FOSRENOL 500 MG CHEWABLE TABLETS

The format of this leaflet has been defined by the Ministry of Health and its content has been checked

and approved by it in 10.2012. The leaflet was updated according to the MoH guidelines in 10.2018.

Patient leaflet in accordance with the

Pharmacists’ Regulations (preparations), 1986

The dispensing of this medicine requires a

physician's prescription.

Read the entire leaflet carefully before you start taking this medicine.

FOSRENOL 500 MG, 750 MG, 1000 MG Chewable tablets

Each chewable tablet contains 500 mg; 750 mg;

1000 mg of the active ingredient Lanthanum (as lanthanum carbonate hydrate)

respectively.

For Inactive ingredients, see section 6: “Additional information” in this leaflet.

Read this leaflet carefully and in its entirety before using this medicine.

This leaflet contains summarized information regarding the medicine. If you have additional questions

please refer to your physician or pharmacist.

This medicine has been prescribed for the treatment of your ailment. Do not pass it on to others. It may

harm them, even if it seems to you that their ailment is similar.

This medicine is not intended for patients below the age of 18 years

The safety and efficacy of

Fosrenol has not been established in children below the age of 18 years.

Attention: Do not swallow! It is imperative to chew the tablet completely.

It is important to take the medicine with or immediately after a meal.

Inform your physician if you are about to have an X-ray examination, since the use of Fosrenol may

affect the results.

1.What is this medicine intended for?

Fosrenol is indicated for reducing phosphate level in the blood, in chronic renal failure patients on

dialysis.

Fosrenol is also indicated in patients with chronic kidney disease not on dialysis with high serum

phosphate levels, in whom a low phosphate diet alone is insufficient to control serum phosphate levels.

Therapeutic activity: Fosrenol is bound in the intestine with dietary phosphorus. This binding prevents its

absorption by the body, and thus Fosrenol helps in lowering the phosphate level in the blood.

Therapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphataemia.

2. Before using the medicine:

Do not use the medicine if:

if you are sensitive (allergic ) to the active ingredient lanthanum carbonate hydrate or to any of the

other ingredients of this medicine (listed in section 6).

if you suffer from hypophosphataemia (low levels of phosphates in the blood).

Special warnings regarding the use of the medicine:

Before using Fosrenol, tell your physician If you suffer or have suffered in the past from:

stomach or intestinal cancer

inflammatory bowel disease including ulcerative colitis or Crohn’s disease

abdominal surgery, or infection or inflammation of the abdomen/bowel (peritonitis)

stomach or intestinal ulcers

blockage of the intestine or slow motility (movement) in the intestine (e.g. constipation and

stomach complications due to diabetes)

reduced liver or kidney function

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 intestine

wall, blockage in the intestine, constipation (see section 4).

Test to perform before using this medicine

If you have reduced kidney function your doctor may decide to check the level of calcium in your blood

from time to time. If you have too little calcium, you may then be given extra calcium.

If you need to have an x-ray, please inform your doctor that you are taking Fosrenol as it may affect the

results.

Other medicines and Fosrenol

If you are taking, or have taken recently, or might take any

other medicines including non-

prescription medicines and nutritional supplements, inform the physician or pharmacist.

Fosrenol can affect how certain drugs are absorbed from your digestive tract. If you are taking any of the

following medicines, you should take them at least two hours before or after taking Fosrenol:

chloroquine – for the treatment of rheumatism or malaria.

ketoconazole – for the treatment of fungal infections

antibiotics such as tetracycline or doxycycline

It is not recommended that you take oral floxacin antibiotics (including ciprofloxacin) within 2 hours

before or 4 hours after taking Fosrenol.

levothyroxine - for an under active thyroid – it should be taken 2 hours before or 2 hours after taking

Fosrenol. Your physician may want to monitor the levels of thyroid-stimulating hormone (TSH) in your

blood more closely.

Using the medicine and food:

Fosrenol should be taken with, or immediately after food. See Section 3 for instructions on how to take

Fosrenol.

Pregnancy and breast-feeding:

Fosrenol should not be taken during pregnancy. If you are pregnant or breast-feeding, think you may be

pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this

medicine.

As it is not known whether the drug can be transferred to a child in breast-milk, you should not breast-

feed whilst taking Fosrenol. If you are breast-feeding, ask your doctor or pharmacist for advice before

taking any medicines.

Driving and using machines:

This medicine may sometimes lead to a feeling of vertigo or dizziness. If you experience these side

effects, be careful while driving or operating machinery.

3. How to use the medicine?

Always use according to the physician's instructions. Check with the physician or pharmacist if you are

not sure.

You should take Fosrenol with, or immediately after food.

Side effects such as nausea and vomiting are more likely if you take Fosrenol before your meal.

The tablets must be chewed completely and not swallowed whole. To aid with chewing, the tablets may

be crushed. Additional fluid is not necessary.

The dosage and manner of treatment will be decided by the physician only.

Your physician will tell you how many tablets you must take with each meal (your daily dose will be

divided between meals). The number of tablets that you take will depend on the amount of phosphate in

the food you eat and your blood phosphate levels.

The usual acceptable dose is 3 tablets a day, divided between the different meals.

Fosrenol works by binding phosphate from the food in your gut. It is very important to take Fosrenol at

every meal. If you change your diet, contact your physician as you may need to take extra Fosrenol.

Your physician will tell you what to do in this case.

Do not exceed the recommended dose.

Tests and follow up

Every 2-3 weeks your doctor will check the level of phosphate in your blood and may increase your dose

until the level of phosphate in your blood is acceptable.

If you have accidently taken a higher dose

If you have taken a higher dose, consult your physician. Symptoms of overdose may include nausea

and headaches.

If you have taken an overdose, or if a child swallowed the medicine by mistake, refer immediately to the

physician or to a hospital emergency room and bring the package of the medicine with you.

If you forgot to take Fosrenol

It is important to take Fosrenol with every meal.

If you forgot to take this medicine at the proper time, take the next dose with your next meal.

Do not take a double dose to make up for a forgotten dose.

If you stop taking the medicine

Follow the treatment as recommended by the physician. Do not discontinue treatment with the medicine,

even if there is an improvement in your condition, without consulting the physician.

Do not take medications in the dark! Check the label and dose every time you take a medicine. Use

glasses if you need them for reading.

If you have further question about the use of this medicine, consult the physician or pharmacist.

4. Side Effects:

Like with any medicine, using Fosrenol can cause side effects in some of the users. Do not be alarmed

when reading the list of side effects. You may experience none of them.

Some side effects could be serious. If you get any of the following side effects, seek immediate

medical attention:

Rupture in the intestinal wall (signs include: severe stomach pain, chills, fever, nausea,

vomiting, or a tender abdomen). This is a rare side effect (may affect up to 1 in 1,000

people).

Blockage in the intestine (signs include: severe bloating; abdominal pain, swelling or

cramps; severe constipation). This is an uncommon side effect (may affect up to 1 in 100

people).

Contact your doctor if you have new or severe constipation, it could be an early sign of

blockage in your intestine. Constipation is a common side effect (may affect 1 in 10

people).

Other less serious side effects include the following:

Very common side effects (may affect more than 1 in 10 people):

Nausea, vomiting, diarrhoea, abdomen pain, headache, itching, rash.

Common side effects (may affect up to 1 in 10 people):

Heartburn, flatulence.

Hypocalcaemia (too little calcium in your blood) is also a common side effect; the

symptoms of which can include tingling in the hands and feet, muscle and abdominal

cramps or spasms of the facial and feet muscles.

Uncommon side effects (may affect up to 1 in 100 people):

Tiredness; feeling of discomfort; chest pain, weakness; swelling of hands and feet; body pain; dizziness;

vertigo; belching; inflammation of the stomach and intestines (gastroenteritis); indigestion; irritable bowel

syndrome; dry mouth; tooth disorders; inflammation of the gullet or mouth; loose stools; increase in

certain liver enzymes, parathyroid hormone; increase in blood aluminium, calcium and glucose; increase

or decrease in blood phosphates; thirst; weight loss; joint pain; muscle pain; weakness and thinning of

the bones (osteoporosis); lack of and increased appetite; inflammation of the larynx; loss of hair;

sweating increased; taste disturbance and increase in white blood cells count.

If any side effect appears, If any side effect gets worse, or if you suffer from a side effect not

mentioned in the leaflet, you should consult the physician.

Side effects can be reported to the Ministry of Health by clicking on the link “Adverse Drug Reactions

Report” that appears on the home page of the Ministry of Health web site (www.health.gov.il), which

leads to an online form for reporting side effects.

Alternatively you can use the following link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=adversEffectMedic@moh.gov.

5. How to Store the Medicine?

Avoid poisoning! This medicine and all other medicines should be kept in a closed place out of the

sight and reach of children and/or infants to avoid poisoning.

Do not induce vomiting unless explicitly instructed to do so by the physician.

Do not use this medicine after the expiry date (exp. date) stated on the package. The expiry date

relates to the last day of that month.

Store at a temperature below 30°C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6. Additional information:

In addition to the active ingredient the medicine also contains:

Dextrates (hydrated), colloidal anhydrous silica, magnesium stearate.

Fosrenol contains Glucose If you have been told by your doctor that you have an intolerance to

some sugars, contact your doctor before taking this medicinal product.

What does the medicine look like and what are the contents of the package?

White, round, flat tablets debossed with ‘S405/500’, ‘S405/750' and 'S405/1000’ on one side, for

Fosrenol 500, 750 and 1000 respectively.

Carton packs containing bottles of the following quantities:

Fosrenol 500 – 45, 90 chewable tablets

Fosrenol 750 – 15, 90 chewable tablets

Fosrenol 1000 – 90 chewable tablets

It is possible that not all packs are marketed.

License holder:

Takeda Israel Ltd.,25 Efal st.,

Petach Tikva 4951125

Manufacturer: Shire Pharmaceutical Contracts Ltd,

1 Kingdom Street, London, W2 6BD, UK

Registration number of the medicine in the National Drug Registry of the Ministry of Health:

Fosrenol 500 mg chewable tablets: 140 50 31968 00

Fosrenol 750 mg chewable tablets: 140 51 31998 00

Fosrenol 1000 mg chewable tablets: 140 52 31969 00

This leaflet was checked and approved by the Ministry of Health in October 2012, and was updated

according to the MoH guidelines in October 2018

The format of this leaflet was determined by the Ministry of Health and its content was checked and

approved by the Ministry of Health in 10.2012, and updated according to the MoH instructions in

10/2018

SUMMARY OF THE PRODUCT CHARACTERISTICS

1

N

AME OF THE

M

EDICINAL

P

RODUCT

Fosrenol 500 mg; 750 mg ; 1000 mg chewable tablets.

2

Q

UALITATIVE AND

Q

UANTITATIVE

C

OMPOSITION

Each chewable tablet contains lanthanum carbonate hydrate corresponding to 500, 750, and 1000 mg

lanthanum, respectively.

Excipient(s) with known effect

Fosrenol

500, 750, and 1000

mg chewable tablets also contain on average

1066, 1599 and 2132

mg respectively

of dextrates, containing glucose.

For the full list of excipients, see section 6.1.

3

P

HARMACEUTICAL

F

ORM

Chewable tablet.

Fosrenol 500 mg chewable tablets:

White, round, 18mm, bevelled-edge flat tablets debossed

with ‘S405/500’ on one side.

Fosrenol 750 mg chewable tablets:

White, round, 20mm, bevelled-edge flat tablets debossed

with ‘S405/750’ on one side.

Fosrenol 1000 mg chewable tablets:

White, round, 22mm, bevelled-edge flat tablets debossed

with ‘S405/1000’ on one side.

4

C

LINICAL

P

ARTICULARS

4.1

Therapeutic indications

Fosrenol is indicated as a phosphate binding agent for use in the control of hyperphosphataemia in

chronic renal failure patients on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

Fosrenol is also indicated in adult patients with chronic kidney disease not on dialysis with serum

phosphate levels

1.78 mmol/L in whom a low phosphate diet alone is insufficient to control serum

phosphate levels.

4.2

Posology and method of administration

Fosrenol is for oral administration.

The tablets must be chewed completely and not swallowed whole. To aid with chewing the tablets

may be crushed.

Adults, including elderly (> 65 years)

Fosrenol should be taken with or immediately after food, with the daily dose divided between meals.

Patients should adhere to recommended diets in order to control phosphate and fluid intake. Fosrenol

is presented as a chewable tablet therefore avoiding the need to take additional fluid. Serum phosphate

levels should be monitored and the dose of Fosrenol titrated every 2-3 weeks until an acceptable serum

phosphate levels is reached, with regular monitoring thereafter.

Control of serum phosphate level has been demonstrated at doses starting from 750 mg per day. The

maximum dose studied in clinical trials, in a limited number of patients, is 3750 mg. Patients who

respond to lanthanum therapy, usually achieve acceptable serum phosphate levels at doses of 1500 –

3000 mg lanthanum per day.

Children and Adolescents

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

section 4.4).

Hepatic impairment

The effect of hepatic impairment on Fosrenol pharmacokinetics has not been 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 sections 4.4 and 5.2).

4.3

Contraindications

Hypersensitivity to

the active substance

or to any of the excipients

listed in section 6.1

Hypophosphataemia.

4.4

Special warnings and precautions for use

Tissue deposition of lanthanum has been shown with Fosrenol in animal studies. In 105 bone

biopsies from patients treated with Fosrenol, some for up to 4.5 years, rising levels of lanthanum

were noted over time (see section 5.1

).Cases of lanthanum deposition in gastrointestinal

mucosa, mainly after long term use, have been reported. The clinical significance of this

finding is yet unknown.

The use of Fosrenol in clinical studies beyond 2 years is currently limited. However, treatment of

subjects with Fosrenol for up to 6 years has not demonstrated a change in the benefit/risk profile.

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).

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.

During treatment with lanthanum carbonate, physicians and patients should remain alert for

signs and symptoms of gastrointestinal disorders, especially constipation and abdominal

pain/distension 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

(see section 4.2)

Serious gastrointestinal complications have been reported in association with unchewed

or incompletely chewed Fosrenol tablets.

Patients with renal insufficiency may develop hypocalcaemia. Fosrenol does not contain calcium.

Serum calcium levels should therefore be monitored at regular time intervals for this patient

population and appropriate supplements given.

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 sections 5.2 and 5.3).

As the liver is the principle organ of elimination of absorbed lanthanum monitoring of liver function

tests is recommended.

Paediatric population

Safety and efficacy of Fosrenol have not been established in children and adolescents; use in children

and adolescents is not recommended (see section 4.2).

Fosrenol should be discontinued if hypophosphataemia develops.

Abdominal x-rays of patients taking lanthanum carbonate may have a radio-opaque appearance typical

of an imaging agent.

Patients with rare glucose-galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

Lanthanum carbonate

hydrate may increase gastric 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).

In healthy subjects, the absorption and pharmacokinetics of lanthanum were not affected by co-

administration of citrate.

Serum levels of fat-soluble vitamins A, D, E and K, were not affected by Fosrenol administration in

clinical studies.

Human volunteer studies have shown that co-administration of Fosrenol with digoxin, warfarin or

metoprolol does not produce clinically-relevant changes in the pharmacokinetic profiles of these

drugs.

In simulated gastric juice, lanthanum carbonate hydrate did not form insoluble complexes with

warfarin, digoxin,

furosemide

, phenytoin, metoprolol or enalapril, suggesting a low potential to affect

the absorption of these drugs.

However, interactions 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.

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 floxacin

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.

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.

Lanthanum carbonate hydrate is not a substrate for cytochrome P450 and does not significantly inhibit

the activities of the major human cytochrome P450 isoenzymes, CYP1A2, CYP2D6, CYP3A4,

CYP2C9 or CYP2C19 in vitro.

4.6

Fertility,

pregnancy and lactation

Pregnancy

There are no adequate data from the use of Fosrenol in pregnant women.

One study in rats showed reproductive foetotoxicity (delayed eye opening and sexual maturation) and

reduced pup weights at high doses (see section 5.3). The potential risk for humans is unknown.

Fosrenol is not recommended for use during pregnancy.

Breast-feeding

It is unknown whether lanthanum is excreted in human breast milk. The excretion of lanthanum in

milk has not been studied in animals. Caution should be used in taking a decision whether to

continue/discontinue breast feeding or to continue/discontinue therapy with Fosrenol, taking into

account the potential benefit of breast feeding to the child and the potential benefit of Fosrenol therapy

to the nursing mother.

Fertility

There are no fertility data available on lanthanum carbonate in humans. In rat toxicology studies,

lanthanum carbonate had no adverse effects on fertility.

4.7

Effects on ability to drive and use machines

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

4.8

Undesirable effects

The most commonly reported adverse drug reactions, with the exception of headache and allergic skin

reactions, are gastrointestinal in nature; these are minimised by taking Fosrenol with food and generally

abated with time with continued dosing (see section 4.2).

The following convention was used for frequency of adverse drug reactions: Very common (≥1/10);

Common (≥1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to < 1/1,000); Very rare

(< 1/10,000), not known (cannot be estimated from the available data).

Infections and Infestations

Uncommon

Gastroenteritis, laryngitis

Blood and lymphatic system disorders

Uncommon

Eosinophilia

Endocrine disorders

Uncommon

Hyperparathyroidism

Metabolism and nutrition disorders

Common

Hypocalcaemia

Uncommon

Hypercalcaemia, hyperglycaemia, hyperphosphataemia,

hypophosphataemia, anorexia, appetite increased

Nervous system disorders

Very Common

Headache

Uncommon

Dizziness, taste alteration

Ear and Labyrinth disorders

Uncommon

Vertigo

Gastrointestinal disorders

Very Common

Abdominal pain, diarrhoea, nausea, vomiting

Common

Constipation, dyspepsia, flatulence

Uncommon

Ileus, ,Subileus, intestinal obstruction , irritable bowel

syndrome, oesophagitis, stomatitis, loose stools,

indigestion , gastrointestinal disorder ( Not otherwise

specified) , dry mouth, tooth disorder , eructation

Rare

Intestinal perforation

Skin and subcutaneous tissue disorders

Uncommon

Alopecia, sweating increased

Musculoskeletal and connective tissue

disorders

Uncommon

Arthralgia, myalgia, osteoporosis

General disorders and administration site

conditions

Uncommon

Asthenia, chest pain, fatigue, malaise, peripheral

oedema, pain, thirst

Investigations

Uncommon

Blood aluminium increased, increase in GGT, increases

in hepatic transaminases, alkaline phosphatase

increased, weight decrease.

Post marketing experience:

During post-approval use of Fosrenol, cases of allergic skin reactions

(including skin rashes, urticaria and pruritus) have been reported which show a close temporal

relationship to lanthanum carbonate therapy. In clinical trials, allergic skin reactions were seen in both

Fosrenol and placebo/active comparator groups at a frequency of very common (≥1/10)

Although there have been a number of additional isolated reactions reported, none of these reactions are

considered unexpected in this patient population.

Transient QT changes have been observed but these were not associated with an increase of cardiac

adverse events.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events

should be reported to the Ministry of Health according to the National Regulation by using an online form

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

4.9

Overdose

No case of overdose has been reported. The highest daily dose of lanthanum

administered to healthy

volunteers during Phase I studies was 4718 mg given for 3 days. The adverse events seen were mild to

moderate and included nausea and headache.

5

P

HARMACOLOGICAL

P

ROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphataemia.

ATC code: V03A E03

Fosrenol contains lanthanum carbonate hydrate. The activity of lanthanum carbonate hydrate

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 stomach, for dietary

phosphate.

Insoluble lanthanum phosphate is formed which reduces the absorption of phosphate from the

gastro-intestinal tract.

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. 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 176 received placebo.

Two placebo-controlled, randomised studies enrolled patients on dialysis after a washout from

previous phosphate binders. After titration of lanthanum carbonate to achieve a serum

phosphate level between 1.3 and 1.8 mmol/L in one study (doses up to 2250 mg/day), or ≤1.8

mmol/L in a second study (doses up to 3000mg/day), patients were randomised to lanthanum

carbonate or placebo as maintenance treatment. After the 4-week randomised placebo-

controlled phase, the serum phosphate concentration rose between 0.5 and 0.6 mmol/L in the

placebo group, in both studies, relative to patients who remained on lanthanum carbonate

therapy. There were 61% patients on lanthanum carbonate who maintained their response,

compared to 23% on placebo.

The active comparator study demonstrated that serum phosphate levels were reduced to target

levels of 1.8 mmol/l at the end of the 5 week titration period, in 51% of the lanthanum group

compared with 57% of the calcium carbonate group. At week 25 the percentage of

randomised patients showing controlled serum phosphate levels was similar in the two

treatment groups, 29% on lanthanum and 30% on calcium carbonate (using a missing=failure

approach). Mean serum phosphate levels were reduced by a similar amount in both treatment

groups.

Further long-term extension studies have demonstrated maintenance of phosphate reduction

for some patients following continued administration of at least 2 years of lanthanum

carbonate.

Hypercalcaemia was reported in 0.4% of patients with Fosrenol compared with 20.2% on

calcium-based binders 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 serum PTH concentrations.

In the long-term bone studies a trend towards increasing bone lanthanum concentrations with

time in the control population was observed from the averaged data, the median rising 3-fold

from a baseline of 53

g/kg at 24 months. In patients treated with lanthanum carbonate, the

bone lanthanum concentration increased during the first 12 months of lanthanum carbonate

treatment up to a median of 1328

g/kg (range 122-5513

g/kg). Median and range

concentrations at 18 and 24 months were similar to 12 months. The median at 54 months was

4246

g/kg (range 1673-9792

g/kg).

Paired bone biopsies (at baseline and at one or two years) in patients randomised to either

Fosrenol or calcium carbonate in one study and patients randomised to either Fosrenol or

alternative therapy in a second study, showed no differences in the development of

mineralization defects between the groups.

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 carbonate hydrate-treated chronic renal failure patients during Phase III

clinical trials revealed concentrations of <0.05 to 0.90 ng/mL in plasma, and <0.006 to 1.0

g/g in bone biopsy samples.

Absorption

Lanthanum carbonate hydrate 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

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) ng/mL, and mean AUC

last

was 31.1

40.5) ng.h/mL. Regular blood level monitoring in 1707 renal dialysis patients taking

lanthanum carbonate hydrate for up to 2 years showed no increase in plasma lanthanum

concentrations over this time period.

Distribution

Lanthanum does not accumulate in plasma in patients or in animals after repeated oral

administration of lanthanum carbonate hydrate. The small fraction of orally administered

lanthanum absorbed is extensively bound to plasma proteins (>99.7%) and in animal studies,

was widely distributed to systemic tissues, predominantly bone, liver and the gastrointestinal

tract, including the mesenteric lymph nodes. In long-term animal studies, lanthanum

concentrations in several tissues, including the gastrointestinal tract, bone and liver increased

over time to levels several orders of magnitude above those in plasma. An apparent steady-

state level of lanthanum was attained in some tissues, e.g. the liver whereas levels in

gastrointestinal tract increased with duration of treatment. Changes in tissue lanthanum levels

after withdrawal of treatment varied between tissues. A relatively high proportion of

lanthanum was retained in tissues for longer than 6 months after cessation of dosing (median

% retained in bone

100% (rat) and

87% (dog), and in the liver

6% (rat) and

82 % (dog).

No adverse effects were associated with the tissue deposition of lanthanum seen in long-term

animal studies with high oral doses of lanthanum carbonate (see 5.3) (See section 5.1 for

information regarding changes in lanthanum concentrations in bone biopsies taken from renal

dialysis patients after one year of treatment with lanthanum containing versus calcium

containing phosphate binders).

Metabolism

Lanthanum is not metabolised.

Studies in chronic renal failure patients with hepatic impairment have not been conducted. In

patients with co-existing 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.

Elimination

Lanthanum is excreted mainly in the faeces with only around 0.000031% of an oral dose

excreted via the urine in healthy subjects (renal clearance approximately 1mL/min,

representing <2% of total plasma clearance).

After intravenous administration to animals, lanthanum is excreted mainly in the faeces (74%

of the dose), both via the bile and direct transfer across the gut wall. Renal excretion was a

minor route.

5.3

Preclinical safety data

Preclinical data reveal no special hazards for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, fertility or genotoxicity.

Lanthanum carbonate hydrate reduced gastric acidity in the rat in a safety pharmacology

study.

In rats administered high doses of lanthanum carbonate hydrate from day 6 of gestation to day

20 post partum there were no maternal effects, but reduced pup weight and delays in some

developmental markers (eye and vaginal opening) were seen. In rabbits given high daily doses

of lanthanum carbonate hydrate during gestation, maternal toxicity with reduced maternal

food intake and body weight gain, increased pre- and post-implantation losses and decreased

pup weight were seen.

Lanthanum carbonate hydrate was not carcinogenic in mice or rats. In mice, an increase in

gastric glandular adenomas was seen in the high-dose group (1500 mg/kg/day). The

neoplastic response in the mouse is considered to be related to an exacerbation of spontaneous

pathological stomach changes and to be of little clinical significance.

Studies in animals have shown deposition of lanthanum in tissues, mainly the gastrointestinal

tract, mesenteric lymph nodes, liver and bone (see section 5.2). However, life-time studies in

healthy animals do not indicate a hazard for man from the use of Fosrenol. Specific

immunotoxicity studies have not been performed.

6

P

HARMACEUTICAL

P

ARTICULARS

6.1

List of excipients

Dextrates (hydrated)

Colloidal anhydrous silica

Magnesium stearate.

6.2

Incompatibilities

Not applicable.

6.3

Shelf-life

The expiry date of the product is indicated on the packaging materials

.

6.4

Special precautions for storage

Store below 30ºC

6.5

Nature and contents of container

White cylindrical HDPE bottles containing a rayon coil fitted with a tamper evident, child

resistant polypropylene screw cap.

Pack sizes

Fosrenol 500 mg

chewable tablets

: 45, 90 tablets

Fosrenol 750 mg

chewable tablets

: 15, 90 tablets

Fosrenol 1000 mg

chewable tablets

: 90 tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7

M

ANUFACTURER

Shire Pharmaceutical Contracts Ltd, 1 Kingdom Street, London, W2 6BD, UK

8

Registration Holder

Takeda Israel Ltd.,25 Efal st., Petach Tikva 4951125

Registration Numbers:

Fosrenol 500 mg

chewable tablets

: 140 50 31968 00

Fosrenol 750 mg

chewable tablets

: 140 51 31998 00

Fosrenol 1000 mg

chewable tablets

: 140 52 31969 00