4.1. Therapeutic indications

Sevelamer is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis or peritoneal dialysis.

Sevelamer 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.

Sevelamer should be used within the context of a multiple therapeutic approach, which could include calcium supplement, 1,25-dihydroxy Vitamin D3 or one of its analogues to control the development of renal bone disease.

4.2. Posology and method of administration

Posology

Starting dose

The recommended starting dose of sevelamer carbonate is 2.4 g or 4.8 g per day based on clinical needs and serum phosphorus level. Sevelamer must be taken 3x per day with meals.

Serum phosphorus level in patients

Total daily dose of sevelamer carbonate to be taken over 3 meals per day

1.78 – 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 2 Titration and maintenance.

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

Titration and Maintenance

Serum phosphorus levels must be monitored and the dose of sevelamer carbonate titrated by 0.8 g 3x per day (2.4 g/day) increment every 2-4 weeks until an acceptable serum phosphorus level is reached, with regular monitoring thereafter.

Patients taking sevelamer carbonate should adhere to their prescribed diets.

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

Special populations

Elderly

No dosage adjustment is necessary in the elderly population.

Hepatic impairment

No studies have been performed in patients with hepatic impairment.

Paediatric population

The safety and efficacy of sevelamer carbonate in children below the age of 6 years or in children with a body surface area (BSA) below 0.75 m2 have not been established. No data are available.

The safety and efficacy of sevelamer carbonate in children over 6 years of age and a BSA > 0.75 m2 have been established. Current available data are described in section 5.1.

For paediatric patients the oral suspension available on the market should be administered, as tablet formulations are not appropriate for this population.

Method of administration

For oral use.

Tablets should be swallowed intact and should not be crushed, chewed, or broken into pieces prior to administration. Sevelamer should be taken with food and not on an empty stomach.

4.3. Contraindications

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

• Hypophosphataemia

• Bowel obstruction.

4.4. Special warnings and precautions for use

The safety and efficacy of sevelamer carbonate have not been established in adult patients with CKD not on dialysis with serum phosphorus < 1.78 mmol/l. Therefore it is currently not recommended for use 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 bowel motion

• active inflammatory bowel disease

• major gastrointestinal tract surgery

Treatment of these patients with sevelamer carbonate should only be initiated after careful benefit/risk assessment. If the therapy is initiated, patients suffering from these disorders should be monitored. Sevelamer carbonate treatment should be re-evaluated in patients who develop severe 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 during treatment with sevelamer hydrochloride (capsules/tablets). Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with sevelamer carbonate. The treatment should be re-evaluated in patients who develop severe constipation or other severe gastrointestinal symptoms.

Fat-soluble vitamins and folate deficiency

Patients with CKD may develop low levels of fat-soluble vitamins A, D, E and K, depending on dietary intake and the severity of their disease. It cannot be excluded that sevelamer carbonate can bind fat-soluble vitamins contained in ingested food. In patients not taking supplemental vitamins but on sevelamer, serum vitamin A, D, E and K status should be assessed regularly. It is recommended that vitamin supplements be given 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 taken apart from their dose of sevelamer carboante. In patients undergoing peritoneal dialysis additional monitoring of fat soluble vitamins and folic acid is recommended, since vitamin A, D, E and K levels were not measured in a clinical study in these patients.

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

Hypocalcaemia/hypercalcaemia

Patients with CKD may develop hypocalcaemia or hypercalcaemia. sevelamer carboante does not contain any calcium. Serum calcium levels should therefore be monitored at regular intervals and elemental calcium should be given as a supplement if required.

Metabolic acidosis

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

Peritonitis

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

Swallowing and choking difficulties

Uncommon reports of difficulty swallowing the sevelamer carbonate tablet have been reported. Many of these cases involved patients with co-morbid conditions including swallowing disorders or oesophageal abnormalities. Proper swallowing ability should be carefully monitored in patients with co-morbid conditions. The use of sevelamer carbonate powder available on the market in patients with a history of difficulty swallowing should be considered.

Hypothyroidism

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

Hyperparathyroidism

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

Inflammatory Gastrointestinal Disorders

Cases of serious inflammatory disorders of different parts of the gastrointestinal tract (including serious complications 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). Inflammatory disorders may resolve upon sevelamer discontinuation. Sevelamer carbonate treatment should be re- evaluated in patients who develop severe gastrointestinal symptoms.

Excipient

Sevelamer tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Dialysis

Interaction studies have not been conducted in patients on dialysis.

Ciprofloxacin

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

Ciclosporin, mycophenolate mofetil and tacrolimus in transplant patients

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

Levothyroxine

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

Anti-arrhythmics and anti-seizure medicinal products

Patients taking anti-arrhythmic medicinal products for the control of arrhythmias and anti-seizure medicinal products for the control of seizure disorders were excluded from clinical trials. Therefore, possible reduction in absorption cannot be excluded. The anti-arrhythmic medical product should be taken at least 1 h before or 3 h after sevelamer carbonate, and blood monitoring can be considered.

Proton pump inhibitors (PPI)

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

Bioavailability

Sevelamer carbonate 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 sevelamer carbonate, or the physician should consider monitoring blood levels.

Digoxin, warfarin, enalapril or metoprolol

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

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of sevelamer in pregnant women. Animal studies have shown 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 (see sections 4.4 and 5.3). The potential risk to humans is unknown. Sevelamer carbonate 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.

Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

The safety of sevelamer (as either carbonate and hydrochloride salts) has been investigated in numerous clinical trials involving a total of 969 haemodialysis patients with treatment duration of 4 - 50 weeks (724 patients treated with sevelamer hydrochloride and 245 with sevelamer carbonate), 97 peritoneal dialysis patients with treatment duration of 12 weeks (all treated with sevelamer hydrochloride) and 128 patients with CKD not on dialysis with treatment duration of 8 - 12 weeks (79 patients treatment with sevelamer hydrochloride 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 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 from the available data).

MedDRA System Organ Class

Very Common

Common

Very rare

Not known

Immune system disorders

Hypersensitivity*

Gastrointestinal disorders

Nausea, vomiting, upper abdominal pain, constipation

Diarrhoea, dyspepsia, flatulence, abdominal pain

Intestinal obstruction, ileus/subileus, intestinal perforation1, gastrointestinal haemorrhage*1, intestinal ulceration*1, gastrointestinal necrosis*1, colitis*1, intestinal mass*1

Skin and subcutaneous tissue disorders

Pruritus, rash

Investigations

Crystal deposit intestine*1

*Post-marketing experience

1 See inflammatory gastrointestinal disorders warning in section 4.4.

Paediatric population

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

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 reactions via the MHRA Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Sevelamer hydrochloride, has been given to normal healthy volunteers in doses of up to 14 g per day for 8 days with no undesirable effects. In CKD patients, the maximum average daily dose studied was 14.4 g of sevelamer carbonate in a single daily dose.

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

Appropriate symptomatic treatment should be provided.