Consumer medicine information

Renagel

Sevelamer hydrochloride

BRAND INFORMATION

Brand name

Renagel

Active ingredient

Sevelamer hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Renagel.

What is in this leaflet

This leaflet answers some common questions about Renagel. It does not contain all the available information. It does not take the place of talking to your treating doctor or a trained health care professional.

All medicines have risks and benefits. Your treating doctor has weighed the risks of you taking Renagel against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your treating doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Renagel is used for

The name of your medicine is Renagel. It contains the active ingredient called sevelamer hydrochloride.

Renagel is used to treat hyperphosphataemia, a condition caused by too much dietary phosphorus being retained in your body due to a diseased kidney.

Ask your treating doctor if you have any questions about why this medicine has been prescribed for you.

How it works

Renagel belongs to a class of medicines that are called ion exchange resins.

Renagel helps to remove excess phosphorus that has built up in your body by binding the phosphorus that is in the food that you eat.

Before you use Renagel

When you must not take it

Do not take Renagel if you have an allergy to:

  • any medicine containing sevelamer hydrochloride
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • skin rash, itching or hives

Do not take Renagel if you have:

  • hypophosphatemia, a condition where you do not have enough phosphorus in your body
  • a bowel obstruction

Do not take Renagel if the packaging is torn or shows signs of tampering.

Do not take Renagel after the expiry date (EXP) printed on the pack has passed.

If you take this medicine after the expiry date it may have no effect at all, or worse, an unexpected effect.

If you are not sure whether you should start taking this medicine, talk to your treating doctor.

Before you start to take it

You must tell your treating doctor if you have:

  • allergies to any other medicines or substances such as foods, preservatives or dyes
  • swallowing problems
  • severe constipation
  • problems with movement in your stomach and bowel
  • active inflammation of the bowel
  • undergone major surgery on your stomach or bowel
  • you have or have had any other medical conditions, including a bowel obstruction or hypophosphatemia
  • if you are pregnant or breast-feeding, think you may be pregnant on are planning to have a baby

If you have not told your treating doctor about any of the above, tell them before you take Renagel.

Taking other medicines

Tell your treating doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by Renagel or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your treating doctor will advise you.

The effects of medicines such as ciclosporin, mycophenolate mofetil and tacrolimus (medicines used to suppress the immune system) may be reduced by Renagel. Your doctor will advise you if you are taking these medicines.

Renagel should not be taken at the same time as ciprofloxacin (an antibiotic).

How to take Renagel

How much to take

Your treating doctor may initially prescribe 1 - 2 Renagel 800 mg tablets three times a day with your meals. Your doctor may adjust your dosage during treatment depending on your blood test results. The average daily dose of Renagel is 3 Renagel 800mg tablets per meal

Follow all directions given to you by your treating doctor and pharmacist carefully. These directions may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle, ask your treating doctor or pharmacist for help.

How to take it

Swallow Renagel tablets whole with a glass of water. Do not chew them. If you are having difficulty swallowing Renagel tablets, speak to your healthcare professional.

When the contents of Renagel come into contact with water they expand making them hard to swallow, therefore do NOT crush, chew or break the tablets into pieces before you take them.

How long to take it

Renagel helps lower your dietary phosphate. It does not cure your condition. Therefore, you must continue to take it as directed by your treating doctor if you expect to lower your phosphate level and keep it down. You may have to take phosphate-lowering medicine for the rest of your life. If you stop taking Renagel, your phosphate levels may rise again. It is important to keep taking your medicine even if you feel well.

Do not stop taking Renagel. Your treating doctor may need to change the dose of your other medicines if you stop Renagel, so you should only stop when your treating doctor tells you to.

If you forget to take it

If you miss a dose, do not take an extra dose to make up for the one you missed. Just go back to taking your tablets as you would normally.

It is important to try to take Renagel as prescribed by your treating doctor.

If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your treating doctor or Poisons Information Centre [Australia telephone 13 11 26; in New Zealand telephone 0800 POISON or 0800 764 766], or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much Renagel. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention. Keep telephone numbers of these places handy

While you are using Renagel

Things you must do

If you become pregnant while you are taking Renagel tell your treating doctor.

If you are about to be started on any new medicine tell your treating doctor and pharmacist that you are taking Renagel.

Be sure to keep all your doctor's appointments so your progress can be checked.

Your doctor will check your progress and monitor your phosphorus levels from time to time. This helps to ensure you are getting the right dose of Renagel.

Things you must not do

Do not give Renagel to anyone else, even if they have the same condition as you.

Do not use Renagel to treat any other complaints unless your treating doctor tells you to.

Do not stop taking your medicine or lower the dosage without checking with your treating doctor.

Side effects

Check with your treating doctor as soon as possible if you do not feel well or have any problems while taking Renagel, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, Renagel can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Ask your treating doctor or pharmacist any questions you may have.

Tell your treating doctor if you notice any of the following and they worry you:

  • vomiting
  • nausea
  • constipation
  • diarrhoea
  • flatulence
  • indigestion
  • abdominal pain
  • cold
  • ongoing cough
  • pain in limb or joint or back
  • headache
  • mechanical complication of implant
  • loss of appetite
  • high blood pressure.

Tell your doctor immediately if you notice any of the following symptoms:

  • rash, itching or hives on the skin
  • severe constipation
  • vomiting blood or material that looks like coffee grounds, bleeding from the rectum, black sticky bowel motions (stools) or bloody diarrhoea
  • fever or high temperature.

If any of the following happen, tell your doctor immediately or go to the Accident and Emergency at your nearest hospital:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body

Other side effects not listed above may occur in some patients. Tell your treating doctor if you notice anything making you feel unwell when you are taking, or soon after you have finished taking, Renagel.

After using Renagel

Storage

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep well.

Keep Renagel in a cool dry place where the temperature stays below 25°C with the lid tightly closed. Do not put Renagel in the refrigerator. Do not store it or any other medicine in the bathroom or near a sink. Do not leave it in the car or on the window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your treating doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Renagel 800mg tablets are oval off-white film coated tablets imprinted with "Renagel 800" printed on one side and blank on the other side.

AUSTR 101553

Ingredients

Active ingredient: sevelamer hydrochloride

Other ingredients: colloidal anhydrous silica, stearic acid, OPADRY complete film coating system 06A29064 Clear, OPACODE WB monogramming ink NS-78-17715 BLACK.

Renagel does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Sponsor

In Australia this product is registered by:

sanofi-aventis australia pty ltd
12-24 Talavera Rd
Macquarie Park NSW 2113
Toll Free Number (medical information): 1800 818 806
E-mail: [email protected]

In New Zealand this product is distributed by:

sanofi-aventis new zealand limited
Level 8
56 Cawley Street
Ellerslie
Auckland
New Zealand
Toll Free Number (medical information): 0800 283 684
E-mail: [email protected]

This leaflet was prepared in February 2020

Further information is available via the App below.

Login code to access Renagel App: kidney

renagel-ccdsv6-cmiv15-25feb20

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Renagel

Active ingredient

Sevelamer hydrochloride

Schedule

S4

 

1 Name of Medicine

Sevelamer hydrochloride.

2 Qualitative and Quantitative Composition

Renagel 800 mg tablets contain 800 mg sevelamer hydrochloride on an anhydrous basis.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film coated tablets.
Renagel tablets are oval off-white film coated tablets imprinted with "Renagel 800" on one side and blank on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Renagel is indicated for the management of hyperphosphataemia in adult patients with stage 4 and 5 chronic kidney disease.

4.2 Dose and Method of Administration

Dose.

Starting dose.

The recommended starting dose for patients not taking a phosphate binder is 800 to 1600 mg (see Table 1), which can be administered as one to two Renagel 800 mg tablets with each meal based on serum phosphorus level.
When patients are converting from a calcium based phosphate binder, Renagel should be given in equivalent doses on a (mg to mg) weight basis compared to the patient's previous calcium based phosphate binder (see Table 2). Serum phosphorus levels should be closely monitored and the dose of Renagel adjusted accordingly with the goal of lowering serum phosphorus. Serum phosphorus should be tested every 2 to 3 weeks until a stable serum phosphorus level is reached, and on a regular basis thereafter.

Dose titration for all patients taking Renagel.

The dosage should be gradually adjusted based on the serum phosphorus concentration with a goal of lowering serum phosphorus. The dose may be increased or decreased by one tablet per meal at two week intervals as necessary (see Table 3). The average dose in a one year Phase 3 trial designed to lower serum phosphorus to 1.62 mmol/L or less was approximately three Renagel 800 mg tablets per meal. The average actual daily dose used in the chronic phase of a one year clinical study was 7 grams of sevelamer hydrochloride.

Method of administration.

Patients should be advised not to chew the tablets as sevelamer hydrochloride swells on contact with moisture. Patients should swallow the tablets whole with water.

4.3 Contraindications

Renagel is contraindicated in patients with hypophosphataemia or bowel obstruction.
Renagel is also contraindicated in patients known to be hypersensitive to sevelamer hydrochloride or any of the other components of the tablet, see Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

General.

The safety and efficacy of Renagel in patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders, severe constipation, major GI tract surgery or in pre-dialysis patients have not been established. Consequently, caution should be exercised when Renagel is used in patients with these GI disorders.

Swallowing and choking difficulties.

Uncommon case reports of difficulty swallowing the Renagel tablet have been reported. Many of these cases involved patients with contributing co-morbid conditions affecting the ability to swallow including swallowing disorders or oroesophageal abnormalities. Caution should be exercised when Renagel tablets are used in these patients.

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 routine follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia.

Metabolic acidosis.

Patients with chronic kidney disease are predisposed to metabolic acidosis. Renagel does not contain alkali supplementation: serum bicarbonate and chloride levels should be monitored.

Fat-soluble vitamins.

Depending on dietary intake and the nature of chronic kidney disease, dialysis patients may develop low vitamin A, D, E and K levels. 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 these vitamins should be supplemented if necessary.
In clinical trials there was no evidence of reduction in serum levels of vitamins with the exception of a one year clinical trial in which Renagel treatment was associated with reduction of 25-hydroxyvitamin D (normal range 10 to 55 microgram/mL) from 39 ± 22 microgram/mL to 34 ± 22 microgram/mL (p < 0.01). Most patients in Renagel clinical trials received vitamin supplements, which is typical of patients on haemodialysis. Indirect evidence of a reduction in vitamin K levels (an increase in haemorrhage corrected by vitamin K supplementation) was also seen in animals.
In nonclinical studies in rats and dogs, sevelamer hydrochloride reduced vitamin D, E and folic acid levels at doses of 0.6-10 g/kg/day which are 6-100 times the recommended average clinical dose based on a mg/kg basis.

Gastrointestinal disorders.

Cases of serious inflammatory disorders of the gastrointestinal tract (with complications including haemorrhage, perforation, ulceration, necrosis, colitis, and colonic/ cecal mass) associated with the presence of sevelamer crystals have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Inflammatory disorders may resolve upon Renagel discontinuation. Treatment with Renagel should be re-evaluated in patients who develop severe gastrointestinal symptoms.

Instructions to patients.

The contents of Renagel expand in water, thus tablets should be swallowed intact and should not be crushed, chewed or broken into pieces prior to administration (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

No data available.

Paediatric use.

The safety and effectiveness of Renagel in patients below the age of 18 years have not been established.

Effects on laboratory tests.

No information available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interaction studies have not been conducted in patients on dialysis.
Renagel was studied in human drug-drug interaction studies with digoxin, warfarin, enalapril, metoprolol, iron and ciprofloxacin.
In interaction studies in healthy volunteers, Renagel had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol. However, the bioavailability of ciprofloxacin was decreased by approximately 50% when co-administered with Renagel in a single dose study. Consequently, Renagel 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 any of these agents in combination with sevelamer and after its withdrawal.
During post-marketing experience, very rare cases of increased TSH levels have been reported in patients co-administered Renagel and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medications.
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.
Renagel may affect the bioavailability of other medicinal products. When administering a medicinal product where a reduction in the bioavailability of that product could have a clinically significant effect on its 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.
Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from clinical trials. Special precautions should be taken when prescribing Renagel to patients also taking these medications.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Sevelamer hydrochloride administered orally to male and female rats prior to and throughout mating, at doses up to 4.5 g/kg/day (15 times the maximum tested human dose on a mg/kg basis of a 50 kg person) did not alter mating or fertility.
(Category B3)
There was no evidence of teratogenicity in rabbits or rats following oral administration of sevelamer hydrochloride during the period of organogenesis at respective doses 1.5 and 4.5 g/kg/day (5 and 15 times, respectively, on a mg/kg basis for a 50 kg human). In rats receiving doses of 1.5 and 4.5 g/kg/day during organogenesis, there was reduced or irregular ossification of foetal bones at exposures of 5 and 15 times the maximum tested human dose. In rabbits receiving 1 g/kg/day during organogenesis, there was an increase in early resorptions leading to a reduction in the number of live foetuses per liter at an exposure 3.3 times the maximum recommended human dose.
Oral administration of sevelamer hydrochloride to female rats throughout gestation and lactation at doses of 0.1-1 g/kg/day (exposure 0.3-3.3 times the maximum recommended human dose) did not affect the birth or growth of their offspring or their postnatal development.
The safety of sevelamer hydrochloride in human pregnancy has not been established and, because animal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
In pregnant rats given dietary doses of 0.5, 1.5 or 4.5 g/kg/day of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of foetal bones, probably due to a reduced absorption of fat soluble vitamin D, occurred in mid and high dose groups (human equivalent doses less than the maximum clinical trial dose of 13 g). In pregnant rabbits given oral doses of 100, 500 or 1000 mg/kg/day 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).
 Oral administration of sevelamer hydrochloride to female rats throughout gestation and lactation did not have any adverse effects on offspring (see Section 4.6 Fertility, Pregnancy and Lactation).
No adequate and controlled studies have been conducted using sevelamer in nursing mothers. Renagel tablets should be used during breastfeeding only if the potential benefit justifies the potential risks.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

In a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse events reported for sevelamer hydrochloride (N = 99) were similar to those reported for the active control group (N = 101), except for those in the MedDRA gastrointestinal disorders system organ class (SOC) that were more frequent (see Table 4). Gastrointestinal adverse events were the most frequently occurring (≥ 5% of patients) treatment emergent adverse events possibly or probably related to Renagel; and a major reason for drop out in the Renagel group (see Table 5).
In a placebo controlled study with a treatment duration of two weeks, treatment emergent adverse events possibly or probably related to Renagel (N = 24) included dyspepsia (8.3%) and vomiting (4.2%). In a crossover study with treatment durations of eight weeks each, the treatment emergent events possibly or probably related to Renagel (N = 82) included dyspepsia (8.5%), diarrhoea (4.9%), nausea (4.9%), vomiting (4.9%), anorexia (3.7%), and gastrointestinal disorder (3.7%). In a long-term, open label extension trial the treatment emergent events possibly or probably related to Renagel (N = 192) included nausea (7.3%), abdominal pain (5.2%) and dyspepsia (4.7%).
In a parallel design study with a treatment duration of 12 weeks, the adverse events reported for sevelamer hydrochloride in peritoneal dialysis patients (N = 97) were similar to adverse events observed in haemodialysis patients. Adverse events possibly related to sevelamer hydrochloride included dyspepsia (12.4%), diarrhoea (5.2%), nausea (5.2%), constipation (4.1%), pruritus (4.1%), abdominal distension (3.1%), vomiting (3.1%), fatigue (3.1%), anorexia (3.1%) and arthralgia. The most frequently occurring serious adverse event was peritonitis (8.2%) reported as unrelated to sevelamer hydrochloride.

Post-marketing experience.

Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
During post-marketing experience, the following adverse events have been reported in patients receiving Renagel: hypersensitivity, pruritus, rash, abdominal pain and uncommon cases of ileus, intestinal obstruction and intestinal perforation. Constipation might be a preceding symptom indicating the development of intestinal obstruction. Hence, patients with severe constipation should be monitored carefully while being treated with Renagel.
Cases of serious inflammatory disorders of the gastrointestinal tract (with complications including haemorrhage, perforation, ulceration, necrosis, colitis, and intestinal mass) associated with the presence of sevelamer crystals have been reported (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

Renagel has been given to normal healthy volunteers in doses of up to 14.4 grams per day for 8 days with no adverse effects. There are no reported overdoses of Renagel in patients. Since Renagel is not absorbed, the risk of systemic toxicity is low.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia), or the National Poisons Information Centre on 0800 POISON or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Treatment of hyperphosphatemia. ATC code: V03AE02.

Mechanism of action.

Patients with end-stage renal disease (ESRD) retain phosphorus and can develop hyperphosphataemia. Renagel contains sevelamer, a non-absorbed phosphate binding poly(allylamine hydrochloride) polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines become partially protonated in the intestine and interact with phosphorus molecules through ionic and hydrogen bonding. By binding phosphorus in the dietary tract, sevelamer lowers the phosphorus concentration in the serum. Renagel decreases the incidence of hypercalcaemic episodes as compared to patients using calcium based phosphate binders alone, probably because the product itself does not contain calcium.
Renagel treatment also results in a lowering of low density lipoprotein (LDL) and total serum cholesterol levels by increasing faecal excretion of bile acids.
High serum phosphorus can precipitate serum calcium resulting in ectopic calcification. When the product of serum calcium and phosphorus concentrations (Ca x P) exceeds 4.46 (mmol/L)2, there is an increased risk that ectopic calcification will occur. Hyperphosphataemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency. An increase in parathyroid hormone (PTH) levels is characteristic of patients with chronic renal failure. Increased levels of PTH can lead to the bone disease osteitis fibrosa. A decrease in serum phosphorus may decrease serum PTH levels.

Clinical trials.

In vitro studies have shown that the capsule and tablet formulations bind phosphate to a similar extent. Since Renagel does not contain aluminium, it does not cause aluminium intoxication.
The ability of Renagel to lower serum phosphorus in endstage renal disease (ESRD) patients on haemodialysis was demonstrated in three Phase 2 studies with treatment duration ranging from 2 to 12 weeks and two Phase 3 studies with treatment duration of 8 weeks each. Four of the five studies were open label, dose titration studies. One of the Phase 2 studies was a placebo controlled study. The Phase 3 crossover study, described below, had a control arm. About half the patients from these studies (N = 192) were treated with Renagel capsules in a long-term open label extension study of 44 weeks.
In a crossover study of sevelamer and calcium acetate, 84 ESRD patients on haemodialysis who were hyperphosphataemic (serum phosphorus > 1.94 mmol/L) following a 2 week phosphate binder washout period were randomised to receive either Renagel for 8 weeks followed by calcium acetate for 8 weeks or calcium acetate for 8 weeks followed by Renagel for 8 weeks. Treatment periods were separated by a 2 week phosphate binder washout period. Patients started on Renagel capsules or calcium acetate tablets 3 times per day with meals. Over each 8 week treatment period, at three separate time points the dose of either agent could be titrated up one capsule or tablet per meal (3 per day) to control serum phosphorus. Renagel and calcium acetate both significantly decreased mean serum phosphorus by about 0.65 mmol/L (see Table 6).
Figure 1 illustrates that the proportion of patients achieving a given level of serum phosphorus lowering is comparable between the two treatment groups. For example, about half the patients in each group had a decrease of at least 0.65 mmol/L at endpoint. Successful control of serum phosphorus in chronic kidney disease patients is multifactorial including reduction of dietary phosphate intake, removal of phosphate with dialysis and inhibition of intestinal phosphate absorption with phosphate binders. As seen in Figure 1, some of the patients in GTC-36-301 did not respond to sevelamer treatment. Not all patients achieve phosphorus control with sevelamer alone, especially at the doses administered in this study (average actual daily dose 4.3 g/day). Later studies which employed higher doses of sevelamer (i.e. GTC-49-301 average actual daily dose 6.5 g/day) had a better rate of phosphorus response.
Average daily consumption at the end of treatment was 4.9 g sevelamer (range of 0.0 to 12.6 g) and 5.0 g of calcium acetate (range of 0.0 to 17.8 g). During calcium acetate treatment, 22% of patients developed serum calcium ≥ 2.75 mmol/L on at least one occasion versus 5% for sevelamer (p < 0.05). Thus the risk of developing hypercalcaemia is less with Renagel compared to calcium acetate.
Mean LDL cholesterol and mean total cholesterol declined significantly on Renagel capsules treatment (-24% and -15%, respectively). Neither LDL nor total cholesterol changed on calcium acetate treatment. Triglycerides, high density lipoprotein (HDL) cholesterol and albumin did not change on either treatment.
Similar reductions in serum phosphorus and LDL cholesterol were observed in an 8 week open label, uncontrolled study of 172 end-stage renal disease patients on haemodialysis.
In a parallel study of Renagel and calcium acetate or calcium carbonate, two hundred ESRD patients on haemodialysis who were hyperphosphataemic (serum phosphorus > 1.78 mmol/L) following a two week phosphate binder washout period were randomised to receive Renagel 800 mg tablets (N = 99) or calcium, either calcium acetate (N = 54) or calcium carbonate (N = 47). Seventy seven percent of Renagel patients (N = 76) and 80% of the calcium patients (N = 81) completed the full 52 weeks of treatment with the major reason for dropout in the Renagel group was gastrointestinal adverse events. Calcium acetate and calcium carbonate produced comparable decreases in serum phosphorus. At week 52, using last observation carried forward, Renagel and calcium both significantly decreased mean serum phosphorus (see Table 7).
Figure 2, a plot of the phosphorus change from baseline for the completers, illustrates the durability of response for patients who are able to remain on treatment.
Average daily consumption at the end of the treatment was 6.5 g of sevelamer (range of 0.8 to 13 g) or approximately eight 800 mg tablets (range of 1 to 16 tablets), 4.6 g of calcium acetate (range of 0.7 to 9.5 g) and 3.9 g of calcium carbonate treatment, 34% of patients developed serum calcium corrected for albumin ≥ 2.75 mmol/L on at least one occasion versus 7% for Renagel (p < 0.05). Thus the risk of developing hypercalcaemia is less with Renagel compared to calcium salts.
Mean LDL cholesterol and mean total cholesterol declined significantly (p < 0.05) on Renagel treatment (-32% and -20%, respectively) compared to calcium (+0.2% and -2%, respectively); triglycerides, HDL cholesterol and albumin did not change.
In a parallel study of sevelamer hydrochloride or calcium acetate in peritoneal dialysis patients, one hundred and forty three patients on peritoneal dialysis who were hyperphosphatemic (serum phosphorus > 5.5 mg/dL) following a two week phosphate binder washout period were randomized to receive Renagel 800 mg tablets (N = 97) or calcium acetate (N = 46). Treatment for 12 weeks with Renagel was non-inferior to calcium acetate in reducing serum phosphorus. There were statistically significant changes in serum phosphorus (p < 0.001) from baseline for both the Renagel (1.61 mg/dL from 7.48 mg/dL) and calcium acetate (-1.81 mg/dL from 7.29 mg/dL) groups.
Average daily consumption at the end of treatment was 5.9 g for Renagel (range of 0.8 to 14.3 g) and 4.3 g for calcium acetate (range of 1.7 to 9.0 g). During calcium acetate treatment, 18% of patients had a serum calcium corrected for albumin ≥ 11.0 mg/dL at the end of the study versus 2% for Renagel (p = 0.001).
There appeared to be a trend for a decrease from baseline for total, LDL and non-HDL cholesterol levels. The long-term impact of Renagel on cardiovascular related morbidity and mortality, as a result of total, LDL and non-HDL reduction, is unclear.

