Renagel 800 mg film-coated tablets

Each tablet contains 800 mg sevelamer hydrochloride.

For a full list of excipients, see section 6.1.

Film-coated tablet (tablet)

The off-white, oval tablets are imprinted with “Renagel 800” on one side.

Renagel is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis or peritoneal dialysis. 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 control the development of renal bone disease.

Posology

Starting dose

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

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

Titration and maintenance

Serum phosphate levels should be closely monitored and the dose of Renagel adjusted accordingly with the goal of lowering serum phosphate to 1.76 mmol/l (5.5 mg/dl) or less. Serum phosphate should be tested every two to three weeks until a stable serum 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 dose used in the chronic phase of a one year clinical study was 7 grams of sevelamer.

Paediatric population

The safety and efficacy of this product has not been established in patients below the age of 18 years. Renagel is not recommended in children below the age of 18 years.

Renal impairment

The safety and efficacy of this product has not been established in predialysis patients. Renagel is not recommended in these patients.

Method of administration

For oral use

Patients should take Renagel with meals and adhere to their prescribed diets. The tablets must be swallowed whole. Do not chew.

• Hypersensitivity to sevelamer or to any of the excipients..

• 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, diverticulosis, retention 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.

Intestinal obstruction and ileus/subileus

In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with Renagel. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with Renagel. Renagel treatment should be re-eva luated in patients who develop severe constipation or other severe gastrointestinal symptoms.

Fat-soluble vitamins

Depending on diet intake and the nature of end stage renal failure, dialysis patients may develop low vitamin A, D, E and K levels. It cannot be excluded that Renagel can bind fatsoluble vitamins contained in ingested food. Therefore, in patients not taking these vitamins, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of thromboplastin time should be considered and the vitamins should be supplemented if necessary. Additional monitoring of vitamins and folic acid is recommended in patients receiving peritoneal dialysis, since in the clinical study, 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.

Hypocalcaemia/hypercalcaemia

Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. Renagel does not contain calcium. Serum calcium levels should be monitored as is done in normal follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia.

Metabolic acidosis

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

Peritonitis

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 clinical study with Renagel, a number of peritonitis cases were reported. Therefore, patients on PD should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis.

Anti-arrhythmic and anti-seizure medicinal products

Caution should be exercised when prescribing Renagel to patients also taking antiarrhythmias and antiseizure medicinal products (see section 4.5).

Hypothyroidism

Closer monitoring of patients with hypothyroidism co-administered with sevelamer hydrochloride and levothryroxine 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 absorption and accumulation of sevelamer during long-term chronic treatment cannot be totally excluded (see section 5.2 Pharmacokinetics).

Hyperparathyroidism

Renagel alone is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism 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 lower the intact parathyroid hormone (iPTH) levels.

Serum chloride

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

Interaction studies have not been conducted in patients on dialysis.

In interaction studies in healthy volunteers, Renagel decreased the bioavailability of ciprofloxacin 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 medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from clinical trials. Caution should be exercised when prescribing Renagel to patients also taking these medications.

During post marketing experience, very rare cases of increased TSH levels have been reported in patients co-administered Renagel and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medications.

Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus have been reported in transplant patients when coadministered with Renagel without any clinical consequences (i.e graft rejection). The possibility of an interaction cannot be excluded and a close monitoring of blood concentrations of mycophenolate mofetil, ciclosporin and tacrolimus should be considered during the use 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.

Renagel is not absorbed and may affect the bioavailability of other medicinal products. When administering any medicinal product where a reduction in the bioavailability could have a clinically significant effect on safety or efficacy, the medicinal product should be administered at least one hour before or three hours after Renagel, or the physician should consider monitoring blood levels.

Pregnancy:

The safety of Renagel has not been established in pregnant women. In animal studies there was no evidence that sevelamer induced embryo-foetal toxicity. Renagel should only be given to pregnant women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the foetus (See 5.3 Preclinical safety data).

Lactation:

The safety of Renagel has not been established in lactating women. Renagel should only be given to lactating women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the infant (See 5.3 Preclinical safety data).

No studies on the effects on ability to drive and use machines have been performed.

In parallel design studies involving 244 haemodialysis patients with treatment duration of up to 54 weeks and 97 peritoneal dialysis patients with treatment duration of 12 weeks, the most frequently occurring ( 5% of patients) adverse reactions possibly or probably related to Renagel were all in the gastrointestinal disorders system organ class. Adverse reactions from these studies (299 patients) and from uncontrolled clinical trials (384 patients) are listed by frequency in the table below. The reporting rate is classified as very common (1/10), common (1/100, <1/10), uncommon (1/1,000, <1/100), rare (1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated form the available data).

Post-marketing experience: During post-approval use of Renagel, cases of pruritus, rash, abdominal pain, intestinal obstruction, ileus/subileus, diverticulitis and intestinal perforation have been reported.

No case of overdose has been reported.

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

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 the polymer backbone. These amines become partially protonated in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract, sevelamer lowers the phosphate concentration in the serum.

In clinical trials, selevamer has been shown to be effective in reducing serum phosphorus in patients receiving haemodialysis or peritoneal dialysis.

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

Sevelamer has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. In clinical trials mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2 weeks is maintained with long-term treatment. Triglycerides, HDL cholesterol and albumin did not change.

In the clinical studies in haemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on serum intact parathyroid hormone (iPTH). In the 12 week study involving peritoneal dialysis patients however, similar iPTH reductions were seen compared with patients receiving calcium acetate. In patients with secondary hyperparathyroidism 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 lower the intact parathyroid hormone (iPTH) levels.

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

Renagel is not absorbed from the gastrointestinal tract according to a single dose pharmacokinetic study in healthy volunteers. Pharmacokinetic studies have not been carried out in renal failure patients (see section 4.4 Special warnings and special precautions for use).

In preclinical studies in rats and dogs, Renagel at a dose of 10 times the maximum human doses reduced 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 copper was 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 have indicated that Renagel does not have genotoxic potential. Also the medicinal product is not absorbed in the gastrointestinal tract.

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

Tablet core:

Silica, colloidal anhydrous

Stearic acid

Film-coating:

Hypromellose

Diacetylated monoglycerides

Printing ink:

Iron oxide black (E172)

Propylene glycol

Hypromellose

Not applicable

3 years

Do not store above25ºC.

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

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

Package sizes are:

6 bottles of 30 tablets

1bottle of 100 tablets

1 bottle of 180 tablets

2 bottles of 180 tablets

3 bottles of 180 tablets

Not all pack sizes may be marketed.

No special requirements.

Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands

EU/1/99/123/008

EU/1/99/123/009

EU/1/99/123/010

EU/1/99/123/011

EU/1/99/123/012

EU/1/99/123/013

Date of first authorisation: 28/01/2000

Renewal date: 02/02/2010

06/2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.