Leaflet RENAGEL 800mg film-coated tablets

Renagel 800 mg film-coated tablets

Each tablet contains 800 mg sevelamer hydrochloride.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Off-white oval and film-coated tablet, engraved with “RG800” on one side.

Renagel is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis orperitoneal dialysis. Renagel should be used within the context of a multiple therapeutic approach, whichcould include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to control thedevelopment of renal bone disease.

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

Serum phosphate level in patients not on Starting dose of Renagel 800phosphate binders mg tablets1.76 - 2.42 mmol/L (5.5-7.5 mg/dl) 1 tablet, 3 times per day> 2.42 mmol/L (>7.5 mg/dl) 2 tablets, 3 times per day

For patients previously on phosphate binders, Renagel should be given on a gram for gram basis withmonitoring of serum phosphorus levels to ensure optimal daily doses.

Serum phosphate levels should be closely monitored and the dose of sevelamer hydrochloride titratedby 0.8 g three times per day (2.4 g/day) increments with the goal of lowering serum phosphate to 1.76mmol/L (5.5 mg/dl) or less. Serum phosphate should be tested every two to three weeks until a stableserum phosphate level is reached and on a regular basis thereafter.

The dose range may vary between 1 and 5 tablets of 800 mg per meal. The average actual daily doseused in the chronic phase of a one year clinical study was 7 grams of sevelamer.

The safety and efficacy of this product have not been established in patients below the age of 18 years.

The safety and efficacy of this product have not been established in predialysis patients.

For oral use

Patients should take Renagel with meals and adhere to their prescribed diets. The tablets must beswallowed whole. Do not crush, chew or break into pieces prior to administration.

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

* Hypophosphataemia

* Bowel obstruction.

Efficacy and safety of Renagel has not been studied in patients with:

* swallowing disorders

* active inflammatory bowel disease

* gastrointestinal motility disorders including untreated or severe gastroparesis, diverticulosisretention of gastric contents and abnormal or irregular bowel motion

* patients with a history of major gastrointestinal surgery

Therefore caution should be exercised when Renagel is used in patients with these disorders.

In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients duringtreatment with sevelamer hydrochloride. Constipation may be a preceding symptom. Patients who areconstipated should be monitored carefully while being treated with sevelamer hydrochloride. Renageltreatment should be re-evaluated in patients who develop severe constipation or other severegastrointestinal symptoms.

Fat-soluble vitamins

Depending on diet intake and the nature of end stage renal failure, dialysis patients may develop lowvitamin A, D, E and K levels. It cannot be excluded that Renagel can bind fat-soluble vitaminscontained in ingested food. Therefore, in patients not taking these vitamins, monitoring vitamin A, Dand E levels and assessing vitamin K status through the measurement of thromboplastin time shouldbe considered and the vitamins should be supplemented if necessary. Additional monitoring ofvitamins and folic acid is recommended in patients receiving peritoneal dialysis, since in the clinicalstudy, vitamin A, D, E and K levels were not measured in these patients.

Folate deficiency

There is at present insufficient data to exclude the possibility of folate deficiency during long term

Renagel treatment.

Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. Renagel does notcontain calcium. Serum calcium levels should be monitored as is done in normal follow-up of adialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia.

Patients with chronic renal failure are predisposed to developing metabolic acidosis. Worsening ofacidosis has been reported upon switching from other phosphate binders to sevelamer in a number ofstudies where lower bicarbonate levels in the sevelamer-treated patients compared to patients treatedwith calcium-based binders were observed. Closer monitoring of serum bicarbonate levels is thereforerecommended.

Patients receiving dialysis are subject to certain risks for infection specific to the dialysis modality.

Peritonitis is a known complication in patients receiving peritoneal dialysis (PD) and in a clinicalstudy with Renagel, a number of peritonitis cases were reported. Therefore, patients on PD should beclosely monitored to ensure the reliable use of appropriate aseptic technique with the promptrecognition and management of any signs and symptoms associated with peritonitis.

Uncommon reports of difficulty swallowing the Renagel tablet have been reported. Many of thesecases involved patients with co-morbid conditions including swallowing disorders or oesophagealabnormalities. Caution should be exercised when Renagel is used in patients with difficultyswallowing.

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

Long term chronic treatment

As data on the chronic use of sevelamer for over one year are not yet available, potential absorptionand accumulation of sevelamer during long-term chronic treatment cannot be totally excluded (seesection 5.2).

