SEVELAMER CARBONATE BIOGARAN 800 mg Film-coated Tablet Fl/180

Sevelamer carbonate........................................................................................................................................ 800 mg

For one film-coated tablet

Excipient with known effect: each film-coated tablet contains 286,25 mg of lactose monohydrate.

SEVELAMER CARBONATE BIOGARAN is indicated for the control of hyperphosphatemia in adults on haemodialysis or peritoneal dialysis.

SEVELAMER CARBONATE BIOGARAN is also indicated for the control of hyperphosphatemia in adults with chronic kidney disease (CKD) not on dialysis, whose serum phosphate level is greater than or equal to 1,78 mmol/l.

SEVELAMER CARBONATE BIOGARAN must be used as part of a multiple therapeutic approach, which may include calcium supplementation, vitamin 1,25-dihydroxy D3 or an analogue, to prevent the development of renal osteodystrophy.

Dosage

Initial dose

The recommended initial dose of sevelamer carbonate is 2,4 g or 4,8 g per day depending on clinical needs and serum phosphate level. SEVELAMER CARBONATE BIOGARAN must be taken three times a day with meals.

* With subsequent dose increase, see section "Dose titration and maintenance dosage"

In patients previously on phosphate binders (sevelamer hydrochloride or calcium-based binders), SEVELAMER CARBONATE BIOGARAN must be administered at an equivalent dose in grams while monitoring serum phosphate levels until optimal daily doses are reached.

Dose escalation and maintenance dosage

Serum phosphate levels must be monitored and the dose of sevelamer carbonate increased in steps of 0,8 g three times a day (2,4 g per day) every 2-4 weeks until an acceptable serum phosphate level is achieved. Thereafter, regular monitoring must be maintained.

Patients receiving sevelamer carbonate should follow the diet that has been prescribed for them.

In clinical practice, treatment must be continuous in order to balance serum phosphate levels, and the expected daily dose is, on average, approximately 6 g per day.

Special populations

Elderly patients

No dose adjustment is necessary in elderly patients.

Patients with hepatic impairment

No studies have been conducted in patients with hepatic impairment.

Paediatric population

The safety and efficacy of SEVELAMER CARBONATE BIOGARAN in children aged less than 6 years or whose SC is less than 0,75 m2 have not been established. No data are available.

The safety and efficacy of SEVELAMER CARBONATE BIOGARAN in children aged more than 6 years and whose SC > 0,75 m2 have not been evaluated. The data currently available are described in the section Pharmacodynamics.

For the paediatric population, since the tablets are not suitable, the oral suspension must be administered.

Method of administration

By oral route.

The tablets must be swallowed whole, without being crushed, chewed or cut into pieces before administration. SEVELAMER CARBONATE BIOGARAN must be taken during a meal or a snack and must not be taken on an empty stomach.

• Hypersensitivity to the active substance or to any of the excipients listed in section Composition.
• Hypophosphataemia.
• Intestinal obstruction.

The safety and efficacy of sevelamer carbonate have not been studied in adults with non-dialysed chronic kidney disease whose serum phosphate level is less than 1,78 mmol/L. Therefore, it is currently not recommended in these patients.

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

• dysphagia;
• swallowing disorders;
• severe gastrointestinal motility disorders including untreated or severe gastroparesis, retention of gastric contents and abnormal or irregular stools;
• active inflammatory bowel disease;
• major gastrointestinal surgery.

Treatment of these patients with SEVELAMER CARBONATE BIOGARAN must be initiated only after careful assessment of the benefit/risk ratio. If treatment is initiated, patients with these disorders must be monitored. Treatment with SEVELAMER CARBONATE BIOGARAN must be re-evaluated in patients who develop constipation or other severe gastrointestinal symptoms.

Intestinal obstruction and ileus/subileus

In very rare cases, intestinal obstruction and ileus / subileus have been observed in patients taking sevelamer hydrochloride (capsules/tablets), which contains the same active molecular moiety as sevelamer carbonate. Constipation may be a precursor symptom. Constipated patients must be closely monitored during treatment with SEVELAMER CARBONATE BIOGARAN. Treatment must be re-evaluated in patients if constipation or severe gastrointestinal symptoms occur.

Fat-soluble vitamins and folate deficiency

Patients with chronic kidney disease may present with low levels of the fat-soluble vitamins A, D, E and K, depending on dietary intake and the severity of their disease. Binding of fat-soluble vitamins present in the diet by sevelamer carbonate cannot be excluded. In patients taking sevelamer who do not take vitamin supplements, serum concentrations of vitamins A, D, E and K must be assessed regularly.

It is recommended to give vitamin supplements as needed and to prescribe vitamin D supplements (approximately 400 IU of native vitamin D per day) to patients with chronic kidney disease who are not on dialysis. These supplements may be incorporated into a multivitamin preparation to be taken apart from the sevelamer carbonate dose. In patients on peritoneal dialysis, additional monitoring of fat-soluble vitamins and folic acid is recommended. Indeed, concentrations of vitamins A, D, E and K were not measured in these patients during clinical studies.

Currently available data do not exclude the possibility of folate deficiency during long-term treatment with sevelamer carbonate. In patients taking sevelamer who are not receiving folic acid supplementation, folate levels should be assessed regularly.

Hypocalcaemia/hypercalcaemia

Patients with chronic kidney disease are at risk of developing hypocalcaemia or hypercalcaemia. Sevelamer carbonate does not contain calcium. Serum calcium should therefore be monitored at regular intervals and calcium supplementation should be given if necessary.

Metabolic acidosis

Patients with CKD are susceptible to developing metabolic acidosis. Good clinical practice therefore recommends monitoring serum bicarbonate levels.

Peritonitis

Dialysed patients are subject to certain infection risks inherent to the dialysis technique used. Peritonitis is a known complication in patients on peritoneal dialysis. In a clinical trial with sevelamer hydrochloride, more cases of peritonitis were reported in the sevelamer group than in the control group. Patients on peritoneal dialysis should be closely monitored to ensure aseptic conditions are respected and that any signs and symptoms associated with peritonitis are promptly identified and managed.

Difficulty swallowing and risk of choking

Rare cases of difficulty swallowing SEVELAMER CARBONATE BIOGARAN tablets have been reported. For the most part, these were patients with comorbidities, including swallowing disorders or oesophageal abnormalities. The ability to swallow properly should be closely monitored in patients with comorbidities. Administration of sevelamer carbonate powder should be considered in patients with a history of swallowing difficulty.

Hypothyroidism

Closer monitoring of patients with hypothyroidism receiving sevelamer carbonate and levothyroxine concomitantly is recommended (see section Interactions).

Hyperparathyroidism

Sevelamer carbonate is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism, sevelamer carbonate should be used as part of a multiple therapeutic approach, which may include calcium supplements, 1,25-dihydroxy vitamin D3 or an analogue, to reduce intact Parathyroid Hormone (iPTH) levels.

Disorders iGastrointestinal inflammatory disorders

Cases of severe inflammatory disorders affecting different parts of the gastrointestinal tract (including serious complications such as haemorrhage, perforation, ulceration, necrosis, colitis and colonic mass/mass at the caecum) associated with the presence of sevelamer crystals have been reported (see section Adverse effects).

Inflammatory disorders may resolve upon discontinuation of sevelamer. Treatment with sevelamer carbonate should be reassessed in patients presenting with severe gastrointestinal symptoms..

Lactose intolerance

Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) must not take this medicine.

Dialysis

No interaction study has been performed in dialysis patients.

Ciprofloxacin

In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active molecular moiety as sevelamer carbonate, decreased the bioavailability of ciprofloxacin by approximately 50% when both medicinal products were administered concomitantly, in a single-dose study. Therefore, sevelamer carbonate must not be administered at the same time as ciprofloxacin.

Ciclosporin, mycophenolate mofetil and tacrolimus in transplant patients

A decrease in cyclosporine, mycophenolate mofetil and tacrolimus levels has been reported in transplant patients when administered concomitantly with sevelamer hydrochloride, without clinical consequences (e.g., graft rejection). The possibility of an interaction therefore cannot be excluded, and close monitoring of blood concentrations of cyclosporine, mycophenolate mofetil and tacrolimus should be considered when co-administered with SEVELAMER CARBONATE BIOGARAN and after its discontinuation.

Levothyroxine

Very rare cases of hypothyroidism have been reported in patients concomitantly receiving sevelamer hydrochloride, which contains the same active molecular moiety as sevelamer carbonate, and levothyroxine. Closer monitoring of thyroid-stimulating hormone (TSH) levels is therefore recommended in patients receiving sevelamer carbonate and levothyroxine.

Antiarrhythmics and anticonvulsants

Patients receiving antiarrhythmics for arrhythmia or anticonvulsants for convulsive disorders were excluded from clinical trials. A possible reduction in absorption therefore cannot be excluded. Antiarrhythmics should be taken at least one hour before or three hours after SEVELAMER CARBONATE BIOGARAN, and blood monitoring may be considered.

Proton pump inhibitors

Since marketing, very rare cases of increased phosphate concentrations have been reported in patients treated concomitantly with proton pump inhibitors and sevelamer carbonate. PPIs should be prescribed with caution in patients who are treated in combination with SEVELAMER CARBONATE BIOGARAN. Serum phosphate levels should be monitored and the dosage of SEVELAMER CARBONATE BIOGARAN adjusted accordingly.

Bioavailability

Sevelamer carbonate is not absorbed and may affect the bioavailability of other medicinal products. Medicinal products whose reduced bioavailability may have a significant clinical impact on their safety or efficacy should be administered at least one hour before or three hours after taking sevelamer carbonate. If this is not possible, monitoring of blood levels should be considered by the physician.

Digoxin, warfarin, enalapril or metoprolol

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

Pregnancy

There are no data on the use of sevelamer in pregnant women. Studies in animals have shown reproductive toxicity when sevelamer was administered at high doses to rats (see section ). It has also been demonstrated that sevelamer reduces the absorption of several vitamins, including folic acid (see sections ). The potential clinical risk is not known. Sevelamer carbonate should only be administered to pregnant women if absolutely necessary, after careful assessment of the benefit/risk ratio, both for the mother and for the foetus. Preclinical safety). It has also been demonstrated that sevelamer reduces the absorption of several vitamins, including folic acid (see sections Warnings and precautions and Preclinical safety). The potential clinical risk is not known. Sevelamer carbonate should only be administered to pregnant women if absolutely necessary, after careful assessment of the benefit/risk ratio, both for the mother and for the fetus.

Breast-feeding

There is no data on the excretion of sevelamer in breast milk. As sevelamer is not absorbed, its excretion in breast milk is unlikely. The decision to continue or stop breastfeeding, or to continue or discontinue treatment with sevelamer carbonate, must take into account the benefit of breastfeeding for the child and the benefit of sevelamer carbonate treatment for the mother.

Fertility

There is no data on the effect of sevelamer on male fertility. Animal studies have shown that sevelamer had no effect on the fertility of male and female rats, exposed to doses equivalent in humans to twice the maximum dose of 13 g/day used in clinical trials, based on a comparison of relative AUCs.

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

Summary of the safety profile

The most frequent adverse reactions (≥ 5 % of patients) all belonged to the system organ class "Gastrointestinal disorders". Most of these adverse reactions were of mild to moderate intensity.

List of adverse reactionsin table form

The safety of sevelamer (as carbonate or hydrochloride) has been studied in numerous clinical trials, involving a total of 969 hemodialysis patients treated over a period of 4 to 50 weeks (724 patients treated with sevelamer hydrochloride and 245 with sevelamer carbonate), 97 peritoneal dialysis patients treated over a period of 12 weeks (all treated with sevelamer hydrochloride), and 128 patients with chronic kidney disease not on dialysis treated over a period of 8 to 12 weeks (79 patients treated with sevelamer hydrochloride and 49 with sevelamer carbonate).

Adverse reactions occurring during clinical trials or reported spontaneously since marketing are listed by frequency in the table below. The frequency classification of adverse events is as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10 000 to < 1/1000), very rare (< 1/10 000), frequency not known (cannot be estimated from the available data).

*post-marketing1See the warning on gastrointestinal inflammatory disorders in section Warnings and precautions

Reporting of suspected adverse reactions

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. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: www.signalement-sante.gouv.fr.

Sevelamer hydrochloride, which contains the same active molecular fragment as sevelamer carbonate, has been administered to healthy volunteers at doses of up to 14 grams per day for eight days, without adverse effects. In patients with chronic renal failure, the maximum average daily dose studied was 14,4 grams of sevelamer carbonate as a single dose. The symptoms observed in cases of overdose are similar to the adverse effects listed in section Adverse effects, mainly including constipation and other known gastrointestinal disorders. Appropriate symptomatic treatment must be instituted.

Pharmacotherapeutic class: Medicinal products for hyperkalaemia and hyperphosphataemia, ATC code: V03AE02.

Mechanism of action

SEVELAMER CARBONATE BIOGARAN contains sevelamer, a non-absorbed cross-linked phosphate-binding polymer, free of metal and calcium. Sevelamer contains several amines separated by a carbon atom from the polymer backbone, which are protonated in the stomach. These protonated amines bind negative ions, such as dietary phosphates, in the intestines.

Pharmacodynamic effect

Through chelation of phosphates in the gastrointestinal tract and reduction of absorption, sevelamer reduces serum phosphate concentration. Regular monitoring of serum phosphate levels must always be carried out during administration of a phosphate binder.

Clinical efficacy and safety

In two randomised clinical trials (crossover designs), sevelamer carbonate in tablets or powder administered three times daily demonstrated therapeutic equivalence with sevelamer hydrochloride. It is therefore effective in controlling serum phosphate levels in haemodialysis patients with chronic renal failure.

The first study demonstrated that sevelamer carbonate tablets administered three times daily were equivalent to sevelamer hydrochloride tablets administered three times daily in 79 haemodialysis patients treated over two randomised treatment periods of 8 weeks (the time-weighted mean serum phosphate concentrations were 1,5 ± 0,3 mmol/l for sevelamer carbonate and sevelamer hydrochloride). The second study demonstrated that sevelamer carbonate powder administered three times daily was equivalent to sevelamer hydrochloride tablets administered three times daily in 31 haemodialysis patients with hyperphosphataemia (defined as a serum phosphate level ≥ 1,78 mmol/l) over two randomised treatment periods of 4 weeks (the time-weighted mean serum phosphate concentrations were 1,6 ± 0,5 mmol/l for sevelamer carbonate powder and 1,7 ± 0,4 mmol/l for sevelamer hydrochloride tablets).

In clinical trials conducted in haemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on iPTH. Nevertheless, during a 12-week study conducted in peritoneal dialysis patients, reductions in iPTH comparable to those in patients receiving calcium acetate were observed. In patients with secondary hyperparathyroidism, sevelamer carbonate should be used as part of a multiple therapeutic approach, which may include calcium supplements, vitamin 1,25-dihydroxy D or an analogue, to reduce iPTH levels.3 or an analogue, to reduce iPTH levels.

Sevelamer binds bile acids in vitro and in vivo in animal models. Binding of bile acids by ion-exchange resins is a well-known method for lowering cholesterol. In clinical trials of sevelamer, mean total cholesterol and LDL cholesterol levels decreased by 15-39 %. The decrease in cholesterol levels was observed after 2 weeks of treatment and was maintained during prolonged treatment. Triglyceride, HDL cholesterol and albumin levels did not change after treatment with sevelamer.

Since sevelamer binds bile acids, it may disrupt the absorption of fat-soluble vitamins such as vitamins A, D, E and K.

Sevelamer does not contain calcium and reduces the incidence of hypercalcaemic episodes compared with calcium-based phosphate chelators alone. It has been shown that the effects of sevelamer on phosphate and calcium were maintained throughout a study with one year of follow-up. This information is taken from studies in which sevelamer hydrochloride was used.

Paediatric population

The safety and efficacy of sevelamer carbonate in the paediatric population with hyperphosphataemia and CKD were evaluated in a multicentre study with a fixed-dose period of 2 weeks, randomised and placebo-controlled, followed by a dose-titration period of 6 months, open-label, single-arm. A total of 101 patients (aged 6 to 18 years with a body surface area between 0,8 m2 and 2,4 m2) were randomised in the study. Forty-nine (49) patients received sevelamer carbonate and 51 patients received placebo during the fixed-dose period of 2 weeks. Subsequently, all patients received sevelamer carbonate during the dose-titration period of 26 weeks. The primary endpoint was met, meaning that sevelamer carbonate reduced serum phosphate levels by a mean difference of - 0,90 mg/dL (least squares method) compared with placebo, and the secondary efficacy endpoints were also met. In paediatric patients with hyperphosphataemia secondary to CKD, sevelamer carbonate significantly reduced serum phosphate levels compared with placebo during the fixed-dose period of 2 weeks. The therapeutic response was maintained in paediatric patients receiving sevelamer carbonate during the open-label dose-titration period of 6 months. Twenty-seven percent of paediatric patients reached an age-appropriate serum phosphate level at the end of treatment. In the subgroups of patients on haemodialysis and peritoneal dialysis, these figures were 23% and 15%, respectively. The therapeutic response during the fixed-dose period of 2 weeks was not affected by SC; however, no therapeutic response was observed in paediatric patients with a phosphate level below 7,0 mg/dL. The majority of adverse effects reported as related, or possibly related, to sevelamer carbonate were gastrointestinal in nature. No new risk or signal was identified with the use of sevelamer carbonate during the study.

No pharmacokinetic study has been performed on sevelamer carbonate. Sevelamer hydrochloride, which contains the same active molecular moiety as sevelamer carbonate, is not absorbed from the gastrointestinal tract, as confirmed in an absorption study conducted in healthy volunteers.

In a one-year clinical trial, no sign of sevelamer accumulation was observed. However, the potential absorption and accumulation of sevelamer during long-term chronic treatment (> one year) cannot be fully excluded.

Preclinical data from conventional safety pharmacology, repeated-dose toxicity or genotoxicity studies on sevelamer did not reveal any particular risk for humans.

Carcinogenicity studies on oral sevelamer hydrochloride were conducted in mice (doses up to 9 g/kg/day) and in rats (0,3, 1 or 3 g/kg/day). An increased incidence of transitional cell papillomas of the bladder in male rats was observed in the high-dose group (equivalent to a human dose twice the maximum dose of 14,4 g used in trials). No increase in tumour incidence was observed in mice (dose equivalent to a human dose 3 times higher than the maximum dose used in the clinical trial).

In a cytogenetic test in vitro on mammalian cells with metabolic activation, sevelamer hydrochloride caused a statistically significant increase in the number of structural chromosomal aberrations. Sevelamer hydrochloride was not mutagenic in the Ames bacterial mutation test.

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

Skeletal ossification deficits were observed at several sites in foetuses of female rats given intermediate and high doses of sevelamer (dose equivalent to a human dose below the maximum dose of 14,4 g used in the clinical trial). The effects may result from vitamin D depletion.

In pregnant female rabbits given oral doses of sevelamer hydrochloride by gavage during organogenesis, an early increase in foetal resorptions occurred in the high-dose group (dose equivalent to a human dose twice the maximum dose used in the clinical trial).

Sevelamer hydrochloride did not impair the fertility of male and female rats in a dietary administration study in which females were treated for 14 days before mating and throughout gestation, and males for the 28 days preceding mating. The highest dose used in this study was 4,5 g/kg/day (human-equivalent dose of 2 times the maximum dose of 13 g/day used in clinical trials, based on a comparison of relative AUCs).

3 years.

This medicine does not require any particular storage precautions.

No special requirements for disposal.

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree