Afinitor

Afinitor 2.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with "LCL" on one side and "NVR" on the other.
Each tablet contains 2.5 mg everolimus.
Afinitor 5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with "5" on one side and "NVR" on the other.
Each tablet contains 5 mg everolimus.
Afinitor 10 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with "UHE" on one side and "NVR" on the other.
Each tablet contains 10 mg everolimus.
Afinitor 2 mg dispersible tablets: White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with "D2" on one side and "NVR" on the other.
Each dispersible tablet contains 2 mg everolimus.
Afinitor 5 mg dispersible tablets: White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with "D5" on one side and "NVR" on the other.
Each dispersible tablet contains 5 mg everolimus.
Excipient with known effect: Each 2.5 mg, 5 mg, or 10 mg tablet contains 74 mg, 149 mg, or 297 mg lactose, respectively.
Each 2 mg or 5 mg dispersible tablet contains 1.96 mg or 4.90 mg lactose, respectively.
Excipients/Inactive Ingredients: Butylated hydroxytoluene (E321), Magnesium stearate, Lactose monohydrate, Hypromellose, Crospovidone type A.
Tablet: Lactose anhydrous.
Dispersible tablet: Mannitol, Microcrystalline cellulose, Colloidal anhydrous silica.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors. ATC code: L01EG02.
Pharmacology: Pharmacodynamics: Mechanism of action: Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with the translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell cycle, angiogenesis and glycolysis. Everolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour angiogenic processes. S6K1 is thought to phosphorylate the activation function domain 1 of the oestrogen receptor, which is responsible for ligand-independent receptor activation [Tablet (Oncology Indications) only]. In patients with TSC, treatment with everolimus increases VEGF-A and decreases VEGF-D levels [Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet only]. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to reduce glycolysis in solid tumours in vitro and in vivo.
Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: Two primary regulators of mTORC1 signalling are the oncogene suppressors tuberin-sclerosis complexes 1 & 2 (TSC1, TSC2). Loss of either TSC1 or TSC2 leads to elevated rheb-GTP levels, a ras family GTPase, which interacts with the mTORC1 complex to cause its activation. mTORC1 activation leads to a downstream kinase signalling cascade, including activation of the S6 kinases. In TSC syndrome, inactivating mutations in the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body.
Dispersible tablet: Besides pathological changes in brain tissue (such as cortical tubers) which may cause seizures, the mTOR pathway is also implicated in the pathogenesis of epilepsy in TSC. The mTOR regulates protein synthesis and multiple downstream cellular functions that may influence neuronal excitability and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Preclinical studies in models of mTOR dysregulation in the brain demonstrated that treatment with an mTOR inhibitor such as everolimus could prolong survival, suppress seizures, prevent the development of new-onset seizures and prevent premature death. In summary, everolimus is highly active in this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 inhibition. However, the exact mechanism of action in the reduction of seizures associated with TSC is not fully elucidated.
Clinical efficacy and safety: Other studies: Stomatitis is the most commonly reported adverse reaction in patients treated with Afinitor (see Precautions and Adverse Reactions). In a post-marketing single-arm study in postmenopausal women with advanced breast cancer (N=92), topical treatment with dexamethasone 0.5 mg/5 ml alcohol-free oral solution was administered as a mouthwash (4 times daily for the initial 8 weeks of treatment) to patients at the time of initiating treatment with Afinitor (everolimus, 10 mg/day) plus exemestane (25 mg/day) to reduce the incidence and severity of stomatitis. The incidence of Grade ≥2 stomatitis at 8 weeks was 2.4% (n=2/85 evaluable patients) which was lower than historically reported. The incidence of Grade 1 stomatitis was 18.8% (n=16/85) and no cases of Grade 3 or 4 stomatitis were reported. The overall safety profile in this study was consistent with that established for everolimus in the oncology and tuberous sclerosis complex (TSC) settings, with the exception of a slightly increased frequency of oral candidiasis which was reported in 2.2% (n=2/92) of patients.
Tablet (Oncology Indications): Hormone receptor-positive advanced breast cancer: BOLERO-2 (study CRAD001Y2301), a randomised, double-blind, multicentre phase III study of Afinitor + exemestane versus placebo + exemestane, was conducted in postmenopausal women with oestrogen receptor-positive, HER2/neu negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomisation was stratified by documented sensitivity to prior hormonal therapy and by the presence of visceral metastasis. Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥24 weeks) from at least one 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 study was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on the investigator's assessment (local radiology). Supportive PFS analyses were based on an independent central radiology review.
Secondary endpoints included overall survival (OS), objective response rate, clinical benefit rate, safety, change in quality of life (QoL) and time to ECOG PS (Eastern Cooperative Oncology Group performance status) deterioration.
A total of 724 patients were randomised in a 2:1 ratio to the combination everolimus (10 mg daily) + exemestane (25 mg daily) (n=485) or to the placebo + exemestane arm (25 mg daily) (n=239). At the time of the final OS analysis, the median duration of everolimus treatment was 24.0 weeks (range 1.0-199.1 weeks). The median duration of exemestane treatment was longer in the everolimus + exemestane group at 29.5 weeks (1.0-199.1) compared to 14.1 weeks (1.0-156.0) in the placebo + exemestane group.
The efficacy results for the primary endpoint were obtained from the final PFS analysis (see Table 1 and Figure 1). Patients in the placebo + exemestane arm did not cross over to everolimus at the time of progression.

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The estimated PFS treatment effect was supported by planned subgroup analysis of PFS per investigator assessment. For all analysed subgroups (age, sensitivity to prior hormonal therapy, number of organs involved, status of bone-only lesions at baseline and presence of visceral metastasis, and across major demographic and prognostic subgroups) a positive treatment effect was seen with everolimus + exemestane with an estimated hazard ratio (HR) versus placebo + exemestane ranging from 0.25 to 0.60.
No differences in the time to ≥5% deterioration in the global and functional domain scores of QLQ-C30 were observed in the two arms.
BOLERO-6 (Study CRAD001Y2201), a three-arm, randomised, open-label, phase II study of everolimus in combination with exemestane versus everolimus alone versus capecitabine in the treatment of postmenopausal women with oestrogen receptor-positive, HER2/neu negative, locally advanced, recurrent, or metastatic breast cancer after recurrence or progression on prior letrozole or anastrozole.
The primary objective of the study was to estimate the HR of PFS for everolimus + exemestane versus everolimus alone. The key secondary objective was to estimate the HR of PFS for everolimus + exemestane versus capecitabine.
Other secondary objectives included the evaluation of OS, objective response rate, clinical benefit rate, safety, time to ECOG performance deterioration, time to QoL deterioration, and treatment satisfaction (TSQM). No formal statistical comparisons were planned.
A total of 309 patients were randomised in a 1:1:1 ratio to the combination of everolimus (10 mg daily) + exemestane (25 mg daily) (n=104), everolimus alone (10 mg daily) (n=103), or capecitabine (1250 mg/m² dose twice daily for 2 weeks followed by one week rest, 3-week cycle) (n=102). At the time of data cut-off, the median duration of treatment was 27.5 weeks (range 2.0-165.7) in the everolimus + exemestane arm, 20 weeks (1.3-145.0) in the everolimus arm, and 26.7 weeks (1.4-177.1) in the capecitabine arm.
The result of the final PFS analysis with 154 PFS events observed based on local investigator assessment showed an estimated HR of 0.74 (90% CI: 0.57, 0.97) in favour of the everolimus + exemestane arm relative to everolimus arm. The median PFS was 8.4 months (90% CI: 6.6, 9.7) and 6.8 months (90% CI: 5.5, 7.2), respectively. (See Figure 2.)

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For the key secondary endpoint PFS the estimated HR was 1.26 (90% CI: 0.96, 1.66) in favour of capecitabine over the everolimus + exemestane combination arm based on a total of 148 PFS events observed.
Results of the secondary endpoint OS were not consistent with the primary endpoint PFS, with a trend observed favouring the everolimus alone arm. The estimated HR was 1.27 (90% CI: 0.95, 1.70) for the comparison of OS in the everolimus alone arm relative to the everolimus + exemestane arm. The estimated HR for the comparison of OS in the everolimus + exemestane combination arm relative to capecitabine arm was 1.33 (90% CI: 0.99, 1.79).
Advanced neuroendocrine tumours of pancreatic origin (pNET): RADIANT-3 (study CRAD001C2324), a phase III, multicentre, randomised, double-blind study of Afinitor plus best supportive care (BSC) versus placebo plus BSC in patients with advanced pNET, demonstrated a statistically significant clinical benefit of Afinitor over placebo by a 2.4-fold prolongation of median progression-free survival (PFS) (11.04 months versus 4.6 months), (HR 0.35; 95% CI: 0.27, 0.45; p<0.0001) (see Table 2 and Figure 3).
RADIANT-3 involved patients with well- and moderately-differentiated advanced pNET whose disease had progressed within the prior 12 months. Treatment with somatostatin analogues was allowed as part of BSC.
The primary endpoint for the study was PFS evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). Following documented radiological progression, patients could be unblinded by the investigator. Those randomised to placebo were then able to receive open-label Afinitor.
Secondary endpoints included safety, objective response rate, response duration and overall survival (OS).
In total, 410 patients were randomised 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). Fifty-eight percent of the patients in both arms received prior systemic therapy. The median duration of blinded study treatment was 37.8 weeks (range 1.1-129.9 weeks) for patients receiving everolimus and 16.1 weeks (range 0.4-147.0 weeks) for those receiving placebo.
Following disease progression or after study unblinding, 172 of the 203 patients (84.7%) initially randomised to placebo crossed over to open-label Afinitor. The median duration of open-label treatment was 47.7 weeks among all patients; 67.1 weeks in the 53 patients randomised to everolimus who switched to open-label everolimus and 44.1 weeks in the 172 patients randomised to placebo who switched to open-label everolimus. (See Table 2 and Figure 3.)

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Advanced neuroendocrine tumours of gastrointestinal or lung origin: RADIANT-4 (study CRAD001T2302), a randomised, double-blind, multicentre, phase III study of Afinitor plus best supportive care (BSC) versus placebo plus BSC was conducted in patients with advanced, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin without a history of and no active symptoms related to carcinoid syndrome.
The primary endpoint for the study was progression-free survival (PFS) evaluated by Response Evaluation Criteria in Solid Tumors (RECIST), based on independent radiology assessment. Supportive PFS analysis was based on local investigator review. Secondary endpoints included overall survival (OS), overall response rate, disease control rate, safety, change in quality of life (FACT-G) and time to World Health Organisation performance status (WHO PS) deterioration.
A total of 302 patients were randomised in a 2:1 ratio to receive either everolimus (10 mg daily) (n=205) or placebo (n=97). Demographics and disease characteristics were generally balanced (median age 63 years [range 22 to 86], 76% Caucasian, history of prior somatostatin analogue [SSA] use). The median duration of blinded treatment was 40.4 weeks for patients receiving Afinitor and 19.6 weeks for those receiving placebo. After primary PFS analysis, 6 patients from the placebo arm crossed over to open-label everolimus.
The efficacy results for the primary endpoint PFS (independent radiological review) were obtained from the final PFS analysis (see Table 3 and Figure 4). The efficacy results for PFS (investigator radiological review) were obtained from the final OS analysis (see Table 3).

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In supportive analyses, positive treatment effect has been observed in all subgroups with the exception of the subgroup of patients with ileum as primary site of tumour origin (Ileum: HR=1.22 [95% CI: 0.56 to 2.65]; Non-ileum: HR=0.34 [95% CI: 0.22 to 0.54]; Lung: HR=0.43 [95% CI: 0.24 to 0.79]) (see Figure 5).

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The final overall survival (OS) analysis did not show a statistically significant difference between those patients who received Afinitor or placebo during the blinded treatment period of the study (HR=0.90 [95% CI: 0.66 to 1.22]).
No difference in the time to definitive deterioration of WHO PS (HR=1.02; [95% CI: 0.65, 1.61]) and time to definitive deterioration in quality of life (FACT-G total score HR=0.74; [95% CI: 0.50, 1.10]) was observed between the two arms.
Advanced renal cell carcinoma: RECORD-1 (study CRAD001C2240), a phase III, international, multicentre, randomised, double-blind study comparing everolimus 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 on or after treatment with VEGFR-TKI (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 Tumours) and assessed via a blinded, independent central review, was the primary endpoint. Secondary endpoints included safety, objective tumour response rate, overall survival, disease-related symptoms, and quality of life. After documented radiological progression, patients could be unblinded by the investigator: those randomised to placebo were then able to receive open-label everolimus 10 mg/day. The Independent Data Monitoring Committee recommended termination of this trial at the time of the second interim analysis as the primary endpoint had been met.
In total, 416 patients were randomised 2:1 to receive Afinitor (n=277) or placebo (n=139). Demographics were well balanced (pooled median age [61 years; range 27-85], 78% male, 88% Caucasian, number of prior VEGFR-TKI therapies [1-74%, 2-26%]). The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving everolimus and 60 days (range 21-295 days) for those receiving placebo.
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 4 and Figure 6).

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Six-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo.
Confirmed objective tumour responses were observed in 5 patients (2%) receiving Afinitor, while none were observed in patients receiving placebo. Therefore, the progression-free survival advantage primarily reflects the population with disease stabilisation (corresponding to 67% of the Afinitor treatment group).
No statistically significant treatment-related difference in overall survival was noted (hazard ratio 0.87; confidence interval: 0.65-1.17; p=0.177). Crossover to open-label Afinitor following disease progression for patients allocated to placebo confounded the detection of any treatment-related difference in overall survival.
Tablet (Tuberous Sclerosis Complex-Related Indications): Renal angiomyolipoma associated with TSC: EXIST-2 (study CRAD001M2302), a randomised, controlled phase III study was conducted to evaluate the efficacy and safety of Afinitor in patients with TSC plus renal angiomyolipoma. Presence of at least one angiomyolipoma ≥3 cm in longest diameter using CT/MRI (based on local radiology assessment) was required for entry.
The primary efficacy endpoint was angiomyolipoma response rate based on independent central radiology review. The analysis was stratified by use of enzyme-inducing antiepileptics at randomisation (yes/no).
Key secondary endpoints included time to angiomyolipoma progression and skin lesion response rate.
A total of 118 patients were randomised, 79 to Afinitor 10 mg daily and 39 to placebo. Median age was 31 years (range: 18 to 61 years; 46.6% were <30 years at enrolment), 33.9% were male, and 89.0% were Caucasian. Of the enrolled patients, 83.1% had angiomyolipomas ≥4 cm (28.8% ≥8 cm), 78.0% had bilateral angiomyolipomas, and 39.0% had undergone prior renal embolisation/nephrectomy; 96.6% had skin lesions at baseline and 44.1% had target SEGAs (at least one SEGA ≥1 cm in longest diameter).
Results showed that the primary objective related to best overall angiomyolipoma response was met with best overall response rates of 41.8% (95% CI: 30.8, 53.4) for the Afinitor arm compared with 0% (95% CI: 0.0, 9.0) for the placebo arm (p<0.0001) (Table 5).
Patients initially treated with placebo were allowed to cross over to everolimus at the time of angiomyolipoma progression and upon recognition that treatment with everolimus was superior to treatment with placebo. At the time of the final analysis (4 years following the last patient randomisation), the median duration of exposure to everolimus was 204.1 weeks (range 2 to 278). The angiomyolipoma best overall response rate had increased to 58.0% (95% CI: 48.3, 67.3), with a rate of stable disease of 30.4% (Table 5).
Among patients treated with everolimus during the study, no cases of angiomyolipoma-related nephrectomy and only one case of renal embolisation were reported. (See Table 5.)

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Consistent treatment effects on angiomyolipoma response rate were observed across all subgroups evaluated (i.e. enzyme-inducing antiepileptic use versus enzyme-inducing antiepileptic non-use, sex, age and race) at the primary efficacy analysis.
In the final analysis, reduction in angiomyolipoma volume improved with longer term treatment with Afinitor. At weeks 12, 96 and 192, ≥30% reductions in volume were observed in 75.0%, 80.6%, and 85.2% of the treated patients, respectively. Similarly, at the same timepoints, ≥50% reductions in volume were observed in 44.2%, 63.3%, and 68.9% of the treated patients, respectively.
Median time to angiomyolipoma progression was 11.4 months in the placebo arm and was not reached in the everolimus arm (HR 0.08; 95% CI: 0.02, 0.37; p<0.0001). Progressions were observed in 3.8% of patients in the everolimus arm compared with 20.5% in the placebo arm. Estimated progression-free rates at 6 months were 98.4% for the everolimus arm and 83.4% for the placebo arm. At the final analysis, median time to angiomyolipoma progression was not reached. Angiomyolipoma progressions were observed in 14.3% of the patients. The estimated angiomyolipoma progression-free rates at 24 months and 48 months were 91.6% and 83.1%, respectively.
At the primary analysis, skin lesion response rates of 26.0% (95% CI: 16.6, 37.2) for the Afinitor arm and 0% (95% CI: 0.0, 9.5) for the placebo arm were observed (p=0.0002). At the final analysis, the skin lesion response rate had increased to 68.2% (95% CI: 58.5, 76.9), with one patient reporting a confirmed complete clinical skin lesion response and no patients experiencing progressive disease as their best response.
In an exploratory analysis of patients with TSC with angiomyolipoma who also had SEGA, the SEGA response rate (proportion of patients with ≥50% reduction from baseline in target lesion volumes in the absence of progression) was 10.3% in the everolimus arm in the primary analysis (versus no responses reported in the 13 patients randomised to placebo with a SEGA lesion at baseline) and increased to 48.0% in the final analysis.
Post-hoc sub-group analysis of EXIST-2 (study CRAD001M2302) carried out at time of primary analysis demonstrated that angiomyolipoma response rate is reduced below the threshold of 5 ng/ml (see Table 6).

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Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: SEGA associated with TSC: Phase III study in SEGA patients: EXIST-1 (Study CRAD001M2301), a randomised, double-blind, multicentre phase III study of Afinitor versus placebo, was conducted in patients with SEGA, irrespective of age. Patients were randomised in a 2:1 ratio to receive either Afinitor or matching placebo. Presence of at least one SEGA lesion ≥1.0 cm in longest diameter using MRI (based on local radiology assessment) was required for entry. In addition, serial radiological evidence of SEGA growth, presence of a new SEGA lesion ≥1 cm in longest diameter, or new or worsening hydrocephalus was required for entry.
The primary efficacy endpoint was SEGA response rate based on independent central radiology review. The analysis was stratified by use of enzyme-inducing antiepileptics at randomisation (yes/no).
Key secondary endpoints in hierarchal order of testing included the absolute change in frequency of total seizure events per 24-hour EEG from baseline to week 24, time to SEGA progression, and skin lesion response rate.
A total of 117 patients were randomised, 78 to Afinitor and 39 to placebo. The two treatment arms were generally well balanced with respect to demographic and baseline disease characteristics and history of prior anti-SEGA therapies. In the total population, 57.3% of patients were male and 93.2% were Caucasian. The median age for the total population was 9.5 years (age range for the Afinitor arm: 1.0 to 23.9; age range for the placebo arm: 0.8 to 26.6), 69.2% of the patients were aged 3 to <18 years and 17.1% were <3 years at enrolment.
Of the enrolled patients, 79.5% had bilateral SEGAs, 42.7% had ≥2 target SEGA lesions, 25.6% had inferior growth, 9.4% had evidence of deep parenchymal invasion, 6.8% had radiographic evidence of hydrocephalus, and 6.8% had undergone prior SEGA-related surgery. 94.0% had skin lesions at baseline and 37.6% had target renal angiomyolipoma lesions (at least one angiomyolipoma ≥1 cm in longest diameter).
The median duration of blinded study treatment was 9.6 months (range: 5.5 to 18.1) for patients receiving Afinitor and 8.3 months (range: 3.2 to 18.3) for those receiving placebo.
Results showed that Afinitor was superior to placebo for the primary endpoint of best overall SEGA response (p<0.0001). Response rates were 34.6% (95% CI: 24.2, 46.2) for the Afinitor arm compared with 0% (95% CI: 0.0, 9.0) for the placebo arm (Table 7). In addition, all 8 patients on the Afinitor arm who had radiographic evidence of hydrocephalus at baseline had a decrease in ventricular volume.
Patients initially treated with placebo were allowed to cross over to everolimus at the time of SEGA progression and upon recognition that treatment with everolimus was superior to treatment with placebo. All patients receiving at least one dose of everolimus were followed until medicinal product discontinuation or study completion. At the time of the final analysis, the median duration of exposure among all such patients was 204.9 weeks (range: 8.1 to 253.7). The best overall SEGA response rate had increased to 57.7% (95% CI: 47.9, 67.0) at the final analysis.
No patient required surgical intervention for SEGA during the entire course of the study. (See Table 7.)

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Consistent treatment effects were observed across all subgroups evaluated (i.e. enzyme-inducing antiepileptic use versus enzyme-inducing antiepileptic non-use, sex and age) at the primary analysis.
During the double-blind period, reduction of SEGA volume was evident within the initial 12 weeks of Afinitor treatment: 29.7% (22/74) of patients had ≥50% reductions in volume and 73.0% (54/74) had ≥30% reductions in volume. Sustained reductions were evident at week 24, 41.9% (31/74) of patients had ≥50% reductions and 78.4% (58/74) of patients had ≥30% reductions in SEGA volume.
In the everolimus treated population (N=111) of the study, including patients who crossed over from the placebo group, tumour response, starting as early as after 12 weeks on everolimus, was sustained at later time points. The proportion of patients achieving at least 50% reductions in SEGA volume was 45.9% (45/98) and 62.1% (41/66) at weeks 96 and 192 after start of everolimus treatment. Similarly, the proportion of patients achieving at least 30% reductions in SEGA volume was 71.4% (70/98) and 77.3% (51/66) at weeks 96 and 192 after start of everolimus treatment.
Analysis of the first key secondary endpoint, change in seizure frequency, was inconclusive; thus, despite the fact that positive results were observed for the two subsequent secondary endpoints (time to SEGA progression and skin lesion response rate), they could not be declared formally statistically significant.
Median time to SEGA progression based on central radiology review was not reached in either treatment arm. Progressions were only observed in the placebo arm (15.4%; p=0.0002). Estimated progression-free rates at 6 months were 100% for the Afinitor arm and 85.7% for the placebo arm. The long-term follow-up of patients randomised to everolimus and patients randomised to placebo who thereafter crossed over to everolimus demonstrated durable responses.
At the time of the primary analysis, Afinitor demonstrated clinically meaningful improvements in skin lesion response (p=0.0004), with response rates of 41.7% (95% CI: 30.2, 53.9) for the Afinitor arm and 10.5% (95% CI: 2.9, 24.8) for the placebo arm. At the final analysis, the skin lesion response rate increased to 58.1% (95% CI: 48.1, 67.7).
Phase II study in patients with SEGA: A prospective, open-label, single-arm phase II study (Study CRAD001C2485) was conducted to evaluate the safety and efficacy of Afinitor in patients with SEGA. Radiological evidence of serial SEGA growth was required for entry.
Change in SEGA volume during the core 6-month treatment phase, as assessed via an independent central radiology review, was the primary efficacy endpoint. After the core treatment phase, patients could be enrolled into an extension phase where SEGA volume was assessed every 6 months.
In total, 28 patients received treatment with Afinitor; median age was 11 years (range 3 to 34), 61% male, 86% Caucasian. Thirteen patients (46%) had a secondary smaller SEGA, including 12 in the contralateral ventricle.
Primary SEGA volume was reduced at month 6 compared to baseline (p<0.001 [see Table 8]). No patient developed new lesions, worsening hydrocephalus or increased intracranial pressure, and none required surgical resection or other therapy for SEGA.

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The robustness and consistency of the primary analysis were supported by the: change in primary SEGA volume as per local investigator assessment (p<0.001), with 75.0% and 39.3% of patients experiencing reductions of ≥30% and ≥50%, respectively; change in total SEGA volume as per independent central review (p<0.001) or local investigator assessment (p<0.001).
One patient met the pre-specified criteria for treatment success (>75% reduction in SEGA volume) and was temporarily taken off trial therapy; however, SEGA re-growth was evident at the next assessment at 4.5 months and treatment was restarted.
Long-term follow-up to a median duration of 67.8 months (range: 4.7 to 83.2) demonstrated sustained efficacy.
Dispersible tablet: Phase III study in patients with TSC and refractory seizures: EXIST-3 (Study CRAD001M2304), a randomised, double-blind, multicentre, three-arm, parallel-group phase III study of Afinitor versus placebo as adjunctive therapy was conducted in TSC patients with refractory partial-onset seizures. In the study, partial-onset seizures were defined as all electroencephalogram (EEG)-confirmed sensory seizures or motor seizures in which a generalised onset had not been demonstrated on a past EEG. Patients were treated with concomitant and stable dose of 1 to 3 antiepileptics prior to study entry. The study consisted of three phases: an 8-week baseline observation phase; an 18-week double-blind, placebo-controlled core treatment phase (composed of titration and maintenance periods), an extension phase of ≥48 weeks in which all patients received Afinitor and a post-extension phase of ≤48 weeks in which all patients received Afinitor.
The study independently tested two different primary endpoints: 1) response rate defined as at least a 50% reduction from baseline in frequency of partial-onset seizures during the maintenance period of the core phase; and 2) percentage reduction from baseline in frequency of partial-onset seizures during the maintenance period of the core phase.
Secondary endpoints included seizure freedom, proportion of patients with >25% seizure frequency reduction from baseline, distribution of reduction from baseline in seizure frequency (≤-25%, >-25% to <25%; ≥25% to <50%; ≥50% to <75%; ≥75% to <100%; 100%), long-term evaluation of seizure frequency and overall quality of life.
A total of 366 patients were randomised in a 1:1.09:1 ratio to Afinitor (n=117) low trough (LT) range (3 to 7 ng/ml), Afinitor (n=130) high trough (HT) range (9 to 15 ng/ml) or placebo (n=119). The median age for the total population was 10.1 years (range: 2.2-56.3; 28.4% <6 years, 30.9% 6 to <12 years, 22.4% 12 to <18 years and 18.3% >18 years). Median duration of treatment was 18 weeks for all three arms in the core phase and 90 weeks (21 months) when considering both the core and extension phases.
At baseline, 19.4% of patients had focal seizures with retained awareness (sensory previously confirmed on EEG or motor), 45.1% had focal seizures with impaired awareness (predominantly non motor), 69.1% had focal motor seizures (i.e. focal motor seizures with impaired awareness and/or secondary generalised seizures), and 1.6% had generalised onset seizures (previously confirmed by EEG). The median baseline seizure frequency across the treatment arms was 35, 38, and 42 seizures per 28 days for the Afinitor LT, Afinitor HT, and placebo groups, respectively. The majority of patients (67%) failed 5 or more antiepileptics prior to the study and 41.0% and 47.8% of patients were taking 2 and ≥3 antiepileptics during the study. The baseline data indicated mild to moderate mental retardation in patients 6-18 years of age (scores of 60-70 on the Adaptive Behavior Composite and Communication, Daily Living Skills, and Socialization Domain Scores).
The efficacy results for the primary endpoint are summarised in Table 9. (See Table 9.)

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Consistent results were found for the supportive analysis of the median percentage reduction from baseline in seizure frequency (other primary endpoint): 29.3% (95% CI: 18.8, 41.9) in the Afinitor LT arm, 39.6% (95% CI: 35.0, 48.7) in the Afinitor HT arm and 14.9% (95% CI: 0.1, 21.7) in the placebo arm. The p-values for superiority versus placebo were 0.003 (LT) and <0.001 (HT).
The seizure-free rate (the proportion of patients who became seizure-free during the maintenance period of the core phase) was 5.1% (95% CI: 1.9, 10.8) and 3.8% (95% CI: 1.3, 8.7) in the Afinitor LT and HT arms, respectively, versus 0.8% (95% CI: 0.0, 4.6) of patients in the placebo arm.
Higher proportions of responders were evident for all response categories in the Afinitor LT and HT arms relative to placebo (see Figure 7). Furthermore, almost twice as many patients in the placebo arm experienced seizure exacerbation relative to the Afinitor LT and HT arms.

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A homogeneous and consistent everolimus effect was observed across all subgroups evaluated for the primary efficacy endpoints by: age categories (Table 10), gender, race and ethnicity, seizure types, seizure frequency at baseline, number and name of concomitant antiepileptics, and TSC features (angiomyolipoma, SEGA, cortical tuber status). The effect of everolimus on infantile/epileptic spasms or on seizures associated with Lennox-Gastaut syndrome has not been studied and is not established for generalised-onset seizures and subjects without cortical tubers. (See Table 10.)

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At the end of the core phase, overall quality of life in patients aged 2 to <11 years (as measured by the mean change from baseline in overall Quality Of Life score [total score] in the Childhood Epilepsy Questionnaire [QOLCE]) was maintained in each Afinitor treatment arm as well as in the placebo arm.
Reduction in seizure frequency was sustained over an evaluation period of approximately 2 years. Based on a sensitivity analysis considering patients who prematurely discontinued everolimus as non-responders, response rates of 38.4% (95% CI: 33.4, 43.7) and 44.4% (95% CI: 38.2, 50.7) were observed after 1 and 2 years of exposure to everolimus, respectively.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Afinitor in all subsets of the paediatric population in neuroendocrine tumours of pancreatic origin, thoracic neuroendocrine tumours and in renal cell carcinoma and in angiomyolipoma (see Dosage & Administration for information on paediatric use).
The European Medicines Agency has deferred the obligation to submit the results of studies with Afinitor in one or more subsets of the paediatric population in refractory epilepsy associated with TSC (see Dosage & Administration for information on paediatric use) [Tablet (Tuberous Sclerosis Complex-Related Indications) only].
The marketing authorisation holder has completed the Paediatric Investigation Plans for Afinitor for refractory seizures associated with TSC. This summary of product characteristics has been updated to include the results of studies with Afinitor in the paediatric population (see Pharmacology: Pharmacokinetics under Actions) (Dispersible tablet only).
Pharmacokinetics: Absorption: In patients with advanced solid tumours, peak everolimus concentrations (C_max) are reached at a median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions or with a light fat-free snack. C_max is dose-proportional between 5 and 10 mg. Everolimus is a substrate and moderate inhibitor of PgP.
Food effect: In healthy subjects, high fat meals reduced systemic exposure to everolimus/Afinitor 10 mg (as measured by AUC) by 22% and the peak plasma/blood concentration C_max by 54%. Light fat meals reduced AUC by 32% and C_max by 42%.
In healthy subjects taking a single 9 mg dose (3 x 3 mg) of Afinitor dispersible tablets in suspension, high fat meals reduced AUC by 11.7% and the peak blood concentration C_max by 59.8%. Light fat meals reduced AUC by 29.5% and C_max by 50.2% [Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet only].
Food, however, had no apparent effect on the post absorption phase concentration-time profile 24 hours post-dose of either dosage form.
Relative bioavailability/bioequivalence [Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet only]: In a relative bioavailability study, AUC_0-inf of 5 x 1 mg everolimus tablets when administered as suspension in water was equivalent to 5 x 1 mg everolimus tablets administered as intact tablets, and C_max of 5 x 1 mg everolimus tablets in suspension was 72% of 5 x 1 mg intact everolimus tablets.
In a bioequivalence study, AUC_0-inf of the 5 mg dispersible tablet when administered as suspension in water was equivalent to 5 x 1 mg intact everolimus tablets, and C_max of the 5 mg dispersible tablet in suspension was 64% of 5 x 1 mg intact everolimus tablets.
Distribution: The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is confined to plasma in cancer patients given everolimus/Afinitor 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In patients with advanced solid tumours, V_d was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment.
Nonclinical studies in rats indicate [Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet only]: A rapid uptake of everolimus in the brain followed by a slow efflux.
The radioactive metabolites of [3H]everolimus do not significantly cross the blood-brain barrier.
A dose-dependent brain penetration of everolimus, which is consistent with the hypothesis of saturation of an efflux pump present in the brain capillary endothelial cells.
The co-administration of the PgP inhibitor, cyclosporine, enhances the exposure of everolimus in the brain cortex, which is consistent with the inhibition of PgP at the blood-brain barrier.
There are no clinical data on the distribution of everolimus in the human brain. Non-clinical studies in rats demonstrated distribution into the brain following administration by both the intravenous and oral routes.
Biotransformation: Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two 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, everolimus is considered to contribute the majority of the overall pharmacological activity.
Elimination: Mean oral clearance (CL/F) of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h. The mean elimination half-life of everolimus is approximately 30 hours.
No specific excretion studies have been undertaken in cancer patients; however, data are available from the studies in transplant patients. 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 administration of everolimus in patients with advanced solid tumours, steady-state AUC_0-τ was dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within 2 weeks. C_max is dose-proportional between 5 and 10 mg. t_max occurs at 1 to 2 hours post-dose. There was a significant correlation between AUC_0-τ and pre-dose trough concentration at steady-state.
Special populations: Hepatic impairment: The safety, tolerability and pharmacokinetics of everolimus/Afinitor were evaluated in two single oral dose studies of Afinitor tablets in 8 and 34 adult subjects with impaired hepatic function relative to subjects with normal hepatic function.
In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh B) was twice that found in 8 subjects with normal hepatic function.
In the second study of 34 subjects with different impaired hepatic function compared to normal subjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC_0-inf) 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 subjects with hepatic impairment based on their Child-Pugh status.
Based on the results of the two studies, dose adjustment is recommended for patients with hepatic impairment (see Dosage & Administration and Precautions).
Renal impairment: In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, 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 population [Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet only]: In patients with SEGA, everolimus C_min was approximately dose-proportional within the dose range from 1.35 mg/m² to 14.4 mg/m².
In patients with SEGA, the geometric mean C_min values normalised to mg/m² dose in patients aged <10 years and 10-18 years were lower by 54% and 40%, respectively, than those observed in adults (>18 years of age), suggesting that everolimus clearance was higher in younger patients. Limited data in patients <3 years of age (n=13) indicate that BSA-normalised clearance is about two-fold higher in patients with low BSA (BSA of 0.556 m²) than in adults. Therefore it is assumed that steady-state could be reached earlier in patients <3 years of age (see Dosage & Administration for dosing recommendations).
The pharmacokinetics of everolimus have not been studied in patients younger than 1 year of age. It is reported, however, that CYP3A4 activity is reduced at birth and increases during the first year of life, which could affect the clearance in this patient population.
A population pharmacokinetic analysis including 111 patients with SEGA who ranged from 1.0 to 27.4 years (including 18 patients 1 to less than 3 years of age with BSA 0.42 m² to 0.74 m²) showed that BSA-normalised clearance is in general higher in younger patients. Population pharmacokinetic model simulations showed that a starting dose of 7 mg/m² would be necessary to attain C_min within the 5 to 15 ng/ml range in patients younger than 3 years of age. A higher starting dose of 7 mg/m² is therefore recommended for patients 1 to less than 3 years of age with SEGA (see Dosage & Administration).
Dispersible tablet: In patients with TSC and refractory seizures receiving Afinitor dispersible tablets, a trend was observed toward lower C_min normalised to dose (as mg/m²) in younger patients. Median C_min normalised to mg/m² dose was lower for the younger age groups, indicating that everolimus clearance (normalised to BSA) was higher in younger patients.
In patients with TSC and refractory seizures Afinitor concentrations were investigated in 9 patients in the age between 1 and <2 years. Doses of 6 mg/m² (absolute doses range 1-5 mg) were administered and resulted in minimal concentrations between 2 and 10 ng/ml (median of 5 ng/ml; total of >50 measurements). No data are available in patients with TSC-seizures below the age of 1 year.
Elderly patients: In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27-85 years) on oral clearance 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.
Pharmacokinetic/pharmacodynamic relationship(s) (Dispersible tablet only): In patients with TSC and refractory seizures, a conditional logistic regression analysis based on the core phase of Study CRAD001M2304 to estimate the probability of seizure response versus Time Normalised (TN)-C_min stratified by age sub-group, indicated that a 2-fold increase in TN-C_min was associated with a 2.172-fold increase (95% CI: 1.339, 3.524) in the odds for a seizure response over the observed TN-C_min ranges of 0.97 ng/ml to 16.40 ng/ml. Baseline seizure frequency was a significant factor in the seizure response (with an odds ratio of 0.978 [95% CI: 0.959, 0.998]). This outcome was consistent with the results of a linear regression model predicting the log of absolute seizure frequency during the maintenance period of the core phase, which indicated that for a 2-fold increase in TN-C_min there was a statistically significant 28% reduction (95% CI: 12%, 42%) in absolute seizure frequency. Baseline seizure frequency and TN-C_min were both significant factors (α=0.05) in predicting the absolute seizure frequency in the linear regression model.
Toxicology: Preclinical safety data: The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, 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; pancreas (degranulation and vacuolation of exocrine cells in monkeys and minipigs, respectively, and degeneration of islet cells in monkeys), 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 minipigs.
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 minipigs, 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 above, and sperm motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg, which is within the range of therapeutic exposure and which caused a reduction in male fertility. There was evidence of reversibility.
In animal reproductive studies female fertility was not affected. However, oral doses of everolimus in female rats at ≥0.1 mg/kg (approximately 4% of the AUC_0-24h in patients receiving the 10 mg daily dose) resulted in increases in pre-implantation loss.
Everolimus crossed the placenta and was toxic to the foetus. 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 (e.g. sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits, embryotoxicity was evident in an increase in late resorptions.
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 [Tablet (Oncology Indications)] or 4.3 [Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet] and 0.2 times the estimated clinical exposure.
Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: In juvenile rat toxicity studies, systemic toxicity included decreased body weight gain, food consumption, and delayed attainment of some developmental landmarks, 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 reactions of everolimus as compared to adult animals. Toxicity study with juvenile monkeys did not show any relevant toxicity.

Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: Subependymal giant cell astrocytoma (SEGA) associated with TSC: Afinitor is indicated for the treatment of adult and paediatric patients with SEGA associated with TSC who require therapeutic intervention but are not amenable to surgery. The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.
Tablet (Oncology Indications): Hormone receptor-positive advanced breast cancer: Afinitor is indicated for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor.
Neuroendocrine tumours of pancreatic origin: Afinitor is indicated for the treatment of unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease.
Neuroendocrine tumours of gastrointestinal or lung origin: Afinitor is indicated for the treatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin in adults with progressive disease (see Precautions and Pharmacology: Pharmacodynamics under Actions).
Renal cell carcinoma: Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy.
Tablet (Tuberous Sclerosis Complex-Related Indications): Renal angiomyolipoma associated with tuberous sclerosis complex (TSC): Afinitor is indicated for the treatment of adult patients with renal angiomyolipoma associated with TSC who are at risk of complications (based on factors such as tumour size or presence of aneurysm, or presence of multiple or bilateral tumours) but who do not require immediate surgery.
The evidence is based on analysis of change in sum of angiomyolipoma volume.
Dispersible tablet: Refractory seizures associated with tuberous sclerosis complex (TSC): Afinitor is indicated as adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalisation, are associated with TSC.

Treatment with Afinitor should be initiated and supervised by a physician experienced in the use of anticancer therapies and in the treatment of patients with TSC and therapeutic drug monitoring.
Posology: Tablet (Oncology Indications): For the different dose regimens Afinitor is available as 2.5 mg, 5 mg and 10 mg tablets.
The recommended dose is 10 mg everolimus once daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
If a dose is missed, the patient should not take an additional dose, but take the next prescribed dose as usual.
Dose adjustment due to adverse reactions: Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of Afinitor therapy. For adverse reactions of Grade 1, dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily.
Table 11 summarises the dose adjustment recommendations for specific adverse reactions (see also Precautions). (See Table 11.)

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Tablet (Tuberous Sclerosis Complex-Related Indications): Renal angiomyolipoma associated with TSC: The recommended dose is 10 mg of everolimus once daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose.
SEGA associated with TSC: Careful titration may be required to obtain the optimal therapeutic effect. Doses that will be tolerated and effective vary between patients. Concomitant antiepileptic therapy may affect the metabolism of everolimus and may contribute to this variance (see Interactions).
Dosing is individualised based on Body Surface Area (BSA) using the Dubois formula, where weight (W) is in kilograms and height (H) is in centimetres: BSA = (W^0.425 x H^0.725) x 0.007184.
The recommended starting dose for Afinitor for the treatment of patients with SEGA is 4.5 mg/m². A higher starting dose of 7 mg/m² is recommended for patients 1 to less than 3 years of age based on pharmacokinetic simulations (see Pharmacology: Pharmacokinetics under Actions). Different strengths of Afinitor tablets can be combined to attain the desired dose.
Everolimus whole blood trough concentrations should be assessed at least 1 week after commencing treatment. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. The dose may be increased to attain a higher trough concentration within the target range to obtain optimal efficacy, subject to tolerability.
Individualised dosing should be titrated by increasing the dose by increments of 2.5 mg to attain the target trough concentration for optimal clinical response. Efficacy, safety, concomitant therapy, and the current trough concentration should be considered when planning for dose titration. Individualised dose titration can be based on simple proportion: New everolimus dose = current dose x (target concentration/current concentration).
For example, a patient's current dose based on BSA is 2.5 mg with a steady state concentration of 4 ng/ml. In order to achieve a target concentration above the lower C_min limit of 5 ng/ml, e.g. 8 ng/ml, the new everolimus dose would be 5 mg (an increase of 2.5 mg from the current daily dose). In cases where the revised dose is not a multiple of 2.5 mg, it should be rounded to the next available tablet strength.
Dosing recommendations for paediatric patients with SEGA are consistent with those for the adult SEGA population, except for patients in the range from 1 year to less than 3 years of age, and those with hepatic impairment (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions).
SEGA volume should be evaluated approximately 3 months after commencing Afinitor therapy, with subsequent dose adjustments taking changes in SEGA volume, corresponding trough concentration, and tolerability into consideration.
Once a stable dose is attained, trough concentrations should be monitored every 3 to 6 months in patients with changing BSA, or every 6 to 12 months in patients with stable BSA, for the duration of treatment.
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose.
Dose adjustments due to adverse reactions: Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of Afinitor therapy. For adverse reactions of Grade 1, dose adjustment is usually not required. If dose reduction is required, the recommended dose is approximately 50% lower than the daily dose previously administered. For dose reductions below the lowest available strength, alternate day dosing should be considered.
Table 12 summarises dose adjustment recommendations for specific adverse reactions (see also Precautions). (See Table 12.)

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Therapeutic drug monitoring: Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is required for patients treated for SEGA. Trough concentrations should be assessed at least 1 week after the initial dose, after any change in dose or pharmaceutical form, after initiation of or change in co-administration of CYP3A4 inhibitors (see Precautions and Interactions) or after any change in hepatic status (Child-Pugh) (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions). Trough concentrations should be assessed 2 to 4 weeks after initiation of or change in co-administration of CYP3A4 inducers (see Precautions and Interactions) since the natural degradation time of the induced enzymes has to be taken into account.
Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is an option to be considered for patients treated for renal angiomyolipoma associated with TSC (see Pharmacology: Pharmacodynamics under Actions) after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see Precautions and Interactions) or after any change in hepatic status (Child-Pugh) (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions).
When possible, the same assay and laboratory for therapeutic drug monitoring should be used throughout the treatment.
Switching pharmaceutical forms: Afinitor is available in two pharmaceutical forms: tablets and dispersible tablets. Afinitor tablets and Afinitor dispersible tablets are not to be used interchangeably. The two pharmaceutical forms must not be combined to achieve the desired dose. The same pharmaceutical form must be used consistently, as appropriate for the indication being treated.
When switching pharmaceutical forms, the dose should be adjusted to the closest milligram strength of the new pharmaceutical form and the everolimus trough concentration should be assessed at least 1 week later (see "Therapeutic drug monitoring" as previously mentioned).
Dispersible tablet: Careful titration may be required to obtain the optimal therapeutic effect. Doses that will be tolerated and effective vary between patients. Concomitant antiepileptic therapy may affect the metabolism of everolimus and may contribute to this variance (see Interactions).
Dosing is individualised based on Body Surface Area (BSA) using the Dubois formula, where weight (W) is in kilograms and height (H) is in centimetres: BSA = (W^0.425 x H^0.725) x 0.007184.
Starting dose and target trough concentrations in SEGA associated with TSC: The recommended starting dose for Afinitor for the treatment of patients with SEGA is 4.5 mg/m². A higher starting dose of 7 mg/m² is recommended for patients 1 to less than 3 years of age based on pharmacokinetic simulations (see Pharmacology: Pharmacokinetics under Actions). Different strengths of Afinitor dispersible tablets can be combined to attain the desired dose.
Dosing recommendations for paediatric patients with SEGA are consistent with those for the adult SEGA population, except for patients in the range from 1 year to less than 3 years of age, and those with hepatic impairment (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions).
Starting dose and target trough concentrations in TSC with refractory seizures: The recommended starting dose for Afinitor for the treatment of patients with seizures is shown in Table 13. Different strengths of Afinitor dispersible tablets can be combined to attain the desired dose. (See Table 13.)

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Dosing recommendations for paediatric patients with seizures are consistent with those for the adult population, except for patients in the range from 2 years to less than 6 years of age (see Table 13 as previously mentioned), and those with hepatic impairment (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions).
Dose monitoring: Everolimus whole blood trough concentrations should be assessed at least 1 week after commencing treatment. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. The dose may be increased to attain a higher trough concentration within the target range to obtain optimal efficacy, subject to tolerability.
Titration: Individualised dosing should be titrated by increasing the dose by increments of 1 to 4 mg to attain the target trough concentration for optimal clinical response. Efficacy, safety, concomitant therapy, and the current trough concentration should be considered when planning for dose titration. Individualised dose titration can be based on simple proportion: New everolimus dose = current dose x (target concentration/current concentration).
For example, a patient's current dose based on BSA is 4 mg with a steady-state concentration of 4 ng/ml. In order to achieve a target concentration above the lower C_min limit of 5 ng/ml, e.g. 8 ng/ml, the new everolimus dose would be 8 mg (an increase of 4 mg from the current daily dose).
Long-term monitoring: For patients with TSC who have SEGA, SEGA volume should be evaluated approximately 3 months after commencing Afinitor therapy, with subsequent dose adjustments taking changes in SEGA volume, corresponding trough concentration, and tolerability into consideration.
For patients with TSC who have SEGA and patients with TSC and refractory seizures, once a stable dose is attained, trough concentrations should be monitored every 3 to 6 months in patients with changing BSA, or every 6 to 12 months in patients with stable BSA, for the duration of treatment.
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose.
Dose adjustments due to adverse reactions: Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of Afinitor therapy. For adverse reactions of Grade 1, dose adjustment is usually not required. If dose reduction is required, the recommended dose is approximately 50% lower than the daily dose previously administered. For dose reductions below the lowest available strength, alternate day dosing should be considered.
Table 12 summarises dose adjustment recommendations for specific adverse reactions (see also Precautions). (See Table 12 as previously mentioned).
Therapeutic drug monitoring: Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is required. Trough concentrations should be assessed at least 1 week after the initial dose, after any change in dose or pharmaceutical form, after initiation of or change in co-administration of CYP3A4 inhibitors (see Precautions and Interactions) or after any change in hepatic status (Child-Pugh) (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions). Trough concentrations should be assessed 2 to 4 weeks after initiation of or change in co-administration of CYP3A4 inducers (see Precautions and Interactions) since the natural degradation time of the induced enzymes has to be taken into account. When possible, the same assay and laboratory for therapeutic drug monitoring should be used throughout the treatment.
Switching pharmaceutical forms: Afinitor is available in two pharmaceutical forms: tablets and dispersible tablets. Afinitor tablets and Afinitor dispersible tablets are not to be used interchangeably. The two pharmaceutical forms must not be combined to achieve the desired dose. The same pharmaceutical form must be used consistently, as appropriate for the indication being treated.
When switching pharmaceutical forms, the dose should be adjusted to the closest milligram strength of the new pharmaceutical form and the everolimus trough concentration should be assessed at least 1 week later (see "Therapeutic drug monitoring" as previously mentioned).
Special populations: Elderly patients (≥65 years): No dose adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: Tablet (Oncology Indications): Mild hepatic impairment (Child-Pugh A) - the recommended dose is 7.5 mg daily.
Moderate hepatic impairment (Child-Pugh B) - the recommended dose is 5 mg daily.
Severe hepatic impairment (Child-Pugh C) - Afinitor is only recommended if the desired benefit outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded.
Dose adjustments should be made if a patient's hepatic (Child-Pugh) status changes during treatment (see also Precautions and Pharmacology: Pharmacokinetics under Actions).
Tablet (Tuberous Sclerosis Complex-Related Indications): Patients with renal angiomyolipoma associated with TSC: Mild hepatic impairment (Child-Pugh A): The recommended dose is 7.5 mg daily.
Moderate hepatic impairment (Child-Pugh B): The recommended dose is 5 mg daily.
Severe hepatic impairment (Child-Pugh C): Afinitor is only recommended if the desired benefit outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Dose adjustments should be made if a patient's hepatic (Child-Pugh) status changes during treatment.
Patients with SEGA associated with TSC: Patients <18 years of age: Afinitor is not recommended for patients <18 years of age with SEGA and hepatic impairment.
Patients ≥18 years of age: Mild hepatic impairment (Child-Pugh A): 75% of the recommended starting dose calculated based on BSA (rounded to the nearest strength).
Moderate hepatic impairment (Child-Pugh B): 50% of the recommended starting dose calculated based on BSA (rounded to the nearest strength).
Severe hepatic impairment (Child-Pugh C): Afinitor is only recommended if the desired benefit outweighs the risk. In this case, 25% of the dose calculated based on BSA (rounded to the nearest strength) must not be exceeded.
Everolimus whole blood trough concentrations should be assessed at least 1 week after any change in hepatic status (Child-Pugh).
Dispersible tablet: Patients <18 years of age: Afinitor is not recommended for patients <18 years of age with SEGA or refractory seizures and hepatic impairment.
Patients ≥18 years of age: Mild hepatic impairment (Child-Pugh A): 75% of the recommended starting dose calculated based on BSA (rounded to the nearest strength).
Moderate hepatic impairment (Child-Pugh B): 50% of the recommended starting dose calculated based on BSA (rounded to the nearest strength).
Severe hepatic impairment (Child-Pugh C): Votubia is only recommended if the desired benefit outweighs the risk. In this case, 25% of the dose calculated based on BSA (rounded to the nearest strength) must not be exceeded.
Everolimus whole blood trough concentrations should be assessed at least 1 week after any change in hepatic status (Child-Pugh).
Paediatric population: Tablet (Oncology Indications): The safety and efficacy of Afinitor in children aged 0 to 18 years have not been established. No data are available.
Tablet (Tuberous Sclerosis Complex-Related Indications): The safety and efficacy of Afinitor in children aged 0 to 18 years with renal angiomyolipoma associated with TSC in the absence of SEGA have not been established. No data are available.
The safety, efficacy and pharmacokinetic profile of Afinitor in children below the age of 1 year with TSC who have SEGA have not been established. No data are available (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
Clinical study results did not show an impact of Afinitor on growth and pubertal development.
Dispersible tablet: The safety, efficacy and pharmacokinetic profile of Afinitor in children below the age of 1 year with TSC who have SEGA have not been established. No data are available (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
The safety, efficacy and pharmacokinetic profile of Afinitor has not been established in children below the age of 2 years with TSC and refractory seizures. Currently available data are described in Pharmacology: Pharmacokinetics under Actions, but no recommendation on a posology can be made.
Clinical study results did not show an impact of Afinitor on growth and pubertal development.
Method of administration: Tablet (Oncology Indications): Afinitor should be administered orally once daily at the same time every day, consistently either with or without food (see Pharmacology: Pharmacokinetics under Actions). Afinitor tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed.
Tablet (Tuberous Sclerosis Complex-Related Indications): Afinitor must be administered orally once daily at the same time every day, consistently either with or without food (see Pharmacology: Pharmacokinetics under Actions). Afinitor tablets are to be swallowed whole with a glass of water. The tablets must not be chewed or crushed. For patients with TSC who have SEGA and are unable to swallow tablets, Afinitor tablet(s) can be dispersed completely in a glass with approximately 30 ml of water by gently stirring until the tablet(s) is(are) fully disintegrated (approximately 7 minutes), immediately prior to drinking. After the dispersion has been swallowed, any residue must be re-dispersed in the same volume of water and swallowed (see Pharmacology: Pharmacokinetics under Actions).
Dispersible tablet: Afinitor must be administered orally once daily at the same time every day, consistently either with or without food (see Pharmacology: Pharmacokinetics under Actions).
Afinitor dispersible tablets are to be taken as a suspension only and must not be swallowed whole, chewed, or crushed. The suspension can be prepared either in an oral syringe or in a small glass. Care should be taken to ensure the entire dose is ingested.
The suspension must be administered immediately after preparation. If not administered within 30 minutes of preparation when using an oral syringe or 60 minutes when using a small glass, the suspension must be discarded and a new suspension must be prepared (see Shelf life under Storage). Only water should be used as the vehicle.
For further details on handling, see Special precautions for disposal and other handling under Cautions for Usage.

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been given with acceptable acute tolerability in the adult population. General supportive measures should be initiated in all cases of overdose.
Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: It is essential to assess everolimus blood levels in cases of suspected overdose. Everolimus is not considered dialysable to any relevant degree (less than 10% was removed within 6 hours of haemodialysis).
Paediatric population: A limited number of paediatric patients have been exposed to doses higher than 10 mg/m²/day. No signs of acute toxicity have been reported in these cases.

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in Description.

Non-infectious pneumonitis: Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. Non-infectious pneumonitis (including interstitial lung disease) has been frequently reported in patients taking Afinitor/everolimus in the advanced renal cell carcinoma (RCC) setting (see Adverse Reactions). Some cases were severe and on rare occasions, a fatal outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea, and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of appropriate investigations. Opportunistic infections such as Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) should be ruled out in the differential diagnosis of non-infectious pneumonitis (see Infections as follows). Patients should be advised to report promptly any new or worsening respiratory symptoms.
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue Afinitor therapy without dose adjustments. If symptoms are moderate (Grade 2) or severe (Grade 3), consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Afinitor may be reinitiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet only].
For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) may be considered.
Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: For cases where symptoms of non-infectious pneumonitis are severe, Afinitor therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Afinitor may be reinitiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances.
Infections: Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens (see Adverse Reactions). Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis, candidiasis or Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) and viral infections including reactivation of hepatitis B virus, have been described in patients taking Afinitor/everolimus. Some of these infections have been severe (e.g. leading to sepsis [including septic shock], respiratory or hepatic failure) and occasionally fatal in adult and paediatric patients (see Adverse Reactions).
Physicians and patients should be aware of the increased risk of infection with Afinitor. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor.
If a diagnosis of invasive systemic fungal infection is made, the Afinitor treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.
Cases of Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome, have been reported in patients who received everolimus. PJP/PCP may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP/PCP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.
Hypersensitivity reactions: Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see Contraindications).
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors: Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see Interactions).
Stomatitis: Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported adverse reaction in patients treated with Afinitor (see Adverse Reactions). Stomatitis mostly occurs within the first 8 weeks of treatment. A single-arm study in postmenopausal breast cancer patients treated with Afinitor (everolimus) plus exemestane suggested that an alcohol-free corticosteroid oral solution, administered as a mouthwash during the initial 8 weeks of treatment, may decrease the incidence and severity of stomatitis (see Pharmacology: Pharmacodynamics under Actions). Management of stomatitis may therefore include prophylactic (in adults) and/or therapeutic use of topical treatments, such as an alcohol-free corticosteroid oral solution as a mouthwash. However products containing alcohol, hydrogen peroxide, iodine and thyme derivatives should be avoided as they may exacerbate the condition. Monitoring for and treatment of fungal infection is recommended, especially in patients being treated with steroid-based medicinal products. Antifungal agents should not be used unless fungal infection has been diagnosed (see Interactions).
Haemorrhage [Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet only]: Serious cases of haemorrhage, some with a fatal outcome, have been reported in patients treated with everolimus in the oncology setting. No serious cases of renal haemorrhage were reported in the TSC setting.
Caution is advised in patients taking Afinitor, particularly during concomitant use with active substances known to affect platelet function or that can increase the risk of haemorrhage as well as in patients with a history of bleeding disorders. Healthcare professionals and patients should be vigilant for signs and symptoms of bleeding throughout the treatment period, especially if risk factors for haemorrhage are combined.
Renal failure events: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Afinitor (see Adverse Reactions). Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.
Laboratory tests and monitoring: Renal function: Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients treated with Afinitor (see Adverse Reactions). Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein or serum creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter.
Blood glucose: Hyperglycaemia has been reported in patients taking Afinitor (see Adverse Reactions). Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. More frequent monitoring is recommended when Afinitor is co-administered with other medicinal products that may induce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting a patient on Afinitor.
Blood lipids: Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) has been reported in patients taking Afinitor. Monitoring of blood cholesterol and triglycerides prior to the start of Afinitor therapy and periodically thereafter, as well as management with appropriate medical therapy, is also recommended.
Haematological parameters: Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported in patients treated with Afinitor (see Adverse Reactions). Monitoring of complete blood count is recommended prior to the start of Afinitor therapy and periodically thereafter.
Functional carcinoid tumours [Tablet (Oncology Indications) only]: In a randomised, double-blind, multi-centre trial in patients with functional carcinoid tumours, Afinitor plus depot octreotide was compared to placebo plus depot octreotide. The study did not meet the primary efficacy endpoint (progression-free-survival [PFS]) and the overall survival (OS) interim analysis numerically favoured the placebo plus depot octreotide arm. Therefore, the safety and efficacy of Afinitor in patients with functional carcinoid tumours have not been established.
Prognostic factors in neuroendocrine tumours of gastrointestinal or lung origin [Tablet (Oncology Indications) only]: In patients with non-functional gastrointestinal or lung neuroendocrine tumours and good prognostic baseline factors, e.g. ileum as primary tumour origin and normal chromogranin A values or without bone involvement, an individual benefit-risk assessment should be performed prior to the start of Afinitor therapy. Limited evidence of PFS benefit was reported in the subgroup of patients with ileum as primary tumour origin (see Pharmacology: Pharmacodynamics under Actions).
Interactions: Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP) should be avoided. If co-administration of a moderate CYP3A4 and/or PgP inhibitor or inducer cannot be avoided, the clinical condition of the patient should be monitored closely. Monitoring of everolimus through concentrations and dose adjustments of Afinitor can be taken into consideration based on predicted AUC (see Interactions).
Concomitant treatment with potent CYP3A4/PgP inhibitors result in dramatically increased plasma/blood concentrations of everolimus (see Interactions). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Afinitor and potent inhibitors is not recommended.
Caution should be exercised when Afinitor is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Afinitor is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine, ergot alkaloid derivatives or carbamazepine), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see Interactions).
Hepatic impairment: Tablet (Oncology Indications): Exposure to everolimus was increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Afinitor is only recommended for use in patients with severe hepatic impairment (Child-Pugh C) if the potential benefit outweighs the risk (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
No clinical safety or efficacy data are currently available to support dose adjustment recommendations for the management of adverse reactions in patients with hepatic impairment.
Tablet (Tuberous Sclerosis Complex-Related Indications): Afinitor is not recommended for use in patients: ≥18 years of age and concomitant severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions); <18 years of age with SEGA and concomitant hepatic impairment (Child-Pugh A, B and C) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Dispersible tablet: Afinitor is not recommended for use in patients: ≥18 years of age with SEGA or refractory seizures and concomitant severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions); <18 years of age with SEGA or refractory seizures and concomitant hepatic impairment (Child-Pugh A, B and C) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Vaccinations: The use of live vaccines should be avoided during treatment with Afinitor (see Interactions).
For paediatric patients (with SEGA) who do not require immediate treatment, completion of the recommended childhood series of live virus vaccinations is advised prior to the start of therapy according to local treatment guidelines [Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet only].
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Wound healing complications: Impaired wound healing is a class effect of rapamycin derivatives, including everolimus/Afinitor. Caution should therefore be exercised with the use of Afinitor in the peri-surgical period.
Radiation therapy complications: Serious and severe radiation reactions (such as radiation oesophagitis, radiation pneumonitis and radiation skin injury), including fatal cases, have been reported when everolimus was taken during, or shortly after, radiation therapy. Caution should therefore be exercised for the potentiation of radiotherapy toxicity in patients taking everolimus in close temporal relationship with radiation therapy.
Additionally, radiation recall syndrome (RRS) has been reported in patients taking everolimus who had received radiation therapy in the past. In the event of RRS, interrupting or stopping everolimus treatment should be considered.
Effects on ability to drive and use machines: Afinitor has minor or moderate influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with Afinitor.

Women of childbearing potential/Contraception in males and females: Women of childbearing potential must use a highly effective method of contraception (e.g. oral, injected, or implanted non-oestrogen-containing hormonal method of birth control, progesterone-based contraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device [IUD], and/or female/male sterilisation) while receiving everolimus, and for up to 8 weeks after ending treatment. Male patients should not be prohibited from attempting to father children.
Pregnancy: There are no adequate data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown.
Everolimus is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding: It is not known whether everolimus is excreted in human breast milk. However, in rats, everolimus and/or its metabolites readily pass into the milk (see Pharmacology: Toxicology: Preclinical safety data under Actions). Therefore, women taking everolimus should not breast-feed during treatment and for 2 weeks after the last dose.
Fertility: The potential for everolimus to cause infertility in male and female patients is unknown, however amenorrhoea (secondary amenorrhoea and other menstrual irregularities) and associated luteinising hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients (see also Pharmacology: Toxicology: Preclinical safety data under Actions for preclinical observations on the male and female reproductive systems). Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: Tablet (Oncology Indications): The safety profile is based on pooled data from 2,879 patients treated with Afinitor in eleven clinical studies, consisting of five randomised, double-blind, placebo controlled phase III studies and six open-label phase I and phase II studies, related to the approved indications.
The most common adverse reactions (incidence ≥1/10) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anaemia, dysgeusia, pneumonitis, oedema peripheral, hyperglycaemia, asthenia, pruritus, weight decreased, hypercholesterolaemia, epistaxis, cough and headache.
The most frequent Grade 3-4 adverse reactions (incidence ≥1/100 to <1/10) were stomatitis, anaemia, hyperglycaemia, infections, fatigue, diarrhoea, pneumonitis, asthenia, thrombocytopenia, neutropenia, dyspnoea, proteinuria, lymphopenia, haemorrhage, hypophosphataemia, rash, hypertension, pneumonia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased and diabetes mellitus. The grades follow CTCAE Version 3.0 and 4.03.
Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: Three randomised, double-blind, placebo-controlled pivotal phase III studies, including double-blind and open label treatment periods, and a non-randomised, open-label, single-arm phase II study contribute to the safety profile of Afinitor (n=612, including 409 patients <18 years of age; median duration of exposure 36.8 months [range 0.5 to 83.2]).
EXIST-3 (CRAD001M2304): This was a randomised, double-blind, controlled, phase III trial comparing adjunctive treatment of low and high everolimus exposure (low trough [LT] range of 3-7 ng/ml [n=117] and high trough [HT] range of 9-15 ng/ml [n=130]) versus placebo (n=119), in patients with TSC and refractory partial-onset seizures receiving 1 to 3 antiepileptics. The median duration of the double-blind period was 18 weeks. The cumulative median duration exposure to Afinitor (361 patients who took at least one dose of everolimus) was 30.4 months (range 0.5 to 48.8).
EXIST-2 (CRAD001M2302): This was a randomised, double-blind, controlled, phase III trial of everolimus (n=79) versus placebo (n=39) in patients with either TSC plus renal angiomyolipoma (n=113) or sporadic lymphangioleiomyomatosis (LAM) plus renal angiomyolipoma (n=5). The median duration of blinded study treatment was 48.1 weeks (range 2 to 115) for patients receiving Afinitor and 45.0 weeks (range 9 to 115) for those receiving placebo. The cumulative median duration of exposure to Afinitor (112 patients who took at least one dose of everolimus) was 46.9 months (range 0.5 to 63.9).
EXIST-1 (CRAD001M2301): This was a randomised, double-blind, controlled, phase III trial of everolimus (n=78) versus placebo (n=39) in patients with TSC who have SEGA, irrespective of age. The median duration of blinded study treatment was 52.2 weeks (range 24 to 89) for patients receiving Afinitor and 46.6 weeks (range 14 to 88) for those receiving placebo. The cumulative median duration of exposure to Afinitor (111 patients who took at least one dose of everolimus) was 47.1 months (range 1.9 to 58.3).
CRAD001C2485: This was a prospective, open-label, single-arm phase II study of everolimus in patients with SEGA (n=28). The median duration of exposure was 67.8 months (range 4.7 to 83.2).
The adverse events considered to be associated with the use of Afinitor (adverse reactions), based upon the review and medical assessment of all adverse events reported in the previously mentioned studies, are described as follows.
The most frequent adverse reactions (incidence ≥1/10) from the pooled safety data are (in decreasing order): stomatitis, pyrexia, nasopharyngitis, diarrhoea, upper respiratory tract infection, vomiting, cough, rash, headache, amenorrhoea, acne, pneumonia, urinary tract infection, sinusitis, menstruation irregular, pharyngitis, decreased appetite, fatigue, hypercholesterolaemia, and hypertension.
The most frequent grade 3-4 adverse reactions (incidence ≥1%) were pneumonia, stomatitis, amenorrhoea, neutropenia, pyrexia, menstruation irregular, hypophosphataemia, diarrhoea, and cellulitis. The grades follow CTCAE Version 3.0 and 4.03.
Tabulated list of adverse reactions: Tablet (Oncology Indications): Table 14 presents the frequency category of adverse reactions reported in the pooled analysis considered for the safety pooling. Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 14.)

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Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: Table 15 shows the incidence of adverse reactions based on pooled data of patients receiving everolimus in the three TSC studies (including both the double-blind and open-label extension phase, where applicable). Adverse reactions are listed according to MedDRA system organ class. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 15.)

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Description of selected adverse reactions: In clinical studies and post-marketing spontaneous reports, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an expected event during periods of immunosuppression.
In clinical studies and post marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome), proteinuria and increased serum creatinine. Monitoring of renal function is recommended (see Precautions).
In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases of Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome (see Precautions).
In clinical studies and post-marketing spontaneous reports, angioedema has been reported with and without concomitant use of ACE inhibitors (see Precautions).
Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: Additional adverse reactions of relevance observed in oncology clinical studies and post-marketing spontaneous reports, were cardiac failure, pulmonary embolism, deep vein thrombosis, impaired wound healing and hyperglycaemia.
Tablet (Oncology Indications): In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases of amenorrhoea (secondary amenorrhoea and other menstrual irregularities).
Tablet (Tuberous Sclerosis Complex-Related Indications): In clinical studies, everolimus has been associated with haemorrhage events. On rare occasions, fatal outcomes were observed in the oncology setting (see Precautions). No serious cases of renal haemorrhage were reported in the TSC setting.
Dispersible tablet: In clinical studies, everolimus has been associated with haemorrhage events. On rare occasions, fatal outcomes were observed in the oncology setting (see Precautions). No serious cases of renal haemorrhage were reported in the TSC setting.
Paediatric population: Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: In the pivotal phase II study, 22 of the 28 SEGA patients studied were below the age of 18 years and in the pivotal phase III study, 101 of the 117 SEGA patients studied were below the age of 18 years. In the pivotal phase III study in patients with TSC and refractory seizures, 299 of the 366 patients studied were below the age of 18 years. The overall type, frequency and severity of adverse reactions observed in children and adolescents have been generally consistent with those observed in adults, with the exception of infections which were reported at a higher frequency and severity in children below the age of 6 years. A total of 49 out of 137 patients (36%) aged <6 years had Grade 3/4 infections, compared to 53 out of 272 patients (19%) aged 6 to <18 years and 27 out of 203 patients (13%) aged ≥18 years. Two fatal cases due to infection were reported in 409 patients aged <18 years receiving everolimus.
Elderly patients: In the safety pooling, 37% of the Afinitor-treated patients were ≥65 years of age. The number of patients with an adverse reaction leading to discontinuation of the medicinal product was higher in patients ≥65 years of age (20% vs. 13%). The most common adverse reactions leading to discontinuation were pneumonitis (including interstitial lung disease), stomatitis, fatigue and dyspnoea.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of 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.
Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are listed in Tables 16, 17 and 18 as follows.
CYP3A4 and PgP inhibitors increasing everolimus concentrations: Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by decreasing metabolism or the efflux of everolimus from intestinal cells.
CYP3A4 and PgP inducers decreasing everolimus 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.
Tablet (Oncology Indications): See Table 16.

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Tablet (Tuberous Sclerosis Complex-Related Indications): See Table 17.

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Dispersible tablet: See Table 18.

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Agents whose plasma concentration may be altered by everolimus: Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut cannot be excluded. An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A substrate probe, with everolimus resulted in a 25% increase in midazolam C_max and a 30% increase in midazolam AUC_(0-inf). The effect is likely to be due to inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability of orally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure of systemically administered CYP3A4 substrates is not expected (see Precautions).
Tablet (Tuberous Sclerosis Complex-Related Indications) and Dispersible tablet: In EXIST-3 (Study CRAD001M2304), everolimus increased pre-dose concentrations of the antiepileptics carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about 10%. The increase in the pre-dose concentrations of these antiepileptics may not be clinically significant but dose adjustments for antiepileptics with a narrow therapeutic index, e.g carbamazepine, may be considered. Everolimus had no impact on pre-dose concentrations of antiepileptics that are substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide).
Tablet (Oncology Indications): Co-administration of everolimus and depot octreotide increased octreotide C_min with a geometric mean ratio (everolimus/placebo) of 1.47. A clinically significant effect on the efficacy response to everolimus in patients with advanced neuroendocrine tumours could not be established.
Co-administration of everolimus and exemestane increased exemestane C_min and C_2h by 45% and 64%, respectively. However, the corresponding oestradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse reactions 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.
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors: Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (see Precautions).
Concomitant ketogenic diet (Dispersible tablet only): The effect of a ketogenic diet may be mediated through mTOR inhibition. In the absence of clinical data, the possibility of an additive effect on adverse events cannot be excluded when everolimus is given in conjunction with a ketogenic diet.
Vaccinations: The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with Afinitor. 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 (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines.
Radiation treatment: Potentiation of radiation treatment toxicity has been reported in patients receiving everolimus (see Precautions and Adverse Reactions).

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: Important information for caregivers: The extent of absorption of everolimus through topical exposure is not known. Therefore caregivers are advised to avoid contact with the suspension. Hands should be washed thoroughly before and after preparation of the suspension.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instructions for use and handling (Dispersible tablet only): Using an oral syringe: The prescribed dose of Afinitor dispersible tablets should be placed in a 10 ml oral dosing syringe graduated in 1 ml increments. A total of 10 mg of Afinitor dispersible tablets per syringe using a maximum of 5 dispersible tablets must not be exceeded. If a higher dose or number of tablets is required, an additional syringe must be prepared. The dispersible tablets must not be broken or crushed. Approximately 5 ml of water and 4 ml of air should be drawn into the syringe. The filled syringe should be placed into a container (with the tip pointing up) for 3 minutes, until the Afinitor dispersible tablets are in suspension. The syringe should be gently inverted 5 times immediately prior to administration. After administration of the prepared suspension, approximately 5 ml of water and 4 ml of air should be drawn into the same syringe, and the contents should be swirled to suspend remaining particles. The entire contents of the syringe should be administered.
Using a small glass: The prescribed dose of Afinitor dispersible tablets should be placed in a small glass (maximum size 100 ml) containing approximately 25 ml of water. A total of 10 mg of Afinitor dispersible tablets per glass using a maximum of 5 dispersible tablets must not be exceeded. If a higher dose or number of tablets is required, an additional glass must be prepared. The dispersible tablets must not be broken or crushed. Three minutes must be allowed for suspension to occur. The contents should be gently stirred with a spoon and then administered immediately. After administration of the prepared suspension, 25 ml of water should be added and be stirred with the same spoon to re-suspend any remaining particles. The entire contents of the glass should be administered.
A complete set of instructions for use is provided at "Instructions for use" under Patient Counselling Information.

Store in the original package in order to protect from light and moisture.
Dispersible tablet: Do not store above 30°C.

Dispersible tablet: Instructions for Use: Read and follow these instructions carefully so that you know how to correctly prepare the medicine. This will look like a cloudy liquid (known as an oral suspension).
Use an oral syringe or a small glass for preparing and taking the Afinitor suspension only - do not use it for anything else.
Important information: Take Afinitor dispersible tablets as a suspension only.
These instructions are for taking a dose between 2 mg and 10 mg.
The most you can take at one time using the oral syringe or small glass is 10 mg, using a maximum of 5 dispersible tablets.
If you need to take a higher dose or need to use more than 5 dispersible tablets, split the dose and repeat the steps using the same oral syringe or small glass.
Ask your doctor or pharmacist about how to split the dose if you are not sure.
Caregivers should try to avoid skin contact with the oral suspension.
Only use water (drinkable tap water or non-sparkling bottled water) to prepare the oral suspension. Do not use juice or any other liquids.
The patient must drink the suspension immediately after it is prepared. If the patient does not drink it within 30 minutes, an oral syringe has been used or within 60 minutes, or a small glass has been used, throw it away and prepare a new suspension.
Instructions for caregivers preparing the suspension using an oral syringe: You will need: The blister with Afinitor dispersible tablets; Scissors to open the blister; 10 ml oral syringe with 1 ml increments (for single use); 2 clean glasses; Approximately 30 ml of water.
Getting ready: 1. Wash and dry your hands.
2. Take the 10 ml oral syringe and pull out the plunger, removing it completely from the barrel of the syringe.
Adding the dispersible tablets: 3. Use scissors to open the blister along the dotted line. Remove the dispersible tablets from the blister. Place them into the barrel of the oral syringe straight away.
4. Re-insert the plunger into the barrel of the oral syringe. Push the plunger in until it touches the dispersible tablets.
Adding water: 5. Fill a small glass with water (drinkable tap water or non-sparkling bottled water). Put the tip of the syringe into the water. Draw up about 5 ml of water by slowly pulling the plunger out until it is at the 5 ml mark on the syringe.
Note: The amount of water in the oral syringe does not need to be exact but all the tablets should be covered. If any tablets get stuck in the dry upper part of the oral syringe, gently tap the oral syringe until they fall down into the water.
Mixing the medicine: 6. Hold the oral syringe with the tip pointing up. Pull the plunger slowly down to draw in air until it is at the 9 ml mark on the syringe.
7. Put the filled oral syringe in the clean, empty glass with the tip pointing up. Wait for 3 minutes - until the dispersible tablets have completely broken apart.
8. Mix the medicine by slowly turning the oral syringe upside down and back again five times just before using the dose. Do not shake it. Use the oral suspension immediately. If you do not use it within 30 minutes, throw it away and prepare a new suspension.
Removing air: 9. Hold the oral syringe with the tip pointing upwards. Push the plunger up slowly to remove most of the air (it is okay for a small amount of air to remain around the tip).
Taking the medicine: 10. Put the oral syringe into the patient's mouth. Push the plunger in slowly to release the full contents of the oral syringe.
11. Carefully remove the oral syringe from the patient's mouth.
Making sure all of the medicine has been taken: 12. Insert the tip of the oral syringe into the glass filled with water. Draw up 5 ml of water by slowly pulling the plunger up.
13. Hold the oral syringe with the tip pointing up. Pull the plunger slowly down to draw in air until it is at the 9 ml mark on the syringe.
14. With the tip of the oral syringe pointing upwards, swirl the water around to collect any medicine that is left inside.
15. Hold the oral syringe with the tip pointing upward. Push the plunger up slowly to remove most of the air.
16. Put the oral syringe into the patient's mouth. Push the plunger in slowly to release the full contents of the oral syringe.
17. Carefully remove the oral syringe from the patient's mouth.
If the total prescribed dose is more than 10 mg or has to be prepared using more than 5 dispersible tablets, repeat steps 2 to 17 to finish giving the dose.
Cleaning up: 18. Ask your pharmacist how to throw away the oral syringe.
19. Wash and dry your hands.
Instructions for patients or caregivers preparing the suspension using a small glass: You will need: Blister with Afinitor dispersible tablets; Scissors to open the blister; 1 small glass (maximum size 100 ml); 30 ml dose cup for measuring water; Approximately 50 ml of water to prepare the suspension; Spoon for stirring.
Getting ready: 1. Wash and dry your hands.
Adding water: 2. Add about 25 ml of water to the 30 ml dose cup. The amount of water added does not need to be exact.
3. Pour the water from the dose cup into the small glass.
Adding the dispersible tablets: 4. Use scissors to open the blister along the dotted line. Remove the dispersible tablets from the blister.
5. Add the dispersible tablets into the water.
Mixing the medicine: 6. Wait for 3 minutes until the dispersible tablets have completely broken apart.
7. Gently stir the contents of the glass with a spoon and then proceed immediately to step 8.
Taking the medicine: 8. The patient must immediately drink all of the oral suspension from the glass. If the suspension is not used within 60 minutes, throw it away and prepare a new suspension.
Making sure all of the medicine has been taken: 9. Refill the glass with the same amount of water (about 25 ml). Stir the contents with the spoon to remove any medicine left on the glass and spoon.
10. The patient must drink all of the oral suspension from the glass.
If the total prescribed dose is more than 10 mg or has to be prepared using more than 5 dispersible tablets, repeat steps 2 to 10 to finish taking the dose.
Cleaning up: 11. Wash the glass and the spoon thoroughly with clean water. Wipe the glass and spoon with a clean paper towel. Store them in a dry and clean place until next time. 12. Wash and dry your hands.

Targeted Cancer Therapy

L01EG02 - everolimus ; Belongs to the class of mammalian target of rapamycin (mTOR) kinase inhibitors. Used in the treatment of cancer.

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