Consumer medicine information

Fosrenol

Lanthanum

BRAND INFORMATION

Brand name

Fosrenol

Active ingredient

Lanthanum

Schedule

SUMMARY CMI

FOSRENOL^®

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 taking FOSRENOL?

FOSRENOL contains the active ingredient lanthanum carbonate hydrate. FOSRENOL is used to lower the phosphate level in the blood of adult patients with chronic kidney disease.

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

2. What should I know before I take FOSRENOL?

Do not use if you have ever had an allergic reaction to FOSRENOL 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 take FOSRENOL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FOSRENOL 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 take FOSRENOL?

Always take this medicine exactly as your doctor or pharmacist has told you
FOSRENOL tablets must be chewed completely and not swallowed whole. Patients who have chewing difficulty, the tablets can be crushed.
FOSRENOL should be taken with or immediately after food.

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

5. What should I know while taking FOSRENOL?

Things you should do	Remind any doctor, dentist, or pharmacist you visit or any new medicines you are about to start, that you are using FOSRENOL. If you need to have an X-ray or an endoscopy, please inform your doctor that you are taking FOSRENOL, as it may affect the results.
Things you should not do	Do not use any other medicines while taking FOSRENOL unless you have discussed this with your doctor or pharmacist. FOSRENOL tablets must be chewed completely and not swallowed whole.
Driving or using machines	Dizziness, nausea, and vertigo are uncommon side effects of FOSRENOL; which may affect your ability to drive or operate machinery.
Looking after your medicine	Keep your medicine in a cool, dry place where the temperature stays below 25°C Keep FOSRENOL where children cannot reach it.

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

6. Are there any side effects?

The common side effects include nausea, vomiting, diarrhoea, headache, stomach pain, constipation, itching, skin rash, low calcium (hypocalcaemia), blockage in the intestine.

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

FOSRENOL^®

Active ingredient: lanthanum carbonate hydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using FOSRENOL. 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 FOSRENOL.

Where to find information in this leaflet:

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

1. Why am I taking FOSRENOL?

FOSRENOL contains the active ingredient lanthanum carbonate hydrate.

Phosphorous is found in your body as "phosphate" and is needed for building strong teeth and bones as well as keeping other parts of your body healthy. When your kidneys fail to work properly, phosphate can build up in the blood. This buildup of excess phosphate is called hyperphosphataemia.

FOSRENOL is a phosphate binder and is used to lower the amount of phosphate in your body. It prevents the body from absorbing the phosphate from the food you eat.

The phosphate in the food binds to FOSRENOL and is carried through the digestive tract to be eliminated in your stool.

2. What should I know before I use FOSRENOL?

FOSRENOL chewable tablets are not suitable for everyone.

Do not use FOSRENOL if:

you are allergic to lanthanum carbonate, or any of the ingredients listed at the end of this leaflet
always check the ingredients to make sure you can use this medicine
you have bowel blockage (obstruction), no movement in your bowels (ileus), or you are unable to defecate due to faecal impaction
you have too little phosphate in your blood (hypophosphataemia).

Check with your doctor if you have:

reduced liver function. It is possible that your liver will not be able to 'clean' FOSRENOL from your body adequately
a disease involving the gastrointestinal tract
inflammatory bowel disease including ulcerative colitis or Crohn's disease
a history of stomach ulcer
a history of blockage of the bowel
previously had abdominal surgery, or infection or inflammation of the abdomen/bowel (peritonitis)
reduced kidney function
taken any medicines for any other condition.

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.

Some medicines can have harmful effects on the breast-fed baby. FOSRENOL may be passed into breast milk and therefore is not recommended for mothers who breast feed their babies.

Warnings

It is very important to chew completely FOSRENOL tablets and not to swallow them whole or incompletely chewed. This will reduce the risk of adverse gastrointestinal complications like rupture in the intestinal wall, blockage in the intestine, constipation (see also section 6).
If you need to have an x-ray, please inform your doctor that you are taking FOSRENOL as it may affect the results.
If you need to have a gastrointestinal endoscopy, please inform your doctor that you are taking FOSRENOL it might detect lanthanum deposits in the digestive tract.

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 interfere with FOSRENOL and affect how it works.

FOSRENOL can affect the uptake of certain medicines from the gut.

Such medicines should be taken at least 2 hours before or 2 hours after taking FOSRENOL.

The following drugs are affected:

chloroquine (against rheumatism and malaria)
ketoconazole (against fungal infections)
certain antibiotics (tetracycline, doxycycline)
thyroxine (used for deficiency of thyroid hormone).

Quinolone antibiotics such as ciprofloxacin and norfloxacin should be taken at least 2 hours before or four hours after FOSRENOL.

4. How do I take FOSRENOL?

How much to take

Always take FOSRENOL exactly as your doctor has instructed you.

Your doctor will tell you how many tablets you must take with each meal (your daily dose will be divided between three meals). The number of tablets that you take will depend on:
- your diet (the amount of phosphate in the food you eat)
- your blood phosphate level.
To start with, the daily dose of FOSRENOL will usually be 1 tablet with each meal (3 tablets per day). Your doctor will then check the level of phosphate in your blood and may then increase this dose to a level that is correct for you.

When to take FOSRENOL

FOSRENOL works by binding phosphate from the food in your gut. It is very important to take FOSRENOL during or immediately after every meal.

If you eat extra meals, or eat between meals, you may need to take extra FOSRENOL. Your doctor will tell you what to do in this case.

How to take FOSRENOL

FOSRENOL tablets must be chewed completely and not swallowed whole.
For those patients who have dentures or those who have difficulty chewing you can crush the tablets.

If you forget to take FOSRENOL

It is important to take FOSRENOL with every meal.

If you forget to take your FOSRENOL, then take the next dose with your next meal. Do not take a double dose to make up for the dose you missed.

If you took too much FOSRENOL

If you think that you have taken too much FOSRENOL, 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.

Symptoms of overdose may include nausea, vomiting and headaches. You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking FOSRENOL?

Things you should do

Keep all your doctor's appointments so your progress can be checked.

Tell all doctors, dentists and pharmacists who are treating you that you are having treatment with FOSRENOL.

Remind them if any new medicines are about to be started, or if you are about to have a medical or dental procedure.

If you need to have an x-ray of your stomach or abdomen, please tell your doctor that you are taking FOSRENOL as it may affect the results of the x-ray.

If you need to have a gastrointestinal endoscopy, please inform your doctor that you are taking FOSRENOL because the endoscopist might detect lanthanum deposits in the digestive tract.

Like most medicines FOSRENOL is not recommended during pregnancy or while breastfeeding. It is uncertain whether FOSRENOL can affect the unborn child. If it is necessary for you to receive this medicine, your doctor will discuss the risks and benefits of taking FOSRENOL.

If pregnancy occurs during your treatment, you must immediately inform your doctor.

Things you should not do

Do not stop using this medicine suddenly. Your doctor will decide how long to continue your treatment with FOSRENOL.
Do not use any other medicines while taking FOSRENOL unless you have discussed this with your doctor or pharmacist.
This includes medicines you can buy without a prescription from a pharmacy, supermarket, or health food shop.
Do not use FOSRENOL to treat any complaint other than directed by your doctor. It may not be safe to use FOSRENOL for another complaint.
FOSRENOL should only be used by the person for whom it was prescribed.
Do not administer FOSRENOL to someone else even if they have the same condition as you. It may not be safe for another person to use FOSRENOL.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how FOSRENOL affects you.

Dizziness and vertigo (a feeling of dizziness or "spinning") are uncommon side effects reported by some patients taking FOSRENOL. If you experience these side effects it may affect your ability to drive or operate machinery.

Looking after your medicine

Keep your medicine in the original pack until it is time to take it. Keep your medicine in a cool, dry place where the temperature stays below 25°C.

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.

Do not take FOSRENOL after the expiry date stated on the bottle label.

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.

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 effects	What to do
nausea vomiting diarrhoea headache stomach pain Indigestion flatulence constipation bronchitis and rhinitis dizziness (from low blood pressure) tiredness weakness dry mouth weight decrease thinning of the bones (osteoporosis) joint pain loss of hair itching; skin rash increase sweating taste disturbance reduced appetite swelling ankles	Speak to your doctor if you have any of these less serious side effects and they worry you. Stomach side effects are more likely if you take FOSRENOL before your meal. You should always take FOSRENOL during or immediately after your food.

Serious side effects

Serious side effects	What to do
blockage in the intestine: symptoms include severe bloating, severe abdominal pain, swelling or cramps; severe constipation hypocalcaemia (too little calcium in your blood) symptoms include tingling in the hands and feet, muscle and abdominal cramps or spasms of the facial and feet muscles chest pain	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 FOSRENOL contains

Active ingredient	500 mg, 750 mg, or 1000 mg of lanthanum as lanthanum carbonate hydrate.
Other ingredients	Dextrates, silicon dioxide, magnesium stearate

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

What FOSRENOL looks like

FOSRENOL chewable tablets are available in the following strengths and pack sizes:

FOSRENOL 500 mg: White, round, bevel-edged flat tablets debossed with 'S405/500' on one side (45 tablets per bottle; 2 bottles per carton).

FOSRENOL 750 mg: White to off-white round, flat bevelled edge tablets debossed on one side with 'S405' above '750' (15 tablets per bottle; 6 bottles per carton).

FOSRENOL 1000 mg: White to off-white round, flat bevelled edge tablets debossed on one side with 'S405' above '1000' (15 tablets per bottle; 6 bottles per carton).

Australian Registration Numbers

AUST R 106960 (FOSRENOL 500 mg)
AUST R 106962 (FOSRENOL 750 mg)
AUST R 106964 (FOSRENOL 1000 mg)

Not all pack sizes may be supplied.

Who distributes FOSRENOL

Takeda Pharmaceuticals Australia Pty Ltd
Level 39
225 George Street
Sydney, NSW 2000
Australia
www.takeda.com/en-au
Phone: 1800 012 612

This leaflet was prepared in April 2023.

FOSRENOL^® and the FOSRENOL Logo^® are registered trademarks of Shire International Licensing BV.

TAKEDA^® and the TAKEDA Logo^® are registered trademarks of Takeda Pharmaceutical Company Limited.

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Fosrenol

Active ingredient

Lanthanum

Schedule

1 Name of Medicine

Lanthanum carbonate hydrate.

2 Qualitative and Quantitative Composition

Fosrenol is presented as chewable tablets. Each tablet contains lanthanum carbonate hydrate corresponding to 500 mg, 750 mg or 1000 mg lanthanum.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet, chewable.

Fosrenol 500 mg.

White, round, bevel-edged flat tablets debossed with 'S405/500' on one side.

Fosrenol 750 mg.

White to off-white round, flat bevel-edged tablets debossed on one side with 'S405' above '750'.

Fosrenol 1000 mg.

White to off-white round, flat bevel-edged tablets debossed on one side with 'S405' above '1000'.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of hyperphosphataemia in adults with chronic renal failure on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

4.2 Dose and Method of Administration

Patients should adhere to recommended diets in order to control phosphate and fluid intake.
Fosrenol tablets must be chewed completely before swallowing. The tablets may be crushed as an aid to chewing. Intact tablets must not be swallowed whole.

Adults, including elderly (> 65 years).

For patients taking Fosrenol for the first time, the starting dose may be determined individually based on serum phosphate concentration as indicated in the following table (Table 1):

Fosrenol should be taken with or immediately after food, with the daily dose divided between meals, i.e. three times daily. Serum phosphate levels should be monitored and the dose of Fosrenol titrated every 2-3 weeks until an acceptable serum phosphate level is reached, with regular monitoring thereafter.
Control of serum phosphate level has been demonstrated at doses from 750 mg with most patients achieving acceptable serum phosphate levels at 1500-3000 mg lanthanum per day.

Hepatic impairment.

The effect of hepatic impairment on Fosrenol pharmacokinetics has not been formally assessed. Due to its mechanism of action and the lack of liver metabolism, doses in hepatic impairment should not be modified, but patients should be monitored carefully (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Fosrenol has not been established in patients below the age of 18 years.

