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

Sevelamer Carbonate 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 carbonate 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.

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 Carbonate must be taken three times per day with meals.

*Plus subsequent titrating, see section “Titration and maintenance”

For patients previously on phosphate binders (Sevelamer hydrochloride or calcium based), Sevelamer Carbonate 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 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.

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.

Paediatric population

The safety and efficacy of Sevelamer Carbonate have not been established in children below the age of 6 years or in children with a BSA below 0.75 m2.

For Paediatric patients the oral suspension should be administered, as tablet formulations are not appropriate for this population.

Method of administration

Oral use.

Tablets should be swallowed intact and should not be crushed, chewed, or broken into pieces prior to administration.

Sevelamer Carbonate should be taken with food and not on an empty stomach.

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

Therefore caution should be exercised when it is used in these patients.

Intestinal obstruction and ileus/sub ileus

In very rare cases, intestinal obstruction and ileus/sub ileus 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 Carbonate. The treatment should be re-evaluated in patients who develop severe constipation or other severe

Gastrointestinal symptoms.

Fat-soluble vitamins

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.

Folate deficiency

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

Hypocalcaemia/hypercalcaemia

Patients with CKD may develop hypocalcaemia or hypercalcaemia. Sevelamer carbonate 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 Lamsiv tablet have been reported. Many of these cases involved patients with co-morbid conditions including swallowing disorders or oesophageal abnormalities. Caution should be exercised when it is used in patients with difficulty swallowing. The use of Sevelamer carbonate powder 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).

Long-term chronic treatment

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 (see section 5.2).

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 bleeding, perforation, ulceration, necrosis, colitis) associated with the presence of Sevelamer crystals have been reported in literature. However, the causality of the Sevelamer crystals in initiating such disorders has not been demonstrated. Sevelamer carbonate treatment should be re-evaluated in patients who develop severe gastrointestinal symptoms.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per 800 mg that is to say essentially 'sodium-free'.

Dialysis

Interaction studies have not been conducted in patients on dialysis.

Ciprofloxacin

In interaction studies in healthy volunteers, Sevelamer hydrochloride, which contains the same active moiety as Sevelamer carbonate, 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 coadministered 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. Caution should be exercised when prescribing Sevelamer carbonate to patients also taking these medicinal products.

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.

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.

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.

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 breastfeeding 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.

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

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).

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.

To report any side effect(s):

·         Saudi Arabia:

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 undesirable effects. In CKD patients, the maximum average daily dose studied was

14.4 grams of Sevelamer carbonate in a single daily dose.

Pharmacotherapeutic group: All other therapeutic products, drugs for treatment of hyperkalemia and hyperphosphataemia. ATC code: V03AE02.

Mechanism of action

Lamsev 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 effect

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.

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.

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).

Mannitol, Crospovidone, Hydroxypropyl Cellulose, Colloidal silicon dioxide, Talc, Glyceryl Behenate, Aquarius TM Prime BBN119000 clear and Opacode Black S-1- 17823.

Not applicable.

Store below 30oC.

Keep the bottle container tightly closed in order to protect from moisture. Keep this medicine out of the sight and reach of children.

180’s HDPE Container.

No special requirements.