VELPHORO 500mg chewable tablets medication leaflet

Velphoro 500 mg chewable tablets

Each chewable tablet contains sucroferric oxyhydroxide corresponding to 500 mg iron.

The sucroferric oxyhydroxide contained in one tablet is comprised of polynuclear iron (III)-oxyhydroxide (containing 500 mg iron), 750 mg sucrose and 700 mg starches (potato starch andpregelatinised maize starch).

For the full list of excipients, see section 6.1.

Chewable tablet.

Brown, circular tablets embossed with PA500 on one side. Tablets have a 20 mm diameter and athickness of 6.5 mm.

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 is indicated for the control of serum phosphorus levels in paediatric patients 2 years of ageand older with CKD stages 4-5 (defined by a glomerular filtration rate <30 mL/min/1.73 m²) or with

CKD on dialysis.

Velphoro should be used within the context of a multiple therapeutic approach, which could includecalcium supplement, 1,25­dihydroxy vitamin D3 or one of its analogues, or calcimimetics to controlthe development of renal bone disease.

Starting dose for adults and adolescents (≥12 years of age)

The recommended starting dose is 1,500 mg iron (3 tablets) per day, divided across the meals of theday.

Titration and maintenance for adults and adolescents (≥12 years of age)

Serum phosphorus levels must be monitored and the dose of sucroferric oxyhydroxide up or downtitrated in increments of 500 mg iron (1 tablet) per day every 2 - 4 weeks until an acceptable serumphosphorus level is reached, with regular monitoring afterwards.

In clinical practice, treatment will be based on the need to control serum phosphorus levels, thoughpatients who respond to Velphoro therapy usually achieve optimal serum phosphorus levels at doses of1,500 - 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 thenext meal.

Maximum tolerated daily dose for adults and adolescents (≥12 years of age)

The maximum recommended dose is 3,000 mg iron (6 tablets).

Starting dose, titration and maintenance for paediatric patients (2 to <12 years of age)

Velphoro is also available as 125 mg oral powder in sachet for use in paediatric patients 2 to <12 yearsof age. The choice of the formulation depends on patient’s age, preference, characteristics andcompliance. When transitioning between formulations, the same recommended dose should be used.

Recommended starting doses and dose titrations of Velphoro for paediatric patients 2 to <12 years ofage are shown in the Table 1.

Table 1 Recommended starting doses and dose titrations for paediatric patients 2 to<12 years of age

Patient age Dose increases or Maximum

Daily starting dose(years) decreases recommended daily dose≥2 to <6 500 mg 125 or 250 mg 1,250 mg≥6 to <9 750 mg 125, 250 or 375 mg 2,500 mg≥9 to <12 1,000 mg 250 or 500 mg 3,000 mg

For patients 2 to <6 years of age oral powder should be administered, as the chewable tabletformulation is not appropriate for this age group.

For patients 6 to <12 years of age Velphoro chewable tablets may be prescribed instead of or incombination with Velphoro oral powder in case the daily dose is 1,000 mg iron (2 chewable tablets) ormore.

Serum phosphorus levels must be monitored and the dose of sucroferric oxyhydroxide up or downtitrated in increments per day every 2 - 4 weeks until an acceptable serum phosphorus level is reached,with regular monitoring afterwards.

Paediatric population <2 years of age

The safety and efficacy of Velphoro in children below the age of 2 years has not been established. Nodata are available.

Velphoro is indicated for the control of serum phosphorus levels in adult CKD patients on HD or PD.

There is no clinical data available in patients with earlier stages of renal impairment.

Patients with severe hepatic impairment were excluded from participating in clinical studies withsucroferric oxyhydroxide. However, no evidence of hepatic impairment or significant alteration ofhepatic enzymes were observed in the clinical studies with sucroferric oxyhydroxide. See furtherinformation in section 4.4.

Elderly population (≥65 years of age)

Velphoro has been administered to over 248 seniors (≥65 years of age) according to the approveddosing regimen. Of the total number of subjects in clinical studies of sucroferric oxyhydroxide, 29.7%were aged 65 years and over, while 8.7% were aged 75 years and over. No special dose andadministration guidelines were applied to seniors in these studies and the dosing schedules were notassociated with any significant concerns.

Oral use.

Velphoro is a chewable tablet that must be taken with meals. In order to maximise the adsorption ofdietary phosphate, the total daily dose should be divided across the meals of the day. Patients are notrequired to drink more fluid than they normally would and should adhere to their prescribed diets.

Tablets must be chewed or crushed; tablets must not be swallowed whole.

* Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

* Haemochromatosis 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 hepaticdisorders and patients with major gastrointestinal surgery have not been included in clinical studieswith Velphoro. Velphoro treatment should only be used in these patients following careful assessmentof benefit/risk.

Discoloured stool

Sucroferric oxyhydroxide can cause discoloured (black) stool. Discoloured (black) stool may visuallymask gastrointestinal bleeding (see section 4.5).

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 medicinal product.

It may be harmful to the teeth.

Velphoro contains potato starch and pregelatinised maize starch. Patients with diabetes should takenotice that one tablet of Velphoro is equivalent to approximately 1.4 g of carbohydrates (equivalent to0.116 bread units).

Velphoro is almost not absorbed from the gastrointestinal tract. Although the potential for interactionswith medicinal products seems low, for concomitant treatment with medicinal products with a narrowtherapeutic 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 considermeasuring blood levels. When administering any medicinal product that is already known to interactwith iron (like alendronate and doxycycline) or has the potential to interact with sucroferricoxyhydroxide based only on in vitro studies like levothyroxine, the medicinal product should beadministered at least one hour before or two hours after 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 inhealthy human male and female subjects with losartan, furosemide, digoxin, warfarin, and omeprazole.

Concomitant administration of Velphoro did not affect the bioavailability of these medicinal productsas measured by the area under the curve (AUC).

Data from clinical studies have shown that sucroferric oxyhydroxide does not affect the lipid loweringeffects of HMG-CoA reductase inhibitors (e.g., atorvastatin and simvastatin). In addition, post-hocanalyses from clinical studies demonstrated no impact of Velphoro on iPTH lowering effect of oral

Vitamin D analogues. Vitamin D and 1,25­dihydroxy Vitamin D levels remained unchanged.

Velphoro does not affect guaiac based (Haemoccult) or immunological based (iColo Rectal and

Hexagon Obti) faecal occult blood tests.

There are no available clinical data from the use of sucroferric oxyhydroxide on exposed humanpregnancies.

Reproductive and developmental toxicity studies in animals revealed no risk with respect topregnancy, embryonic/foetal development, parturition or postnatal development (see section 5.3).

Sucroferric oxyhydroxide should only be used by pregnant women if clearly needed following carefulassessment of benefit/risk.

There are no available clinical data from the use of Velphoro in breast-feeding women. Sinceabsorption of iron from this medicinal product is minimal (see section 5.2), excretion of iron fromsucroferric oxyhydroxide in breast milk is unlikely. A decision on whether to continue breast-feedingor to continue therapy with sucroferric oxyhydroxide should be made taking into account the benefit ofbreast-feeding to the child and the benefit of Velphoro therapy to the mother.

There are no data on the effect of Velphoro on fertility in humans. In animal studies, there were noadverse effects on mating performance, fertility, and litter parameters following treatment withsucroferric oxyhydroxide (see section 5.3).

Velphoro has no or negligible influence on the ability to drive and use machines.

The current safety profile of Velphoro is based on a total of 778 patients on haemodialysis and57 patients on peritoneal dialysis, who received sucroferric oxyhydroxide treatment of up to 55 weeks.

In these clinical trials, approximately 43% of the patients experienced at least one adverse reactionduring Velphoro treatment, and 0.36% of the adverse reactions were reported as serious. The majorityof the adverse reactions reported from trials were gastrointestinal disorders, with the most frequentlyreported adverse reactions being diarrhoea and discoloured faeces (very common). The vast majorityof these gastrointestinal disorders occurred early during treatment and abated with time with continueddosing. No dose-dependent trends were observed in the adverse reaction profile of Velphoro.

Adverse reactions reported from the use of Velphoro at doses from 250 mg iron/day to 3,000 mgiron/day in these patients (n=835) are listed in Table 2.

The reporting rate is classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon(≥1/1,000 to <1/100).

Table 2 Adverse reactions detected in clinical trials

System organ class Very common Common Uncommon

Metabolism and Hypercalcaemianutrition disorders Hypocalcaemia

Nervous system Headachedisorders

Respiratory, thoracic Dyspnoeaand mediastinaldisorders

Gastrointestinal Diarrhoea* Nausea Abdominal distensiondisorders Faeces discoloured Constipation Gastritis

Vomiting Abdominal discomfort

Dyspepsia Dysphagia

Abdominal pain Gastro-oesophageal

Flatulence reflux disease (GORD)

Tooth discolouration Tongue discolouration

Skin and subcutaneous Pruritus Rashtissue disorders

General disorders and Product taste abnormal Fatigueadministration siteconditions

*Diarrhoea

Diarrhoea occurred in 11.6% of patients in clinical trials. In the 55 weeks long term studies, themajority of these diarrhoea adverse reactions were transient, occurred early during treatmentinitiation and led to treatment discontinuation in 3.1% of the patients.

In general, the safety profile of Velphoro in paediatric (2 to <18 years of age) and adult patients wascomparable. The adverse reactions most frequently reported were gastrointestinal disorders includingdiarrhoea (very common, 16.7%), vomiting (common, 6.1%), gastritis (common, 3.0%) anddiscoloured faeces (common, 3.0%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Any instances of overdose of Velphoro (e.g. hypophosphataemia) should be treated by standardclinical practice.

Pharmacotherapeutic group: All other therapeutic products; drugs for treatment of hyperkalaemia andhyperphosphataemia; ATC code: V03AE05

Velphoro contains sucroferric oxyhydroxide which is comprised of polynuclear iron(III)-oxyhydroxide(pn-FeOOH), sucrose and starches. Phosphate binding takes place by ligand exchange betweenhydroxyl groups and/or water and the phosphate ions throughout the physiological pH range of thegastrointestinal tract.

Serum phosphorus levels are reduced as a consequence of the reduced dietary phosphate absorption.

One phase 3 clinical study has been performed in patients with CKD on dialysis to investigate theefficacy 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 withhyperphosphataemia (serum phosphorus levels ≥1.94 mmol/L) were treated with sucroferricoxyhydroxide at a starting dose of 1,000 mg iron/day followed by an 8­week dose titration period.

Non-inferiority to sevelamer carbonate was determined at week 12. Subjects were continued on theirstudy medication from week 12 to week 55. From week 12 to 24, dose titrations were allowed for bothtolerability and efficacy reasons. Treatment of patient sub-populations from week 24 to week 27 withmaintenance dose of sucroferric oxyhydroxide (1,000 to 3,000 mg iron/day) or low dose (250 mgiron/day) of sucroferric oxyhydroxide demonstrated superiority of the maintenance dose.

In Study-05A, 1,055 patients on haemodialysis (N=968) or peritoneal dialysis (N=87) with serumphosphorus ≥1.94 mmol/L following a 2 - 4­week phosphate binder washout period, were randomisedand treated with either sucroferric oxyhydroxide, at a starting dose of 1,000 mg iron/day (N=707), oractive-control (sevelamer carbonate, N=348) for 24 weeks. At the end of week 24, 93 patients onhaemodialysis whose serum phosphorus levels were controlled (<1.78 mmol/L) with sucroferricoxyhydroxide in the first part of the study, were re-randomised to continue treatment with either theirweek 24 maintenance dose (N=44 or a non-effective low dose control 250 mg iron/day, N=49) ofsucroferric oxyhydroxide for a further 3 weeks.

Following completion of Study-05A, 658 patients (597 on haemodialysis and 61 on peritonealdialysis) were treated in the 28­week extension study (Study-05B) with either sucroferricoxyhydroxide (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 forsucroferric oxyhydroxide (reduction by 0.7 mmol/L). Corresponding levels for sevelamer carbonate atbaseline 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 andcalcium-phosphorus product levels were reduced as a consequence of the reduced dietary phosphateabsorption.

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% atweek 12 and 51.9% and 55.2% at week 52, for sucroferric oxyhydroxide and sevelamer carbonate,respectively.

The mean daily dose of Velphoro over 55 weeks of treatment was 1,650 mg iron and the mean dailydose 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 adultpatients on haemodialysis (N=1,198) or peritoneal dialysis (N=160), who were followed in routineclinical practice for 12 to 36 months (safety analysis set, N=1,365). During the study, 45% (N=618) ofthese 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 by14% (N=194) and 9% (N=128) of patients, respectively. The incidence of diarrhoea was highest in thefirst week and decreased with duration of use. Diarrhoea was of mild to moderate intensity in mostpatients and resolved in the majority of patients within 2 weeks. Discoloured (black) faeces is expectedfor an oral iron-based compound, and may visually mask gastrointestinal bleeding. For 4 of the 40documented concomitant gastrointestinal bleeding events, Velphoro-related stool discolouration wasreported as causing an insignificant delay in diagnosis of gastrointestinal bleeding, without affectingpatient health. In the remaining cases, no delay in diagnosis of gastrointestinal bleeding has beenreported.

The results from this study showed that the effectiveness of Velphoro in a real-life setting (includingconcomitant use of other phosphate binders in 45% of patients), was in line with that observed in thephase 3 clinical study.

An open label clinical study investigated the efficacy and safety of Velphoro in paediatric patients 2years of age and older with CKD, and hyperphosphatemia (CKD stages 4-5 (defined by a glomerularfiltration rate <30 mL/min/l .73 m²) or with CKD on dialysis). Eighty-five subjects were randomisedto Velphoro (N=66) or active control calcium acetate arm (N=19) for a 10-week dose titration (Stage1), followed by a 24-week safety extension (Stage 2). Most patients were ≥12 years of age (66%).

Eighty percent of patients were CKD patients on dialysis (67% on haemodialysis and 13% onperitoneal dialysis) and 20% were CKD patients not on dialysis.

The limited difference in reduction in mean serum phosphorus level from baseline to the end of Stage1 in the Velphoro group (N=65) was not statistically significant with -0.120 (0.081) mmol/L (95% CI:

- 0.282, 0.043) based on the mixed model calculations with actual data showing a mean of 2.08mmol/L at baseline and 1.91 mmol/L at the end of Stage 1 (reduction by 0.17 mmol/L). The effect wasmaintained during Stage 2, although some fluctuations in mean effect over time were noticed (0.099(0.198) mmol/L (95% CI: -0.306, 0.504)).

The percentage of subjects with serum phosphorus levels within normal ranges increased from 37% atbaseline to 61% at the end of Stage 1, and was 58% at the end of Stage 2, showing the sustainablephosphorus lowering effect of sucroferric oxyhydroxide. Among subjects whose serum phosphoruswas above age-related normal ranges at baseline (N=40), serum phosphorus levels showed statisticallysignificant decrease from baseline to the end of Stage 1, with the LS mean (SE) change -0.87 (0.30)mg/dL (95% CI: -1.47, -0.27; p=0.006).

The safety profile of Velphoro in paediatric patients was generally comparable to that previouslyobserved in adult patients.

Velphoro works by binding phosphate in the gastrointestinal tract and thus the serum concentration isnot relevant for its efficacy. Due to the insolubility and degradation characteristics of Velphoro, noclassical 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 dosedependent effects were observed in healthy volunteers.

The active moiety of Velphoro, pn-FeOOH, is practically insoluble and therefore not absorbed. Itsdegradation 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 active substance, 2,000 mg iron in 1 day was investigatedin 16 CKD patients (8 pre-dialysis and 8 haemodialysis patients) and 8 healthy volunteers with lowiron stores (serum ferritin <100 mcg/L). In healthy subjects, the median uptake of radiolabelled iron inthe 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 ofradiolabelled iron were very low and confined to the erythrocytes.

The distribution studies in humans were not performed. Non-clinical studies in several species (ratsand 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 andbone marrow, and utilized by incorporation into red blood cells.

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 ironfrom Velphoro is low.

In vitro data suggest that the sucrose and starch components of the active substance can be digested toglucose and fructose, and maltose and glucose, respectively. These compounds can be absorbed in theblood.

In animal studies with rats and dogs administered 59Fe-Velphoro active substance orally, radiolabellediron was recovered in the faeces but not the urine.

Nonclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity and genotoxicity.

Effects seen in the rabbit embryo-foetal development toxicity study (skeletal variations and incompleteossificaton) are related to exaggerated pharmacology, and likely not relevant for patients. Otherreproduction toxicity studies showed no adverse effects.

Carcinogenicity studies were performed in mice and rats. There was no clear evidence of acarcinogenic effect in mice. Mucosal hyperplasia, with diverticulum/cyst formation was observed inthe colon and caecum of mice after 2­years treatment, but this was considered a species-specific effectwith no diverticula/cysts seen in long term studies in rats or dogs. In rats, there was a slightly increasedincidence of benign C­cell adenoma in the thyroid of male rats given the highest dose of sucroferricoxyhydroxide. This is thought to be most likely an adaptive response to the pharmacological effect ofthe medicinal product, and not clinically relevant.

Woodberry flavour

Neohesperidin-dihydrochalcone

Magnesium stearate

Colloidal anhydrous silica

Not applicable.

3 years

Shelf life after first opening of the bottle: 90 days

Store in the original package in order to protect from moisture.

High density polyethylene (HDPE) bottle with child-resistant polypropylene closure and foil inductionseal, containing a molecular sieve desiccant and cotton. Pack sizes of 30 or 90 chewable tablets.

Child-resistant aluminium/aluminium perforated unit-dose blister, each blister containing 6 chewabletablets. Pack sizes of 30 × 1 or multipack of 90 (3 packs of 30 × 1) chewable tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Vifor Fresenius Medical Care Renal Pharma France100-101 Terrasse Boieldieu

Tour Franklin La Défense 892042 Paris la Défense Cedex

France

EU/1/14/943/001

EU/1/14/943/002

EU/1/14/943/003

EU/1/14/943/004

Date of first authorisation: 26 August 2014

Date of latest renewal: 25 March 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.