2014年9月10日，新型磷酸盐结合剂Velphoro（sucroferric oxyhydroxide）已获FDA批准，用于治疗慢性肾脏病（CKD）透析患者的高磷血症（hyperphosphatemia），以控制其血清磷水平。 Velphoro（以前称为PA21）是一种铁基（iron-based）、无钙、可咀嚼的磷酸盐结合剂，该药的获批，为接受透析治疗的慢性肾脏病（CKD）患者控制其血清磷水平提供了一种新的有效的治疗选择，该药将于2014年在美国上市。 Velphoro的获批，是基于一项关键性III期临床试验的结果。该项研究在正接受透析治疗的慢性肾脏病（CKD）患者中开展，研究结果表明，与标准的护理药物碳酸司维拉姆（sevelamer carbonate）相比，Velphoro以较少的药丸数量，成功地控制了患者的高磷血症，52周后，用于控制高磷血症的平均每天剂量仅为3.3粒/天，达到了研究的主要和次要终点。 高磷血症（hyperphosphatemia）是指血液中磷水平的异常升高，是正在接受透析治疗的慢性肾脏病（CKD）患者中一种常见且严重的疾病。大多数透析患者需接受磷酸盐结合剂治疗。 然而，尽管目前已有多种不同的磷酸盐结合剂可用，但高达50%的患者仍无法达到并维持其目标血清磷水平。在一些患者中，因高的服药负担导致的非依从性（non-compliance）和较差的耐受性，似乎是导致血清磷水平控制不足的关键因素。平均而言，透析患者每天需服约19粒药物，而磷酸盐结合剂占到了其中的约50%。而Velphoro的推荐起始剂量仅为每日3片（每餐1片）。 目前，Velphoro在欧盟、瑞士、新加坡的监管审查正在进行中，预计将于2014年上半年得出审查决定。进一步的监管申请正在准备中。 Velphoro 500mg chewable tablets(Sucroferric Oxyhydroxide)之前也叫作PA21 1. Name of the medicinal product Velphoro 500 mg chewable tablets 2. Qualitative and quantitative composition Each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide also known as a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. The active ingredient sucroferric oxyhydroxide contains 750 mg sucrose and 700 mg starches. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Chewable tablet. Brown, circular tablets embossed with PA500 on one side. Tablets have a 20 mm diameter and a thickness of 6.5 mm. 4. Clinical particulars 4.1 Therapeutic indications Velphoro is indicated for the control of serum phosphorus levels in adult chronic kidney disease (CKD) patients on haemodialysis (HD) or peritoneal dialysis (PD). Velphoro should be used within the context of a multiple therapeutic approach, which could include calcium supplement, 1,25-dihydroxy vitamin D3 or one of its analogues, or calcimimetics to control the development of renal bone disease. 4.2 Posology and method of administration Posology Starting dose The recommended starting dose of Velphoro is 1,500 mg iron (3 tablets) per day, divided across the meals of the day. Velphoro is for oral administration only and must be taken with meals. Patients receiving Velphoro should adhere to their prescribed diets. Titration and maintenance Serum phosphorus levels must be monitored and the dose of Velphoro up or down titrated in increments of 500 mg iron (1 tablet) per day every 2-4 weeks until an acceptable serum phosphorus level is reached, with regular monitoring afterwards. In clinical practice, treatment will be based on the need to control serum phosphorus levels, though patients who respond to Velphoro therapy usually achieve optimal serum phosphorus levels at doses of 1,500 mg-2,000 mg iron per day (3 to 4 tablets). If one or more doses are missed, the normal dose of the medicinal product should be resumed with the next meal. Maximum tolerated daily dose The maximum recommended dose is 3,000 mg iron (6 tablets) per day. Paediatric population The safety and efficacy of Velphoro in children below the age of 18 years has not yet been established. No data are available. Elderly population (≥65 years of age) Velphoro has been administered to over 245 seniors (≥65 years of age) according to the approved dosing regimen. Of the total number of subjects in clinical studies of Velphoro, 29.7 % were aged 65 and over, while 8.7% were aged 75 and over. No special dose and administration guidelines were applied to seniors in these studies and the dosing schedules were not associated with any significant concerns. Renal impairment Velphoro is indicated for the control of serum phosphorus levels in adult CKD patients on HD or PD. There is no clinical data available with Velphoro in patients with earlier stages of renal impairment. Hepatic impairment Generally, patients with severe hepatic impairment were excluded from participating in clinical studies with Velphoro. However, no evidence of hepatic impairment or significant alteration of hepatic enzymes were observed in the clinical studies with Velphoro. Method of administration Oral use. Velphoro is a chewable tablet that must be taken with meals. In order to maximise the adsorption of dietary phosphate, the total daily dose should be divided across the meals of the day. Patients are not required to drink more fluid than they normally would. Tablets must be chewed and not swallowed whole; tablets may be crushed. 4.3 Contraindications • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Haemochromatosis and any other iron accumulation disorders. 4.4 Special warnings and precautions for use Peritonitis, gastric and hepatic disorders and gastrointestinal surgery Patients with a recent history of peritonitis (within the last 3 months), significant gastric or hepatic disorders and patients with major gastrointestinal surgery have not been included in clinical studies with Velphoro. Velphoro should only be used in these patients following careful assessment of benefit/risk. Information about sucrose and starches (carbohydrates) Velphoro contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. May be harmful to the teeth. Velphoro contains starches. Patients with allergy to gluten or diabetics should take notice that one tablet of Velphoro is equivalent to 0.116 bread units (equivalent to approximately 1.4 g of carbohydrates). Discoloured stool Velphoro can cause discoloured (black) stool. Discoloured (black) stool may visually mask gastrointestinal bleeding (see section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction Velphoro is almost not absorbed from the gastrointestinal tract. Although the potential for interactions with medicinal products seems low, for concomitant treatment with medicinal products with a narrow therapeutic window, the clinical effect and adverse events should be monitored, on initiation or dose-adjustment of either Velphoro or the concomitant medicinal product, or the physician should consider measuring blood levels. When administering any medicinal product that is already known to interact with iron (like alendronate and doxycycline) or has the potential to interact with Velphoro based only on in vitro studies like cephalexin, levothyroxine, doxercalciferol and paricalcitol, the medicinal product should be administered at least one hour before or two hours after Velphoro. In vitro studies with the following active substances did not show any relevant interaction: cinacalcet, ciprofloxacin, clopidogrel, enalapril, hydrochlorothiazide, metformin, metoprolol, nifedipine, pioglitazone and quinidine. Drug-drug interaction studies have only been performed in healthy volunteers. They have been conducted in healthy human male and female subjects with losartan, furosemide, digoxin, warfarin, and omeprazole. Concomitant administration of Velphoro did not affect the bioavailability of these medicinal products as measured by the area under the curve (AUC). Data from clinical studies have shown that Velphoro does not affect the lipid lowering effects of HMG-CoA reductase inhibitors (e.g., atorvastatin and simvastatin). Vitamin D and 1,25-dihydroxy Vitamin D levels remained unchanged. Velphoro does not affect guaiac based (Haemoccult) or immunological based (iColo Rectal and Hexagon Obti) faecal occult blood tests. 4.6 Fertility, pregnancy and lactation Pregnancy There are no available clinical data from the use of sucroferric oxyhydroxide on exposed human pregnancies. Reproductive and developmental toxicity studies in animals revealed no risk with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see section 5.3). Velphoro should only be used by pregnant women if clearly needed following careful assessment of benefit/risk. Breast-feeding There are no available clinical data from the use of Velphoro in breast-feeding women. Since absorption of iron from Velphoro is minimal (see section 5.2), excretion of iron from Velphoro in breast milk is unlikely. A decision on whether to continue breast-feeding or to continue therapy with Velphoro should be made taking into account the benefit of breast-feeding to the child and the benefit of Velphoro therapy to the mother. Fertility There are no data on the effect of Velphoro on fertility in humans. In animal studies, there were no adverse effects on mating performance, fertility, and litter parameters following treatment with Velphoro (see section 5.3). 4.7 Effects on ability to drive and use machines Velphoro has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The current safety profile of Velphoro is based on a total of 778 patients on haemodialysis and 57 patients on peritoneal dialysis, who received Velphoro treatment of up to 55 weeks. In these clinical trials, approximately 43% of patients experienced at least one adverse reaction during Velphoro treatment, which were reported as serious adverse reactions in 0.36%. The majority of the adverse drug reactions (ADRs) reported from trials were gastrointestinal disorders, with the most frequently reported ADRs being diarrhoea and discoloured faeces (very common). The vast majority of these gastrointestinal disorders occurred early during treatment and abated with time with continued dosing. No dose-dependent trends were observed in the ADR profile of Velphoro. Tabulated list of adverse reactions ADRs reported from the use of Velphoro at doses from 250 mg iron/day to 3,000 mg iron/day in these patients (n=835) are listed in Table 1. Table 1 Adverse drug reactions detected in clinical trials System Organ Class Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Metabolism and nutrition disorders     Hypercalcaemia Hypocalcaemia Nervous system disorders     Headache Respiratory, thoracic and mediastinal disorders     Dyspnoea Gastrointestinal disorders Diarrhoea* Discoloured faeces Nausea Constipation Vomiting Dyspepsia Abdominal pain Flatulence Tooth discolouration Abdominal distension Gastritis Abdominal discomfort Dysphagia Gastro-oesophageal reflux disease (GORD) Tongue discolouration Skin and subcutaneous tissue disorders     Pruritus Rash General disorders and administration site conditions   Product taste abnormal Fatigue Description of selected adverse reactions *Diarrhoea Diarrhoea occurred in 11.6% of patients in clinical trials. In the 55 weeks long term studies, the majority of these treatment-related diarrhoea adverse events were transient, occurred early during treatment initiation and led to treatment discontinuation in 3.1% of the patients. 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 4.9 Overdose Any instances of overdose of Velphoro should be treated by standard clinical practice. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphataemia; ATC code: V03AE05 Mechanism of action Velphoro contains a mixture of polynuclear iron(III)-oxyhydroxide (pn-FeOOH), sucrose and starches. Phosphate binding takes place by ligand exchange between hydroxyl groups and/or water and the phosphate ions throughout the physiological pH range of the gastrointestinal tract. Serum phosphorus levels are reduced as a consequence of the reduced dietary phosphate absorption. Clinical efficacy One phase 3 clinical study has been performed in patients with CKD on dialysis to investigate the efficacy and safety of Velphoro in this population. This study was an open-label, randomised, active-controlled (sevelamer carbonate), parallel group study for up to 55 weeks. Adult patients with hyperphosphataemia (serum phosphorus levels ≥1.94 mmol/L) were treated with Velphoro at a starting dose of 1,000 mg iron/day followed by an 8-week dose titration period. Non-inferiority to sevelamer carbonate was determined at week 12. Subjects were continued on their study medication from week 12 to week 55. From week 12 to 24, dose titrations were allowed for both tolerability and efficacy reasons. Treatment of patient sub-populations from week 24 to week 27 with maintenance dose of Velphoro (1,000 to 3,000 mg iron/day) or low dose (250 mg iron/day) of Velphoro demonstrated superiority of the maintenance dose. In Study-05A, 1,055 patients on hemodialysis (N=968) or peritoneal dialysis (N=87) with serum phosphorus ≥1.94 mmol/L following a 2-4 week phosphate binder washout period, were randomized and treated with either Velphoro, at a starting dose of 1,000 mg/day (N=707), or active-control (sevelamer carbonate, N=348) for 24 weeks. At the end of week 24, 93 patients on hemodialysis whose serum phosphorus levels were controlled (<1.78 mmol/L) with Velphoro in the first part of the study, were re-randomized to continue treatment with either their week 24 maintenance dose (N=44 or a non-effective low dose control 250 mg/day, N=49) of Velphoro for a further 3 weeks. Following completion of Study-05A, 658 patients (597 on hemodialysis and 61 on peritoneal dialysis) were treated in the 28-week extension study (Study-05B) with either Velphoro (N=391) or sevelamer carbonate (N=267) according to their original randomization. Mean serum phosphorus levels were 2.5 mmol/L at baseline and 1.8 mmol/L at week 12 for Velphoro (reduction by 0.7 mmol/L). Corresponding levels for sevelamer carbonate at baseline were 2.4 mmol/L and 1.7 mmol/L at week 12 (reduction by 0.7 mmol/L), respectively. The serum phosphorus reduction was maintained over 55 weeks. Serum phosphorus levels and calcium-phosphorus product levels were reduced as a consequence of the reduced dietary phosphate absorption. The response rates, defined as the proportion of subjects achieving serum phosphorus levels within the KDOQI (Kidney Disease Outcomes Quality Initiative) recommended range were 45.3% and 59.1% at week 12 and 51.9% and 55.2% at week 52, for Velphoro and sevelamer carbonate, respectively. The mean daily dose of Velphoro over 55 weeks of treatment was 1,650 mg iron and the mean daily dose of sevelamer carbonate was 6,960 mg. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Velphoro in one or more subsets of the paediatric population in the treatment of hyperphosphataemia (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Velphoro works by binding phosphate in the gastrointestinal tract and thus the serum concentration is not relevant for its efficacy. Due to the insolubility and degradation characteristics of Velphoro, no classical pharmacokinetic studies can be carried out, e.g., determination of the distribution volume, area under the curve, mean residence time, etc. In 2 Phase 1 studies, it was concluded that the potential for iron overload is minimal and no dose-dependent effects were observed in healthy volunteers. Absorption The active moiety of Velphoro, pn-FeOOH, is practically insoluble and therefore not absorbed. Its degradation product, mononuclear iron species, can however be released from the surface of pn-FeOOH and be absorbed. The absolute absorption studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that systemic absorption was very low (≤1% of the administered dose). The iron uptake from radiolabelled Velphoro drug substance, 2,000 mg in 1 day was investigated in 16 CKD patients (8 pre-dialysis and 8 haemodialysis patients) and 8 healthy volunteers with low iron stores (serum ferritin <100 mcg/L). In healthy subjects, the median uptake of radiolabelled iron in the blood was estimated to be 0.43% (range 0.16 – 1.25%) on Day 21, in pre-dialysis patients 0.06% (range 0.008 – 0.44%) and in haemodialysis patients 0.02% (range 0 – 0.04%). Blood levels of radiolabelled iron were very low and confined to the erythrocytes. Distribution The distribution studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that pn-FeOOH is distributed from the plasma to the liver, spleen and bone marrow, and utilized by incorporation into red blood cells. In patients, absorbed iron is expected to be also distributed to the target organs, i.e. liver, spleen and bone marrow, and utilized by incorporation into red blood cells. Biotransformation The active moiety of Velphoro, pn-FeOOH, is not metabolised. However, the degradation product of Velphoro, mononuclear iron species, can be released from the surface of polynuclear iron(III)-oxyhydroxide and be absorbed. Clinical studies have demonstrated that the systemic absorption of iron from Velphoro is low. In vitro data suggest that the sucrose and starch components of the drug substance can be digested to glucose and fructose, and maltose and glucose, respectively. These compounds can be absorbed in the blood. Elimination In animal studies with rats and dogs administered 59Fe-Velphoro drug substance orally, radiolabelled iron was recovered in the faeces but not the urine. 5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Effects seen in the rabbit embryo-foetal development toxicity study (skeletal variations and incomplete ossificaton) are related to exaggerated pharmacology, and likely not relevant for patients. Other reproduction toxicity studies showed no adverse effects. Carcinogenicity studies were performed in mice and rats. There was no clear evidence of a carcinogenic effect in mice. Mucosal hyperplasia, with diverticulum/cyst formation was observed in the colon and caecum of mice after 2 years treatment, but this was considered a species-specific effect with no diverticula/cysts seen in long term studies in rats or dogs. In rats, there was a slightly increased incidence of benign C-cell adenoma in the thyroid of male rats given the highest dose of sucroferric oxyhydroxide. This is thought to be most likely an adaptive response to the pharmacological effect of the drug, and not clinically relevant. 6. Pharmaceutical particulars 6.1 List of excipients Woodberry flavour Neohesperidin-dihydrochalcone Magnesium stearate Colloidal anhydrous silica 6.2 Incompatibilities Not applicable. 6.3 Shelf life 30months Shelf life after first opening of the bottle: 45 days 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container High density polyethylene (HDPE) bottle with child-resistant polypropylene closure and foil induction seal, containing a molecular sieve desiccant and cotton. Pack sizes of 30 or 90 chewable tablets. Child-resistant aluminium/aluminium blister, each blister containing 6 chewable tablets. Pack sizes of 30 or 90 chewable tablets (multipack containing 3 individual packs of 30 chewable tablets each). Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Vifor Fresenius Medical Care Renal Pharma France 7-13 Boulevard Paul-Emile Victor 92521 Neuilly-sur-Seine France 8. Marketing authorisation number(s) EU/1/14/943/001 EU/1/14/943/002 EU/1/14/943/003 EU/1/14/943/004 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 26 August 2014. 10. Date of revision of the text Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 欧盟批准高磷血症药物Velphoro，将降低患者用药负担 欧盟批准了ViforFresenius Medical Care Renal制药公司的高磷血症药物Velphoro。Velphoro(Sucroferric Oxyhydroxide)之前也叫作PA21，该药物在欧盟的获批基于其III期临床试验数据，数据显示这款药物能控制血液中磷的蓄积。与目前慢性肾病透析患者的标准治疗药物即赛诺菲旗下的Renvela（sevelamercarbonate），其用药负担更低。 透析患者平均每天要服用19片药物，磷酸盐结合剂能占这些药物中大约50%。Velphoro所推荐的起始用药剂量是每天三片（即每餐一片），所以提高了很多这款药物的依从性。 Velphoro由瑞士Vifor制药公司开发，其所有权利在2011年被转移给了Vifor Fresenius Medical Care Renal制药。于2013年11月，这款药物在美国获批并由Fresenius Medical Care North America公司于2014年3月份在美国投放市场。 ---------------------------------------------- 产地国家: 美国 原产地英文商品名: Velphoro 500mg chewable tablets 90 tabs 原产地英文药品名: SUCROFERRIC OXYHYDROXIDE 中文参考商品译名: Velphoro咀嚼片 500毫克/片 90片/盒 中文参考药品译名: 羥基氧化蔗糖鐵 生产厂家英文名: VIFOR FRESENIUS ---------------------------------------------- 产地国家: 英国 原产地英文商品名: Velphoro 500mg chewable tablets 90tabs 原产地英文药品名: SUCROFERRIC OXYHYDROXIDE 中文参考商品译名: Velphoro咀嚼片 500毫克/片 90片/盒 中文参考药品译名: 羥基氧化蔗糖鐵 生产厂家英文名: VIFOR FRESENIUS ---------------------------------------------- 产地国家: 英国 原产地英文商品名: Velphoro 500mg chewable tablets 30tabs 原产地英文药品名: SUCROFERRIC OXYHYDROXIDE 中文参考商品译名: Velphoro咀嚼片 500毫克/片 30片/盒 中文参考药品译名: 羥基氧化蔗糖鐵 生产厂家英文名: VIFOR FRESENIUS