抗肿瘤药长春氟宁(vinflunine) Javlor 25 mg/ml concentrate for solution for infusion Javlor 25 mg/mL concentrate for solution for infusion
Dose adjustments due to toxicity Table 2: Dose adjustments due to toxicity
*National Cancer Institute, Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0)
*National Cancer Institute, Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0) 1 NCI CTC Grade 2 constipation is defined as requiring laxatives, Grade 3 as an obstipation requiring manual evacuation or enema, Grade 4 as an obstruction or toxic megacolon. Mucositis Grade 2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as “life-threatening”. 2 NCI CTC Grade 3 nausea is defined as no significant intake, requiring intravenous fluids. Grade 3 vomiting as ≥ 6 episodes in 24 hours over pretreatment; or need for intravenous fluids. Paediatric population There is no relevant use of Javlor in the paediatric population. Method of administration Precautions to be taken before handling or administering the medicinal product Javlor must be diluted prior to administration. Javlor is for single use only. For instructions on dilution of the medicinal product before administration, see section 6.6. Javlor MUST ONLY be administered intravenously. Javlor should be administered by a 20-minute intravenous infusion and NOT be given by rapid intravenous bolus. Either peripheral lines or a central catheter can be used for vinflunine administration. When infused through a peripheral vein, vinflunine can induce venous irritation (see section 4.4). In case of small or sclerosed veins, lymphoedema or recent venipuncture of the same vein, the use of a central catheter may be preferred. To avoid extravasations it is important to be sure that the needle is correctly introduced before starting the infusion. In order to flush the vein, administration of diluted Javlor should always be followed by at least an equal volume of sodium chloride 9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion. For detailed instructions on administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or other vinca alkaloids. Recent (within 2 weeks) or current severe infection. Baseline ANC < 1,500/mm3 for the first administration, baseline ANC < 1,000/mm3 for subsequent administrations (see section 4.4). Platelets < 100,000/mm3(see section 4.4). Breast-feeding (see section 4.6). 4.4 Special warnings and precautions for use Hematological toxicity Neutropenia, leucopenia, anaemia and thrombocytopenia are frequent adverse reactions of vinflunine. Adequate monitoring of complete blood counts should be conducted to verify the ANC, platelet and haemoglobin values before each vinflunine infusion (see section 4.3). Initiation of vinflunine is contraindicated in subjects with baseline ANC < 1,500/mm3 or platelets < 100,000/mm3. For subsequent administrations, vinflunine is contraindicated in subjects with baseline ANC < 1,000/mm3 or platelets < 100,000/mm3. The recommended dose should be reduced in patients with haematological toxicity (see section 4.2). Gastrointestinal disorders Grade ≥ 3 constipation occurred in 15.3% of treated patients. NCI CTC Grade 3 constipation is defined as an obstipation requiring manual evacuation or enema, Grade 4 constipation as an obstruction or toxic megacolon. Constipation is reversible and can be prevented by special dietary measures such as oral hydration and fibre intake, and by administration of laxatives such as stimulant laxatives or faecal softners from day 1 to day 5 or 7 of the treatment cycle. Patients at high risk of constipation (concomitant treatment with opiates, peritoneal carcinomas, abdominal masses, prior major abdominal surgery) should be medicated with an osmotic laxative from day 1 to day 7 administered once a day in the morning before breakfast. In case of Grade 2 constipation, defined as requiring laxatives, for 5 days or more or Grade ≥ 3 of any duration, the dose of vinflunine should be adjusted (see section 4.2). In case of any Grade ≥ 3 gastrointestinal toxicity (except vomiting or nausea) or of mucositis (Grade 2 for 5 days or more or Grade ≥ 3 of any duration) dose adjustment is required. Grade 2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as “life-threatening” (see Table 2 in section 4.2). Cardiac disorders Few QT interval prolongations have been observed after the administration of vinflunine. This effect may lead to an increased risk of ventricular arrhythmias although no ventricular arrhythmias were observed with vinflunine. Nevertheless, vinflunine should be used with caution in patients with increase of the proarrhythmic risk (e.g. congestive heart failure, known history of QT interval prolongation, hypokalaemia) (see section 4.8). The concomittant use of two or more QT/QTc interval prolonging substances is not recommended (see section 4.5). Special attention is recommended when vinflunine is administered to patients with prior history of myocardial infarction/ischaemia or angina pectoris (see section 4.8). Ischaemic cardiac events may occur, especially in patients who have underlying cardiac disease. Thus, patients receiving Javlor should be vigilantly monitored by physicians for the occurrence of cardiac events. Caution should be exercised in patients with a history of cardiac disease and the benefit / risk assessment should be carefully evaluated regularly. Discontinuation of vinflunine should be considered in patients who develop cardiac ischaemia. Posterior Reversible Encephalopathy Syndrome (PRES) Cases of PRES have been observed after administration of vinflunine. The typical clinical symptoms are, with various degrees: neurological (headache, confusion, seizure, visual disorders), systemic (hypertension), and gastrointestinal (nausea, vomiting). Radiological signs are white matter abnormalities in the posterior regions of the brain. Blood pressure should be controlled in patients developing symptoms of PRES. To confirm the diagnosis, brain imaging is recommended. Clinical and radiological features usually resolved rapidly without sequelae after treatment discontinuation. Discontinuation of vinflunine should be considered in patients who develop neurological signs of PRES (see section 4.8). Hepatic impairment The recommended dose should be reduced in patients with hepatic impairment (see section 4.2). Renal impairment The recommended dose should be reduced in patients with moderate or severe renal impairment (see section 4.2). Elderly patients (≥ 75 years) The recommended dose should be reduced in patients 75 years old and beyond (see section 4.2). Interactions The concomitant use of potent inhibitors or potent inducers of CYP3A4 with vinflunine should be avoided (see section 4.5). Administration Intrathecal administration of Javlor may be fatal. When infused through a peripheral vein, vinflunine can induce Grade 1 (22% of the patients, 14.1% of the cycles), Grade 2 (11.0% of the patients, 6.8% of the cycles) or Grade 3 (0.8% of the patients, 0.2% of the cycles) venous irritation. All cases resolved rapidly without treatment discontinuation. Instructions for administration should be followed as described in section 6.6. Contraception Men and women with reproductive potential must use an effective method of contraception during the treatment and up to 3 months after the last vinflunine administration (see section 4.6). 4.5 Interaction with other medicinal products and other forms of interactionIn vitro studies showed that vinflunine had neither inducing effects on CYP1A2, CYP2B6 or CYP3A4 activity nor inhibition effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. In vitro studies showed that vinflunine is a Pgp-substrate like other vinca alkaloids, but with a lower affinity. Therefore, risks of clinically significant interactions should be unlikely. No pharmacokinetic interaction was observed in patients when vinflunine was combined with either cisplatin, carboplatin, capecitabine or gemcitabine. No pharmacokinetic interaction was observed in patients when vinflunine was combined with doxorubicin. However, this combination was associated with a particularly high risk of haematological toxicity. A phase I study evaluating the effect of ketoconazole treatment (a potent CYP3A4 inhibitor) on vinflunine pharmacokinetics indicated that co-administration of ketoconazole (400 mg orally once daily for 8 days) resulted in a 30% and 50% increase in blood exposures to vinflunine and its metabolite 4Odeacetyl-vinflunine (DVFL), respectively. Therefore the concomitant use of vinflunine and potent CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole and grapefruit juice) or inducers (such as rifampicin and Hypericum perforatum (St John's wort)) should be avoided since they may increase or decrease vinflunine and DVFL concentrations (see section 4.4 and 5.2). The concomitant use of vinflunine with others QT/QTc interval prolonging medicinal products should be avoided (see section 4.4). A pharmacokinetic interaction between vinflunine and pegylated/liposomal doxorubicin was observed, resulting in a 15% to 30% apparent increase in vinflunine exposure and a 2 to 3-fold apparent decrease of doxorubicin AUC, whereas for doxorubicinol, the concentrations of the metabolite were not affected. According to an in vitro study, such changes could be related to adsorption of vinflunine on the liposomes and a modified blood distribution of both compounds. Therefore, caution should be excercised when this type of combination is used. A possible interaction with paclitaxel and docetaxel (CYP3 substrates) has been suggested from an in vitro study (slight inhibition of vinflunine metabolism). No specific clinical studies of vinflunine in combination with these compounds have been carried out yet. The concomitant use of opioids could enhance the risk of constipation. 4.6 Fertility, pregnancy and lactation Contraception in males and females Both male and female patients should take adequate contraceptive measures up to three months after the discontinuation of the therapy. Pregnancy There are no data available on the use of vinflunine in pregnant women. Studies in animals have shown embryotoxicity and teratogenicity (see section 5.3). On the basis of the results of animal studies and the pharmacological action of the medicinal product, there is a potential risk of embryonic and foetal abnormalities. Vinflunine should therefore not be used during pregnancy, unless it is strictly necessary. If pregnancy occurs during treatment, the patient should be informed about the risk for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered. Genetic counselling is also recommended for patients wishing to have children after therapy. Breast-feeding It is unknown whether vinflunine or its metabolites are excreted in human milk. Due to the possible very harmful effects on the infants, breast-feeding during treatment with vinflunine is contraindicated (see section 4.3). Fertility Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinflunine. 4.7 Effects on ability to drive and use machines Javlor may cause adverse reactions such as fatigue (very common) and dizziness (common) which may lead to a minor or moderate influence on the ability to drive and use machines..Patients should be advised not to drive or use machines if they experience any adverse reaction with a potential impact on the ability to perform these activities (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The most frequent treatment-related adverse reactions reported in the two phase II and one phase III trials in patients with transitional cell carcinoma of the urothelium (450 patients treated with vinflunine) were haematological disorders, mainly neutropenia and anaemia; gastrointestinal disorders, especially constipation, anorexia, nausea, stomatitis/mucositis, vomiting, abdominal pain and diarrhoea, and general disorders such as asthenia/fatigue. Tabulated list of adverse reactions Adverse reactions are listed below by System Organ Class, frequency and grade of severity (NCI CTC version 2.0). Frequency of adverse reactions is 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 available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 4 Adverse reactions observed in patients with transitional cell carcinoma of the urothelium treated with vinflunine
aadverse reactions reported from post-marketing experience bfrequency calculated on the basis of non-TCCU clinical trial Adverse reactions in all indications Adverse reactions occurring in patients with transitional cell carcinoma of the urothelium and in patients with other disease than this indication and potentially severe or adverse reactions that are a class effect of the vinca alkaloids are described below: Blood and lymphatic system disorders Grade 3/4 neutropenia was observed in 50.2% of patients. Severe anaemia and thrombocytopenia were less common (respectively 10.4and 3.5%).). Febrile neutropenia defined as ANC < 1,000/mm3and fever ≥ 38.5°C of unknown origin without clinically microbiologically documented infection (NCI CTC version 2.0) was observed in 5.3%of patients. Infection with Grade 3/4 neutropenia was observed in 3.3%of patients. Overall 7 patients (0.5% of the treated population) died from infection as a complication occurring during neutropenia. Gastrointestinal disorders Constipation is a class effect of the vinca alkaloids: 12% of patients experienced severe constipation during treatment with vinflunine. Grade 3/4 ileus reported in 1.8% of patients was reversible when managed by medical care. Constipation is managed by medical care (see section 4.4). Nervous system disorders Sensory peripheral neuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by 0.1% patients. All resolved during the study. Rare cases of Posterior Reversible Encephalopathy Syndrome have been reported (see section 4.4). Cardiovascular disorders Cardiac effects are a known class effect of the vinca alkaloids. Myocardial infarction or ischaemia were experienced by 0.6% of the patients and most of them had a pre-existing cardiovascular disease or risk factors. One patient died after myocardial infarction and another one due to a cardiopulmonary arrest. Few QT interval prolongations have been observed after the administration of vinflunine. Respiratory, thoracic and mediastinal disorders Dyspnoea occurred in 3.3% of the patients but was rarely severe (Grade 3/4: 1.2%). Bronchospam was reported in one patient treated with vinflunine for a different setting from the indication. 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: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland IMB Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie 4.9 Overdose The main toxic effect due to an overdose with vinflunine is bone marrow suppression with a risk of severe infection. There is no known antidote for vinflunine overdose. In case of overdose, the patient should be kept in a specialised unit and vital functions should be closely monitored. Other appropriate measures should be taken, such as blood transfusions, administration of antibiotics and growth factors. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antineoplasic agents, vinca alkaloids and analogues, ATC code: L01CA05 Mechanism of action Vinflunine binds to tubulin at or near to the vinca binding sites inhibiting its polymerisation into microtubules, which results in treadmilling suppression, disruption of microtubule dynamic, mitotic arrest and apoptosis. In vivo, vinflunine displays significant antitumor activity against a broad spectrum of human xenografts in mice both in terms of survival prolongation and tumour growth inhibition. Clinical efficacy and safety One phase III and two phase II trials support the use of Javlor for treatment of advanced or metastatic transitional cell carcinoma of the urothelium as second-line therapy after failure of a prior platinum-containing regimen. In the two multi-centre open-label, single-arm phase II clinical trials a total of 202 patients were treated with vinflunine. In the multi-centre, open-label controlled phase III clinical trial, 253 patients were randomised to treatment with vinflunine + BSC (best supportive care) and 117 patients to the BSC arm. The median overall survival was 6.9 months (vinflunine + BSC) vs. 4.6 months (BSC), but the difference did not reach statistical significance; hazard ratio 0.88 (95% CI 0.69, 1.12). However a statistically significant effect was seen on progression-free survival. Median PFS was 3.0 months (vinflunine + BSC) vs 1.5 months (BSC) (p=0.0012). In addition a pre-specified multivariate analysis performed on the ITT population demonstrated that vinflunine had a statistically significant treatment effect (p=0.036) on overall survival when prognostic factors (PS, visceral involvement, alkaline phosphatases, haemoglobin, pelvic irradiation) were taken into consideration; hazard ratio 0.77 (95% CI 0.61, 0.98). A statistically significant difference on overall survival (p=0.040) was also seen in the eligible population (which excluded 13 patients with clinically significant protocol violations at baseline who were not eligible for treatment); hazard ratio 0.78 (95% CI 0.61, 0.99). This is considered the most relevant population for the efficacy analysis, as it most closely reflects the population intended for treatment. Efficacy was demonstrated in both patients with or without prior cisplatin use. In the eligible population, the subgroup analyses according to the prior cisplatin use versus BSC on overall survival (OS) showed a HR (95% CI) = [0.64 (0.40 – 1.03); p=0.0821] in the absence of prior cisplatin, and a HR (95% CI) = [0.80 (0.60 – 1.06); p=0.1263] in the presence of prior cisplatin. When adjusted on prognostic factors, the analyses of OS in the subgroups of patients without or with prior cisplatin showed a HR (95% CI) = [0.53 (0.32 – 0.88); p=0.0143] and a HR (95% CI) = [0.70 (0.53 – 0.94); p=0.0174], respectively. In the subgroup analyses of prior cisplatin use versus BSC for progression free survival (PFS), the results were: HR (95% CI) = [0.55 (0.34 – 0.89); p=0.0129] in the absence of prior cisplatin, and a HR (95% CI) = [0.64 (0.48 – 0.85); p=0.0040] in the presence of prior cisplatin. When adjusted on prognostic factors, the analyses of PFS in the subgroups of patients without or with prior cisplatin showed a HR (95% CI) = [0.51(0.31 – 0.86); p=0.0111] and a HR (95% CI) = [0.63(0.48 – 0.84); p=0.0016], respectively. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Javlor in all subsets of the paediatric population in the treatment of ureter and bladder carcinoma and the treatment of breast carcinoma (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Vinflunine pharmacokinetics is linear in the range of administered doses (from 30 mg/m² to 400 mg/m2) in cancer patients. Blood exposure to vinflunine (AUC), significantly correlated with severity of leucopenia, neutropenia and fatigue. Distribution Vinflunine is moderately bound to human plasma proteins (67.2±1.1%) with a ratio between plasma and whole blood concentrations of 0.80±0.12. Protein binding mainly involves high density lipoproteins and serum albumin and is non-saturable on the range of vinflunine concentrations observed in patients. Binding to alpha-1 acid glycoprotein and to platelets is negligible (< 5%). The terminal volume of distribution is large, 2422±676 litres (about 35 l/kg) suggesting extensive distribution into tissues. Biotransformation All metabolites identified are formed by the cytochrome CYP3A4 isoenzyme, except for 4-O-deacetylvinflunine (DVFL), the only active metabolite and main metabolite in blood which is formed by multiple esterases. Elimination Vinflunine is eliminated following a multi-exponential concentration decay, with a terminal half-life (t1/2) close to 40 h. DVFL is slowly formed and more slowly eliminated than vinflunine (t1/2 of approximately 120 h). The excretion of vinflunine and its metabolites occurs through faeces (2/3) and urine (1/3). In a population pharmacokinetic analysis in 372 patients (656 pharmacokinetic profiles), the total blood clearance was 40 l/h with low inter and intra-individual variability (25% and 8%, respectively, expressed as coefficient of variation). Pharmacokinetics in special populations Hepatic impairment No modification of vinflunine and DVFL pharmacokinetics was observed in 25 patients presenting varying degrees of hepatic impairment, compared to patients with normal hepatic function. This was further confirmed by the population pharmacokinetic analysis (absence of relationship between vinflunine clearance and biology markers of hepatic impairment). However, dose adjustments are recommended in patients with liver impairment (see section 4.2). Renal impairment A pharmacokinetic phase I study was performed in 2 groups of patients with renal impairment classified according to the calculated creatinine clearance (CrCl) values: group 1 (n=13 patients) with moderate impairment (40 mL/min ≤ CrCl ≤ 60 mL/min) and group 2 (n=20 patients) with severe impairment (20 mL/min ≤ CrCl < 40 mL/min). The pharmacokinetic results of this study indicated a reduction of vinflunine clearance when CrCl is decreased. This is further confirmed by the population pharmacokinetic analysis (56 patients with CrCl between 20 mL/min and 60 mL/min), showing that vinflunine clearance is influenced by the creatinine clearance value (Cockcroft and Gault formula). Dose adjustments are recommended in patients with moderate and severe renal impairment (see section 4.2). Elderly (≥ 75 years) A pharmacokinetic phase I study of vinflunine was performed in elderly patients (n=46). Vinflunine doses were adjusted according to 3 age groups as shown below:
Vinflunine clearance was significantly decreased in patients ≥ 80 years old as compared to a control group of younger patients < 70 years. |
长春氟宁注射剂|Javlor(vinflunine)简介:
抗肿瘤药长春氟宁(vinflunine)商品名Javlor开发与上市厂商本品由法国Pierre Fabre公司研制,2010年5月在英国首次上市。适应证本品适用于含铂化疗失败的成人晚期或转移性泌尿道上皮移行细胞癌的治疗。药理 ... 责任编辑:admin |
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