RENVELA 800 MG TABLETS

4LE0112B

1.

NAME OF THE MEDICINAL PRODUCT

Renvela 800 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 800 mg sevelamer carbonate anhydrous.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablet).

The white to off-white tablets are imprinted with “RENVELA 800” on one side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Renvela is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis

or peritoneal dialysis.

Renvela is also indicated for the control of hyperphosphataemia in adult patients with chronic kidney

disease not on dialysis with serum phosphorus > 1.78 mmol/l.

Renvela should be used within the context of a multiple therapeutic approach, which could include

calcium supplement, 1,25-dihydroxy Vitamin D

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. Renvela must be taken three times 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 as per instructions

For patients previously on phosphate binders (sevelamer hydrochloride or calcium based), Renvela

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 every

2-4 weeks until an acceptable serum phosphorus level is reached, with regular monitoring thereafter.

Patients taking Renvela 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

Renvela is not indicated in children below the age of 18 years.

Method of administration

Oral use

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

administration.

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

Renvela is not indicated in children below the age of 18 years.

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 Renvela should only be initiated after careful benefit/risk

assessment. If the therapy is initiated, patients suffering from these disorders should be monitored.

Renvela 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 Renvela. 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 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 chronic kidney disease 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 Renvela 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 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 D

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.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per tablet that is to say essentially ‘sodium-

free’.

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, 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 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 one hour before or three hours after Renvela, and blood monitoring can be

considered.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 Renvela. The phosphate

serum level should be monitored and the Renvela 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

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).

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

perforation

gastrointestinal

hemorrhage*

intestinal

ulceration*

gastrointestinal

necrosis*

colitis*

intestinal mass*

Skin and

subcutaneous

tissue disorders

Pruritus, rash

Investigations

Crystal deposit

intestine*

*Post-marketing experience

See inflammatory gastrointestinal disorders warning in section 4.4

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected

adverse events should be reported to the Ministry of Health according to the National Regulation by

using an online form: https://sideeffects.health.gov.il/

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

other

known

gastrointestinal

disorders.

Appropriate

symptomatic treatment should be provided.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: All other therapeutic products, drugs for treatment of hyperkalemia and

hyperphosphataemia. ATC code: V03A E02.

Mechanism of action

Renvela 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.

Clinical efficacy and safety

In two randomised, cross over clinical trials, sevelamer carbonate in both tablet and powder

formulations when administered three times per day has been shown to be therapeutically equivalent

to sevelamer hydrochloride and therefore effective in controlling serum phosphorus in CKD patients

on haemodialysis.

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 D

or one of its analogues to lower the iPTH levels.

Sevelamer has been shown to bind bile acids

in vitro

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 total-cholesterol 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.

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

Tablet core:

Microcrystalline cellulose

Purified water

Sodium chloride

Zinc stearate

Film-coating:

Hypromellose

Diacetylated monoglycerides

Purified water

Printing ink:

Purified water

Iron oxide black

Isopropyl alcohol

Propylene glycol

Hypromellose

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

Shelf life after opening: 30 days

6.4

Special precautions for storage

Do not store above 30°C. Keep the bottle tightly closed to protect from moisture.

6.5

Nature and contents of container

HDPE bottles with a polypropylene cap and a foil induction seal.

Each bottle contains 30 tablets or 180 tablets.

Packs of 30 or 180 tablets and a multipack containing 180 (6 bottles of 30) tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7. MANUFACTURER

Genzyme Europe B.V., Amsterdam, The Netherlands.

8. MARKETING AUTHORISATION HOLDER

Sanofi-Aventis Israel ltd. 10 Beni Gaon, POB 8090, Netanya

The leaflet has been revised on 04/2020.