Renagel alone is not indicated for the control of hyperparathyroidism. In patients with secondaryhyperparathyroidism Renagel should be used within the context of a multiple therapeutic approach,which could include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to lowerthe intact parathyroid hormone (iPTH) levels.

Serum chloride

Serum chloride may increase during Renagel treatment as chloride may be exchanged for phosphorusin the intestinal lumen. Although no clinically significant serum chloride increase has been observed inthe clinical studies, serum chloride should be monitored as is done in the routine follow-up of adialysis patient. One gram of Renagel contains approximately 180 mg (5.1 mEq) chloride.

Inflammatory Gastrointestinal Disorders

Cases of serious inflammatory disorders of different parts of the gastrointestinal tract (includingserious complications such as haemorrhage, perforation, ulceration, necrosis, colitis and colonic/caecalmass) associated with the presence of sevelamer crystals have been reported (see section 4.8).

Inflammatory disorders may resolve upon sevelamer discontinuation. Sevelamer hydrochloridetreatment should be re-evaluated in patients who develop severe gastrointestinal symptoms.

Interaction studies have not been conducted in patients on dialysis.

In interaction studies in healthy volunteers, sevelamer hydrochloride decreased the bioavailability ofciprofloxacin by approximately 50% when co-administered with Renagel in a single dose study.

Consequently, Renagel should not be taken simultaneously with ciprofloxacin.

Patients taking anti-arrhythmic medicinal products for the control of arrhythmias and anti-seizuremedicinal products for the control of seizure disorders were excluded from clinical trials. Cautionshould be exercised when prescribing sevelamer hydrochloride to patients also taking these medicinalproducts.

During post marketing experience, very rare cases of increased thyroid stimulating hormone (TSH)levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine.

Closer monitoring of TSH levels is therefore recommended in patients receiving both medicinalproducts.

Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus have been reported in transplantpatients when coadministered with sevelamer hydrochloride without any clinical consequences (i.egraft rejection). The possibility of an interaction cannot be excluded and a close monitoring of bloodconcentrations of mycophenolate mofetil, ciclosporin and tacrolimus should be considered during theuse of combination and after its withdrawal.

In interaction studies in healthy volunteers, Renagel had no effect on the bioavailability of digoxin,warfarin, enalapril or metoprolol.

During post-marketing experience, very rare cases of increased phosphate levels have been reported inpatients taking proton pump inhibitors co-administered with sevelamer hydrochloride.

Renagel 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 hourbefore or three hours after Renagel, or the physician should consider monitoring blood levels.

The safety of sevelamer hydrochloride has not been established in pregnant women. In animal studiesthere was no evidence that sevelamer induced embryo-foetal toxicity. Renagel should only be given topregnant women if clearly needed and after a careful risk/benefit analysis has been conducted for boththe mother and the foetus (see section 5.3).

The safety of sevelamer hydrochloride has not been established in breast-feeding women. Renagelshould only be given to breast-feeding women if clearly needed and after a careful risk/benefit analysishas been conducted for both the mother and the infant (see section 5.3).

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

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 gastrointestinaldisorders system organ class.

In parallel design studies involving 244 haemodialysis patients with treatment duration of up to 54weeks and 97 peritoneal dialysis patients with treatment duration of 12 weeks were conducted.

Adverse reactions from these studies (299 patients), from uncontrolled clinical trials (384 patients),and that were spontaneously reported from post-marketing experience are listed by frequency in thetable below. The reporting rate is classified as 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 form the available data).

MedDRA Very Common Uncommon Very Rare Not known

System Organ Common

Class

Immune system Hypersensitivity*disorders

Metabolism and Acidosis,nutrition increaseddisorders serumchloridelevels

Gastrointestinal Nausea, Diarrhoea, Abdominal pain,disorders vomiting dyspepsia, intestinalflatulence, obstruction,upper ileus/subileus,abdominal diverticulitis,pain, intestinalconstipation perforation1,gastrointestinalhemorrhage*1,intestinalulceration*1,gastrointestinalnecrosis*1,colitis*1,intestinalmass*1

Skin and Pruritus, rashsubcutaneoustissue disorders

Investigations Crystal depositintestine*1

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

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.

Renagel has been given to normal healthy volunteers in doses up to 14 grams, the equivalent ofseventeen 800 mg tablets per day for eight days with no undesirable effects.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Treatment of hyperphosphatemia. ATC code: V03AE02.

Renagel contains sevelamer, a non-absorbed phosphate binding poly (allylamine hydrochloride)polymer, free of metal and calcium. It contains multiple amines separated by one carbon from thepolymer backbone. These amines become partially protonated in the intestine and interact withphosphate molecules through ionic and hydrogen bonding. By binding phosphate in thegastrointestinal tract, sevelamer lowers the phosphate concentration in the serum.

In clinical trials, sevelamer has been shown to be effective in reducing serum phosphorus in patientsreceiving haemodialysis or peritoneal dialysis.

Sevelamer decreases the incidence of hypercalcaemic episodes as compared to patients using calciumbased phosphate binders alone, probably because the product itself does not contain calcium. Theeffects on phosphate and calcium were proven to be maintained throughout a study with one yearfollow-up.

Sevelamer has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bileacid binding by ion exchange resins is a well-established method of lowering blood cholesterol. Inclinical trials mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2weeks is maintained with long-term treatment. Triglycerides, HDL cholesterol and albumin did notchange.

In the clinical studies in haemodialysis patients, sevelamer alone did not have a consistent andclinically significant effect on serum intact parathyroid hormone (iPTH). In the 12 week studyinvolving peritoneal dialysis patients however, similar iPTH reductions were seen compared withpatients receiving calcium acetate. In patients with secondary hyperparathyroidism Renagel should beused within the context of a multiple therapeutic approach, which could include calcium supplements,1,25-dihydroxy Vitamin D3 or one of its analogues to lower the iPTH levels.

In a clinical trial of one-year duration, Renagel had no adverse effect on bone turnover ormineralisation compared to calcium carbonate.

Renagel is not absorbed from the gastrointestinal tract according to a single dose pharmacokineticstudy in healthy volunteers. Pharmacokinetic studies have not been carried out in renal failure patients(see section 4.4).

In preclinical studies in rats and dogs, Renagel at a dose of 10 times the maximum human dosesreduced absorption of fat soluble vitamins D, E and K, and folic acid.

In a study in rats, administering sevelamer in 15-30 x the human dose, an increase in serum copperwas detected. This was not confirmed in a dog study or in clinical trials.

Currently, no formal carcinogenicity data are available. However, in vitro and in vivo studies haveindicated that Renagel does not have genotoxic potential. Also the medicinal product is not absorbed inthe gastrointestinal tract.

In reproduction studies there was no evidence that sevelamer induced embryolethality, foetotoxicity orteratogenicity at the doses tested (up to 1 g/kg/day in rabbits and up to 4.5 g/kg/day in rats). Deficits inskeletal ossification were observed in several locations in fetuses of female rats dosed with sevelamerat 8-20 times the maximum human dose of 200 mg/kg. The effects may be secondary to vitamin Dand/or vitamin K depletion at these high doses.

Silica, colloidal anhydrous

Stearic acid

Hypromellose (E464)

Diacetylated monoglycerides

Not applicable

3 years

Do not store above 25ºC.

Keep the bottle tightly closed in order to protect from moisture.

HDPE bottles, with a child resistant polypropylene closure and a foil induction seal.

Package sizes are:1 bottle of 100 film-coated tablets1 bottle of 180 film-coated tabletsmultipacks containing 180 film-coated tablets (6 bottles of 30 tablets)multipacks containing 360 film-coated tablets (2 bottles of 180 tablets)multipacks containing 540 film-coated tablets (3 bottles of 180 tablets)

Not all pack sizes may be marketed.

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

Sanofi Winthrop Industrie82 Avenue Raspail94250 Gentilly

France

EU/1/99/123/008 1 bottle of 180 film-coated tablets

EU/1/99/123/009 multipacks containing 360 film-coated tablets (2 bottles of 180 tablets)

EU/1/99/123/010 multipacks containing 540 film-coated tablets (3 bottles of 180 tablets)

EU/1/99/123/011 1 bottle of 100 film-coated tablets

EU/1/99/123/012 1 bottle of 180 film-coated tablets without outer carton

EU/1/99/123/013 multipacks containing 180 film-coated tablets (6 bottles of 30 tablets)

Date of first authorisation: 28 January 2000

Date of latest renewal: 19 November 2014

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

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