Fosrenol 1000 mg Tuggtablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

19-01-2021

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:
1000 mg
Läkemedelsform:
Tuggtablett
Sammansättning:
lantan(III)karbonattetrahydrat 1908 mg Aktiv substans; dextrat, hydratiserat Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 90 (6 x 15) tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
55733
Tillstånd datum:
2017-07-12

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

10-06-2019

Produktens egenskaper Produktens egenskaper - engelska

06-07-2018

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

12-02-2013

Läs hela dokumentet

Bipacksedel: Information till patienten

Fosrenol

®

1 000 mg tuggtabletter

lantan

Läs noga igenom denna bipacksedel innan du börjar ta detta läkemedel. Den innehåller

information som är viktig för dig.

Spara denna information, du kan behöva läsa den igen.

Om du har ytterligare frågor vänd dig till läkare eller apotekspersonal.

Detta läkemedel har ordinerats enbart åt dig. Ge det inte till andra. Det kan skada dem, även om

de uppvisar sjukdomstecken som liknar dina.

Om du får biverkningar, tala med läkare eller apotekspersonal. Detta gäller även eventuella

biverkningar som inte nämns i denna information. Se avsnitt 4.

I denna bipacksedel finns information om följande

Vad Fosrenol är och vad det används för

Vad du behöver veta innan du tar Fosrenol

Hur du tar Fosrenol

Eventuella biverkningar

Hur Fosrenol ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Fosrenol är och vad det används för

Fosrenol används för att sänka fosfatnivån i blodet hos vuxna patienter med kronisk njursjukdom.

Hos patienter vars njurar inte fungerar normalt, kan njurarna inte reglera blodets fosfatnivå. Detta

leder till att mängden fosfat i blodet stiger (läkare kan kalla detta hyperfosfatemi).

Fosrenol är ett läkemedel som sänker kroppens upptag av fosfat från födan genom att binda till det i

magtarmkanalen. Fosfat som är bundet till Fosrenol kan inte absorberas genom tarmväggen.

Lantan som finns i Fosrenol kan också vara godkänd för att behandla andra sjukdomar som inte nämns

i denna produktinformation. Fråga läkare, apotekspersonal eller annan hälsovårdspersonal om du har

ytterligare frågor och följ alltid deras instruktion.

2.

Vad du behöver veta innan du tar Fosrenol

Ta inte Fosrenol

om du är allergisk mot lantankarbonathydrat eller något annat innehållsämne i detta läkemedel

(anges i avsnitt 6).

om du har för lite fosfat i blodet (hypofosfatemi).

Varningar och försiktighet

Tala med läkare eller apotekspersonal innan du tar Fosrenol om du vet att du har, har haft eller har

genomgått något av följande:

cancer i mage eller tarm

inflammatorisk tarmsjukdom inklusive ulcerös kolit eller Crohns sjukdom

bukoperation, eller infektion eller inflammation i buken/tarmen (bukhinneinflammation)

magsår eller tarmsår

blockering i tarmen eller långsam motilitet (rörlighet) i tarmen (t.ex. förstoppning och

magkomplikationer på grund av diabetes)

nedsatt lever- eller njurfunktion.

Det är mycket viktigt att tugga Fosrenol tabletter ordentligt och inte svälja dem hela eller ofullständigt

tuggade. Detta minskar risken för biverkningar i magtarmkanalen såsom bristning i tarmväggen,

blockering i tarmen eller förstoppning (se avsnitt 4).

Om du har nedsatt njurfunktion kan läkaren vilja kontrollera kalciumnivån i ditt blod emellanåt. Om

du har för lite kalcium kan du då komma att ges extra kalcium.

Om du måste röntgas, vänligen informera din läkare att du tar Fosrenol, då detta kan påverka

resultatet.

Andra läkemedel och Fosrenol

Tala om för läkare eller apotekspersonal om du tar, nyligen har tagit eller kan tänkas ta andra

läkemedel.

Fosrenol kan påverka hur vissa läkemedel tas upp från din magtarmkanal. Om du tar klorokin (mot

reumatism och malaria), ketokonazol (mot svampinfektioner) eller antibiotika innehållande tetracyklin

eller doxycyklin, ska dessa läkemedel inte tas inom 2 timmar före eller efter intag av Fosrenol.

Du bör inte ta orala antibiotika innehållande floxacin (inklusive ciprofloxacin) inom 2 timmar före

eller 4 timmar efter du har tagit Fosrenol.

Om du tar levotyroxin (på grund av en underaktiv sköldkörtel) ska det inte tas inom 2 timmar före

eller efter att du har tagit Fosrenol. Din läkare kan vilja kontrollera nivåerna av

sköldkörtelstimulerande hormon (TSH) i blodet noggrannare.

Fosrenol med mat och dryck

Fosrenol ska tas i samband med eller omedelbart efter mat. Se avsnitt 3 för instruktioner om hur du

ska ta Fosrenol.

Graviditet och amning

Du bör inte använda Fosrenol under graviditet. Om du är gravid eller ammar, tror att du kan vara

gravid eller planerar att skaffa barn, rådfråga läkare eller apotekspersonal innan du använder detta

läkemedel.

Eftersom det är okänt om läkemedlet kan överföras till barnet via bröstmjölken, bör du inte amma

medan du använder Fosrenol. Om du ammar, rådfråga läkare eller apotekspersonal innan du tar något

läkemedel.

Körförmåga och användning av maskiner

Yrsel och svindel (en känsla av yrsel eller av att det ”snurrar”) är mindre vanliga biverkningar som har

rapporterats av patienter som tagit Fosrenol. Om du upplever dessa biverkningar kan det påverka din

förmåga att köra bil eller använda maskiner.

Du är själv ansvarig för att bedöma om du är i kondition att framföra motorfordon eller utföra arbete

som kräver skärpt uppmärksamhet. En av faktorerna som kan påverka din förmåga i dessa avseenden

är användning av läkemedel på grund av deras effekter och/eller biverkningar. Beskrivning av dessa

effekter och biverkningar finns i andra avsnitt. Läs därför all information i denna bipacksedel för

vägledning. Diskutera med din läkare eller apotekspersonal om du är osäker.

Fosrenol innehåller glukos

Om du inte tål vissa sockerarter ska du tala med din läkare innan du använder detta läkemedel.

3.

Hur du tar Fosrenol

Ta alltid detta läkemedel enligt läkarens eller apotekspesonalens anvisningar. Rådfråga läkare eller

apotekspersonal om du är osäker.

Du bör ta Fosrenol i samband med eller omedelbart efter mat. Om du tar Fosrenol innan måltid är det

mer sannolikt att du får biverkningar såsom illamående och kräkningar.

Tabletterna måste tuggas sönder helt och får inte sväljas hela. För att underlätta tuggandet kan

tabletterna krossas. Vätska behövs inte.

Tala med din läkare om du tycker att det är svårt att tugga tabletterna. Läkemedlet finns även

tillgängligt som oralt pulver.

Din läkare kommer att tala om för dig hur många tabletter du ska ta vid varje måltid (dagsdosen

fördelas på måltiderna). Det antal tabletter du ska ta beror på:

vad du äter (mängden fosfat i det du äter)

fosfatnivån i ditt blod.

När du börjar med Fosrenol är den dagliga dosen vanligtvis 1 tablett vid varje måltid (3 tabletter per

dag).

Din läkare kommer att kontrollera fosfatnivån i ditt blod med 2-3 veckors mellanrum och kan

eventuellt öka din dos tills dess att fosfatnivån i ditt blod är acceptabel.

Fosrenol binder fosfat i födan i din tarm. Därför är det viktigt att du tar Fosrenol vid varje måltid. Om

du ändrar din diet kontakta läkaren eftersom du kan behöva ta extra Fosrenol. Din läkare kommer att

tala om för dig vad du ska göra i detta fall.

Om du har tagit för stor mängd av Fosrenol

Om du fått i dig för stor mängd läkemedel eller om t.ex. ett barn fått i sig läkemedlet av misstag

kontakta läkare, sjukhus eller Giftinformationscentralen (tel: 112) för bedömning av risken samt

rådgivning. Symtom på överdosering kan vara illamående och huvudvärk.

Om du har glömt att ta Fosrenol

Det är viktigt att du tar Fosrenol vid varje måltid.

Om du glömt att ta dina Fosrenoltabletter tar du nästa dos vid nästa måltid. Ta inte dubbel dos för att

kompensera för glömd dos.

4.

Eventuella biverkningar

Liksom alla läkemedel kan detta läkemedel orsaka biverkningar, men alla användare behöver inte få

dem.

Vissa biverkningar kan vara allvarliga. Kontakta läkare omedelbart om du får någon av

följande biverkningar:

Bristning i tarmväggen (symtom i form av svåra magsmärtor, frossa, feber, illamående,

kräkningar eller ömhet i buken). Detta är en sällsynt biverkning (kan förekomma hos upp till 1

av 1 000 användare).

Blockering i tarmen (symtom i form av svåra väderspänningar, magsmärtor, svullnad eller

kramper, svår förstoppning). Detta är en mindre vanlig biverkning (kan förekomma hos upp till

1 av 100 användare).

Kontakta din läkare om du upplever nyuppkommen eller förvärrad förstoppning. Det kan

vara ett tidigt tecken på en blockering i tarmen. Förstoppning är en vanlig biverkning (kan

förekomma hos 1 av 10 användare).

Övriga mindre allvarliga biverkningar inkluderar följande:

Mycket vanliga biverkningar (kan förekomma hos fler än 1 av 10 användare):

illamående, kräkningar, diarré, magsmärtor, huvudvärk, klåda, utslag.

Vanliga biverkningar (kan förekomma hos upp till 1 av 10 användare):

halsbränna, väderspänning.

hypokalcemi (för lite kalcium i blodet) är också en vanlig biverkning. Symtom på hypokalcemi

kan vara stickningar i händer och fötter, kramper i muskler och buk eller spasmer i ansiktets och

fötternas muskler.

Mindre vanliga biverkningar (kan förekomma hos upp till 1 av 100 användare):

trötthet, olustkänslor, bröstsmärtor, svaghet, svullna händer och fötter, kroppssmärtor, yrsel,

svindel, rapningar, mag-tarminflammation (gastroenterit), matsmältningsbesvär, irritabel tarm,

muntorrhet, tandsjukdomar, inflammation i matstrupe eller munhåla, lös avföring, förhöjda

halter av vissa leverenzymer, paratyreoideahormon, aluminium, kalcium och glukos i blodet,

förhöjda eller minskade fosfatnivåer i blodet, törst, viktminskning, ledsmärtor, muskelsmärtor,

försvagning och urkalkning av skelettet (benskörhet), nedsatt aptit, ökad aptit, inflammation i

struphuvudet, håravfall, ökad svettning, smakförändringar och en ökning av antalet vita

blodkroppar.

Rapportering av biverkningar

Om du får biverkningar, tala med läkare eller apotekspersonal. Detta gäller även eventuella

biverkningar som inte nämns i denna information. Du kan också rapportera biverkningar direkt (se

detaljer nedan). Du kan också rapportera biverkningar direkt (se detaljer nedan). Genom att rapportera

biverkningar kan du bidra till att öka informationen om läkemedels säkerhet.

Läkemedelsverket

Box 26

751 03 Uppsala

Webbplats: www.lakemedelsverket.se

5.

Hur Fosrenol ska förvaras

Förvara detta läkemedel utom syn- och räckhåll för barn.

Inga särskilda förvaringsanvisningar.

Används före utgångsdatum som anges på kartongen och burkens etikett. Utgångsdatumet är den sista

dagen i angiven månad.

Läkemedel ska inte kastas i avloppet eller bland hushållsavfall. Fråga apotekspersonalen hur man

kastar läkemedel som inte längre används. Dessa åtgärder är till för att skydda miljön.

6.

Förpackningens innehåll och övriga upplysningar

Innehållsdeklaration

Den aktiva substansen är 1 000 mg lantan (som lantankarbonathydrat).

Övriga innehållsämnen är dextrater (hydrerade), vattenfri kolloidal kiseldioxid och magnesiumstearat.

Läkemedlets utseende

Fosrenol är en vit, rund, platt tuggtablett med snedkant med ”S405/1000” präglat på tablettens ena

sida.

Parallellimportör

Paranova Läkemedel AB, Solna

Ompackare

Paranova Pack B.V., Lelystad, Nederländerna

Tillverkare

Hamol Limited, Nottingham, Storbritannien och

RB NL Brands B.V., Schiphol, Nederländerna

Denna bipacksedel ändrades senast 2021-01-19

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

N

AME OF THE

M

EDICINAL

P

RODUCT

Fosrenol 1000 mg chewable tablets.

2.

Q

UALITATIVE AND

Q

UANTITATIVE

C

OMPOSITION

Each chewable tablet contains lanthanum carbonate hydrate corresponding to 1000 mg lanthanum.

Excipient(s) with known effect

Chewable tablets also contain on average 2132 mg of dextrates, containing glucose.

For the full list of excipients, see section 6.1.

3.

P

HARMACEUTICAL

F

ORM

Chewable tablet.

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 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

10,15 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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