Renagel · 4.6 Fertility, pregnancy and lactation · 1

HOS-083998 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile 5 The most frequently occurring (≥5% of patients) adverse reactions were all in the gastrointestinal disorders system organ class. Tabulated list of adverse reactions Parallel design studies involving 244 haemodialysis patients with treatment duration of up to 54 weeks and 97 peritoneal dialysis patients with treatment duration of 12 weeks were conducted. Adverse reactions from these studies (299 patients), from uncontrolled clinical trials (384 patients), and that were spontaneously reported from post-marketing experience are listed by frequency in the table below. The reporting rate is classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). MedDRA Very Common Uncommon Very Rare Not known System Organ Common Class Immune system Hypersensitivity* disorders Metabolism and Acidosis, nutrition increased disorders serum chloride levels Gastrointestinal Nausea, Diarrhoea, Abdominal pain, disorders vomiting dyspepsia, intestinal flatulence, obstruction, upper ileus/subileus, abdominal diverticulitis, pain, intestinal constipation perforation1, gastrointestinal hemorrhage*1, intestinal ulceration*1,

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HOS-084004 · has-adverse-reaction-information · PDF-Seite 14

Summary of the safety profile The most frequently occurring (≥5% of patients) adverse reactions were all in the gastrointestinal disorders system organ class. Tabulated list of adverse reactions In parallel design studies involving 244 haemodialysis patients with treatment duration of up to 54 weeks and 97 peritoneal dialysis patients with treatment duration of 12 weeks were conducted. Adverse reactions from these studies (299 patients), from uncontrolled clinical trials (384 patients), and that were spontaneously reported from post-marketing experience are listed by frequency in the table below. The reporting rate is classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated form the available data). MedDRA Very Common Uncommon Very Rare Not known System Organ Common Class Immune system Hypersensitivity* disorders Metabolism and Acidosis, nutrition increased disorders serum chloride levels Gastrointestinal Nausea, Diarrhoea, Abdominal pain, disorders vomiting dyspepsia, intestinal flatulence, obstruction, upper ileus/subileus, abdominal diverticulitis, pain, intestinal constipation perforation1, gastrointestinal hemorrhage*1, intestinal ulceration*1,

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HOS-083994 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to sevelamer or to any of the excipients listed in section 6.1. • Hypophosphataemia • Bowel obstruction.

HOS-084000 · has-contraindication-information · PDF-Seite 11

• Hypersensitivity to sevelamer or to any of the excipients listed in section 6.1. • Hypophosphataemia • Bowel obstruction.

HOS-083999 · has-indication-information · PDF-Seite 10

Renagel is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis or peritoneal dialysis. Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to control the development of renal bone disease.

HOS-083993 · has-indication-information · PDF-Seite 2

Renagel is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis or peritoneal dialysis. Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to control the development of renal bone disease.

HOS-084002 · has-interaction-information · PDF-Seite 12

Dialysis Interaction studies have not been conducted in patients on dialysis. Ciprofloxacin In interaction studies in healthy volunteers, sevelamer hydrochloride decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with Renagel in a single dose study. Consequently, Renagel should not be taken simultaneously with ciprofloxacin. 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 hydrochloride to patients also taking these medicinal products. 12 Levothyroxine During post marketing experience, very rare cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medicinal products. Ciclosporin, mycophenolate mofetil and tacrolimus in transplant patients Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus have been reported in transplant patients when coadministered with sevelamer hydrochloride without any clinical consequences (i.e graft rejection). The possibility of an interaction cannot be excluded and a close monitoring of blood concentrations of mycophenolate mofetil, ciclosporin and tacrolimus should be considered during the use of combination and after its withdrawal. Digoxin, warfarin, enalapril or metoprolol In interaction studies in healthy volunteers, Renagel 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 hydrochloride. Bioavailability Renagel 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 Renagel, or the physician should consider monitoring blood levels.

HOS-083996 · has-interaction-information · PDF-Seite 4

Dialysis Interaction studies have not been conducted in patients on dialysis. Ciprofloxacin In interaction studies in healthy volunteers, sevelamer hydrochloride decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with Renagel in a single dose study. Consequently, Renagel should not be taken simultaneously with ciprofloxacin. 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 4 should be exercised when prescribing sevelamer hydrochloride to patients also taking these medicinal products. Levothyroxine During post marketing experience, very rare cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medicinal products. Ciclosporin, mycophenolate mofetil and tacrolimus in transplant patients Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus have been reported in transplant patients when coadministered with sevelamer hydrochloride without any clinical consequences (i.e graft rejection). The possibility of an interaction cannot be excluded and a close monitoring of blood concentrations of mycophenolate mofetil, ciclosporin and tacrolimus should be considered during the use of combination and after its withdrawal. Digoxin, warfarin, enalapril or metoprolol In interaction studies in healthy volunteers, Renagel 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 hydrochloride. Bioavailability Renagel 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 Renagel, or the physician should consider monitoring blood levels.

HOS-084003 · has-pregnancy-information · PDF-Seite 13

Pregnancy The safety of sevelamer hydrochloride has not been established in pregnant women. In animal studies there was no evidence that sevelamer induced embryo-foetal toxicity. Renagel 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 (see section 5.3). Breast-feeding The safety of sevelamer hydrochloride has not been established in breast-feeding women. Renagel should only be given to breast-feeding women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the infant (see section 5.3). 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.

HOS-083997 · has-pregnancy-information · PDF-Seite 5

Pregnancy The safety of sevelamer hydrochloride has not been established in pregnant women. In animal studies there was no evidence that sevelamer induced embryo-foetal toxicity. Renagel 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 (see section 5.3). Breast-feeding The safety of sevelamer hydrochloride has not been established in breast-feeding women. Renagel should only be given to breast-feeding women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the infant (see section 5.3). 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.

HOS-084001 · has-warning-information · PDF-Seite 11

Efficacy and safety of Renagel has not been studied in patients with: • swallowing disorders • active inflammatory bowel disease • gastrointestinal motility disorders including untreated or severe gastroparesis, diverticulosis retention of gastric contents and abnormal or irregular bowel motion • patients with a history of major gastrointestinal surgery Therefore caution should be exercised when Renagel is used in patients with these disorders. Intestinal obstruction and ileus/subileus In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with sevelamer hydrochloride. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with sevelamer hydrochloride. Renagel treatment should be re-evaluated in patients who develop severe constipation or other severe gastrointestinal symptoms. Fat-soluble vitamins Depending on diet intake and the nature of end stage renal failure, dialysis patients may develop low vitamin A, D, E and K levels. It cannot be excluded that Renagel can bind fat-soluble vitamins contained in ingested food. Therefore, in patients not taking these vitamins, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of thromboplastin time should be considered and the vitamins should be supplemented if necessary. Additional monitoring of vitamins and folic acid is recommended in patients receiving peritoneal dialysis, since in the clinical study, vitamin A, D, E and K levels were not measured in these patients. Folate deficiency There is at present insufficient data to exclude the possibility of folate deficiency during long term Renagel treatment. Hypocalcaemia/hypercalcaemia Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. Renagel does not contain calcium. Serum calcium levels should be monitored as is done in normal follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia. Metabolic acidosis Patients with chronic renal failure are predisposed to developing metabolic acidosis. Worsening of acidosis has been reported upon switching from other phosphate binders to sevelamer in a number of studies where lower bicarbonate levels in the sevelamer-treated patients compared to patients treated with calcium-based binders were observed. Closer monitoring of serum bicarbonate levels is therefore r

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HOS-083995 · has-warning-information · PDF-Seite 3

Efficacy and safety of Renagel has not been studied in patients with: • swallowing disorders • active inflammatory bowel disease • gastrointestinal motility disorders including untreated or severe gastroparesis, diverticulosis retention of gastric contents and abnormal or irregular bowel motion • patients with a history of major gastrointestinal surgery Therefore caution should be exercised when Renagel is used in patients with these disorders. Intestinal obstruction and ileus/subileus In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with sevelamer hydrochloride. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with sevelamer hydrochloride. Renagel treatment should be re-evaluated in patients who develop severe constipation or other severe gastrointestinal symptoms. Fat-soluble vitamins Depending on diet intake and the nature of end stage renal failure, dialysis patients may develop low vitamin A, D, E and K levels. It cannot be excluded that Renagel can bind fat-soluble vitamins contained in ingested food. Therefore, in patients not taking these vitamins, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of thromboplastin time should be considered and the vitamins should be supplemented if necessary. Additional monitoring of vitamins and folic acid is recommended in patients receiving peritoneal dialysis, since in the clinical study, vitamin A, D, E and K levels were not measured in these patients. Folate deficiency There is at present insufficient data to exclude the possibility of folate deficiency during long term Renagel treatment. Hypocalcaemia/hypercalcaemia Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. Renagel does not contain calcium. Serum calcium levels should be monitored as is done in normal follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia. Metabolic acidosis Patients with chronic renal failure are predisposed to developing metabolic acidosis. Worsening of acidosis has been reported upon switching from other phosphate binders to sevelamer in a number of studies where lower bicarbonate levels in the sevelamer-treated patients compared to patients treated with calcium-based binders were observed. Closer monitoring of serum bicarbonate levels is therefore r

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