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.

SUMMARY CMI

RENAGEL®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Renagel?

Renagel contains the active ingredient 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.

For more information, see Section 1. Why am I using Renagel? in the full CMI.

2. What should I know before I use Renagel?

Do not use if you have ever had an allergic reaction to Renagel or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Renagel? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Renagel and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Renagel?

  • Your treating doctor will tell you how many tablets to take each day. The initial dose is usually 1 - 2 tablets three times a day with meals. Your doctor may adjust your dosage depending on your blood test results.
  • Renagel tablets should be swallowed whole with a glass of water during mealtimes. Do not chew, crush, or break the tablets into pieces before taking them.

More instructions can be found in Section 4. How do I use Renagel? in the full CMI.

5. What should I know while using Renagel?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Renagel.
  • Keep your doctor's appointments so your progress can be checked. Your doctor will check your progress and monitor your phosphate levels from time to time.
Things you should not do
  • Give Renagel to anyone else, even if they have the same condition as you.
  • Use Renagel to treat any other complaints unless your treating doctor tells you to.
  • Stop taking Renagel or change the dosage without checking with your treating doctor.
Driving or using machines
  • Be careful while you drive or use any machines or tools until you know how Renagel affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep your tablets in the bottle until it is time to take them.
  • 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, in the bathroom, near a sink, in the car or on windowsills.

For more information, see Section 5. What should I know while using Renagel? in the full CMI.

6. Are there any side effects?

Common side effects: vomiting, nausea, constipation, heartburn, diarrhoea, abdominal pain, flatulence, headache.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

RENAGEL®

Active ingredient: Sevelamer hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Renagel. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Renagel.

Where to find information in this leaflet:

1. Why am I using Renagel?
2. What should I know before I use Renagel?
3. What if I am taking other medicines?
4. How do I use Renagel?
5. What should I know while using Renagel?
6. Are there any side effects?
7. Product details

1. Why am I using Renagel?

Renagel contains the active ingredient sevelamer hydrochloride. 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.

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

2. What should I know before I use Renagel?

Warnings

Do not use Renagel if:

  • you are allergic to sevelamer hydrochloride, or any of the ingredients listed at the end of this leaflet.
  • you have hypophosphatemia, a condition where you do not have enough phosphorus in your body.
  • you have a bowel obstruction.
  • the packaging is torn or shows sign of tampering.
  • the expiry date (EXP) printed on the pack has passed.

Check with your 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.
  • any other medical conditions.
  • take any medicines for any other conditions.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins, or supplements 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.

Medicines that may be affected by Renagel include:

  • ciclosporin
  • mycophenolate mofetil
  • tacrolimus
  • ciprofloxacin

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Renagel.

4. How do I use Renagel?

How much to take?

  • Follow the instructions provided by your treating doctor and pharmacist carefully. These directions may differ from the information contained within this leaflet.
  • Your treating doctor may initially prescribe 1 - 2 Renagel 800mg tablets three times a day with meals. Your doctor may adjust your dosage during treatment depending on your blood test results.

When to take Renagel?

  • Renagel tablets should be taken with meals.
  • The tablets should be swallowed whole with a glass of water. Do not chew, crush, or break the tablets into pieces before taking them.
  • When the contents of Renagel tablets are exposed to water, they expand making them hard to swallow.
  • If you are having difficulty swallowing Renagel tablets, speak to your healthcare professional.

How long to take Renagel for?

  • Renagel helps lower your body's retention of dietary phosphate. It does not cure your condition. Therefore, you must continue to take it for as long as your treating doctor directs you to.
  • You may have to take Renagel for the rest of your life. If you stop taking Renagel, your phosphate levels may rise again. It is important to keep taking Renagel even if you feel well.

If you forget to use Renagel

Renagel should be taken at the same times each day. If you miss your dose at the usual time, do not take an extra dose to make up for the one you missed.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

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

If you take too much Renagel

If you think that you have taken too much Renagel, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Renagel?

Things you must do

Call your doctor straight away if you:

  • become pregnant while you are taking Renagel.
  • start to feel unwell or have any problems while you are taking Renagel, even if you do not think the problems are related to Renagel or are not listed in this leaflet.

Remind any doctor, dentist, or pharmacist you visit that you are using Renagel.

Things you must not do:

  • give Renagel to anyone else, even if they have the same condition as you.
  • use Renagel to treat any other complaints unless your treating doctor tells you to.
  • stop taking Renagel or change the dosage without checking with your treating doctor.

Things you should do:

  • keep your doctor's appointments so your progress can be checked. Your doctor will check your progress and monitor your phosphate levels from time to time. This helps to ensure you are getting the correct dose of Renagel.

Driving or using machines

Be careful while you drive or use any machines or tools until you know how Renagel affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your tablets in the bottle until it is time to take them. If your 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.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat, or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Vomiting
  • Nausea
  • Constipation
  • Dyspepsia (heartburn)
  • Diarrhoea
  • Abdominal pain
  • Flatulence (passing wind)
  • Headache
Speak to your doctor if you have any of these less serious side effects and they worry you.
They are generally mild and do not normally require treatment to be interrupted.

Serious side effects

Serious side effectsWhat to do
  • Rash, itching or hives (red raised circular bumps) on the skin
  • Severe constipation (prolonged absence of bowel movement, major bloating and/or severe abdominal pain)
  • Vomiting blood or material that looks like coffee grounds
  • Bleeding from the rectum, black sticky bowel movements, bloody diarrhoea
  • Fever or high temperature
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
Allergy-related symptoms:What to do
  • Shortness of breath
  • Wheezing or difficulty breathing
  • Swelling of the face, lips, tongue or other parts of the body
Stop taking Renagel and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Renagel contains

Active ingredient
(main ingredient)		Each tablet contains 800mg of sevelamer hydrochloride
Other ingredients
(inactive ingredients)
  • Colloidal anhydrous silica
  • Stearic acid
  • OPADRY complete film coating system 06A29064 Clear
Potential allergensRenagel does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What Renagel looks like

Renagel 800mg tablets are oval off-white film coated tablets with "RG800" engraved on one side and blank on the other side. (AUST R 101553).

Who distributes Renagel

Distributed by:
sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Freecall: 1800 818 806
Email: [email protected]

This leaflet was prepared in June 2024.
renagel-ccdsv6-cmiv16-03jun24

Published by MIMS July 2024

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 with "RG800" engraved 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.

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).

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.

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 packs of 180 tablets.

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)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes