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英文药名：Votubia（everolimus Tablets） 中文药名：依维莫司片 生产厂家：诺华(Novartis)
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 section 5.1) after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see sections 4.4 and 4.5) or after any change in hepatic status (Child-Pugh) (see “Hepatic impairment” below and section 5.2). When possible, the same assay and laboratory for therapeutic drug monitoring should be used throughout the treatment. Special populations Elderly patients (≥65 years) No dose adjustment is required (see section 5.2). Renal impairment No dose adjustment is required (see section 5.2). Hepatic impairment 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): Votubia 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 sections 4.4 and 5.2). 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: Votubia 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): 25% of the recommended starting dose calculated based on BSA (rounded to the nearest strength) • Severe hepatic impairment (Child-Pugh C): not recommended Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after any change in hepatic status (Child-Pugh). Paediatric population The safety and efficacy of Votubia 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 and efficacy of Votubia in children below the age of 1 year with TSC who have SEGA have not been established. No data are available (see section 5.1). The potential for growth/developmental delays with long-term treatment is unknown (see section 5.3). Method of administration Votubia must be administered orally once daily at the same time every day, consistently either with or without food (see section 5.2). Votubia 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, Votubia 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 section 5.2). Switching pharmaceutical forms Votubia is available in two pharmaceutical forms: tablets and dispersible tablets. Votubia tablets and Votubia dispersible tablets are not to be used interchangeably. The two pharmaceutical forms must not be combined to achieve the desired dose. One pharmaceutical form or the other must be used. 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 approximately 2 weeks later (see “Therapeutic drug monitoring” above). 4.3 Contraindications Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Non-infectious pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. Non-infectious pneumonitis (including interstitial lung disease) was described very commonly in patients taking everolimus in the advanced renal cell carcinoma (RCC) setting (see section 4.8). 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. 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 Votubia therapy without dose adjustments. If symptoms are moderate, consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Votubia may be reinitiated at a daily dose approximately 50% lower than the dose previously administered. For cases where symptoms of non-infectious pneumonitis are severe, Votubia therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Votubia 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 protozoal infections, including infections with opportunistic pathogens (see section 4.8). Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus, have been described in patients taking everolimus in the oncology setting. Some of these infections have been severe (e.g. leading to sepsis, respiratory or hepatic failure) and occasionally fatal. Physicians and patients should be aware of the increased risk of infection with Votubia. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Votubia. While taking Votubia, 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 Votubia. If a diagnosis of invasive systemic fungal infection is made, Votubia treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy. 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 section 4.3). 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 section 4.5). Oral ulceration Mouth ulcers, stomatitis and oral mucositis have been observed in patients treated with Votubia (see section 4.8). In such cases topical treatments are recommended, but alcohol- or hydrogen peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed (see section 4.5). Haemorrhage 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 Votubia, 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 Votubia (see section 4.8). 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 Votubia (see section 4.8). Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein or serum creatinine, is recommended prior to the start of Votubia therapy and periodically thereafter. Blood glucose Hyperglycaemia has been reported in patients taking Votubia (see section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Votubia therapy and periodically thereafter. More frequent monitoring is recommended when Votubia is co-administered with other medicinal products that may induce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting a patient on Votubia. Blood lipids Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) has been reported in patients taking Votubia. Monitoring of blood cholesterol and triglycerides prior to the start of Votubia 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 Votubia (see section 4.8). Monitoring of complete blood count is recommended prior to the start of Votubia therapy and periodically thereafter. 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, dose adjustments of Votubia may be required (see section 4.5). Concomitant treatment with potent CYP3A4 inhibitors result in dramatically increased blood concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Votubia and potent inhibitors is not recommended. Caution should be exercised when Votubia is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Votubia is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see section 4.5). Hepatic impairment Votubia is not recommended for use in patients: • with renal angiomyolipoma associated with TSC and concomitant severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk (see sections 4.2 and 5.2). • ≥18 years of age with SEGA and concomitant severe hepatic impairment (Child-Pugh C) (see sections 4.2 and 5.2). • <18 years of age with SEGA and concomitant hepatic impairment (Child-Pugh A, B and C) (see sections 4.2 and 5.2). Vaccinations The use of live vaccines should be avoided during treatment with Votubia (see section 4.5). 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. Wound healing complications Impaired wound healing is a class effect of rapamycin derivatives, including Votubia. Caution should therefore be exercised with the use of Votubia in the peri-surgical period. Lactose Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction 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 Table 2 below. 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. Table 2 Effects of other active substances on 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 Cmax 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 section 4.4). 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 section 4.4). Vaccinations The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with Votubia. The use of live vaccines should be avoided during treatment with Votubia. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines. 4.6 Fertility, pregnancy and lactation 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 section 5.3). 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 breast milk. However, in rats, everolimus and/or its metabolites readily pass into the milk (see section 5.3). Therefore, women taking everolimus should not breast-feed. Fertility The potential for everolimus to cause infertility in male and female patients is unknown, however secondary amenorrhoea and associated luteinising hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients (see also section 5.3 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 section 5.3). 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with Votubia. 4.8 Undesirable effects Summary of the safety profile Two randomised, double-blind, placebo-controlled pivotal phase III studies and a phase II study contribute to the safety profile of Votubia. • 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 Votubia and 45.0 weeks (range 9 to 115) for those receiving placebo. No difference was evident between the two arms as regards the proportion of patients who discontinued because of ADRs (2.5% on everolimus versus 2.6% on placebo). • 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 Votubia and 46.6 weeks (range 14 to 88) for those receiving placebo. No patients discontinued study drug because of ADRs. • CRAD001C2485: This was a prospective, open-label, single-arm phase II study of everolimus in patients with SEGA (n=28). At the last cut-off, 16 of the 28 SEGA patients had been exposed to everolimus for ≥45 months. The most frequent adverse reactions (incidence ≥1/10 and suspected by the investigator to be related to treatment) from the pooled safety data are (in decreasing order): stomatitis, upper respiratory tract infections and hypercholesterolaemia. The most frequent grade 3-4 adverse reactions (incidence ≥1%) were stomatitis, neutropenia, amenorrhoea and gastroenteritis viral. The grades follow CTCAE Version 3.0. Tabulated summary of adverse reactions Table 3 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. Table 3 Adverse reactions reported in TSC studies
In clinical studies, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an expected reaction 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 section 4.4). In clinical studies, everolimus has been associated with haemorrhage events. On rare occasions, fatal outcomes were observed in the oncology setting (see section 4.4). No serious cases of renal haemorrhage were reported in the TSC setting. 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. Paediatric population 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 phase III study, frequency, type 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, especially in children below the age of 3 years. Older people In the oncology safety pooling, 37% of the patients treated with everolimus were ≥65 years of age. The number of patients with an adverse reaction leading to discontinuation of everolimus was higher in patients ≥65 years of age (23% vs. 14%). The most common adverse reactions leading to discontinuation were pneumonitis, fatigue, dyspnoea, and stomatitis. 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose 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. It is essential to assess everolimus blood levels in cases of suspected overdose. General supportive measures should be initiated in all cases of 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. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein kinase inhibitors, ATC code: L01XE10 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 can reduce levels of vascular endothelial growth factor (VEGF). In patients with TSC, treatment with everolimus increases VEGF-A and decreases VEGF-D levels. 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. 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 tuberous sclerosis complex syndrome, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body. TSC1 mutations account for 20–25% of all mutations identified, and TSC2 mutations account for the remainder. In a mouse neuronal model of TSC in which TSC1 is ablated in most neurons during cortical development, everolimus improved median survival from 33 days to more than 100 days, and behaviour, phenotype, and weight gain all also markedly improved. There was brain penetration, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream marker of mTORC1. Neurofilament abnormalities, myelination and cell enlargement were all improved by the treatment, although dysplastic neuronal features persisted, and there were only modest changes in dendritic spine density and length. Strikingly, mice treated with everolimus for 23 days only (postnatal days 7–30) displayed a persistent improvement in phenotype, with median survival of 78 days. In summary, everolimus is a highly effective therapy for this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 and Akt signalling and, consequently, cell size and myelination. Although caution is appropriate, the results suggest the possibility that everolimus may have benefit in the treatment of TSC brain disease, including infantile spasms. Clinical efficacy and safety Renal angiomyolipoma associated with TSC EXIST-2 (study CRAD001M2302), a randomised, controlled phase III study was conducted to evaluate the efficacy and safety of Votubia 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 antiepileptic drugs (EIAEDs) 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 Votubia 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 response rates of 41.8% (95% CI: 30.8, 53.4) for the Votubia arm compared with 0% (95% CI: 0.0, 9.0) for the placebo arm (p<0.0001) (Table 4). Table 4 EXIST-2 - Angiomyolipoma response
Angiomyolipoma shrinkage was evident within the initial 12 weeks of treatment with Votubia: 75.7% of patients had ≥30% reductions and 41.9% had ≥50% reductions at the time of the first radiological evaluation. Sustained responses were evident at subsequent timepoints: at Week 24, 80.3% of patients had ≥30% reductions and 54.9% had ≥50% reductions. 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. Skin lesion response rates of 26.0% (95% CI: 16.6, 37.2) for the Votubia arm and 0% (95% CI: 0.0, 9.5) for the placebo arm were observed (p=0.0002). Further clinical benefit, such as improvement in disease-related symptoms or reduction of serious risks, has not been demonstrated. Post-hoc sub-group analysis of EXIST-2 (study CRAD001M2302) demonstrated that angiomyolipoma response rate is reduced below the threshold of 5 ng/ml (Table 5). Table 5 EXIST-2 - Angiomyolipoma response rates by time-averaged Cmin category
Phase III study in SEGA patients EXIST-1 (Study CRAD001M2301), a randomised, double-blind, multicentre phase III study of Votubia versus placebo, was conducted in patients with SEGA, irrespective of age. Patients were randomised in a 2:1 ratio to receive either Votubia 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 antiepileptic drugs (EIAEDs) 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 Votubia 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 Votubia 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 angiomyolipomas (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 Votubia and 8.3 months (range: 3.2 to 18.3) for those receiving placebo. Results showed that Votubia 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 Votubia arm compared with 0% (95% CI: 0.0, 9.0) for the placebo arm (Table 6). In addition, all 8 patients on the Votubia arm who had radiographic evidence of hydrocephalus at baseline had a decrease in ventricular volume and no patient required surgical intervention during the course of this study. Table 6 EXIST-1 – SEGA response
2 SEGA responses were confirmed with a repeat scan. Response was defined as: ≥50% reduction in the sum of SEGA volume relative to baseline, plus no unequivocal worsening of non-target SEGA lesions, plus absence of new SEGA ≥1 cm in longest diameter, plus no new or worsening hydrocephalus Consistent treatment effects were observed across all subgroups evaluated (i.e. EIAED use versus EIAED non-use, sex and age). SEGA shrinkage was evident within the initial 12 weeks of Votubia treatment: 73.0% of patients had ≥30% reductions and 29.7% had ≥50% reductions at the time of the first radiological evaluation (week 12). Sustained reductions were evident at subsequent timepoints: at week 24, 78.4% of patients had ≥30% reductions and 41.9% had ≥50% reductions. 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 Votubia arm and 85.7% for the placebo arm. Votubia 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 Votubia arm and 10.5% (95% CI: 2.9, 24.8) for the placebo arm. 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 Votubia 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 Votubia; 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 7]). No patient developed new lesions, worsening hydrocephalus or increased intracranial pressure, and none required surgical resection or other therapy for SEGA. Table 7 Change in primary SEGA volume over time
− 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 within 3 months and treatment was restarted. Long-term follow-up to a median duration of 45.7 months (range: 4.7 to 58.5) demonstrated sustained efficacy. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Votubia in all subsets of the paediatric population in angiomyolipoma (see section 4.2 for information on paediatric use). Other information This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary. 5.2 Pharmacokinetic properties Absorption In patients with advanced solid tumours, peak everolimus concentrations (Cmax) 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. Cmax 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 Votubia 10 mg (as measured by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post absorption phase concentration-time profile. Relative bioavailability/bioequivalence In a relative bioavailability study, AUC0-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 Cmax of 5 x 1 mg everolimus tablets in suspension was 72% of 5 x 1 mg intact everolimus tablets. In a bioequivalence study, AUC0-inf of the 5 mg dispersible tablet when administered as suspension in water was equivalent to 5 x 1 mg intact everolimus tablets, and Cmax 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 of cancer patients given Votubia 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, Vd was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment. Nonclinical studies in rats indicate: • 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 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 AUC0- was dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within two weeks. Cmax is dose-proportional between 5 and 10 mg. tmax occurs at 1 to 2 hours post-dose. There was a significant correlation between AUC0- and pre-dose trough concentration at steady-state. Special populations Hepatic impairment The safety, tolerability and pharmacokinetics of Votubia were evaluated in two single oral dose studies of Votubia 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. AUC0-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 sections 4.2 and 4.4). 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 In patients with SEGA, everolimus Cmin 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 Cmin 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. 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. 5.3 Preclinical safety data The non-clinical 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 AUC0-24h 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. 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. The potential for growth/developmental delays with long-term treatment in SEGA patients is unknown. 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 4.3 and 0.2 times the estimated clinical exposure. 6. Pharmaceutical particulars 6.1 List of excipients Butylated hydroxytoluene (E321) Magnesium stearate Lactose monohydrate Hypromellose Crospovidone type A Lactose anhydrous 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 25°C. Store in the original package in order to protect from light and moisture. 6.5 Nature and contents of container Aluminium/polyamide/aluminium/PVC blister containing 10 tablets. Packs containing 10, 30 or 100 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling 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. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 8. Marketing authorisation number(s) EU/1/11/710/006-008 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 02 September 2011 Date of latest renewal: 06 September 2013 10. Date of revision of the text 19 June 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
依维莫司片|Votubia（everolimus Tablets）简介：
英文药名：Votubia（everolimus Tablets）
中文药名：依维莫司片
生产厂家：诺华(Novartis)药品介绍2012年11月5日，欧盟委员会（EC）已批准Votubia（everolimus，依维莫司，在美国商品名为Afinitor ） ... 责任编辑：admin |
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