4.3 Contraindications

Hypersensitivity to lanthanum or any of the excipients in the product.
Bowel obstruction, ileus, and faecal impaction.
Hypophosphataemia.

4.4 Special Warnings and Precautions for Use

Tissue deposition of lanthanum, particularly in bone, liver and the stomach wall, has been shown with Fosrenol in animal studies. Deposition of lanthanum in bone has been studied (see Effects on bone). Results from long-term studies (studies 301, 303 and 307) demonstrated that bone lanthanum concentration had no apparent effect on bone health or treatment outcome for up to 4.5 years. There is no clinical data examining the potential deposition of lanthanum in other tissues. The long-term clinical effects of lanthanum deposition in tissues are not known. The risk benefit of longer-term therapy with Fosrenol should be considered.

Gastrointestinal disorders.

There have been cases of gastrointestinal obstruction, ileus, subileus, and gastrointestinal perforation reported in association with lanthanum, some requiring surgery or hospitalisation (see Section 4.8 Adverse Effects (Undesirable Effects)). Some of the cases are found to have lanthanum deposition or Product residue in the gastrointestinal tract.
Lanthanum deposition in gastroduodenal mucosa is demonstrated endoscopically as whitish lesions of different sizes and shapes. Also, various pathological features were identified in gastroduodenal mucosa with lanthanum deposition, such as chronic or active inflammation, glandular atrophy, regenerative changes, foveolar hyperplasia, intestinal metaplasia, and neoplasia.
Exercise caution in all patients predisposed to gastrointestinal obstruction, ileus, subileus and perforation; for example those with altered gastrointestinal anatomy (e.g. diverticular disease, peritonitis, history of gastrointestinal surgery, gastrointestinal cancer and gastrointestinal ulceration), hypomotility disorders (e.g. constipation, diabetic gastroparesis) and when used with medications known to potentiate these effects. Some cases were reported in patients with no history of gastrointestinal disease.
During treatment with lanthanum carbonate, physicians and patients should remain vigilant for signs and symptoms of gastrointestinal disorders, especially constipation and abdominal pain/distention which may indicate bowel obstruction, ileus or subileus.
Treatment with lanthanum carbonate should be re-evaluated in patients who develop severe constipation or other severe gastrointestinal signs and symptoms.
Patients with acute peptic ulcer, ulcerative colitis, Crohn's disease or bowel obstruction were not included in clinical studies with Fosrenol.
Fosrenol tablets must be chewed completely and not swallowed whole. Serious gastrointestinal complications have been reported in association with unchewed or incompletely chewed tablets (see Section 4.2 Dose and Method of Administration).

Use in hepatic impairment.

Lanthanum is not metabolised by liver enzymes but it is most likely excreted in the bile. Conditions resulting in a marked reduction of bile flow may be associated with incrementally slower elimination of lanthanum, which may result in higher plasma levels and increased tissue deposition of lanthanum (see Section 5.2 Pharmacokinetic Properties). Caution should therefore be exercised in these patients and monitoring of liver function may be required.

Use in renal impairment.

Patients with renal insufficiency may develop hypocalcaemia. Fosrenol does not contain calcium. Serum calcium levels should therefore be monitored at the regular time intervals for this patient population and appropriate supplements given.

Use in the elderly.

No data available.

Paediatric use.

The efficacy and safety of Fosrenol has not been studied in children, therefore, the consequence of lanthanum deposition in growing bones and risk of growth retardation is not known.

Effects on laboratory tests.

Abdominal X-rays of patients taking lanthanum carbonate may have a radio-opaque appearance typical of an imaging agent.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The drug interaction profile of Fosrenol is characterised by the potential of lanthanum to bind to drugs with anionic functions (e.g. carboxyl, carbonyl and hydroxyl groups).
Forsenol has a low potential for systemic drug/drug interactions because of the very low bioavailability of lanthanum and because it is not a substrate or inhibitor of major cytochrome P450 enzyme groups. In vitro tests indicate that no significant inhibition of the activities of the major human cytochrome P450 isoenzymes, CYP1A2, CYP2D6, CYP3A4/5, CYP2C9/10 or CYP2C19 is expected at therapeutic concentrations.
Lanthanum is extensively bound in human plasma and isolated human plasma protein preparations, including albumin, transferrin, and alpha-1-acid glycoprotein (99.7 to > 99.9%).
Lanthanum carbonate may increase gastrointestinal pH.
It is recommended that compounds, which are known to interact with antacids, should not be taken within 2 hours of dosing with Fosrenol (e.g. chloroquine, hydroxychloroquine and ketoconazole).
Serum levels of fat soluble vitamins A, D, E and K, were not affected by Fosrenol administration in clinical studies.
Interaction with drugs such as tetracycline and doxycycline are theoretically possible and if these compounds are to be co-administered, it is recommended that they are not to be taken within 2 hours of dosing with Fosrenol.

In vitro interactions with other medicines.

Gastric fluid.

The potential for a physico-chemical interaction (precipitation) between lanthanum and six commonly used medications (warfarin, digoxin, furosemide, phenytoin, metoprolol, and enalapril) was investigated in simulated gastric fluid. The results suggest that precipitation in the stomach of insoluble complexes of these drugs with lanthanum is unlikely.
The therapeutic activity of Fosrenol depends on the acidity of the gastric environment. The potential for drugs which alter gastric acidity (for example proton pump inhibitors) to alter the therapeutic activity of Fosrenol has not been examined in trials but should be considered.

In vivo interactions with other medicines.

In healthy subjects, the absorption and pharmacokinetics of a single dose of 1000 mg of Fosrenol is unaffected by co-administration of citrate. No clinically relevant effects of lanthanum were found on the absorption and pharmacokinetic profiles of digoxin (0.5 mg), metoprolol (100 mg), or warfarin (10 mg) in healthy subjects co-administered lanthanum carbonate (three doses of 1000 mg on the day prior to exposure and one dose of 1000 mg on the day of coadministration). Potential pharmacodynamic interactions between lanthanum and these drugs (e.g. bleeding time or prothrombin time) were not evaluated. None of the drug interaction studies was done with the maximum recommended therapeutic dose of lanthanum carbonate. No drug interaction studies assessed the effects of drugs on phosphate binding by lanthanum carbonate.
Co-administration of Fosrenol with quinolone antibiotics may reduce the extent of absorption as a result of complex formation. The bioavailability of oral ciprofloxacin was decreased by approximately 50% when taken with Fosrenol in a single dose study in healthy volunteers. It is recommended that oral quinolone formulations are taken at least 2 hours before or 4 hours after Fosrenol.
Phosphate binders (including Fosrenol) have been shown to reduce the absorption of levothyroxine. The bioavailability of levothyroxine was decreased by approximately 40% when taken together with Fosrenol. Consequently, thyroid hormone replacement therapy should not be taken within 2 hours of dosing with Fosrenol and closer monitoring of TSH levels is recommended in patients receiving both medicinal products.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effects of lanthanum carbonate on fertility. Lanthanum carbonate administered to female and male rats prior to and throughout mating at oral doses up to 2000 mg/kg/day (half the clinical exposure based on AUC at 3000 mg/day) did not alter mating or fertility.
(Category B3)
There was no evidence of teratogenicity in rats or rabbits following oral administration of lanthanum carbonate during the period of organogenesis at doses up to 2000 (rat) and 1500 (rabbit) mg/kg/day (0.5-1.2 times the clinical exposure based on AUC at 3000 mg/day). Increased implantation loss, and delayed skeletal ossification occurred in rabbits at ≥ 1500 mg/kg/day, in association with maternal toxicity. There are no adequate data from the use of Fosrenol in pregnant women. The safety of lanthanum carbonate in human pregnancy has not been established. Fosrenol should not be used during pregnancy unless the potential benefit justifies the potential risk.
There is some evidence that lanthanum can be excreted in human breast milk. The excretion of lanthanum in milk following oral treatment with lanthanum carbonate has not been studied in animals. Post-natal development was delayed in the offspring of rats receiving oral doses of lanthanum carbonate at 2000 mg/kg/day. Women taking Fosrenol should stop breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

Fosrenol may induce dizziness, nausea, and vertigo, which may impair the ability to drive and use machinery.

4.8 Adverse Effects (Undesirable Effects)

The safety of Fosrenol for use in patients with end-stage renal failure (ESRF) in both hemodialysis and peritoneal dialysis patients was initially examined in three short-term, placebo-controlled, double-blind studies, three long-term, comparator-controlled studies, and three long-term open-label studies. These studies have provided a total safety database of 1754 patients treated with lanthanum carbonate hydrate and represents a mean exposure of 272.1 days (median 184.0 days, range 1-1123 days).
The most common adverse events (≥ 5% in either treatment group) in two long-term open label Phase III trials that included 1215 patients treated with lanthanum carbonate hydrate and 944 with alternative therapy are detailed in Table 2.
The adverse events in the long-term, open label, active controlled, study of Fosrenol vs. alternative therapy (Study 307) have been adjusted for mean exposure differences between the treatment groups (with a mean exposure of 1.0 years on lanthanum and 1.4 years on alternative therapy). The adjustment for mean exposure was achieved by multiplying the observed adverse event rates in the alternative therapy group by 0.74.
Overall, approximately 24% of all ESRF patients who participated in these clinical studies reported a drug related adverse reaction, as determined by the investigator. No individual ADR was reported at a frequency greater than 10%. The most commonly reported adverse drug reactions, with the exception of headache, are gastrointestinal in nature. Gastrointestinal reactions were the most common leading to discontinuation. Gastrointestinal reactions can be minimized by taking Fosrenol with food and generally abated with time with continued dosing (see Section 4.2 Dose and Method of Administration).
Table 3 presents the very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000) reactions were reported with Fosrenol in clinical trials to date.

Post-marketing experience.

Table 4 presents all adverse drug reactions derived from post-marketing reports and based on all safety information available, sorted by MedDRA SOC and decreasing category of frequency.

Transient QT changes have been observed but these were not associated with any adverse events.

Reporting suspected adverse effects.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

The symptoms associated with overdose are known adverse reactions such as headache, nausea and vomiting. As Fosrenol is only pharmacologically active within the gut, supportive therapy is recommended for overdose.
For information on the management of overdose, contact the Poisons Information Centre telephone: 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fosrenol (lanthanum carbonate hydrate) has been developed as a dietary phosphate-binding agent. Phosphate absorption from the gastrointestinal tract is effectively decreased by the formation of highly insoluble complexes that are largely unable to pass through the wall of the gastrointestinal tract and are eliminated by excretion.
Fosrenol is indicated for the treatment of hyperphosphataemia. Fosrenol contains lanthanum carbonate hydrate. The activity of lanthanum carbonate as a phosphate binder is dependent on the high affinity of lanthanum ions, which are released from the carbonate salt in the acid environment of the upper gastrointestinal tract, for dietary phosphate. Insoluble lanthanum phosphate is formed which reduces the absorption of phosphate from the gastrointestinal tract.
Several studies have shown that lanthanum can be used to control hyperphosphataemia associated with chronic renal failure through dose titration and that effect is maintained with long-term use. A lower incidence of hypercalcaemia was reported with Fosrenol (0.4%) compared with calcium-based binders (20.2%) in comparative studies.
Serum PTH concentrations may fluctuate depending on a patient's serum calcium, phosphate and vitamin D status. Fosrenol has not been shown to have any direct effects on PTH secretion.

Clinical trials.

A total of 1130 patients with chronic renal failure treated with maintenance haemodialysis or CAPD were studied in two Phase II and two Phase III studies (LAM-IV-202, 204, 301 and 302). Three studies were placebo controlled (1 fixed dose and 2 titrated dose designs) and one included calcium carbonate as an active comparator. During these studies, 1016 patients received lanthanum carbonate, 267 received calcium carbonate and 95 received placebo.
The first Phase III study (301) was a two-part study designed to assess the reduction of serum phosphate by Fosrenol compared to calcium carbonate. The study had 2 parts: part 1 was a 5-week titration phase after randomization to Fosrenol or calcium carbonate where patients were titrated to a target phosphate level of 1.8 mmol/L. Part 2 was a 20-week maintenance phase where patients maintained their doses of binder and plasma phosphate levels assessed. The study endpoints were % patients achieving target phosphate levels at the end of the titration and maintenance periods. The plasma phosphate levels from this study are presented in Table 5. Serum phosphate levels were reduced to target levels of 1.8 mmol/L at the end of the 5-week titration period, in 58% of the lanthanum group compared with 70% of the calcium carbonate group. Following 25 weeks of treatment, the proportions controlled were 66% (lanthanum carbonate) and 64% (calcium carbonate).

The second Phase III study (302) was a double-blind, placebo-controlled study designed to assess the maintenance in reduction in serum phosphate levels after an open-label titration phase with Fosrenol to achieve a target phosphate concentration of 1.8 mmol/L. This was followed by a 4-week double-blind phase where patients were randomised to continue to receive Fosrenol or a comparable number of placebo tablets. The endpoint of this study was the plasma phosphate concentrations after 4 weeks of treatment on Fosrenol or placebo. A total of 93 patients completed the open-label phase and were randomised to Fosrenol or placebo. The plasma phosphate levels at the end of the open-label titration and at each week of the double-blind study are presented in Table 6.

A Phase II randomised, double-blind, placebo-controlled study (SPD405-206) was also conducted in chronic kidney disease stage 3 and 4 patients not undergoing dialysis but requiring treatment with phosphate binders. The primary endpoint was achievement of a target serum phosphate concentration of ≤ 1.49 mmol/L. Eighty patients were randomised to receive Fosrenol vs 41 patients on placebo. The ITT population consisted of 56 patients on Fosrenol vs 34 patients on placebo (there were a large number of discontinuations mainly due to patients' baseline not being above the target serum phosphate level after the washout phase). Patients were treated for up to 8 weeks. At the end of the study the mean dose of Fosrenol was 2645.3 mg/day. 44.6% of Fosrenol patients had achieved the target phosphate concentration compared to 26.5% of patients on placebo. The difference was not statistically significant (p = 0.12). The mean change from baseline to end of treatment for serum phosphate in the Fosrenol group was -0.18 mmol/L compared to -0.06 mmol/L in the placebo group.

Hyperphosphataemia.

Lanthanum has been demonstrated to be an effective binder of dietary phosphate for use in controlling the hyperphosphataemia of chronic renal failure. Multiple studies have shown that lanthanum can reliably be used to achieve serum phosphate reductions to target levels through dose titration and to effectively maintain control of serum phosphate levels with long-term use. Maintenance of target phosphate levels was shown to be similar between lanthanum and calcium treatments.
The lowest effective dose of lanthanum that is effective in the control of serum phosphate levels was established to be approximately 750 mg/day. Doses of up to 3000 mg lanthanum resulted in a reduction of serum phosphate to within target control levels in most patients.
No difference in level of control was observed between those patients on haemodialysis and those receiving CAPD. In addition no difference in the effectiveness of lanthanum carbonate administration was noted between patients under or over 65 years of age.

Effects on bone.

Overall, Fosrenol and standard treatments, including calcium carbonate, produced similar effects on the bones of dialysis patients.
Results from histology and histomorphometry of human biopsy samples evaluated to date from the three clinical studies (Study 301 where patients had been treated with lanthanum carbonate for up to 4.5 years, Studies 303 and 307) showed no evidence of osteomalacia or other adverse bone pathology. In Study 303, a randomised study to investigate the effect of Fosrenol with calcium carbonate, results showed that Fosrenol produced marginally greater improvements towards normal values than calcium carbonate for many of the bone primary and secondary response variables in addition to the general improvements in bone growth and turnover parameters. In Study 307, a study where patients had been treated for 2 years, no statistical differences in bone parameters between patients randomised to receive standard therapy or Fosrenol were observed. Analysis of data from paired bone biopsies (at baseline and at one or two years) in patients randomised to either Fosrenol or calcium carbonate in Study 303 and patients randomised to either Fosrenol or alternative therapy in Study 307, showed no differences in the development of mineralisation defects between the groups. An analysis of adverse events in the bone study participants in these studies did not show any increase in adverse events related to the musculoskeletal system, including fractures. Fosrenol, therefore, does not appear to harm bone following treatment for up to 4.5 years.

5.2 Pharmacokinetic Properties

As binding between lanthanum and dietary phosphorus occurs in the lumen of the stomach and upper small intestine, the therapeutic effectiveness of Fosrenol is not dependent on levels of lanthanum in the plasma.
Lanthanum is present in the environment. Measurement of background levels in non-lanthanum treated chronic renal failure patients during Phase III clinical trials revealed concentrations of < 0.05 to 0.90 nanogram/mL in plasma, and < 0.006 to 1.02 microgram/g in bone biopsy samples.

Absorption.

Lanthanum carbonate has low aqueous solubility (< 0.01 mg/mL at pH 7.5) and is minimally absorbed following oral administration. Absolute oral bioavailability is estimated to be < 0.002% in humans.
In healthy subjects, plasma AUC and C_max increased as a function of dose, but in a less than proportional manner, after single oral doses of 250 to 1000 mg lanthanum, consistent with dissolution-limited absorption. The apparent plasma elimination half-life in healthy subjects was 36 hours.
In renal dialysis patients dosed for 10 days with 1000 mg lanthanum 3 times daily, the mean (± SD) peak plasma concentration was 1.06 (± 1.04) nanogram/mL, and mean AUC_last was 31.1 (± 40.5) nanogram.h/mL. Regular blood level monitoring in 1707 renal dialysis patients taking lanthanum carbonate for up to 2 years showed no increase in plasma lanthanum concentrations over this time period.

Distribution.

Orally administered lanthanum is distributed predominantly within the gastrointestinal tract. The small fraction absorbed is extensively bound to human plasma proteins (> 99.7%), and binding is high capacity and nonspecific. In long-term animal studies, at oral doses up to 17 times a human dose of 3000 mg/day, lanthanum concentrations in the majority of tissues were less than 1 microgram/g. Concentrations in brain and cerebrospinal fluid (CSF) were below or around the assay quantification limit (0.01 microgram/g for brain and 0.05 nanogram/mL for CSF) and median steady-state concentrations were up to 8.2 microgram/g in bone, 11.1 microgram/g in liver and 2.2 mg/g in the stomach wall. Rodents, but not dogs, treated at doses 4 times the human dose of 3000 mg/day showed submucosal inflammation and epithelial hyperplasia of the stomach. No other adverse effects were associated with these concentrations. Lanthanum levels in these tissues dissipated very slowly after the cessation of oral dosing, with a half-life > 26 weeks. Cases of lanthanum deposition in gastrointestinal mucosa, mainly after long term use, have been reported. The clinical significance of this is yet unknown.

Metabolism.

Lanthanum is not metabolised. Studies in chronic renal failure patients with hepatic impairment have not been conducted. In patients with coexisting hepatic disorders at the time of entry into Phase III clinical studies, there was no evidence of increased plasma exposure to lanthanum or worsening hepatic function after treatment with Fosrenol for periods up to 2 years.

Excretion.

Lanthanum is excreted mainly in the faeces (> 90%) with only around 0.000031% of an oral dose excreted via the urine in healthy subjects.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro assays for gene mutations (bacteria and CHO cells) and in vivo studies for chromosomal or DNA damage did not provide evidence of genotoxic potential. An in vitro chromosome aberration assay in CHO cells had an equivocal outcome.

Carcinogenicity.

Lanthanum carbonate, at doses 13 times higher than the clinical dose of 3000 mg/day, caused a slight increase in gastric adenomas in mice. This response was considered to be an exacerbation of spontaneous stomach pathology and secondary to changes in the gastric environment caused by lanthanum carbonate administration. Gastric pathology was confined to rodents.

6 Pharmaceutical Particulars

6.1 List of Excipients

Fosrenol tablets also contain the excipients dextrates, silicon dioxide and magnesium stearate.

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.

6.5 Nature and Contents of Container

Fosrenol is supplied as chewable tablets in white cylindrical HDPE bottles fitted with polypropylene caps and is available in the following presentation and pack sizes: