1. Name Of The Medicinal Product
Renvela 800 mg film
2. Qualitative And Quantitative Composition
Each tablet contains 800 mg sevelamer carbonate.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film
The white to off
4. Clinical Particulars
4.1 Therapeutic Indications
Renvela is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis or peritoneal dialysis.
Renvela is also indicated for the control of hyperphosphataemia in adult patients with chronic kidney disease not on dialysis with serum phosphorus > 1.78 mmol/l.
Renvela should be used within the context of a multiple therapeutic approach, which could include calcium supplement, 1,25-dihydroxy Vitamin D3 or one of its analogues to control the development of renal bone disease.
4.2 Posology And Method Of Administration
Posology
Starting dose
The recommended starting dose of sevelamer carbonate is 2.4 g or 4.8 g per day based on clinical needs and serum phosphorus level. Renvela must be taken three times per day with meals.
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*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
Patients taking Renvela should adhere to their prescribed diets.
In clinical practice, treatment will be continuous based on the need to control serum phosphorus levels and the daily dose is expected to be an average of approximately 6 g per day.
Paediatric population
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.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients.
• Hypophosphataemia
• Bowel obstruction.
4.4 Special Warnings And Precautions For Use
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:
• 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
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
Folate deficiency
There is at present insufficient data to exclude the possibility of folate deficiency during long term Renvela treatment.
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 D3 or one of its analogues to lower the intact parathyroid hormone (iPTH) levels.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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.
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.
4.6 Pregnancy And Lactation
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
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.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on ability to drive and use machines have been performed.
4.8 Undesirable Effects
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 (
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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.
4.9 Overdose
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. Pharmacological Properties
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
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 D3 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
Because sevelamer binds bile acids, it may interfere with the absorption of fat soluble vitamins such as A, D, E and K.
Sevelamer does not contain calcium and decreases the incidence of hypercalcaemic episodes as compared to patients using calcium based phosphate binders alone. The effects of sevelamer on phosphorus and calcium were proven to be maintained throughout a study with one year follow-up. This information was obtained from studies in which sevelamer hydrochloride was used.
5.2 Pharmacokinetic Properties
Pharmacokinetic studies have not been carried out with sevelamer carbonate. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, is not absorbed from the gastrointestinal tract, as confirmed by an absorption study in healthy volunteers.
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. Pharmaceutical Particulars
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)
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 And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
8. Marketing Authorisation Number(S)
EU/1/09/521/001
EU/1/09/521/002
EU/1/09/521/003
9. Date Of First Authorisation/Renewal Of The Authorisation
10/06/2009
10. Date Of Revision Of The Text
09/2010
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.
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