SEVELAMER CARBONATE 2.4 G POWDER FOR ORAL SUSPENSION - summary of medicine characteristics

Sevelamer carbonate 2.4 g powder for oral suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet contains 2.4 g sevelamer carbonate.

For the full list of excipients, see section 6.1.

Powder for oral suspension. Off-white to yellow powder

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

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

Starting dose

Adults

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

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 based on the patient’s BSA category. Sevelamer must be taken three times per day with meals or snacks.

Plus subsequent titrating, see section “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

*Adults

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

In clinical practice, treatment will be continuous based on the need to control serum phosphorus levels and the 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, serumphosphorus levels must be monitored and the dose of sevelamer carbonate titrated in increments based on patient’s BSA, three times per day every 2–4 weeks until an acceptable serum phosphorus level is reached, with regular monitoring thereafter.

Paediatric dose based on BSA (m2)

Patients taking sevelamer carbonate should adhere to their prescribed diets.

Special populations

Elderly population

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 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 tablet formulations were not tested in this population and therefore are not appropriate for this population.

Method of administration

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. Sevelamer should be taken with food and 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. 100 grams/120 ml) and consumed within 30 minutes. Do not heat [Product name] powder (e.g. microwave) or add to heated foods or liquids.

To achieve the correct dose, a 2.4 g sachet of [Product name] powder may be divided. The [Product name] powder may be measured by volume (ml) using a measuring scoop or measuring spoon. Further instructions are detailed in the Patient Leaflet.

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 chronic kidney disease 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 should only be initiated after careful benefit/risk assessment. If the therapy is initiated, patients suffering from these disorders should be monitored. Sevelamer treatment should be reevaluated 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), which contains the same active moiety as sevelamer carbonate. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with sevelamer. 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 carbonate. 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, folate level should be assessed regularly.

Hypocalcaemia/hy­percalcaemia

Patients with CKD may develop hypocalcaemia or hypercalcaemia. Sevelamer 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.

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

Proton pump inhibitors

During post-marketing experience, very rare cases of increased phosphate levels have been reported in patients taking proton pump inhibitors co-administered with sevelamer carbonate. Caution should be exercised when prescribing PPI to patients concomitantly treated with Sevelamer. The phosphate serum level should be monitored and the Sevelamer 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 nonabsorbed 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 2 times 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 to 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 to 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).

*post-marketing experience

1See inflammatory gastrointestinal disorders warning in section 4.4.

Paediatric population

In general, the safety profile for children and adolescents (6 to 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been given to normal 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 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.

5.1 Pharmacodynamic properties

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

Mechanism of action

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

Pharmacodynamic effects

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

Clinical efficacy and safety

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

The first study demonstrated that sevelamer carbonate tablets dosed three times per day was equivalent to sevelamer hydrochloride tablets dosed three times per day in 79 haemodialysis patients treated over two randomised 8 week treatment periods (mean serum phosphorus time-weighted averages were 1.5 ± 0.3 mmol/l for both sevelamer carbonate and sevelamer hydrochloride). The second study demonstrated that sevelamer carbonate powder dosed three times per day was equivalent to sevelamer hydrochloride tablets dosed three times per day in 31 hyperphospha­taemic (defined as serum phosphorus levels > 1.78 mmol/l) haemodialysis patients over two randomised 4 week treatment periods (mean serum phosphorus time-weighted averages were 1.6 ± 0.5 mmol/l for sevelamer carbonate powder and 1.7 ± 0.4 mmol/l for sevelamer hydrochloride tablets).

In the clinical trials in haemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on iPTH. In a 12 week study involving peritoneal dialysis patients however, similar iPTH reductions were seen compared with patients receiving calcium acetate. 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 iPTH levels.

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 of sevelamer, both the mean totalcholesterol and LDL-cholesterol declined by 15–39%. The decrease in cholesterol 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 to patients using calcium based phosphate binders alone. The effects of sevelamer on phosphorus and calcium were proven to be maintained throughout a study with one year follow-up. This information was obtained from studies in which sevelamer hydrochloride was used.

Paediatric population

The safety and effectiveness of sevelamer carbonate in hyperphosphatemic paediatric patients with CKD was evaluated 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 18 years old with a BSA range of 0.8 m2 to 2.4 m2) were randomised in the study. Forty-nine (49) patients received sevelamer carbonate and 51 received placebo during the 2 week FDP. Thereafter all patients received sevelamer carbonate for the 26-week DTP. The study met its primary endpoint, meaning Sevelamer carbonate reduced serum phosphorus by an LS mean difference of 0.90 mg/dL compared to placebo, and secondary efficacy endpoints. In paediatric patients with hyperphosphatemia secondary to CKD, sevelamer carbonate significantly reduced serum phosphorus levels compared to placebo during a 2-week FDP. The treatment 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 at end of treatment. These figures were 23% and 15% in the subgroup of patients on hemodialysis and peritoneal dialysis, respectively. The treatment response during the 2-week FDP was not affected by BSA, in contrast however, no treatment response was observed in paediatric patients with qualifying phosphorus levels <7.0 mg/dL. Most of adverse events reported as related, or possibly related, to sevelamer carbonate were gastrointestinal in nature. No new risks or safety signals were identified with the use of sevelamer carbonate during the study.

5.2 Pharmacokinetic properties

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 gastrointestinal tract, 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 potential absorption and accumulation of sevelamer during long-term chronic treatment (> one year) cannot be totally excluded.

5.3 Preclinical safety data

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

Carcinogenicity studies with oral sevelamer hydrochloride were conducted in mice (doses of up to 9 g/kg/day) and rats (0.3, 1, or 3 g/kg/day). There was an increased incidence of urinary bladder transitional cell papilloma in male rats of the high dose group (human equivalent dose twice the maximum clinical trial dose of 14.4 g). There was no increased incidence of tumours observed in mice (human equivalent dose 3 times the maximum clinical trial dose).

In an in vitro mammalian cytogenetic test with metabolic activation, sevelamer hydrochloride caused a statistically significant increase in the number of structural chromosome aberrations. Sevelamer hydrochloride 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), and folic acid.

Deficits in skeletal ossification were observed in several locations in foetuses of female rats dosed with sevelamer at intermediate and high doses (human equivalent dose less than the maximum clinical trial dose of 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 increase of early resorptions occurred in the high-dose group (human equivalent dose twice the maximum clinical trial dose).

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose

Carmellose sodium

Sucralose

Lemon flavour

Orange flavour

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

After reconstitution

The oral suspension must be administered within 30 minutes.

6.4 Special precautions for storage

The medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Sachet of polyethylene terepthalate, low density polyethylene and aluminium foil laminate.

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

Not all pack sizes may be marketed.