Renvela 2.4 g powder for oral suspension

last change to revert the Renvela 2.4g sachet SmPC

Patients taking sevelamer carbonate should adhere to their prescribed diets.

Special populations

Elderly population

No dosage adjustment is necessary in the elderly population.

Hepatic impairment

No studies have been performed in patients with hepatic impairment.

Paediatric population

The safety and efficacy of Renvela have not been established in children below the age of 6 years or in children with a BSA below 0.75 m² have not been established. No data are available.

the Ppatient Lleaflet.

Therefore caution should be exercised when it is used in these patients.Treatment of these patients with Renvela should only be initiated after careful benefit/risk assessment. If the therapy is initiated, patients suffering from these disorders should be monitored.  Renvela treatment should be reevaluated in patients who develop severe constipation or other severe gastrointestinal symptoms.

Fat‑soluble vitamins and folate deficiency

Folate deficiency

There is at present insufficient data to exclude the possibility of folate deficiency during long term sevelamer carbonate treatment. In patients not taking supplemental folic acid but on sevelamer, folate level should be assessed regularly.

Swallowing and choking difficulties

Uncommon reports of difficulty swallowing the Renvela tablet have been reported.  Many of these cases involved patients with co-morbid conditions including swallowing disorders or oroesophageal abnormalities. Caution should be exercised when it is used in patients with difficulty swallowing.  The use of sevelamer carbonate powder  in patients with a history of difficulty swallowing should be considered.

Hypothyroidism

Closer monitoring of patients with hypothyroidism co-administered with sevelamer carbonate and levothyroxine is recommended (see section 4.5).

Long‑term chronic treatment

In a clinical trial of one year, no evidence of accumulation of sevelamer was seen. However the potential absorption and accumulation of sevelamer during long‑term chronic treatment (> one year) cannot be totally excluded (see section 5.2).

Hyperparathyroidism

Sevelamer carbonate is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism sevelamer carbonate should be used within the context of a multiple therapeutic approach, which could include calcium as supplements, 1,25-dihydroxy Vitamin D₃ or one of its analogues to lower the intact parathyroid hormone (iPTH) levels.

Inflammatory Ggastrointestinal Ddisorders

Cases of serious inflammatory disorders of different parts of the gastrointestinal tract (including serious complications such as bleeding, perforation, ulceration, necrosis, colitis) associated with the presence of sevelamer crystals have been reported in literature. However, the causality of the sevelamer crystals in initiating such disorders has not been demonstrated. Sevelamer carbonate treatment should be re-evaluated in patients who develop severe gastrointestinal symptoms.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per 0.8 gsachet, that is to say essentially ‘sodium-free’.

4.5     Interaction with other medicinal products and other forms of interaction

Anti-arrhythmics and anti-seizure medicinal products

Patients taking anti-arrhythmic medicinal products for the control of arrhythmias and anti-seizure medicinal products for the control of seizure disorders were excluded from clinical trials. Caution should be exercised when prescribing sevelamer carbonate to patients also taking these medicinal products.Therefore, possible reduction in absorption cannot be excluded. The anti-arrhythmic medicinal product should be taken at least one hour before or three hours after Renvela and blood monitoring can be considered.

Digoxin, warfarin, enalapril or metoprolol

In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol.

Proton pump inhibitors

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

Bioavailability

Sevelamer carbonate is not absorbed and may affect the bioavailability of other medicinal products. When administering any medicinal product where a reduction in the bioavailability could have a clinically significant effect on safety or efficacy, the medicinal product should be administered at least one hour before or three hours after sevelamer carbonate, or the physician should consider monitoring blood levels.

Digoxin, warfarin, enalapril or metoprolol

In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol.

4.6     Fertility, pregnancy and lactation

1. 4.8 Overdose

Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been given to normal healthy volunteers in doses of up to 14 grams per day for eight days with no undesirable effectsadverse reactions. In CKD patients, the maximum average daily dose studied was 14.4 grams of sevelamer carbonate in a single daily dose.

The symptoms observed in case of overdose are similar to adverse reactions listed in section 4.8, including mainly constipation and other known gastrointestinal disorders.

Appropriate symptomatic treatment should be provided.

5.       PHARMACOLOGICAL PROPERTIES

1. 5.2 Pharmacokinetic properties

Pharmacokinetic studies have not been carried out with sevelamer carbonate. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, is not absorbed from the gastrointestinal tract, as confirmed by an absorption study in healthy volunteers.

In a clinical trial of one year, no evidence of accumulation of sevelamer was seen. However the potential absorption and accumulation of sevelamer during long‑term chronic treatment (> one year) cannot be totally excluded.

5.3     Preclinical safety data

7.       MARKETING AUTHORISATION HOLDER

Genzyme Europe B.V.

Paasheuvelweg 25

1105 BP Amsterdam

The Netherlands

Section 4.4: New paragraph ‘Excipients’ added.

Minor changes throughout the 2.4g Powder SmPC in line with the QRD template:

-          Changing ‘Renvela’ to ‘sevelamer carbonate’.

-          ‘Chronic Kidney Disease’ changed to ‘CKD’.

-          Section 5.1 headings added.

-          ‘Body surface area’ change to ‘BSA’.

-          ‘Clinical studies’ changed to ‘clinial trials’.

Section 4.2
Method of administration

For oral use.

Each sachet of 2.4 g of powder is to be dispersed in 60 mL of water prior to administration (see section 6.6). The suspension should be ingested within 30 minutes after being prepared. Renvela should be taken with food and not on an empty stomach.

As an alternative to water, the powder may be pre-mixed with a small amount of beverage or food (e.g. 100grams/120 ml) and consumed within 30 minutes. Do not heat Renvela powder (e.g. microwave) or add to heated foods or liquids

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.

The powder may also be pre-mixed with cold beverage or unheated food (see 4.2). Renvela powder should not be heated (e.g. microwave).

4.1 added

Renvela is indicated for the control of hyperphosphataemia in paediatric patients (>6 years of age and a Body Surface Area (BSA) of >0.75 m²) with chronic kidney disease.

4.2 added:-

Wording amended.

Children/adolescents (>6 years of age and a body surface area (BSA) of >0.75m2)

The recommended starting dose of sevelamer carbonate for children is between 2.4 g and 4.8 g per day based on the patient’s body surface area (BSA) category.  Renvela must be taken three times per day with meals or snacks.           

children below the age of  6 years           or in children with a BSA below 0.75 m2.

For paedi atri c pati ent s the oral suspension should be administered, as tablet formulations are not appropriate for this population.

4.2 deleted:-

Patients taking Renvela should adhere to their prescribed diets.

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

4.8 added:-

Paediatric population

In general, the safety profile for children and adolescents (6 to 18 years of age) is similar to the safety

profile for adults.

5.1 added:-

The safety and effectiveness of sevelamer carbonate in hyperphosphatemic paediatric patients with Chronic Kidney Disease (CKD) was evaluated in a multicenter study with a 2-week, randomized, placebo-controlled, Fixed Dose Period (FDP) followed by a 6-month, single-arm, open-label, Dose Titration Period (DTP). A total of 101 patients (6 to 18 years old with a BSA range of 0.8 m²  to 2.4 m²) were randomized in the study. Forty-nine (49) patients received sevelamer carbonate and 51 received placebo during the 2 week FDP. Thereafter all patients received sevelamer carbonate for the 26-week DTP. The study met its primary endpoint, meaning Sevelamer carbonate reduced serum phosphorus by an LS mean difference of -0.90 mg/dL compared to placebo, and secondary efficacy endpoints. In paediatric patients with hyperphosphatemia secondary to CKD, sevelamer carbonate significantly reduced serum phosphorus levels compared to placebo during a 2-week FDP. The treatment response was maintained in the paediatric patients who received sevelamer carbonate during the 6-month open-label DTP. 27% of paediatric patients reached their age appropriate serum phosphorus level at end of treatment. These figures were 23% and 15% in the subgroup of patients on hemodialysis and peritoneal dialysis, respectively. The treatment response during the 2-week FDP was not affected by body surface area (BSA), in contrast however, no treatment response was observed in pediatric patients with qualifying phosphorus levels <7.0 mg/dL. Most of AEs reported as related, or possibly related, to sevelamer carbonate were gastrointestinal in nature. No new risks or safety signals were identified with the use of sevelamer carbonate during the study

Proton pump inhibitors

During post-marketing experience, very rare cases of increased phosphate levels have been reported in patients taking proton pump inhibitors co-administered with sevelamer hydrochloride.

Changes to sections:

4.6 Fertility, pregnancy and lactation

Addition of “Fertility” in the header. 

Addition to the last paragraph “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.”

4.8 Undesirable effects

Post-marketing experience – Paragraph changed from – “In very rare cases (estimated post-marketing frequency of < 1/10,000), intestinal obstruction and ileus/subileus have been observed in patients during treatment with sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate” to “During post-approval use, cases of pruritus, rash, intestinal obstruction, ileus/subileus, and intestinal perforation have been reported in patients during treatment with sevelamer.”

5.3 Preclinical safety data

In the last paragraph changed the human equivalent dose from 3 to 2 and the maximum clinical trial dose from 14.4 to 13 g/day with addition to “based on a comparison of relative body surface”area.

10 Date of Revision of the Text

Change of date.