RENVELA 2.4g powder for oral suspension medication leaflet

Renvela 2.4 g powder for oral suspension

Each sachet contains 2.4 g sevelamer carbonate.

This medicine contains 25.27 mg propylene glycol alginate (E405) in each 2.4 g sachet.

For the full list of excipients, see section 6.1.

Powder for oral suspension.

Pale yellow powder.

Renvela is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis orperitoneal dialysis.

Renvela is also indicated for the control of hyperphosphataemia in adult patients with chronic kidney disease(CKD) not on dialysis with serum phosphorus ≥ 1.78 mmol/l.

Renvela is indicated for the control of hyperphosphataemia in paediatric patients (>6 years of age and a bodysurface area (BSA) of >0.75 m2) with chronic kidney disease.

Renvela should be used within the context of a multiple therapeutic approach, which could include calciumsupplement, 1,25-dihydroxy Vitamin D3 or one of its analogues to control the development of renal bonedisease.

The recommended starting dose of sevelamer carbonate for adults is 2.4 g or 4.8 g per day based on clinicalneeds and serum phosphorus level. Renvela must be taken three times per day with meals.

Serum phosphorus level in patients Total daily dose of sevelamer carbonate to betaken over 3 meals per day1.78 - 2.42 mmol/l (5.5 - 7.5 mg/dl) 2.4 g*> 2.42 mmol/l (> 7.5 mg/dl) 4.8 g*

*Plus subsequent titrating, see section “Titration and maintenance”

Children/adolescents (>6 years of age and a BSA of >0.75m2)

The recommended starting dose of sevelamer carbonate for children is between 2.4 g and 4.8 g per day basedon the patient’s BSA category. Renvela must be taken three times per day with meals or snacks.

2 Total daily dose of sevelamer carbonate to be

BSA (m )taken over 3 meals/snacks per day>0.75 to <1.2 2.4 g**≥1.2 4.8 g**

**Plus subsequent titrating, see section “Titration and maintenance”

For patients previously on phosphate binders (sevelamer hydrochloride or calcium based), Renvela should begiven on a gram for gram basis with monitoring of serum phosphorus levels to ensure optimal daily doses.

*Adults

For adult patients, serum phosphorus must be monitored and the dose of sevelamer carbonate titrated by 0.8g three times per day (2.4 g/day) increments every 2-4 weeks until an acceptable serum phosphorus level isreached, with regular monitoring thereafter.

In clinical practice, treatment will be continuous based on the need to control serum phosphorus levels andthe daily adult dose is expected to be an average of approximately 6 g per day.

**Children and adolescents (>6 years of age and a BSA of >0.75m2)

For paediatric patients, serum phosphorus levels must be monitored and the dose of sevelamer carbonatetitrated in increments based on patient’s BSA, three times per day every 2-4 weeks until an acceptable serumphosphorus level is reached, with regular monitoring thereafter.

Paediatric dose based on BSA (m2)

BSA (m2) Starting dose Titration increases/decreases

Titrate up/down by 0.4 g three>0.75 to <1.2 0.8 g three times dailytimes daily

Titrate up/down by 0.8 g three≥1.2 1.6 g three times dailytimes daily

Patients taking sevelamer carbonate should adhere to their prescribed diets.

No dosage adjustment is necessary in the elderly population.

No studies have been performed in patients with hepatic impairment.

The safety and efficacy of Renvela in children below the age of 6 years or in children with a BSA below 0.75m2 have not been established. No data are available.

For paediatric patients with a <1.2 BSA (m2), the oral suspension should be administered, as tabletformulations were not tested in this population and therefore are not appropriate for this population.

Oral use.

Each sachet of 2.4 g of powder is to be dispersed in 60 mL of water prior to administration (see section 6.6).

The suspension should be ingested within 30 minutes after being prepared. Renvela should be taken with foodand not on an empty stomach.

As an alternative to water, the powder may be pre-mixed with a small amount of beverage or food (e.g. 100grams/120 ml) and consumed within 30 minutes. Do not heat Renvela powder (e.g. microwave) or add toheated foods or liquids.

If a dose of 0.4 g is to be administered, please use the dedicated 0.8 g powder presentation with dosing spoon.

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

* Hypophosphataemia

* Bowel obstruction.

The safety and efficacy of sevelamer carbonate have not been established in adult patients with chronickidney disease not on dialysis with serum phosphorus < 1.78 mmol/l. Therefore it is currently notrecommended for use in these patients.

The safety and efficacy of sevelamer carbonate have not been established in patients with the followingdisorders:

* dysphagia

* swallowing disorders

* severe gastrointestinal motility disorders including untreated or severe gastroparesis, retention ofgastric contents and abnormal or irregular bowel motion

* active inflammatory bowel disease

* major gastrointestinal tract surgery

Treatment of these patients with Renvela should only be initiated after careful benefit/risk assessment. If thetherapy is initiated, patients suffering from these disorders should be monitored. Renvela treatment shouldbe reevaluated in patients who develop severe constipation or other severe gastrointestinal symptoms.

In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatmentwith sevelamer hydrochloride (capsules/tablets), which contains the same active moiety as sevelamercarbonate. Constipation may be a preceding symptom. Patients who are constipated should be monitoredcarefully while being treated with Renvela. The treatment should be re-evaluated in patients who developsevere constipation or other severe gastrointestinal symptoms.

Patients with CKD may develop low levels of fat-soluble vitamins A, D, E and K, depending on dietaryintake and the severity of their disease. It cannot be excluded that sevelamer carbonate can bind fat-solublevitamins contained in ingested food. In patients not taking supplemental vitamins but on sevelamer, serumvitamin A, D, E and K status should be assessed regularly. It is recommended that vitamin supplements begiven if necessary. It is recommended that CKD patients not on dialysis are given vitamin D supplements(approximately 400 IU of native vitamin D daily) which can be part of a multivitamin preparation to be takenapart from their dose of sevelamer carbonate. In patients undergoing peritoneal dialysis additionalmonitoring of fat-soluble vitamins and folic acid is recommended, since vitamin A, D, E and K levels werenot measured in a clinical study in these patients.

There is at present insufficient data to exclude the possibility of folate deficiency during long term sevelamercarbonate treatment. In patients not taking supplemental folic acid but on sevelamer, folate level should beassessed regularly.

Patients with CKD may develop hypocalcaemia or hypercalcaemia. Sevelamer carbonate does not containany calcium. Serum calcium levels should therefore be monitored at regular intervals and elemental calciumshould be given as a supplement if required.

Patients with CKD are predisposed to developing metabolic acidosis. As part of good clinical practice,monitoring of serum bicarbonate levels is therefore recommended.

Patients receiving dialysis are subject to certain risks for infection specific to dialysis modality. Peritonitis isa known complication in patients receiving peritoneal dialysis and in a clinical trial with sevelamerhydrochloride, a greater number of peritonitis cases were reported in the sevelamer group than in the controlgroup. Patients on peritoneal dialysis should be closely monitored to ensure the correct use of appropriateaseptic technique with the prompt recognition and management of any signs and symptoms associated withperitonitis.

Closer monitoring of patients with hypothyroidism co-administered with sevelamer carbonate andlevothyroxine is recommended (see section 4.5).

Sevelamer carbonate is not indicated for the control of hyperparathyroidism. In patients with secondaryhyperparathyroidism sevelamer carbonate should be used within the context of a multiple therapeuticapproach, which could include calcium as supplements, 1,25-dihydroxy Vitamin D3 or one of its analoguesto lower the intact parathyroid hormone (iPTH) levels.

Cases of serious inflammatory disorders of different parts of the gastrointestinal tract (including seriouscomplications such as haemorrhage, perforation, ulceration, necrosis, colitis and colonic/caecal mass)associated with the presence of sevelamer crystals have been reported (see section 4.8). Inflammatorydisorders may resolve upon sevelamer discontinuation. Sevelamer carbonate treatment should be re-evaluated in patients who develop severe gastrointestinal symptoms.

This medicine contains less than 1 mmol sodium (23 mg) per sachet that is to say essentially ‘sodium-free’.

Interaction studies have not been conducted in patients on dialysis.

In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moietyas sevelamer carbonate, decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with sevelamer hydrochloride in a single dose study. Consequently, sevelamer carbonateshould not be taken simultaneously with ciprofloxacin.

Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus have been reported in transplantpatients when co-administered with sevelamer hydrochloride without any clinical consequences (e.g., graftrejection). The possibility of an interaction cannot be excluded and a close monitoring of bloodconcentrations of ciclosporin, mycophenolate mofetil and tacrolimus should be considered during the use ofcombination and after its withdrawal.

Very rare cases of hypothyroidism have been reported in patients co-administered with sevelamerhydrochloride, which contains the same active moiety as sevelamer carbonate, and levothyroxine. Closermonitoring of thyroid stimulating hormone (TSH) levels is therefore recommended in patients receivingsevelamer carbonate and levothyroxine.

Patients taking anti-arrhythmic medicinal products for the control of arrhythmias and anti-seizure medicinalproducts for the control of seizure disorders were excluded from clinical trials. Therefore, possible reductionin absorption cannot be excluded. The anti-arrhythmic medical product should be taken at least one hourbefore or three hours after Renvela and blood monitoring can be considered.

During post-marketing experience, very rare cases of increased phosphate levels have been reported inpatients taking proton pump inhibitors co-administered with sevelamer carbonate. Caution should beexercised when prescribing PPI to patients concomitantly treated with Renvela. The phosphate serum levelshould be monitored and the Renvela dosage adjusted consequently.

Sevelamer carbonate is not absorbed and may affect the bioavailability of other medicinal products. Whenadministering any medicinal product where a reduction in the bioavailability could have a clinicallysignificant effect on safety or efficacy, the medicinal product should be administered at least one hour beforeor three hours after sevelamer carbonate, or the physician should consider monitoring blood levels.

In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moietyas sevelamer carbonate, had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol.

There are no or limited amount of data from the use of sevelamer in pregnant women. Animal studies haveshown some reproductive toxicity when sevelamer was administered to rats at high doses (see section 5.3).

Sevelamer has also been shown to reduce the absorption of several vitamins including folic acid (seesections 4.4 and 5.3). The potential risk to humans is unknown. Sevelamer carbonate should only be given topregnant women if clearly needed and after a careful risk/benefit analysis has been conducted for both themother and the foetus.

It is unknown whether sevelamer/metabolites are excreted in human milk. The non-absorbed nature ofsevelamer indicates that excretion of sevelamer in breast milk is unlikely. A decision on whether tocontinue/discontinue breast-feeding or to continue/discontinue therapy with sevelamer carbonate should bemade taking into account the benefit of breast-feeding to the child and the benefit of sevelamer carbonatetherapy to the woman.

There are no data from the effect of sevelamer on fertility in humans. Studies in animals have shown thatsevelamer did not impair fertility in male or female rats at exposures at a human equivalent dose 2 times themaximum clinical trial dose of 13 g/day, based on a comparison of relative BSA.

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

The most frequently occurring (≥ 5% of patients) adverse reactions were all in the gastrointestinal disorderssystem organ class. Most of these adverse reactions were mild to moderate in intensity.

The safety of sevelamer (as either carbonate and hydrochloride salts) has been investigated in numerousclinical trials involving a total of 969 haemodialysis patients with treatment duration of 4 to 50 weeks(724 patients treated with sevelamer hydrochloride and 245 with sevelamer carbonate), 97 peritoneal dialysispatients with treatment duration of 12 weeks (all treated with sevelamer hydrochloride) and 128 patients with

CKD not on dialysis with treatment duration of 8 to 12 weeks (79 patients treatment with sevelamerhydrochloride and 49 with sevelamer carbonate).

Adverse reactions that occurred during clinical trials or that were spontaneously reported from post-marketing experience are listed by frequency in the table below. The reporting rate is classified as verycommon (≥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).

MedDRA System Very common Common Very rare Not known

Organ Class

Immune system Hypersensitivity*disorders

Gastrointestinal Nausea, vomiting, Diarrhoea, Intestinaldisorders upper abdominal dyspepsia, obstruction,pain, constipation flatulence, ileus/subileus,abdominal pain intestinalperforation1,gastrointestinalhemorrhage*1,intestinalulceration*1,gastrointestinalnecrosis*1,colitis*1,intestinal mass*1

Skin and Pruritus, rashsubcutaneoustissue disorders

Investigations Crystal depositintestine*1

*post-marketing experience1 See inflammatory gastrointestinal disorders warning in section 4.4

In general, the safety profile for children and adolescents (6 to 18 years of age) is similar to the safetyprofile for adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been given tonormal healthy volunteers in doses of up to 14 grams per day for eight days with no adverse reactions. In

CKD patients, the maximum average daily dose studied was 14.4 grams of sevelamer carbonate in a singledaily dose.

The symptoms observed in case of overdose are similar to adverse reactions listed in section 4.8, includingmainly constipation and other known gastrointestinal disorders.

Appropriate symptomatic treatment should be provided.

Pharmacotherapeutic group: All other therapeutic products, drugs for treatment of hyperkalemia andhyperphosphataemia. ATC code: V03A E02.

Renvela contains sevelamer, a non-absorbed phosphate binding crosslinked polymer, free of metal andcalcium. Sevelamer contains multiple amines separated by one carbon from the polymer backbone whichbecome protonated in the stomach. These protonated amines bind negatively charged ions such as dietaryphosphate in the intestine.

By binding phosphate in the gastrointestinal tract and decreasing absorption, sevelamer lowers thephosphorus concentration in the serum. Regular monitoring of serum phosphorus levels is always necessaryduring phosphate binder administration.

In two randomised, cross over clinical trials, sevelamer carbonate has been shown to be therapeuticallyequivalent to sevelamer hydrochloride and therefore effective in controlling serum phosphorus in CKDpatients on haemodialysis. These also demonstrated that sevelamer carbonate in both tablet and powderformulations are therapeutically equivalent to sevelamer hydrochloride.

The first study demonstrated that sevelamer carbonate tablets dosed three times per day was equivalent tosevelamer hydrochloride tablets dosed three times per day in 79 haemodialysis patients treated over tworandomised 8 week treatment periods (mean serum phosphorus time-weighted averages were1.5 ± 0.3 mmol/l for both sevelamer carbonate and sevelamer hydrochloride). The second studydemonstrated that sevelamer carbonate powder dosed three times per day was equivalent to sevelamerhydrochloride tablets dosed three times per day in 31 hyperphosphataemic (defined as serum phosphoruslevels ≥ 1.78 mmol/l) haemodialysis patients over two randomised 4 week treatment periods (mean serumphosphorus time-weighted averages were 1.6 ± 0.5 mmol/l for sevelamer carbonate powder and1.7 ± 0.4 mmol/l for sevelamer hydrochloride tablets).

In the clinical trials in haemodialysis patients, sevelamer alone did not have a consistent and clinicallysignificant effect on iPTH. In a 12 week study involving peritoneal dialysis patients however, similar iPTHreductions were seen compared with patients receiving calcium acetate. In patients with secondaryhyperparathyroidism sevelamer carbonate should be used within the context of a multiple therapeuticapproach, which could include calcium as supplements, 1,25-dihydroxy Vitamin D3 or one of its analoguesto lower the iPTH levels.

Sevelamer has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acidbinding by ion exchange resins is a well-established method of lowering blood cholesterol. In clinical trialsof sevelamer, both the mean total-cholesterol and LDL-cholesterol declined by 15-39%. The decrease incholesterol has been observed after 2 weeks of treatment and is maintained with long-term treatment.

Triglycerides, HDL-cholesterol and albumin levels did not change following sevelamer treatment.

Because sevelamer binds bile acids, it may interfere with the absorption of fat soluble vitamins such as A, D,

E and K.

Sevelamer does not contain calcium and decreases the incidence of hypercalcaemic episodes as compared topatients using calcium based phosphate binders alone. The effects of sevelamer on phosphorus and calciumwere proven to be maintained throughout a study with one year follow-up. This information was obtainedfrom studies in which sevelamer hydrochloride was used.

The safety and effectiveness of sevelamer carbonate in hyperphosphatemic paediatric patients with CKD wasevaluated in a multicenter study with a 2-week, randomised, placebo-controlled, fixed dose period (FDP)followed by a 6-month, single-arm, open-label, dose titration period (DTP). A total of 101 patients (6 to 18years old with a BSA range of 0.8 m2 to 2.4 m2) were randomised in the study. Forty-nine (49) patientsreceived sevelamer carbonate and 51 received placebo during the 2 week FDP. Thereafter all patientsreceived sevelamer carbonate for the 26-week DTP. The study met its primary endpoint, meaning Sevelamercarbonate reduced serum phosphorus by an LS mean difference of 0.90 mg/dL compared to placebo, andsecondary efficacy endpoints. In paediatric patients with hyperphosphatemia secondary to CKD, sevelamercarbonate significantly reduced serum phosphorus levels compared to placebo during a 2-week FDP. Thetreatment response was maintained in the paediatric patients who received sevelamer carbonate during the 6-month open-label DTP. 27% of paediatric patients reached their age appropriate serum phosphorus level atend of treatment. These figures were 23% and 15% in the subgroup of patients on hemodialysis andperitoneal dialysis, respectively. The treatment response during the 2-week FDP was not affected by BSA, incontrast however, no treatment response was observed in paediatric patients with qualifying phosphoruslevels <7.0 mg/dL. Most of adverse events reported as related, or possibly related, to sevelamer carbonatewere gastrointestinal in nature. No new risks or safety signals were identified with the use of sevelamercarbonate during the study.

Pharmacokinetic studies have not been carried out with sevelamer carbonate. Sevelamer hydrochloride,which contains the same active moiety as sevelamer carbonate, is not absorbed from the gastrointestinaltract, as confirmed by an absorption study in healthy volunteers.

In a clinical trial of one year, no evidence of accumulation of sevelamer was seen. However the potentialabsorption and accumulation of sevelamer during long-term chronic treatment (> one year) cannot be totallyexcluded.

Non-clinical data with sevelamer reveal no special hazard for humans based on conventional studies ofsafety pharmacology, repeated dose toxicity or genotoxicity.

Carcinogenicity studies with oral sevelamer hydrochloride were conducted in mice (doses of up to9 g/kg/day) and rats (0.3, 1, or 3 g/kg/day). There was an increased incidence of urinary bladder transitionalcell papilloma in male rats of the high dose group (human equivalent dose twice the maximum clinical trialdose of 14.4 g). There was no increased incidence of tumours observed in mice (human equivalent dose3 times the maximum clinical trial dose).

In an in vitro mammalian cytogenetic test with metabolic activation, sevelamer hydrochloride caused astatistically significant increase in the number of structural chromosome aberrations. Sevelamerhydrochloride was not mutagenic in the Ames bacterial mutation assay.

In rats and dogs, sevelamer reduced absorption of fat soluble vitamins D, E and K (coagulation factors), andfolic acid.

Deficits in skeletal ossification were observed in several locations in foetuses of female rats dosed withsevelamer at intermediate and high doses (human equivalent dose less than the maximum clinical trial doseof 14.4 g). The effects may be secondary to vitamin D depletion.

In pregnant rabbits given oral doses of sevelamer hydrochloride by gavage during organogenesis, an increaseof early resorptions occurred in the high-dose group (human equivalent dose twice the maximum clinicaltrial dose).

Sevelamer hydrochloride did not impair the fertility of male or female rats in a dietary administration studyin which the females were treated from 14 days prior to mating through gestation and the males were treatedfor 28 days prior to mating. The highest dose in this study was 4.5 g/kg/day (human equivalent dose 2 timesthe maximum clinical trial dose of 13 g/day, based on a comparison of relative BSA).

Propylene glycol alginate (E405)

Citrus Cream flavour

Sodium chloride

Sucralose

Iron oxide yellow (E172)

Not applicable.

3 years.

The oral suspension must be administered within 30 minutes.

The sachet has to be discarded after 24 hours of opening

The medicinal product does not require any special storage conditions.

Sachet of ethylene methacrylic acid copolymer, polyester, LDPE and aluminium foil laminate, with a heatseal.

Each sachet contains 2.4 g of sevelamer carbonate. Each carton contains 60 or 90 sachets.

Not all pack sizes may be marketed.

The powder should be dispersed in 60 mL of water per sachet prior to administration. The suspensionpowder is pale yellow with a citrus flavour.

The powder may also be pre-mixed with cold beverage or unheated food (see 4.2). The powder should not beheated (e.g. microwave).

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

Sanofi Winthrop Industrie82 Avenue Raspail94250 Gentilly

France

EU/1/09/521/006

EU/1/09/521/007

Date of first authorisation: 10 June 2009

Date of latest renewal: 20 February 2019

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

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