner, suggesting saturation of an efflux pump at the blood-brain barrier. Brain penetration of everolimus has also been demonstrated in rats receiving oral doses of everolimus.
Metabolism: Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, it is the main circulating component in human blood. Six (6) main metabolites of everolimus have been detected in human blood, including 3 monohydroxylated metabolites, 2 hydrolytic ring-opened products and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies and showed approximately 100 times less activity than everolimus itself. Hence, the parent substance is considered to contribute the majority of the overall pharmacological activity of everolimus.
Excretion: No specific excretion studies have been undertaken in cancer patients; however, data are available from the transplantation setting. Following the administration of a single dose of radiolabelled everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.
Steady-State Pharmacokinetics: After daily or weekly administration of everolimus in patients with advanced solid tumours, steady-state AUC_0-τ was dose-proportional over the range of 5-10 mg in the daily dosing regimen and 5-70 mg on the weekly regimen. Steady state was achieved within 2 weeks with the daily dosing regimen. C_max is dose-proportional between 5 and 10 mg on the daily and weekly regimens. At doses of ≥20 mg/week, the increase in C_max is less than dose-proportional. T_max occurs at 1-2 hrs post-dose. There was a significant correlation between AUC_0-τ and pre-dose trough concentration at steady state on the daily regimen. The mean elimination half-life of everolimus is approximately 30 hrs.
Patients with Hepatic Impairment: The safety, tolerability and pharmacokinetics of Afinitor were evaluated in a single oral dose study of everolimus in 34 subjects with impaired hepatic function relative to subjects with normal hepatic function. Compared to normal subjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure [ie, AUC_(0-∞)] for subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively. Simulations of multiple dose pharmacokinetics support the dosing recommendations in hepatic impaired subjects based on their Child-Pugh status. Dose adjustment is recommended for patients with hepatic impairment (see Dosage & Administration and Precautions).
Patients with Renal Impairment: In a population pharmacokinetic analysis of 170 patients with advanced cancer, no significant influence of creatinine clearance (25-178 mL/min) was detected on CL/F of everolimus. Post-transplant renal impairment (creatinine clearance range 11-107 mL/min) did not affect the pharmacokinetics of everolimus in transplant patients.
Paediatric Patients: There is no indication for use of Afinitor in the paediatric cancer population (see Dosage & Administration).
Elderly Patients: In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27-85 years) on oral clearance (CL/F: range 4.8-54.5 L/hr) of everolimus was detected.
Ethnicity: Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions.
Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% higher in black transplant patients.
Exposure-Response Relationships: There was a moderate correlation between the decrease in the phosphorylation of 4E-BP1 (P4E-BP1) in tumor tissue and the average everolimus C_min at steady state in blood after daily administration of 5 or 10 mg everolimus. Further data suggest that the inhibition of phosphorylation of the S6 kinase is very sensitive to the mTOR inhibition by everolimus. Inhibition of phosphorylation of elF-4G was complete at all C_min values after the 10 mg daily dose.
A trend suggestive of longer progression-free survival with higher time-normalized everolimus C_min was evident in patients with advanced pancreatic neuroendocrine tumors (pNET, risk ratio 0.73; 95% CI: 0.50-1.08) and in patients with advanced carcinoid tumor (risk ratio 0.66; 95% CI: 0.40-1.08). Everolimus C_min impacted the probability of tumor size reduction (p<0.001) with the odds ratios of 1.62 and 1.46, respectively, for a change in exposure from 5 ng/mL to 10 ng/mL in patients with advanced pNET and in patients with advanced carcinoid tumor.
Toxicology: Nonclinical Safety Data: The preclinical safety profile of everolimus was assessed in mice, rats, mini pigs, monkeys and rabbits. The major target organs were male and female reproductive systems (testicular tubular degeneration, reduced sperm content in epididymides and uterine atrophy) in several species; lungs (increased alveolar macrophages) in rats and mice; and eyes (lenticular anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation of background lesions). There was no indication of kidney toxicity in monkeys or mini pigs.
Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats, coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal tract in mini pigs, skin lesions in mice and monkeys). These findings were generally observed at systemic exposure levels within the range of therapeutic exposure or above, with the exception of the findings in rats, which occurred below therapeutic exposure due to a high tissue distribution.
In a male fertility study in rats, testicular morphology was affected at ≥0.5 mg/kg, and sperm motility, sperm head count and plasma testosterone levels were diminished at 5 mg/kg, which is within the range of therapeutic exposure (52 ng·hr/mL and 414 ng·hr/mL, respectively, compared to 560 ng·hr/mL human exposure at 10 mg/day) and which caused a reduction in male fertility. There was evidence of reversibility.
Female fertility was not affected but everolimus crossed the placenta and was toxic to the conceptus. In rats, everolimus caused embryo/foetotoxicity at systemic exposure below the therapeutic level. This was manifested as mortality and reduced foetal weight. The incidence of skeletal variations and malformations (eg, sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits, embryotoxicity was evident in an increase in late resorptions.
In juvenile rat toxicity studies at doses as low as 0.15 mg/kg/day, systemic toxicity included decreased body weight gain and food consumption and delayed attainment of some developmental landmarks at all doses, with full or partial recovery after cessation of dosing. With the possible exception of the rat-specific lens finding (where young animals appeared to be more susceptible, it appears that there is no significant difference in the sensitivity of juvenile animals to the adverse effects of everolimus as compared to adult animals at doses of 0.5-5 mg/kg/day. No relevant toxicity was evident in juvenile monkeys at doses up to 0.5 mg/kg/day for 4-weeks.
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenic potential in mice and rats up to the highest doses, corresponding respectively to 3.9 and 0.2 times the estimated clinical exposure from a 10-mg daily dose.

Treatment of postmenopausal women with hormone receptor-positive and HER-2 negative advanced breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole.
Adult patients with advanced neuroendocrine tumors (NET) of pancreatic origin; patients with advanced renal cell carcinoma after failure of therapy with sunitinib or sorafenib or after treatment with VEGF targeted therapy.

Treatment with Afinitor should be initiated by a physician experienced in the use of anticancer therapies.
Adults: Dosing in Hormone Receptor-Positive Advanced Breast Cancer, Advanced Neuroendocrine Tumors of Pancreatic Origin and Advanced Renal Cell Carcinoma: Recommended Dose: 10 mg once daily at the same time everyday, consistently with or without food.
Dose Adjustment: Dose adjustment may be required due to side effects or when used with moderate CYP3A4 or Pgp inhibitors or strong CYP3A4 inducers.
Paediatric: Afinitor is not recommended for use in paediatric cancer patients and do not use in patients <18 years due to a lack of data on safety and efficacy.
SEGA: Afinitor is not recommended for use in children <3 years.
Elderly (≥65 years): No dosage adjustment is required (see Pharmacology under Actions).
Hepatic Impairment: For patients with mild hepatic impairment (Child-Pugh class A): Recommended Dose: 7.5 mg daily. Moderate hepatic impairment (Child-Pugh class B): Recommended Dose: 2.5 mg daily. Use in patients with severe hepatic impairment (Child-Pugh class C) is not recommended, unless benefits outweigh the risks; Maximum Dose: 2.5 mg/day.
SEGA: For patients with Child-Pugh class A: Recommended Dose: BSA ≤1.2 m², 2.5 mg every other day; BSA 1.3 m² to 2.1 m², 2.5 mg daily; BSA ≥2.2 m², 5 mg daily. For patients with Child-Pugh class B: Not recommended if BSA ≤1.2 m²; BSA 1.3 m² to 2.1 m², 2.5 mg every other day; BSA ≥2.2 m², 2.5 mg daily. Use of Afinitor not recommended in SEGA patients with Child-Pugh class C. Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after commencing treatment or after any change in hepatic status (Child-Pugh).
Administration: Afinitor should be administered orally once daily at the same time everyday, either with or without food (see Pharmacology under Actions).
Afinitor tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed.
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).
Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been given with acceptable acute tolerability.
General supportive measures should be initiated in cases of overdose.

Hypersensitivity to everolimus, other rapamycin derivatives or any of the excipients of Afinitor.

Noninfectious Pneumonitis: Noninfectious pneumonitis is a class effect of rapamycin derivatives. Cases of noninfectious pneumonitis (including interstitial lung disease) have also been described in patients taking Afinitor (see Adverse Reactions). Some of these have been severe and on rare occasions, a fatal outcome was observed.
A diagnosis of noninfectious pneumonitis should be considered in patients presenting with nonspecific respiratory signs and symptoms eg, hypoxia, pleural effusion, cough or dyspnoea, and in whom infectious, neoplastic and other nonmedicinal causes have been excluded by means of appropriate investigations. Patients should be advised to report promptly any new or worsening respiratory symptoms.
Patients who develop radiological changes suggestive of noninfectious pneumonitis and have few or no symptoms may continue Afinitor therapy without dose alteration. If symptoms are moderate, consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily.
For cases where symptoms of noninfectious pneumonitis are severe, Afinitor therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with Afinitor may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.
Infections: Afinitor has immunosuppressive properties and may predispose patients to infections, especially infections with opportunistic pathogens (see Adverse Reactions). Localised and systemic infections, including pneumonia, other bacterial infections and invasive fungal infections eg, aspergillosis or candidiasis, have been described in patients taking Afinitor. Some of these infections have been severe (eg, leading to respiratory failure) and occasionally have had a fatal outcome. Physicians and patients should be aware of the increased risk of infection with Afinitor, be vigilant for symptoms and signs of infection and institute appropriate treatment promptly.
Treat preexisting invasive fungal infections prior to starting treatment with Afinitor. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy.
Hypersensitivity Reactions: Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see Contraindications).
Oral Ulceration: Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated with Afinitor (see Adverse Reactions). In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed (see Interactions).
Laboratory Tests and Monitoring: Renal Function: Elevations of serum creatinine, usually mild, have been reported in clinical trials (see Adverse Reactions). Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter.
Blood Glucose: Hyperglycaemia has been reported in clinical trials (see Adverse Reactions). The majority of cases occurred in patients who had an abnormal fasting glucose level before taking Afinitor. Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. Optimal glycaemic control should be achieved before starting a patient on Afinitor.
Haematological Parameters: Decreased haemoglobin, neutrophils and platelets have been reported in clinical trials (see Adverse Reactions). Monitoring of complete blood count (CBC) is recommended prior to the start of Afinitor therapy and periodically thereafter.
Drug-Drug Interactions: Co-administration with strong inhibitors of CYP3A4 or PgP should be avoided (see Dosage & Administration and Interactions).
Use with caution when administered in combination with moderate CYP3A4 inhibitors or PgP inhibitors. If Afinitor must be co-administered with a moderate CYP3A4 or PgP inhibitor, the patient should be carefully monitored for undesirable effects and the dose reduced if necessary (see Dosage & Administration and Interactions).
Co-administration with strong inducers of CYP3A4 or PgP should be avoided (see Interactions). If Afinitor must be co-administered with a strong CYP3A4 or PgP inducer, the patient should be carefully monitored for clinical response. Consider a dose increase of Afinitor when co-administered with strong inducers of CYP3A4 or PgP if alternative treatment is not possible (see Dosage & Administration and Interactions).
Hepatic Impairment: Afinitor is not recommended in patients with severe hepatic impairment (Child-Pugh class C) (see Dosage & Administration and Pharmacology under Actions). For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily.
Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor (see Interactions). Examples of live vaccines are: Intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.
Impairment of Fertility: Based on non-clinical findings, male fertility may be compromised by treatment with Afinitor (see Pharmacology: Toxicology under Actions).
Use in Pregnancy: There are no adequate data from the use of Afinitor in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity (see Pharmacology: Toxicology under Actions). The potential risk for humans is unknown. Afinitor should not be given to pregnant women unless the potential benefit outweighs the potential risk to the foetus.
Women of Childbearing Potential: Women of childbearing potential should be advised to use an effective method of contraception while receiving Afinitor and for up to 8 weeks after ending treatment.
Use in Lactation: It is not known whether everolimus is excreted in breast milk. However, in animal studies, everolimus and/or its metabolites readily passed into the milk of lactating rats. Women taking Afinitor should therefore not breastfeed.

Use in Pregnancy: There are no adequate data from the use of Afinitor in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity (see Pharmacology: Toxicology under Actions). The potential risk for humans is unknown. Afinitor should not be given to pregnant women unless the potential benefit outweighs the potential risk to the foetus.
Women of Childbearing Potential: Women of childbearing potential should be advised to use an effective method of contraception while receiving Afinitor and for up to 8 weeks after ending treatment.
Use in Lactation: It is not known whether everolimus is excreted in breast milk. However, in animal studies, everolimus and/or its metabolites readily passed into the milk of lactating rats. Women taking Afinitor should therefore not breastfeed.

Hormone Receptor-Positive Advanced Breast Cancer, Advanced Neuroendocrine Tumors of Pancreatic Origin and Advanced Renal Cell Carcinoma: Summary of the Safety Profile: Information about adverse drug reactions (ADRs) is mainly based on data from 4 randomized, double-blind, placebo-controlled phase III trials: BOLERO-2 (CRAD001Y2301): Afinitor in combination with exemestane in the treatment of postmenopausal women with estrogen receptor-positive locally advanced or metastatic breast cancer who are refractory to letrozole or anastrazole. As of the data cut-off date of the interim analysis (11-Feb-2011), the median duration of treatment was 14.6 weeks for patients receiving Afinitor and 12 weeks for those receiving plabebo plus exemestane.
RADIANT-3 (CRAD001C2324): Afinitor plus best supportive care in patients with advanced pancreatic neuroendocrine tumors. Median duration of blinded study treatment was 37.8 weeks for patients receiving Afinitor and 16.1 weeks for those receiving placebo.
RADIANT-2 (CRAD001C2325): Afinitor plus octreotide depot in patients with advanced neuroendocrine tumors (carcinoid tumors) primarily of gastrointestinal or lung origin. Median duration of blinded study treatment was 37 weeks for patients receiving Afinitor and 36.6 weeks for those receiving placebo.
RECORD-1 (CRAD001C2240): Afinitor plus best supportive care in patients with advanced renal cell carcinoma. Median duration of blinded study treatment was 141 days for patients receiving Afinitor and 60 days for those receiving placebo.
The most common adverse reactions (incidence ≥10%) in at least 1 phase III trial and suspected to be related to treatment by the investigator) were (in decreasing order): Stomatitis, rash, diarrhea, fatigue, infections, asthenia, nausea, peripheral edema, decreased appetite, headache, dysguesia, epistaxis, mucosal inflammation, pneumonitis, decreased weight, vomiting, pruritus, cough, dyspnea, dry skin, nail disorder and pyrexia. The most common grade 3-4 ADRs (incidence ≥2% in at least 1 pivotal trial) were stomatitis, fatigue, diarrhea, infections, pneumonitis and diabetes mellitus.
Summary of Adverse Drug Reactions from Clinical Trials: Very Common (≥10%): Infections, decreased appetite, dysgeusia, headache, cough, pneumonitis, epistaxis, dyspnoea, stomatitis, diarrhoea, nausea, vomiting, rash, dry skin, pruritus, nail disorder, fatigue, asthenia, mucosal inflammation, peripheral oedema, pyrexia, decreased weight. Common (≥1 to <10%): Diabetes mellitus, exacerbation of diabetes mellitus, dehydration, insomnia, hypertension, haemorrhages, pulmonary embolism, haemoptysis, dry mouth, dyspepsia, dysphagia, oral pain, abdominal pain, acne, hand-foot syndrome, erythema, arthralgia, proteinuria, renal failure, increased daytime urination, chest pain. Uncommon (<1%): Pure red cell aplasia, new onset diabetes mellitus, ageusia, congestive cardiac failure, deep vein thrombosis, acute respiratory distress syndrome, impaired wound healing. Cases of hepatitis B reactivation have been observed.
Subependymal Giant Cell Astrocytoma (SEGA): Very Common (≥1/10%): Infections, hypertriglyceridaemia, cough, stomatitis, diarrhoea, dermatitis acneiform, acne, pyrexia, decreased white blood cell count. Common (≥1 to <10%): Pharyngeal inflammation, gastritis, vomiting, mucosal inflammation, increased blood triglycerides, anxiety, somnolence, hypertension, respiratory disorders, dry skin, pityriasis rosea, proteinuria, fatigue, peripheral oedema, ocular hyperaemia, decreased blood immunoglobulin G.
General Disorders and Administration Site Conditions: Common: Chest pain (1.1%). Uncommon: Impaired wound healing (<1%).
Key observed laboratory abnormalities reported in at least 1 pivotal trial at a higher rate in the Afinitor arm than in the placebo arm.
In all 4 phase III trials, the majority of observed key laboratory abnormalities were reported with an incidence of ≥10% (listed in decreasing frequency): Decreased haematology parameters include hemoglobin, lymphocytes, platelets and neutrophils (or collectively as pancytopenia). Increased clinical chemistry parameters include cholesterol, triglycerides, glucose, aspartate transaminases, creatinine, alanine transaminases and bilirubin. Decreased clinical chemistry parameters include phosphate and potassium.
Most of observed abnormalities were mild (grade 1) or moderate (grade 2). Grade 4 abnormalities include reductions in lymphocytes (2.2%), hemoglobin (2%), and potassium (2%), neutrophils, platelets (<1%) and phosphate (<1%) and increases in creatinine (1%), cholesterol (<1%), AST (<1%), ALT (<1%), bilirubin (<1%) and glucose (<1%).
Adverse Reactions of Special Interest: In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infections is an expected event during periods of immunosuppression.
In clinical trials and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal ones) and proteinuria. Monitoring of renal function is recommended (see Precautions).

Everolimus is a substrate of CYP3A4 and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP.
In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.
Agents That May Increase Everolimus Blood Concentrations: Everolimus blood concentrations may be increased by substances that inhibit CYP3A4 activity and thus decrease everolimus metabolism.
Everolimus blood concentrations may be increased by inhibitors of PgP that may decrease the efflux of everolimus from intestinal cells.
Concurrent treatment with strong inhibitors of CYP3A4 or PgP (including but not limited to ketoconazole, itraconazole, ritonavir, clarithromycin and telythromycin; dexamethasone, prednisone and prednisolone) should be avoided.
There was a significant increase in exposure to everolimus (C_max and AUC increased by 3.9- and 15-fold, respectively) in healthy subjects when everolimus was co-administered with ketoconazole (a strong CYP3A4 inhibitor and PgP inhibitor).
Concomitant treatment with moderate inhibitors of CYP3A4 (including but not limited to erythromycin, verapamil, ciclosporin, fluconazole, diltiazem, amprenavir, fosamprenavir or aprepitant) and PgP inhibitors requires caution. Reduce the Afinitor dose if co-administered with moderate CYP3A4/PgP inhibitors (see Dosage & Administration and Precautions).
There was an increase in exposure to everolimus in healthy subjects when everolimus was co-administered with: Erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor; C_max and AUC increased by 2- and 4.4-fold, respectively), verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor; C_max and AUC increased by 2.3- and 3.5-fold, respectively) and ciclosporin (a CYP3A4 substrate and a PgP inhibitor; C_max and AUC increased by 1.8- and 2.7-fold, respectively).
Other moderate inhibitors of CYP3A4 and PgP that may increase everolimus blood concentrations include certain antifungal agents (eg, fluconazole) and calcium-channel blockers (eg, diltiazem).
Grapefruit, grapefruit juice, star fruit, Seville oranges and other foods that are known to affect cytochrome P-450 and PgP activity should be avoided during treatment.
No difference in everolimus C_min was apparent when administered in the presence or absence of substrates of CYP3A4 and/or PgP following treatment with the 10-mg or 5-mg daily dose.
Co-administration of weak inhibitors of CYP3A4 with or without PgP inhibitors had no apparent impact on everolimus C_min following treatment with the 10-mg or 5-mg daily dose regimen.
Agents That May Decrease Everolimus Blood Concentrations: Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells.
Concurrent treatment with strong inducers of CYP3A4 or PgP should be avoided. If Afinitor must be co-administered with a strong CYP3A4 or PgP inducer (eg, rifampicin and rifabutin), it may be necessary to adjust the dose (see Dosage & Administration and Precautions).
Pre-treatment of healthy subjects with multiple doses of rifampicin (a CYP3A4 and PgP inducer) 600 mg daily for 8 days followed by a single dose of everolimus, increased everolimus oral dose clearance nearly 3-fold and decreased C_max by 58% and AUC by 63%.
Other inducers of CYP3A4 that may increase the metabolism of everolimus and decrease everolimus blood levels include St. John's wort (Hypericum perforatum), anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin) and anti-HIV agents (eg, efavirenz, nevirapine).
Agents Whose Plasma Concentration May be Altered by Everolimus: Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between Afinitor and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of Afinitor.
In vitro, everolimus competitively inhibited the metabolism of the CYP3A4 substrate ciclosporin and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. The mean steady state of everolimus C_max with an oral dose of 10 mg daily or 70 mg weekly is more than 12- to 36-fold below the Ki-values of the in vitro inhibition. An effect of everolimus on the metabolism of CYP3A4 and CYP2D6 substrates is therefore unlikely.
A study in healthy subjects demonstrated that co-adminitration of an oral dose of midazolam with everolimus resulted in a 25% increase in midazolam C_max and a 30% increase in midazolam AUC_(0-∞), whereas the metabolic AUC_(0-∞) ratio (1-hydroxy-midazolam/midazolam) and the terminal t_½ of midazolam were not affected. This suggests that increased exposure to midazolam is due to effects of everolimus in the gastrointestinal system when both drugs are taken at the same time. Therefore, everolimus may affect the bioavailability of orally co-administered drugs which are CYP3A4 substrates. Everolimus is unlikely to affect the exposure of other CYP3A4 substrate drugs which are administered by non-oral routes eg, IV, SC and transdermal administrations (see Precautions).
Co-administration of everolimus and octreotide depot increased octreotide C_min with a geometric mean ratio (everolimus/placebo) of 1.47 (90% CI: 1.32-1.64) which was unlikely to have clinically significant effects on the fficacy response to everolimus in patients with advanced neuroendocrine tumors.
Vaccinations: Immunosuppressants may affect the response to vaccination and vaccination during treatment with Afinitor may therefore be less effective. The use of live vaccines should be avoided during treatment with Afinitor (see Precautions). Examples of live vaccines are: Intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.
Co-administration of everolimus and exemestane increased exemestane C_min and C_2hr by 45% and 71%, respectively. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on efficacy or safety.
Caution should be observed when Afinitor is used in combination with orally-administered CYP3A4 substrates with a narrow therapeutic index.
Incompatibilities: Not applicable.

Targeted Cancer Therapy

L01XE10 - everolimus ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.

S

Tab 5 mg (white to slightly yellow, elongated, bevelled edge, no score, engraved with "5" on one side and "NVR" on the other) x 1 x 10's, 3 x 10's. 10 mg (white to slightly yellow, elongated, bevelled edge, no score, engraved with "UHE" on one side and "NVR" on the other) x 1 x 10's, 3 x 10's.