5.2 Pharmacokinetic Properties

Absorption.

A mass balance study using 14C-sevelamer hydrochloride in 16 healthy male and female volunteers showed that sevelamer is not systemically absorbed. No absorption studies have been performed in patients with renal disease.

5.3 Preclinical Safety Data

Genotoxicity.

In an in vitro mammalian cytogenetics 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. Based on the available evidence, sevelamer hydrochloride is considered unlikely to be genotoxic in vivo following oral administration.

Carcinogenicity.

Sevelamer hydrochloride was administered in the diet to rats and mice for two years. In mice and female rats, there was no increase in the incidence of tumours. In male rats, there was an increased incidence of transitional cell papillomas and transitional cell carcinomas in the urinary bladder at a dose of 3 g/kg/day, which is 10 times the maximum daily human dose (mg/kg basis) for a 50 kg person examined in clinical trials. These findings were considered likely to be secondary to increased serum and urinary calcium levels and inflammatory responses in the urinary bladder and their relevance to humans is unknown.

6 Pharmaceutical Particulars

6.1 List of Excipients

Colloidal anhydrous silica, stearic acid, Opadry complete film coating system 06A29064 Clear, Opacode WB monogramming ink NS-78-17715 Black.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Do not refrigerate. Protect from moisture. Keep the container tightly closed.

6.5 Nature and Contents of Container

Renagel tablets are packaged in white high density polyethylene (HDPE) bottles, with a child resistant polypropylene cap and an induction seal.
Renagel 800 mg tablets are available in pack sizes of 180 and 30# tablets.
# Physician starter pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Sevelamer hydrochloride is a white to off white, water insoluble powder. Sevelamer is a partial hydrochloride salt, approximately 40% amine hydrochloride and 60% free base. Sevelamer hydrochloride is hydrophilic, but also insoluble in water.

Chemical structure.

The structure is represented as:
Sevelamer, or poly(allylamine-co-N,N'-diallyl -1,3-diamino-2-hydroxypropane), a cross-linked polymer. The primary amine groups shown in the structure are derived directly from poly(allylamine hydrochloride). The crosslinking groups consist of two secondary amine groups derived from poly(allylamine hydrochloride) and one molecule of epichlorohydrin.

CAS number.

152751-57-0.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes