ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Renvela 800 mg film-coated tablets
2.
Each tablet contains 800 mg sevelamer carbonate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
The white to off-white tablets are imprinted with “RENVELA 800” on one side.
4.
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
3
or one of its analogues to control the development of renal bone
disease.
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.
2
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 Renvela has not been established in children below the age of 18 years.
Renvela is not recommended in children below the age of 18 years.
Method of administration
Tablets should be swallowed intact and should not be crushed, chewed, or broken into pieces prior to
administration.
Hypersensitivity to the active substance or to any of the excipients.
Hypophosphataemia
Bowel obstruction.
Efficacy and safety of Renvela has not been studied in children below the age of 18 years.
The safety and efficacy of Renvela have not been established in adult patients with chronic kidney disease
not on dialysis with serum phosphorus < 1.78 mmol/l. Therefore Renvela is currently not recommended for
use in these patients.
The safety and efficacy of Renvela have not been established in patients with the following disorders:
The safety and efficacy of Renvela
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 Renvela is used in these patients.
Intestinal obstruction and ileus/subileus
In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment
with sevelamer hydrochloride, 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. Renvela 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 Renvela 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 Renvela. 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 Renvela
treatment.
3
Hypocalcaemia/hypercalcaemia
Patients with CKD may develop hypocalcaemia or hypercalcaemia. Renvela 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 study 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.
Anti-arrhythmic and anti-seizure medicinal products
Caution should be exercised when prescribing Renvela to patients also taking anti-arrhythmias and
anti-seizure medicinal products (see section 4.5).
Hypothyroidism
Closer monitoring of patients with hypothyroidism co-administered with sevelamer carbonate and
levothryroxine 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
Renvela is not indicated for the control of hyperparathyroidism. In patients with secondary
hyperparathyroidism Renvela should be used within the context of a multiple therapeutic approach, which
could include calcium as supplements, 1,25 - dihydroxy Vitamin D
3
or one of its analogues to lower the
intact parathyroid hormone (iPTH) levels.
Interaction studies have not been conducted in patients on dialysis.
In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety
as Renvela, decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with
sevelamer hydrochloride in a single dose study. Consequently, Renvela should not be taken simultaneously
with ciprofloxacin.
Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus
have been reported in transplant
patients when co-administered with sevelamer hydrochloride without any clinical consequences (i.e 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.
Very rare cases of hypothyroidism have been reported in patients co-administered 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.
4
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 Renvela to patients also taking these medicinal products.
In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety
as Renvela, had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol.
Renvela 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
Renvela, or the physician should consider monitoring blood levels.
Pregnancy:
There are no data from the use of sevelamer in pregnant women. Studies in animals 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. Renvela 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.
Lactation:
It is unknown whether sevelamer is excreted in human breast 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 Renvela should be made taking
into account the benefit of breast-feeding to the child and the benefit of Renvela 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 body surface area.
No studies on the effects on ability to drive and use machines have been performed.
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).
The most frequently occurring (≥ 5% of patients) undesirable effects possibly or probably related to
sevelamer were all in the gastrointestinal disorders system organ class. Most of these adverse reactions were
mild to moderate in intensity. Data possibly or probably related to sevelamer from these studies are listed by
frequency in the table below. The reporting rate is classified as very common (≥1/10), common (≥1/100,
<1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), not known
(cannot be estimated from the available data).
Gastrointestinal disorders
Very common :
Nausea, vomiting, upper abdominal pain, constipation
Common :
Diarrhoea
,
dyspepsia, flatulence, abdominal pain
5
Post-marketing experience:
During post-approval use, cases of pruritus, rash, intestinal obstruction,
ileus/subileus, and intestinal perforation have been reported in patients during treatment with sevelamer.
No cases of overdose have been reported. 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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Treatment of hyperphosphataemia. ATC code: V03A E02.
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. 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.
In two randomised, cross over clinical studies, 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 studies in haemodialysis patients, sevelamer alone did not have a consistent and clinically
significant effect on serum intact parathyroid hormone (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 Renvela should be used within the context of a
multiple therapeutic approach, which could include calcium as supplements, 1,25 – dihydroxy Vitamin D
3
or
one of its analogues to lower the intact parathyroid hormone (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 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
6
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.
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 tumors 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 body surface area).
6.
6.1
List of excipients
Tablet core:
Microcrystalline cellulose
Sodium chloride
Zinc stearate
Film-coating
:
Hypromellose (E464)
Diacetylated monoglycerides
Printing ink:
Iron oxide black (E172)
7
Propylene glycol
Isopropyl alcohol
Hypromellose (E464)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4
Special precautions for storage
Keep the bottle tightly closed in order to protect from moisture.
This medicinal product does not require any special temperature storage conditions.
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
No special requirements.
7.
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
8.
EU/1/09/521/001
EU/1/09/521/002
EU/1/09/521/003
9.
10/06/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/
8
1.
Renvela 1.6 g powder for oral suspension
2.
Each sachet contains 1.6 g sevelamer carbonate.
For a full list of excipients, see section 6.1.
3.
Powder for oral suspension.
Pale yellow powder.
4.
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
3
or one of its analogues to control the development of renal bone
disease.
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 powder for oral suspension 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.
9
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 Renvela has not been established in children below the age of 18 years. Renvela
is not recommended in children below the age of 18 years.
Method of administration:
The powder should be dispersed in 40 ml of water per sachet prior to administration (see section 6.6). The
suspension should be ingested within 30 minutes after being prepared.
Hypersensitivity to the active substance or to any of the excipients.
Hypophosphataemia
Bowel obstruction.
Efficacy and safety of Renvela has not been studied in children below the age of 18 years.
The safety and efficacy of Renvela have not been established in adult patients with chronic kidney disease
not on dialysis with serum phosphorus < 1.78 mmol/l. Therefore Renvela is currently not recommended for
use in these patients.
The safety and efficacy of Renvela have not been established in patients with the following disorders:
The safety and efficacy of Renvela 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 Renvela is used in these patients.
Intestinal obstruction and ileus/subileus
In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment
with sevelamer hydrochloride, 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. Renvela 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 Renvela 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 Renvela. 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 Renvela
treatment.
10
Hypocalcaemia/hypercalcaemia
Patients with CKD may develop hypocalcaemia or hypercalcaemia. Renvela 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 study 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.
Anti-arrhythmic and anti-seizure medicinal products
Caution should be exercised when prescribing Renvela to patients also taking anti-arrhythmias and
anti-seizure medicinal products (see section 4.5).
Hypothyroidism
Closer monitoring of patients with hypothyroidism co-administered with sevelamer carbonate and
levothryroxine 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
Renvela is not indicated for the control of hyperparathyroidism. In patients with secondary
hyperparathyroidism Renvela should be used within the context of a multiple therapeutic approach, which
could include calcium as supplements, 1,25 - dihydroxy Vitamin D
3
or one of its analogues to lower the
intact parathyroid hormone (iPTH) levels.
Interaction studies have not been conducted in patients on dialysis.
In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety
as Renvela, decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with
sevelamer hydrochloride in a single dose study. Consequently, Renvela should not be taken simultaneously
with ciprofloxacin.
Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus
have been reported in transplant
patients when co-administered with sevelamer hydrochloride without any clinical consequences (i.e 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.
Very rare cases of hypothyroidism have been reported in patients co-administered 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.
11
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 Renvela to patients also taking these medicinal products.
In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety
as Renvela, had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol.
Renvela 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
Renvela, or the physician should consider monitoring blood levels.
Pregnancy:
There are no data from the use of sevelamer in pregnant women. Studies in animals 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. Renvela 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.
Lactation:
It is unknown whether sevelamer is excreted in human breast 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 Renvela should be made taking
into account the benefit of breast-feeding to the child and the benefit of Renvela 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 body surface area.
No studies on the effects on ability to drive and use machines have been performed.
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).
The most frequently occurring (≥ 5% of patients) undesirable effects possibly or probably related to
sevelamer were all in the gastrointestinal disorders system organ class. Most of these adverse reactions were
mild to moderate in intensity. Data possibly or probably related to sevelamer from these studies are listed by
frequency in the table below. The reporting rate is classified as very common (≥1/10), common (≥1/100,
<1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), not known
(cannot be estimated from available data).
Gastrointestinal disorders
Very common :
Nausea, vomiting, upper abdominal pain, constipation
Common :
Diarrhoea
,
dyspepsia, flatulence, abdominal pain
12
Post-marketing experience:
During post-approval use, cases of pruritus, rash,
intestinal obstruction,
ileus/subileus, and intestinal perforation have been reported in patients during treatment with sevelamer.
No cases of overdose have been reported. 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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Treatment of hyperphosphataemia. ATC code: V03A E02.
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. 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.
In two randomised, cross over clinical studies, 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 studies in haemodialysis patients, sevelamer alone did not have a consistent and clinically
significant effect on serum intact parathyroid hormone (iPTH). In the 12 week study involving peritoneal
dialysis patients however, similar iPTH reductions were seen compared with patients receiving calcium
acetate. In patients with secondary hyperparathyroidism Renvela should be used within the context of a
multiple therapeutic approach, which could include calcium as supplements, 1,25 – dihydroxy Vitamin D
3
or
one of its analogues to lower the intact parathyroid hormone (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 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.
13
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.
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 tumors 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 body surface area).
6.
6.1
List of excipients
Propylene glycol alginate
Citrus Cream flavour
Sodium Chloride
Sucralose
Iron oxide yellow (E172)
14
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
The shelf-life for the powder for oral suspension is 3 years.
The reconstituted suspension must be administered within 30 minutes of reconstitution.
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 ethylene methacrylic acid copolymer, polyester, low density polyethylene and aluminium foil
laminate, with a heat seal, containing a single dose.
Each sachet contains 1.6g of sevelamer carbonate. Each carton contains 60 or 90 sachets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
The powder should be dispersed in 40 ml of water per sachet prior to administration. The suspension
powder is pale yellow and has a citrus flavour.
No special requirements for disposal
7.
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
8.
EU/1/09/521/004
EU/1/09/521/005
9.
10/06/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/
.
15
1.
Renvela 2.4 g powder for oral suspension
2.
Each sachet contains 2.4 g sevelamer carbonate.
For a full list of excipients, see section 6.1.
3.
Powder for oral suspension.
Pale yellow powder.
4.
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 patients 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
3
or one of its analogues to control the development of renal bone
disease.
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 powder for oral suspension 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 should 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.
16
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 Renvela has not been established in children below the age of 18 years. Renvela
is not recommended in children below the age of 18 years.
Method of administration
The powder should be dispersed in 60 ml of water per sachet prior to administration. The suspension should
be ingested within 30 minutes after being prepared.
Hypersensitivity to the active substance or to any of the excipients.
Hypophosphataemia
Bowel obstruction.
Efficacy and safety of Renvela has not been studied in children below the age of 18 years.
The safety and efficacy of Renvela have not been established in adult patients with chronic kidney disease
not on dialysis with serum phosphorus < 1.78 mmol/l. Therefore Renvela is currently not recommended for
use in these patients.
The safety and efficacy of Renvela have not been established in patients with the following disorders:
The safety and efficacy of Renvela have not been established in patients with the following disor
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 Renvela is used in these patients.
Intestinal obstruction and ileus/subileus
In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment
with sevelamer hydrochloride, 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. Renvela 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 Renvela 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 Renvela. 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 Renvela
treatment.
17
Hypocalcaemia/hypercalcaemia
Patients with CKD may develop hypocalcaemia or hypercalcaemia. Renvela 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 study 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.
Anti-arrhythmic and anti-seizure medicinal products
Caution should be exercised when prescribing Renvela to patients also taking anti-arrhythmias and
anti-seizure medicinal products (see section 4.5).
Hypothyroidism
Closer monitoring of patients with hypothyroidism co-administered with sevelamer carbonate and
levothryroxine 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
Renvela is not indicated for the control of hyperparathyroidism. In patients with secondary
hyperparathyroidism Renvela should be used within the context of a multiple therapeutic approach, which
could include calcium as supplements, 1,25 - dihydroxy Vitamin D
3
or one of its analogues to lower the
intact parathyroid hormone (iPTH) levels.
Interaction studies have not been conducted in patients on dialysis.
In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety
as Renvela, decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with
sevelamer hydrochloride in a single dose study. Consequently, Renvela should not be taken simultaneously
with ciprofloxacin.
Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus
have been reported in transplant
patients when co-administered with sevelamer hydrochloride without any clinical consequences (i.e 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.
Very rare cases of hypothyroidism have been reported in patients co-administered 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.
18
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 Renvela to patients also taking these medicinal products.
In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety
as Renvela, had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol.
Renvela is not absorbed compound 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 Renvela, or the physician should consider monitoring blood levels.
Pregnancy:
There are no data from the use of sevelamer in pregnant women. Studies in animals 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. Renvela 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.
Lactation:
It is unknown whether sevelamer is excreted in human breast 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 Renvela should be made taking
into account the benefit of breast-feeding to the child and the benefit of Renvela 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 body surface area.
No studies on the effects on ability to drive and use machines have been performed.
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).
The most frequently occurring (≥ 5% of patients) undesirable effects possibly or probably related to
sevelamer were all in the gastrointestinal disorders system organ class. Most of these adverse reactions were
mild to moderate in intensity. Data possibly or probably related to sevelamer from these studies are listed by
frequency in the table below. The reporting rate is classified as very common (≥1/10), common (≥1/100,
<1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), not known
(cannot be estimated from the available data).
Gastrointestinal disorders
Very common :
Nausea, vomiting, upper abdominal pain, constipation
Common :
Diarrhoea
,
dyspepsia, flatulence, abdominal pain
19
Post-marketing experience:
During post-approval use, cases of pruritus, rash,
intestinal obstruction,
ileus/subileus, and intestinal perforation have been reported in patients during treatment with sevelamer.
No cases of overdose have been reported. 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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Treatment of hyperphosphataemia. ATC code: V03A E02.
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. 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.
In two randomised, cross over clinical studies, 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 studies in haemodialysis patients, sevelamer alone did not have a consistent and clinically
significant effect on serum intact parathyroid hormone (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 Renvela should be used within the context of a
multiple therapeutic approach, which could include calcium as supplements, 1,25 – dihydroxy Vitamin D
3
or
one of its analogues to lower the intact parathyroid hormone (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 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.
20
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.
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 tumors 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 body surface area).
6.
6.1
List of excipients
Propylene glycol alginate
Citrus Cream flavour
Sodium chloride
Sucralose
Iron oxide yellow (E172)
21
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
The shelf-life for the powder for oral suspension is 3 years.
The reconstituted suspension must be administered within 30 minutes of reconstitution.
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 ethylene methacrylic acid copolymer, polyester, low density polyethylene and aluminium foil
laminate, with a heat seal, containing a single dose.
Each sachet contains 2.4g of sevelamer carbonate. Each carton contains 60 or 90 sachets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
The powder should be dispersed in 60 ml of water per sachet prior to administration. The suspension
powder is pale yellow with a citrus flavour.
No special requirements for disposal.
7.
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
8.
EU/1/09/521/006
EU/1/09/521/007
9.
10/06/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/
.
22
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
23
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer responsible for batch release
Genzyme Ltd.
37 Hollands Road
Haverhill, Suffolk
CB9 8PB
Genzyme Ireland Ltd.
IDA Industrial Park
Old Kilmeaden Road
Waterford
Ireland
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE
USE OF THE MEDICINAL PRODUCT
The MAH shall agree the details of an educational programme for patients and health care professionals
with the National Competent Authorities and must implement such programme nationally to ensure
provision of educational material to patients and health professionals containing information:
on the risk factors for and prevention of peritonitis in peritoneal dialysis patients.
on the risk factors for and prevention of arterio-venous fistula site complications in HD
(haemodialysis) patients
on the increased risk of vitamin deficiency in chronic kidney disease patients and the need for
vitamin supplementation
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 5 presented in Module
1.8.1. of the Marketing Authorisation Application, is in place and functioning before and whilst the product
is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the
Pharmacovigilance Plan, as agreed in version 1 of the Risk Management Plan (RMP) presented in Module
1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP agreed by the
CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
24
At the request of the EMA
25
ANNEX III
LABELLING AND PACKAGE LEAFLET
26
A. LABELLING
27
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
LABEL - BOTTLE OF 30 TABLETS (WITH OUTER CARTON)
LABEL - BOTTLE OF 180 TABLETS (WITHOUT OUTER CARTON)
1.
Renvela 800 mg film-coated tablets
sevelamer carbonate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 800 mg sevelamer carbonate.
3.
LIST OF EXCIPIENTS
4.
30 film-coated tablets
180 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Tablets must be swallowed whole. Do not chew.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Keep the bottle tightly closed in order to protect from moisture.
28
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
EU/1/09/521/001
EU/1/09/521/003
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Renvela
800 mg
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON – BOTTLE OF 30 TABLETS
OUTER CARTON – 6 BOTTLES OF 30 TABLETS
1.
Renvela 800 mg film-coated tablets
sevelamer carbonate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 800 mg sevelamer carbonate.
3.
LIST OF EXCIPIENTS
4.
30 film-coated tablets
6 bottles of 30 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Tablets must be swallowed whole. Do not chew.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Keep bottle tightly closed in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
30
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
EU/1/09/521/001
EU/1/09/521/002
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Renvela
800 mg
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON - CARTON OF 60 SACHETS
OUTER CARTON - CARTON OF 90 SACHETS
1.
Renvela 1.6 g powder for oral suspension
sevelamer carbonate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sachet contains 1.6 g sevelamer carbonate.
3.
LIST OF EXCIPIENTS
4.
Powder for oral suspension
60 sachets
90 sachets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
The reconstituted suspension must be administered within 30 minutes of reconstitution.
9.
SPECIAL STORAGE CONDITIONS
32
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
EU/1/09/521/004
EU/1/09/521/005
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Renvela
1.6 g
33
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
LABEL - SACHETS
1.
Renvela 1.6 g powder for oral suspension
sevelamer carbonate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sachet contains 1.6 g sevelamer carbonate.
3.
LIST OF EXCIPIENTS
4.
Powder for oral suspension
1.6 g powder
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
The reconstituted suspension must be administered within 30 minutes of reconstitution.
9.
SPECIAL STORAGE CONDITIONS
34
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
EU/1/09/521/004
EU/1/09/521/005
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON - CARTON OF 60 SACHETS
OUTER CARTON - CARTON OF 90 SACHETS
1.
Renvela 2.4 g powder for oral suspension
sevelamer carbonate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sachet contains 2.4 g sevelamer carbonate.
3.
LIST OF EXCIPIENTS
4.
Powder for oral suspension
60 sachets
90 sachets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
The reconstituted suspension must be administered within 30 minutes of reconstitution.
9.
SPECIAL STORAGE CONDITIONS
36
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
EU/1/09/521/006
EU/1/09/521/007
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Renvela
2.4 g
37
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
LABEL - SACHETS
1.
Renvela 2.4 g powder for oral suspension
sevelamer carbonate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sachet contains 2.4 g sevelamer carbonate.
3.
LIST OF EXCIPIENTS
4.
Powder for oral suspension
2.4 g powder
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
The reconstituted suspension must be administered within 30 minutes of reconstitution.
9.
SPECIAL STORAGE CONDITIONS
38
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
EU/1/09/521/006
EU/1/09/521/007
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
39
B. PACKAGE LEAFLET
40
PACKAGE LEAFLET: INFORMATION FOR THE USER
Renvela 800 mg film-coated tablets
sevelamer carbonate
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their
symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
In this leaflet
1. What Renvela is and what it is used for
2. Before you take Renvela
3. How to take Renvela
4. Possible side effects
5. How to store Renvela
6. Further information
1.
WHAT RENVELA IS AND WHAT IT IS USED FOR
Renvela contains sevelamer carbonate as the active ingredient. It binds phosphate from food in the digestive
tract and so reduces serum phosphorus levels in the blood.
Patients who have kidneys that do not work properly are not able to control the level of serum phosphorus in
their blood. The amount of phosphate then rises (your doctor will call this hyperphosphataemia). Increased
levels of serum phosphorus can lead to hard deposits in your body called calcification. These deposits is can
stiffen your blood vessels and make it harder for blood to be pumped around the body. Increased serum
phosphorus can also lead to itchy skin, red eyes, bone pain and fractures.
2.
BEFORE YOU TAKE RENVELA
Do not take Renvela if:
you have low levels of phosphate in your blood (your doctor will check this for you)
you have bowel obstruction
you are allergic (hypersensitive) to the active substance or to any of the other ingredients of the
product (see section 6).
Take special care with Renvela
If any of the following applies to you, please consult your doctor before taking Renvela:
swallowing problems
problems with motility (movement) in your stomach and bowel
being sick frequently
active inflammation of the bowel
have undergone major surgery on your stomach or bowel.
The safety and efficacy in children (below the age of 18 years) has not been established. Therefore Renvela
is not recommended for use in children.
41
Additional treatments
:
Due to either your kidney condition or your dialysis treatment you may:
develop low or high levels of calcium in your blood. Since Renvela does not contain calcium your
doctor might prescribe additional calcium tablets.
have a low amount of vitamin D in your blood. Therefore, your doctor may monitor the levels of
vitamin D in your blood and prescribe additional vitamin D as necessary. If you do not take
multivitamin supplements you may also develop low levels of vitamins A, E, K and folic acid in your
blood and therefore your doctor may monitor these levels and prescribe supplemental vitamins as
necessary.
Special note for patients on peritoneal dialysis:
You may develop peritonitis (infection of your abdominal fluid) associated with your peritoneal dialysis.
This risk can be reduced by careful adherence to sterile techniques during bag changes. You should tell your
doctor immediately if you experience any new signs or symptoms of abdominal distress,
abdominal
swelling, abdominal pain, abdominal tenderness, or abdominal rigidity, constipation, fever, chills, nausea or
vomiting.
You should expect to be monitored more carefully for problems with low levels of vitamins A, D, E, K and
folic acid.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines including medicines
obtained without a prescription.
Renvela should not be taken at the same time as ciprofloxacin (an antibiotic).
If you are taking medicines for heart rhythm problems or for epilepsy, you should consult your doctor when
taking Renvela.
The effects of medicines such as ciclosporin, mycophenolate mofetil and tacrolimus (medicines used to
suppress the immune system) may be reduced by Renvela. Your doctor will advise you if you are taking
these medicines.
Thyroid hormone deficiency may uncommonly be observed in certain people taking levothyroxine (used to
treatment low thyroid hormone levels) and Renvela. Therefore your doctor may monitor the levels of thyroid
stimulating hormone in your blood more closely.
Your doctor will check for interactions between Renvela and other medicines on a regular basis.
Taking Renvela with food and drink
You must take Renvela tablets with meals.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or intend to become pregnant. It is unknown whether Renvela has any
affect on unborn babies.
Tell your doctor if you wish to breast-feed your baby. It is unknown whether Renvela may pass through
breast milk and affect your baby.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines has been performed. If you are affected, do
not drive and do not use any tools or machines.
42
3.
HOW TO TAKE RENVELA
You must take Renvela as prescribed by your doctor. They will base the dose on your serum phosphorus
level.
The recommended starting dose of Renvela tablets for adults and the elderly (> 65 years) is one to two
tablets of 800 mg with each meal, 3 times a day.
The tablets must be swallowed whole. Do not crush, chew or break into pieces.
In some cases where Renvela should be taken at the same time as another medicine. Your doctor may advise
you to take this medicine 1 hour before or 3 hours after Renvela intake, or they may consider monitoring the
blood levels of that medicine.
Your doctor will check the levels of phosphorus in your blood periodically and they may adjust the dose of
Renvela when necessary to reach an adequate phosphate level.
If you take more Renvela than you should
There are no reported overdoses in patients.
In the event of a possible overdose you should contact your doctor immediately.
If you forget to take Renvela
If you have missed one dose, this dose should be omitted and the next dose should be taken at the usual time
with a meal. Do not take a double dose to make up for a forgotten dose.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Renvela
can cause side effects, although not everybody gets them.
The following side effects have been reported in patients taking Renvela:
Very common
(affects more than 1 user in 10):
vomiting, constipation, upper abdominal pain, nausea
Common
(affects 1 to 10 users in 100):
diarrhoea, abdominal pain, indigestion, flatulence
In clinical use, cases of itching, rash, slow intestine motility (movement)/blockages in the intestine, and
perforation in the intestine wall have been reported.
Since constipation may be an early symptom of a blockage in your intestine, please inform your doctor or
pharmacist.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
5.
HOW TO STORE RENVELA
Keep out of the reach and sight of children.
Do not use Renvela after the expiry date stated on the bottle and carton after the letters “EXP”.
Keep the bottle container tightly closed in order to protect from moisture.
This medicinal product does not require any special storage conditions.
43
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Renvela contains
- The active substance is sevelamer carbonate. Each Renvela film-coated tablet contains 800 mg of
sevelamer carbonate
- The other ingredients are microcrystalline cellulose, sodium chloride and zinc stearate. The tablet coating
contains hypromellose (E464) and diacetylated monoglycerides. The printing ink contains iron oxide black
(E172), isopropyl alcohol, propylene glycol and hypromellose (E464).
What Renvela looks like and contents of the pack
Renvela film-coated tablets are white tablets with RENVELA 800 imprinted on one side. The tablets are
packed in high density polyethylene bottles with a polypropylene cap and an induction seal.
Pack sizes:
1 x 30 tablets per bottle
1 x 180 tablets per bottle
180 tablets (6 bottles of 30 tablets)
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder:
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
Manufacturer:
Genzyme Ltd.
37 Hollands Road
Haverhill, Suffolk
CB9 8PB
Genzyme Ireland Ltd.
IDA Industrial Park
Old Kilmeaden Road
Waterford
Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation holder.
44
België/Belgique/Belgien/
Luxembourg/Luxemburg
Genzyme Belgium nv/sa (Belgique/Belgien),
Tél/Tel: + 32 2 714 17 11
Ísland
Vistor hf.
Tel: +354 535 7000
България
Търговско представителство на Genzyme CEE
GmbH
Тел. +359 2 971 1001
Magyarország
Genzyme Europe B.V. Képviselet,
Tel: +36 1 310 7440
Česká republika/Slovenská republika
Genzyme Czech s.r.o.
Tel: : +420 221 722 511
Nederland
Genzyme Europe BV,
Tel: +31 35 6991200
Danmark/Norge/Sverige/Suomi/Finland
Genzyme A/S, (Danmark/Tanska),
Tlf/Puh.: + 45 32712600
Österreich
Genzyme Austria GmbH,
Tel: + 43 1 774 65 38
Deutschland
Genzyme GmbH,
Tel: +49 610236740
Polska/Eesti/Latvija/Lietuva
Genzyme Polska sp. z o.o. (Poola/Polija/Lenkija),
Tel: +48 22 516 24 32
Ελλά/Κύπρς
Genzyme Hellas Ltd. (Ελλά),
Τηλ: +30 210 99 49 270
Portugal
Genzyme Portugal S.A.,
Tel: +351 21 422 0100
España
Genzyme, S.L.U.,
Tel: +34 91 6591670
România
Genzyme CEE GmbH- Reprezentanta pentru
Romania
Tel: +40 21 243 42 28
France
Genzyme S.A.S,
Tél: + 33 (0) 825 825 863
Slovenija
Genzyme Europe B.V. Predstavništvo za Hrvaško
in Slovenijo (Hrvaška),
Tel: +385 1 6386 250
Italia/ Malta
Genzyme Srl (Italia/Italja),
Tel: +39 059 349811
United Kingdom/Ireland
Genzyme Therapeutics (United Kingdom),
Tel: +44 1865 405200
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web site:
45
PACKAGE LEAFLET: INFORMATION FOR THE USER
Renvela 1.6 g powder for oral suspension
sevelamer carbonate
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their
symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
In this leaflet
1. What Renvela is and what it is used for
2. Before you take Renvela
3. How to take Renvela
4. Possible side effects
5. How to store Renvela
6. Further information
1.
WHAT RENVELA IS AND WHAT IT IS USED FOR
Renvela contains sevelamer carbonate as the active ingredient. It binds phosphate from food in the digestive
tract and so reduces serum phosphorus levels in the blood.
Patients who have kidneys that do not work properly are not able to control the level of serum phosphorus in
their blood. The amount of phosphate then rises (your doctor will call this hyperphosphataemia). Increased
levels of serum phosphorus can lead to hard deposits in your body called calcification. These deposits is can
stiffen your blood vessels and make it harder for blood to be pumped around the body. Increased serum
phosphorus can also lead to itchy skin, red eyes, bone pain and fractures.
2.
BEFORE YOU TAKE RENVELA
Do not take Renvela if:
you have low levels of phosphate in your blood (your doctor will check this for you)
you have bowel obstruction
you are allergic (hypersensitive) to the active substance or to any of the other ingredients of the
product (see Section 6).
Take special care with Renvela
If any of the following applies to you, please consult your doctor before taking Renvela:
swallowing problems
problems with motility (movement) in your stomach and bowel
being sick frequently
active inflammation of the bowel
have undergone major surgery on your stomach or bowel.
The safety and efficacy in children (below the age of 18 years) has not been established. Therefore Renvela
is not recommended for use in children.
46
Additional treatments
:
Due to either your kidney condition or your dialysis treatment you may:
develop low or high levels of calcium in your blood. Since Renvela does not contain calcium your
doctor might prescribe additional calcium tablets.
have a low amount of vitamin D in your blood. Therefore, your doctor may monitor the levels of
vitamin D in your blood and prescribe additional vitamin D as necessary. If you do not take
multivitamin supplements you may also develop low levels of vitamins A, E, K and folic acid in your
blood and therefore your doctor may monitor these levels and prescribe supplemental vitamins as
necessary.
Special note for patients on peritoneal dialysis:
You may develop peritonitis (infection of your abdominal fluid) associated with your peritoneal dialysis.
This risk can be reduced by careful adherence to sterile techniques during bag changes. You should tell your
doctor immediately if you experience any new signs or symptoms of abdominal distress,
abdominal
swelling, abdominal pain, abdominal tenderness, or abdominal rigidity, constipation, fever, chills, nausea or
vomiting.
You should expect to be monitored more carefully for problems with low levels of vitamins A, D, E, K and
folic acid.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines including medicines
obtained without a prescription.
Renvela should not be taken at the same time as ciprofloxacin (an antibiotic).
If you are taking medicines for heart rhythm problems or for epilepsy, you should consult your doctor when
taking Renvela.
The effects of medicines such as ciclosporin, mycophenolate mofetil and tacrolimus (medicines used to
suppress the immune system) may be reduced by Renvela. Your doctor will advise you if you are taking
these medicines.
Thyroid hormone deficiency may uncommonly be observed in certain people taking levothyroxine (used to
treat low thyroid hormone levels) and Renvela. Therefore your doctor may monitor the levels of thyroid
stimulating hormone in your blood more closely.
Your doctor will check for interactions between Renvela and other medicines on a regular basis.
Taking Renvela with food and drink
You must take Renvela powder with meals.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or intend to become pregnant. It is unknown whether Renvela has any
affect on unborn babies.
Tell your doctor if you wish to breast-feed your baby. It is unknown whether Renvela may pass through
breast milk and affect your baby.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines has been performed. If you are affected, do
not drive and do not use any tools or machines.
47
3.
HOW TO TAKE RENVELA
You must take Renvela as prescribed by your doctor. They will base the dose on your serum phosphorus
level.
The 1.6 g powder for oral suspension should be dispersed in 40 ml of water per sachet. Drink within
30 minutes of being prepared. It is important to drink all of the liquid and it may be necessary to rinse the
glass with water and drink this as well to ensure that all of the powder is swallowed.
The recommended starting dose for Renvela is 2.4-4.8g per day equally divided over three meals. The exact
starting dose and regimen will be determined by your doctor.
In some cases where Renvela should be taken at the same time as another medicine. Your doctor may advise
you to take this medicine 1 hour before or 3 hours after Renvela intake, or they may consider monitoring the
blood levels of that medicine.
Your doctor will check the levels of phosphorus in your blood periodically and they may adjust the dose of
Renvela when necessary to reach an adequate phosphate level.
If you take more Renvela than you should
There are no reported overdoses in patients.
In the event of a possible overdose you should contact your doctor immediately.
If you forget to take Renvela
If you have missed one dose, this dose should be omitted and the next dose should be taken at the usual time
with a meal. Do not a double dose to make up for a forgotten dose.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Renvela
can cause side effects, although not everybody gets them.
The following side effects have been reported in patients taking Renvela:
Very common
(affects more than 1 user in 10):
vomiting, constipation, upper abdominal pain, nausea
Common
(affects 1 to 10 users in 100):
diarrhoea, abdominal pain, indigestion, flatulence
In clinical use, cases of itching, rash, slow intestine motility (movement)/blockages in the intestine, and
perforation in the intestine wall have been reported.
Since constipation may be an early symptom of a blockage in your intestine, please inform your doctor or
pharmacist.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
5.
HOW TO STORE RENVELA
Keep out of the reach and sight of children.
Do not use Renvela after the expiry date stated on the sachet and carton after the letters “EXP”. The
reconstituted suspension must be administered within 30 minutes of reconstitution.
48
The medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Renvela contains
- The active substance is sevelamer carbonate. Each Renvela sachet contains 1.6 g of sevelamer carbonate.
- The other ingredients are propylene glycol alginate, citrus cream flavour, sodium chloride, sucralose and
iron oxide yellow (E172).
What Renvela looks like and contents of the pack
Renvela powder for oral suspension is a pale yellow powder supplied in a foil sachet with a heat seal. The
foil sachets are packaged in an outer carton.
Pack sizes:
60 sachets per carton
90 sachets per carton
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder:
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
Manufacturer:
Genzyme Ltd.
37 Hollands Road
Haverhill, Suffolk
CB9 8PB
Genzyme Ireland Ltd.
IDA Industrial Park
Old Kilmeaden Road
Waterford
Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation holder.
49
België/Belgique/Belgien/
Luxembourg/Luxemburg
Genzyme Belgium nv/sa (Belgique/Belgien),
Tél/Tel: + 32 2 714 17 11
Ísland
Vistor hf.
Tel: +354 535 7000
България
Търговско представителство на Genzyme CEE
GmbH
Тел. +359 2 971 1001
Magyarország
Genzyme Europe B.V. Képviselet,
Tel: +36 1 310 7440
Česká republika/Slovenská republika
Genzyme Czech s.r.o.
Tel: : +420 221 722 511
Nederland
Genzyme Europe BV,
Tel: +31 35 6991200
Danmark/Norge/Sverige/Suomi/Finland
Genzyme A/S, (Danmark/Tanska),
Tlf/Puh.: + 45 32712600
Österreich
Genzyme Austria GmbH,
Tel: + 43 1 774 65 38
Deutschland
Genzyme GmbH,
Tel: +49 610236740
Polska/Eesti/Latvija/Lietuva
Genzyme Polska sp. z o.o. (Poola/Polija/Lenkija),
Tel: +48 22 516 24 32
Ελλά/Κύπρς
Genzyme Hellas Ltd. (Ελλά),
Τηλ: +30 210 99 49 270
Portugal
Genzyme Portugal S.A.,
Tel: +351 21 422 0100
España
Genzyme, S.L.U.,
Tel: +34 91 6591670
România
Genzyme CEE GmbH- Reprezentanta pentru
Romania
Tel: +40 21 243 42 28
France
Genzyme S.A.S,
Tél: + 33 (0) 825 825 863
Slovenija
Genzyme Europe B.V. Predstavništvo za Hrvaško
in Slovenijo (Hrvaška),
Tel: +385 1 6386 250
Italia/ Malta
Genzyme Srl (Italia/Italja),
Tel: +39 059 349811
United Kingdom/Ireland
Genzyme Therapeutics (United Kingdom),
Tel: +44 1865 405200
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web site:
50
PACKAGE LEAFLET: INFORMATION FOR THE USER
Renvela 2.4 g powder for oral suspension
sevelamer carbonate
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their
symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
In this leaflet
1. What Renvela is and what it is used for
2. Before you take Renvela
3. How to take Renvela
4. Possible side effects
5. How to store Renvela
6. Further information
1.
WHAT RENVELA IS AND WHAT IT IS USED FOR
Renvela contains sevelamer carbonate as the active ingredient. It binds phosphate from food in the digestive
tract and so reduces serum phosphorus levels in the blood.
Patients who have kidneys that do not work properly are not able to control the level of serum phosphorus in
their blood. The amount of phosphate then rises (your doctor will call this hyperphosphataemia). Increased
levels of serum phosphorus can lead to hard deposits in your body called calcification. These deposits can
stiffen your blood vessels and make it harder for blood to be pumped around the body. Increased serum
phosphorus can also lead to itchy skin, red eyes, bone pain and fractures.
2.
BEFORE YOU TAKE RENVELA
Do not take Renvela if:
you have low levels of phosphate in your blood (your doctor will check this for you)
you have bowel obstruction
you are allergic (hypersensitive) to the active substance or to any of the other ingredients of the
product (see Section 6).
Take special care with Renvela
If any of the following applies to you, please consult your doctor before taking Renvela:
swallowing problems
problems with motility (movement) in your stomach and bowel
being sick frequently
active inflammation of the bowel
have undergone major surgery on your stomach or bowel.
The safety and efficacy in children (below the age of 18 years) has not been established. Therefore Renvela
is not recommended for use in children.
51
Additional treatments
:
Due to either your kidney condition or your dialysis treatment you may:
develop low or high levels of calcium in your blood. Since Renvela does not contain calcium your
doctor might prescribe additional calcium tablets.
have a low amount of vitamin D in your blood. Therefore, your doctor may monitor the levels of
vitamin D in your blood and prescribe additional vitamin D as necessary. If you do not take
multivitamin supplements you may also develop low levels of vitamins A, E, K and folic acid in your
blood and therefore your doctor may monitor these levels and prescribe supplemental vitamins as
necessary.
Special note for patients on peritoneal dialysis:
You may develop peritonitis (infection of your abdominal fluid) associated with your peritoneal dialysis.
This risk can be reduced by careful adherence to sterile techniques during bag changes. You should tell your
doctor immediately if you experience any new signs or symptoms of abdominal distress,
abdominal
swelling, abdominal pain, abdominal tenderness, or abdominal rigidity, constipation, fever, chills, nausea or
vomiting.
You should expect to be monitored more carefully for problems with low levels of vitamins A, D, E, K and
folic acid.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines including medicines
obtained without a prescription.
Renvela should not be taken at the same time as ciprofloxacin (an antibiotic).
If you are taking medicines for heart rhythm problems or for epilepsy, you should consult your doctor when
taking Renvela.
The effects of medicines such as ciclosporin, mycophenolate mofetil and tacrolimus (medicines used to
suppress the immune system) may be reduced by Renvela. Your doctor will advise you if you are taking
these medicines.
Thyroid hormone deficiency may uncommonly be observed in certain people taking levothyroxine (used to
treat low thyroid hormone levels) and Renvela. Therefore your doctor may monitor the levels of thyroid
stimulating hormone in your blood more closely.
Your doctor will check for interactions between Renvela and other medicines on a regular basis.
Taking Renvela with food and drink
You must take Renvela powder with meals.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or intend to become pregnant. It is unknown whether Renvela has any
affect on unborn babies.
Tell your doctor if you wish to breast-feed your baby. It is unknown whether Renvela may pass through
breast milk and affect your baby.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines has been performed. If you are affected, do
not drive and do not use any tools or machines.
52
3.
HOW TO TAKE RENVELA
You must take Renvela as prescribed by your doctor. They will base the dose on your serum phosphorus
level.
The 2.4 g powder for oral suspension should be dispersed in 60 ml of water per sachet. Drink within
30 minutes of being prepared. It is important to drink all of the liquid and it may be necessary to rinse the
glass with water and drink this as well to ensure that all of the powder is swallowed.
The recommended starting dose for Renvela is 2.4-4.8g per day equally divided over three meals. The exact
starting dose and regimen will be determined by your doctor.
In some cases where Renvela should be taken at the same time as another medicine. Your doctor may advise
you to take this medicine 1 hour before or 3 hours after Renvela intake, or they may consider monitoring the
blood levels of that medicine.
Your doctor will check the levels of phosphorus in your blood periodically and they may adjust the dose of
Renvela when necessary to reach an adequate phosphate level.
If you take more Renvela than you should
There are no reported overdoses in patients.
In the event of a possible overdose you should contact your doctor immediately.
If you forget to take Renvela
If you have missed one dose, this dose should be omitted and the next dose should be taken at the usual time
with a meal. Do not a double dose to make up for a forgotten dose.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Renvela
can cause side effects, although not everybody gets them.
The following side effects have been reported in patients taking Renvela:
Very common
(affects more than 1 user in 10):
vomiting, constipation, upper abdominal pain, nausea
Common
(affects 1 to 10 users in 100):
diarrhoea, abdominal pain, indigestion, flatulence
In clinical use, cases of itching, rash, slow intestine motility (movement)/blockages in the intestine, and
perforation in the intestine wall have been reported.
Since constipation may be an early symptom of a blockage in your intestine, please inform your doctor or
pharmacist.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
5.
HOW TO STORE RENVELA
Keep out of the reach and sight of children.
Do not use Renvela after the expiry date stated on the sachet and carton after the letters “EXP”. The
reconstituted suspension must be administered within 30 minutes of reconstitution.
53
The medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Renvela contains
- The active substance is sevelamer carbonate. Each Renvela sachet contains 2.4 g of sevelamer carbonate.
- The other ingredients are propylene glycol alginate, citrus cream flavour, sodium chloride, sucralose and
iron oxide yellow (E172).
What Renvela looks like and contents of the pack
Renvela powder for oral suspension is a pale yellow powder supplied in a foil sachet with a heat seal. The
foil sachets are packaged in an outer carton.
Pack sizes:
60 sachets per carton
90 sachets per carton
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder:
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
Manufacturer:
Genzyme Ltd.
37 Hollands Road
Haverhill, Suffolk
CB9 8PB
Genzyme Ireland Ltd.
IDA Industrial Park
Old Kilmeaden Road
Waterford
Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation holder.
54
België/Belgique/Belgien/
Luxembourg/Luxemburg
Genzyme Belgium nv/sa (Belgique/Belgien),
Tél/Tel: + 32 2 714 17 11
Ísland
Vistor hf.
Tel: +354 535 7000
България
Търговско представителство на Genzyme CEE
GmbH
Тел. +359 2 971 1001
Magyarország
Genzyme Europe B.V. Képviselet,
Tel: +36 1 310 7440
Česká republika/Slovenská republika
Genzyme Czech s.r.o.
Tel: +420 221 722 511
Nederland
Genzyme Europe BV,
Tel: +31 35 6991200
Danmark/Norge/Sverige/Suomi/Finland
Genzyme A/S, (Danmark/Tanska),
Tlf/Puh.: + 45 32712600
Österreich
Genzyme Austria GmbH,
Tel: + 43 1 774 65 38
Deutschland
Genzyme GmbH,
Tel: +49 610236740
Polska/Eesti/Latvija/Lietuva
Genzyme Polska sp. z o.o. (Poola/Polija/Lenkija),
Tel: +48 22 516 24 32
Ελλά/Κύπρς
Genzyme Hellas Ltd. (Ελλά),
Τηλ: +30 210 99 49 270
Portugal
Genzyme Portugal S.A.,
Tel: +351 21 422 0100
España
Genzyme, S.L.U,
Tel: +34 91 6591670
România
Genzyme CEE GmbH- Reprezentanta pentru
Romania
Tel: +40 21 243 42 28
France
Genzyme S.A.S,
Tél: + 33 (0) 825 825 863
Slovenija
Genzyme Europe B.V. Predstavništvo za Hrvaško
in Slovenijo (Hrvaška),
Tel: +385 1 6386 250
Italia/ Malta
Genzyme Srl (Italia/Italja),
Tel: +39 059 349811
United Kingdom/Ireland
Genzyme Therapeutics (United Kingdom),
Tel: +44 1865 405200
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web site:
55
Source: European Medicines Agency
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