Velphoro

Sucroferric oxyhydroxide.

Each chewable tablet contains: Sucroferric Oxyhydroxide 2.5 g (Equivalent to 500 mg elemental Iron).

Pharmacotherapeutic group: All other therapeutic products; drugs for treatment of hyperkalaemia and hyperphosphataemia. ATC code: V03AE05.
Pharmacology: Pharmacodynamics: Mechanism of action: Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (Velphoro) (1,000 to 3,000 mg iron/day) or low dose (250 mg iron/day) of Sucroferric Oxyhydroxide (Velphoro) demonstrated superiority of the maintenance dose.
In Study-05A, 1,055 patients on haemodialysis (N=968) or peritoneal dialysis (N=87) with serum phosphorus ≥1.94 mmol/L following a 2-4 week phosphate binder washout period, were randomised and treated with either Sucroferric Oxyhydroxide (Velphoro), at a starting dose of 1,000 mg iron/day (N=707), or active-control (sevelamer carbonate, N=348) for 24 weeks. At the end of week 24, 93 patients on haemodialysis whose serum phosphorus levels were controlled (<1.78 mmol/L) with Sucroferric Oxyhydroxide (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 iron/day, N=49) of Sucroferric Oxyhydroxide (Velphoro) for a further 3 weeks.
Following completion of Study-05A, 658 patients (597 on haemodialysis and 61 on peritoneal dialysis) were treated in the 28-week extension study (Study-05B) with either Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (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 Kidney Disease Outcomes Quality Initiative (KDOQI) recommended range were 45.3 % and 59.1 % at week 12 and 51.9 % and 55.2 % at week 52, for Sucroferric Oxyhydroxide (Velphoro) and sevelamer carbonate, respectively.
The mean daily dose of Sucroferric Oxyhydroxide (Velphoro) over 55 weeks of treatment was 1,650 mg iron and the mean daily dose of sevelamer carbonate was 6,960 mg.
Post-authorisation data: A prospective, non-interventional, post-authorisation safety study (VERIFIE) has been conducted, evaluating the short- and long-term (up to 36 months) safety and effectiveness of Velphoro in adult patients on haemodialysis (N=1,198) or peritoneal dialysis (N=160), who were followed in routine clinical practice for 12 to 36 months (safety analysis set, N=1,365). During the study, 45 % (N=618) of these patients were concomitantly treated with phosphate binder(s) other than Velphoro.
In the safety analysis set, the most common ADRs were diarrhoea and discoloured faeces, reported by 14 % (N=194) and 9 % (N=128) of patients, respectively. The incidence of diarrhoea was highest in the first week and decreased with duration of use. Diarrhoea was of mild to moderate intensity in most patients and resolved in the majority of patients within 2 weeks. Discoloured (black) faeces is expected for an oral iron-based compound, and may visually mask gastrointestinal bleeding. For 4 of the 40 documented concomitant gastrointestinal bleeding events, Velphoro-related stool discolouration was reported as causing an insignificant delay in diagnosis of gastrointestinal bleeding, without affecting patient health. In the remaining cases, no delay in diagnosis of gastrointestinal bleeding has been reported.
The results from this study showed that the effectiveness of Velphoro in a real-life setting (including concomitant use of other phosphate binders in 45 % of patients), was in line with that observed in the phase 3 clinical study.
Paediatric population: The European Medicines Agency has deferred the obligation to submit the results of studies with Sucroferric Oxyhydroxide (Velphoro) in one or more subsets of the paediatric population in the treatment of hyperphosphataemia (see Dosage & Administration for information on pediatric use).
Pharmacokinetics: Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (Velphoro) active substance, 2,000 mg iron 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 Sucroferric Oxyhydroxide (Velphoro), pn-FeOOH, is not metabolised. However, the degradation product of Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (Velphoro) is low.
In vitro data suggest that the sucrose and starch components of the active 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-Sucroferric Oxyhydroxide (Velphoro) active substance orally, radiolabelled iron was recovered in the faeces but not the urine.
Toxicology: 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 (Velphoro). This is thought to be most likely an adaptive response to the pharmacological effect of the medicinal product, and not clinically relevant.

Sucroferric Oxyhydroxide (Velphoro) is indicated for the control of serum phosphorus levels in adult chronic kidney disease (CKD) patients on haemodialysis (HD) or peritoneal dialysis (PD). Sucroferric Oxyhydroxide (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.

Starting dose: The recommended starting dose of Sucroferric Oxyhydroxide (Velphoro) is 1,500 mg iron (3 tablets) per day, divided across the meals of the day. Sucroferric Oxyhydroxide (Velphoro) is for oral administration only and must be taken with meals.
Patients receiving Sucroferric Oxyhydroxide (Velphoro) should adhere to their prescribed diets.
Titration and maintenance: Serum phosphorus levels must be monitored and the dose of Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (Velphoro) therapy usually achieve optimal serum phosphorus levels at doses of 1,500 - 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.
Pediatric population: The safety and efficacy of Sucroferric Oxyhydroxide (Velphoro) in children below the age of 18 years has not yet been established. No data are available.
Elderly population (≥65 years of age): Sucroferric Oxyhydroxide (Velphoro) has been administered to over 248 seniors (≥65 years of age) according to the approved dosing regimen. Of the total number of subjects in clinical studies of Sucroferric Oxyhydroxide (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: Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (Velphoro). However, no evidence of hepatic impairment or significant alteration of hepatic enzymes were observed in the clinical studies with Sucroferric Oxyhydroxide (Velphoro).
Method of administration: Oral use.
Sucroferric Oxyhydroxide (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 and should adhere to their prescribed diets. Tablets must be chewed and not swallowed whole; tablets may be crushed.

Any instances of overdose of Sucroferric Oxyhydroxide (Velphoro) should be treated by standard clinical practice.

Hypersensitivity to the active substance or to any of the excipients silica, magnesium stearate, neohesperidin-dihydrochalcone and woodberry flavor.
Hemochromatosis and any other iron accumulation disorders.

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 Sucroferric Oxyhydroxide (Velphoro). Sucroferric Oxyhydroxide (Velphoro) treatment should only be used in these patients following careful assessment of benefit/risk.
Discoloured stool: Sucroferric Oxyhydroxide (Velphoro) can cause discoloured (black) stool. Discoloured (black) stool may visually mask gastrointestinal bleeding (see as follows).
Information about sucrose and starches (carbohydrates): Sucroferric Oxyhydroxide (Velphoro) contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product. May be harmful to the teeth.
Sucroferric Oxyhydroxide (Velphoro) contains starches. Patients with diabetes should take notice that one tablet of Sucroferric Oxyhydroxide (Velphoro) is equivalent to approximately 1.4 g of carbohydrates (equivalent to 0.116 bread units).
Effects On Ability to Drive and Use Machines: Sucroferric Oxyhydroxide (Velphoro) has no or negligible influence on the ability to drive and use machines.

Pregnancy: There are no available clinical data from the use of Sucroferric oxyhydroxide (Velphoro) 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 Pharmacology: Toxicology: Preclinical safety data under Actions). Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (Velphoro) in breast-feeding women. Since absorption of iron from Sucroferric Oxyhydroxide (Velphoro) is minimal (see Pharmacology: Pharmacokinetics under Actions), excretion of iron from Sucroferric Oxyhydroxide (Velphoro) in breast milk is unlikely. A decision on whether to continue breast-feeding or to continue therapy with Sucroferric Oxyhydroxide (Velphoro) should be made taking into account the benefit of breast-feeding to the child and the benefit of Sucroferric Oxyhydroxide (Velphoro) therapy to the mother.
Fertility: There are no data on the effect of Sucroferric Oxyhydroxide (Velphoro) on fertility in humans. In animal studies, there were no adverse effects on mating performance, fertility, and litter parameters following treatment with Sucroferric Oxyhydroxide (Velphoro) (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: The current safety profile of Sucroferric Oxyhydroxide (Velphoro) is based on a total of 778 patients on haemodialysis and 57 patients on peritoneal dialysis, who received Sucroferric Oxyhydroxide (Velphoro) treatment of up to 55 weeks.
In these clinical trials, approximately 43 % of the patients experienced at least one adverse reaction during Sucroferric Oxyhydroxide (Velphoro) treatment, and 0.36 % of the adverse reactions were reported as serious. 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 Sucroferric Oxyhydroxide (Velphoro).
Tabulated list of adverse reactions: ADRs reported from the use of Sucroferric Oxyhydroxide (Velphoro) at doses from 250 mg iron/day to 3,000 mg iron/day in these patients (n=835) are listed in Table. (See table.)

Click on icon to see table/diagram/image

Pediatric Population: The safety profile of Velphoro in pediatric (2 to <18 years of age) and adult patients was comparable. The adverse reactions most frequently reported were gastrointestinal disorders including diarrhea (very common, 16.7%), vomiting (common, 6.1%), gastritis (common, 3.0%) and discolored feces (common, 3.0%).
ADR Reporting Statement: 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.

Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (Velphoro) based only on in vitro studies like levothyroxine, the medicinal product should be administered at least one hour before or two hours after Sucroferric Oxyhydroxide (Velphoro).
In vitro studies with the following active substances did not show any relevant interaction: acetylsalicylic acid, cephalexin, cinacalcet, ciprofloxacin, clopidogrel, enalapril, hydrochlorothiazide, metformin, metoprolol, nifedipine, pioglitazone and quinidine.
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 Sucroferric Oxyhydroxide (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 Sucroferric Oxyhydroxide (Velphoro) does not affect the lipid lowering effects of HMG-CoA reductase inhibitors (e.g., atorvastatin and simvastatin). In addition, post-hoc analyses from clinical studies demonstrated no impact of Sucroferric Oxyhydroxide (Velphoro) on iPTH lowering effect of oral Vitamin D analogues. Vitamin D and 1,25-dihydroxy Vitamin D levels remained unchanged.
Sucroferric Oxyhydroxide (Velphoro) does not affect guaiac based (Haemoccult) or immunological based (iColo Rectal and Hexagon Obti) faecal occult blood tests.

Incompatibilities: Not applicable.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store at temperatures not exceeding 30 °C.
Keep the bottle tightly closed in order to protect from moisture.
Store in the original package.
Shelf life: Shelf life after first opening of the bottle: 45 days.

Antidotes & Detoxifying Agents

V03AE05 - sucroferric oxyhydroxide ; Belongs to the class of drugs used in the treatment of hyperkalemia and hyperphosphatemia.

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