Fosrenol 750 mg Tuggtablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

01-10-2020

Produktens egenskaper Produktens egenskaper (SPC)

06-07-2018

Aktiva substanser:
lantan(III)karbonattetrahydrat
Tillgänglig från:
Paranova Läkemedel AB
ATC-kod:
V03AE03
INN (International namn):
lanthanum(III)karbonattetrahydrat
Dos:
750 mg
Läkemedelsform:
Tuggtablett
Sammansättning:
dextrat, hydratiserat Hjälpämne; lantan(III)karbonattetrahydrat 1431 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 90 (6 x 15) tabletter
Bemyndigande status:
Avregistrerad
Godkännandenummer:
55732
Tillstånd datum:
2017-07-12

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

13-08-2021

Produktens egenskaper Produktens egenskaper - engelska

06-07-2018

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

12-02-2013

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Package Leaflet: Information for the Patient

FOSRENOL 250 mg chewable tablets

FOSRENOL 500 mg chewable tablets

FOSRENOL 750 mg chewable tablets

FOSRENOL 1000 mg chewable tablets

lanthanum

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Fosrenol is and what it is used for

What you need to know before you take Fosrenol

How to take Fosrenol

Possible side effects

How to store Fosrenol

Contents of the pack and other information

1.

What Fosrenol is and what it is used for

Fosrenol is used to lower the phosphate level in the blood of adult patients with chronic kidney

disease.

Patients who have kidneys that do not work properly are not able to control the level of phosphate in

the blood. The amount of phosphate in the blood then rises (your doctor may call this

hyperphosphataemia).

Fosrenol is a drug which reduces the body's absorption of phosphate from food by binding with it in

your digestive tract. Phosphate which have bonded to Fosrenol cannot be absorbed through the

intestinal wall.

2.

What you need to know before you take Fosrenol

Do not take Fosrenol

if you are allergic to lanthanum carbonate hydrate or any of the other ingredients of this medicine

(listed in section 6).

if you have too little phosphate in your blood (hypophosphataemia)

Warnings and precautions

Talk to your doctor or pharmacist before taking Fosrenol if you know that you have, or have had, any

of the following:

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).

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

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other

medicines.

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

chloroquine (for rheumatism and malaria), ketoconazole (for fungal infections), tetracycline or

doxycycline antibiotics they should not be taken within 2 hours before or after taking Fosrenol.

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

before or 4 hours after taking Fosrenol.

If you are taking levothyroxine (for an under active thyroid) it should not be taken within 2 hours

before or after taking Fosrenol. Your doctor may want to monitor the levels of thyroid-stimulating

hormone (TSH) in your blood more closely.

Fosrenol with food and drink

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

Dizziness and vertigo (a feeling of dizziness or “spinning”) are uncommon side effects reported by

patients taking Fosrenol. If you experience these side effects it may affect your ability to drive or

operate machinery.

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.

3.

How to take Fosrenol

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

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. If you find chewing the tablets difficult, talk to

your doctor as an oral powder form of this medicine is available

Your doctor 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:

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).

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.

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 doctor as you may need to take extra Fosrenol.

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

If you take more Fosrenol than you should

If you take too many tablets contact your doctor to assess the risk and obtain advice. Symptoms of

overdose may be nausea and headaches.

If you forget to take Fosrenol

It is important to take Fosrenol with every meal.

If you forget to take your Fosrenol tablets, then take the next dose with your next meal. Do not take a

double dose to make up for a forgotten dose.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets 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 you 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, stomach 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; swollen 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; increases in certain liver enzymes, parathyroid hormone; aluminium,

calcium and glucose in the blood; increased or reduced phosphate level in the blood; thirst;

weight decrease; joint pain; muscle pain; weakness and thinning of the bones (osteoporosis);

lack of and increased appetite; inflammation of the larynx; loss of hair; increased sweating; taste

disturbance and increased white blood cell count.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed

in this leaflet.

You can also report side effects directly via the national reporting system

(to be completed nationally).

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Fosrenol

Keep this medicine out of the sight and reach of children.

This medicinal product does not require any special storage conditions.

Do not use this medicine after the expiry date which is stated on the carton and the bottle label. The

expiry date refers to the last day of that month.

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.

Contents of the pack and other information

What Fosrenol contains

The active substance is 250 mg, 500 mg 750 mg or 1000 mg lanthanum (as lanthanum

carbonate hydrate).

The other ingredients are dextrates (hydrated), colloidal anhydrous silica and magnesium

stearate.

What Fosrenol looks like and contents of the pack

Fosrenol is a white, round, bevelled-edged flat chewable tablet debossed with either ‘S405/250’ (250

mg), ‘S405/500’ (500 mg), ‘S405/750’ (750 mg) or ‘S405/1000’ (1000 mg) on one side of the tablet.

The tablets are supplied in plastic bottles of 90 tablets (250 mg); 20, 45 tablets, or a multipack

containing 90 (2 packs of 45) chewable tablets (500 mg); 15, 45 tablets, or a multipack containing 90

(6 packs of 15) chewable tablets (750 mg); and 10, 15 tablets, or a multipack containing 90 (6 packs

of 15) chewable tablets (1000 mg).

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The marketing authorisation holder is:

Shire Pharmaceuticals Ireland Limited, Block 2 & 3 Miesian Plaza, 50 – 58 Baggot Street Lower,

Dublin 2, Irland

Tel: +44(0)1256 894 959

E-mail: medinfoEMEA@shire.com

The manufacturer is:

RB NL Brands B.V., Schiphol Boulevard 207, 1118BH, Schiphol, Netherlands

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder.

<To be completed nationally>

This medicine is authorised in the Member States of the European Economic Area and in the United

Kingdom (Northern Ireland) under the following names:

Austria, Belgium, Bulgaria, Cyprus, Czechia, Denmark, Estonia, Finland, France,

Germany, Greece, Hungary, Iceland, Latvia, Lithuania, Luxembourg, Netherlands,

Norway, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom

(Northern Ireland)

Fosrenol

Ireland, Italy , Malta

Foznol

This leaflet was last revised in July 2021.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

N

AME OF THE

M

EDICINAL

P

RODUCT

Fosrenol 750 mg chewable tablets.

2.

Q

UALITATIVE AND

Q

UANTITATIVE

C

OMPOSITION

Each chewable tablet contains lanthanum carbonate hydrate corresponding to 750 mg lanthanum.

Excipient(s) with known effect

Chewable tablets also contain on average 1599 mg of dextrates, containing glucose.

For the full list of excipients, see section 6.1.

3.

P

HARMACEUTICAL

F

ORM

Chewable tablet.

White, round, 20mm, bevelled-edge flat tablets debossed with ‘S405/750’ on one side.

4.

C

LINICAL

P

ARTICULARS

4.1

Therapeutic indications

Fosrenol is indicated in adult patients 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. Fosrenol oral powder can be used in patients who have difficulty chewing the tablets

(see section 4.4).

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.

Paediatric population

The safety and efficacy of Fosrenol in children and adolescents below the age of 18 years has not been

established (see section 4.4 and 5.1).

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 principal 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. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

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.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with

Fosrenol in one or more subsets of the paediatric population in treatment of hyperphosphataemia. See

4.2 for information on paediatric use.

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 (

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

3 years.

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

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

15, 45 tablets. Multipack containing 90 (6 packs of 15) chewable tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7.

M

ARKETING

A

UTHORISATION

H

OLDER

Shire Pharmaceutical Contracts Ltd

1 Kingdom Street

London, W2 6BD

United Kingdom

8.

M

ARKETING

A

UTHORISATION

N

UMBER

(

S

)

(To be completed nationally)

9.

D

ATE OF

F

IRST

A

UTHORISATION

/R

ENEWAL OF THE

A

UTHORISATION

Date of first authorisation:

(DD month YYYY) (to be completed nationally)

Date of latest renewal:

19-March-2014

10.

D

ATE OF

R

EVISION OF THE

T

EXT

6 July 2018

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