SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCTFosrenol 500 mg chewable tablets.
Fosrenol 750 mg chewable tablets.
Fosrenol 1000 mg chewable tablets.
2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Fosrenol 500 mg chewable tablets:
Each chewable tablet contains lanthanum carbonate hydrate corresponding to 500 mg lanthanum.
Fosrenol 750 mg chewable tablets:
Each chewable tablet contains lanthanum carbonate hydrate corresponding to 750 mg lanthanum
Fosrenol 1000 mg chewable tablets:
Each chewable tablet contains lanthanum carbonate hydrate corresponding to 1000 mg lanthanum.
Excipient with known effectFosrenol 500 mg chewable tablets:
Chewable tablets also contain on average 1066 mg of dextrates, containing glucose.
Fosrenol 750 mg chewable tablets:
Chewable tablets also contain on average 1599 mg of dextrates, containing glucose.
Fosrenol 1000 mg chewable tablets:
Chewable tablets also contain on average 2132 mg of dextrates, containing glucose.

For the full list of excipients, see section 6.1.
3.

PHARMACEUTICAL FORM

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.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Fosrenol is indicated as a phosphate binding agent for use in the control of hyperphosphataemia inchronic renal failure (CRF) patients on haemodialysis or continuous ambulatory peritoneal dialysis(CAPD). Fosrenol is also indicated in adult patients with chronic kidney disease not on dialysis withserum 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 ispresented as a chewable tablet therefore avoiding the need to take additional fluid. Serum phosphatelevels should be monitored and the dose of Fosrenol titrated every 2 to 3 weeks until an acceptable serum
phosphate level 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 have notbeen established.

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 notedover time (see section 5.1). Cases of lanthanum deposition in gastrointestinal mucosa, mainly after
long term use, have been reported. Lanthanum deposition in gastroduodenal mucosa is demonstrated
endoscopically as whitish lesions of different sizes and shapes. Also, various pathological features
were identified in gastroduodenal mucosa with lanthanum deposition, such as chronic or active
inflammation, glandular atrophy, regenerative changes, foveolar hyperplasia, intestinal metaplasia andneoplasia.
The use of Fosrenol in clinical studies beyond 2 years is currently limited. However, treatment ofsubjects 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).
Lanthanum treatment in patients predisposed to gastrointestinal obstruction, ileus, subileus andperforation; 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 in subjects with medications
known to potentiate these effects, should only be used after careful consideration.

For all subjects, 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 during treatment with lanthanum carbonate.
Withdrawal of lanthanum carbonate is recommended in patients who develop severe constipation orother severe gastrointestinal signs and symptoms, irrespective of predisposing conditions.
Patients with acute peptic ulcer, ulcerative colitis, Crohn’s disease or bowel obstruction were notincluded in clinical studies with Fosrenol.
Fosrenol tablets must be chewed completely and not swallowed whole to reduce the risk of serious
adverse gastrointestinal complications (see section 4.2).
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 eliminationof 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.

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 coadministration of citrate.
Serum levels of fat-soluble vitamins A, D, E, and K, were not affected by Fosrenol administration inclinical 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 thesedrugs.
In simulated gastric juice, lanthanum carbonate hydrate did not form insoluble complexes withwarfarin, digoxin, furosemide, phenytoin, metoprolol or enalapril, suggesting a low potential to affectthe 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) andreduced 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 inmilk has not been studied in animals. Caution should be used in taking a decision whether tocontinue/discontinue breastfeeding 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 machines.
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 fromthe available data).
Infections and Infestations
Uncommon

Gastroenteritis, laryngitis

Blood and lymphatic system disorders
Uncommon

Eosinophilia

Endocrine disorders
UncommonHyperparathyroidism

Metabolism and nutrition disorders
CommonHypocalcaemia

UncommonHypercalcaemia, hyperglycaemia,
hyperphosphataemia, hypophosphataemia,
anorexia, appetite increased

Nervous system disorders
Very Common

Headache

UncommonDizziness, taste alteration

Ear and Labyrinth disorders
Uncommon

VertigoGastrointestinal disorders
Very Common

Abdominal
vomiting

pain,

diarrhoea,

CommonConstipation, dyspepsia, flatulence

UncommonIleus, 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
General disorders and administrationsite conditions

Arthralgia, myalgia, osteoporosis

nausea,Uncommon

Asthenia, chest pain, fatigue, malaise,
peripheral oedema, pain, thirst

Investigations

1

UncommonBlood aluminium increased, increase in
GGT, increases in hepatic transaminases,
alkaline phosphatase increased, weightdecrease.

Not known

Product residue present1

See Lanthanum deposition in gastrointestinal mucosa warning in section 4.4

Post marketing experience: During post-approval use of Fosrenol, cases of allergic skinreactions (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 afrequency of very common (≥1/10)
Although there have been a number of additional isolated reactions reported, none ofthese reactions are considered unexpected in this patient population.
Transient QT changes have been observed but these were not associated with anincrease of cardiac adverse events.
Reporting of suspected adverse reactions
Side effects can be reported to the Ministry of Health by clicking on the link “Adverse
Drug Reactions Repot” that appears on the home page of the Ministry of Health website (www.health.gov.il), which leads to an online form for reporting side effects.
Alternatively, you can use the following link:/https://sideeffects.health.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 tomoderate and included nausea and headache.
5.

PHARMACOLOGICAL PROPERTIES

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 aphosphate binder is dependent on the high affinity of lanthanum ions, which are released from thecarbonate 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 fromprevious 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 3000 mg/day), patients were randomised to lanthanum carbonate or placebo as
maintenance treatment. After the 4-week randomised placebo-controlled phase, the serum phosphateconcentration rose between 0.5 and 0.6 mmol/L in the placebo group, in both studies, relative topatients 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 werereduced by a similar amount in both treatment groups.
Further long-term extension studies have demonstrated maintenance of phosphate reduction for somepatients 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 calciumbased binders in comparative studies. Serum PTH concentrations may fluctuate depending on apatient’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 inthe control population was observed from the averaged data, the median rising 3-fold from a baselineof 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 of1328g/kg (range 122-5513 g/kg). Median and range concentrations at 18 and 24 months weresimilar 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 asecond 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 uppersmall intestine, the therapeutic effectiveness of Fosrenol is not dependent on levels of lanthanum in theplasma.
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 minimallyabsorbed following oral administration. Absolute oral bioavailability is estimated to be < 0.002% inhumans.
In healthy subjects, plasma AUC and Cmax increased as a function of dose, but in a less thanproportional manner, after single oral doses of 250 to 1000 mg lanthanum, consistent with dissolutionlimited 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 AUClast was 31.1 ( 40.5) ng.h/mL.
Regular blood level monitoring in 1707 renal dialysis patients taking lanthanum carbonate hydrate forup 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 administrationof lanthanum carbonate hydrate. The small fraction of orally administered lanthanum absorbed isextensively bound to plasma proteins (> 99.7%) and in animal studies, was widely distributed tosystemic tissues, predominantly bone, liver and the gastrointestinal tract, including the mesentericlymph nodes. In long-term animal studies, lanthanum concentrations in several tissues, including thegastrointestinal 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. theliver 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 oflanthanum 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 animalstudies 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).
Biotransformation
Lanthanum is not metabolised.
Studies in chronic renal failure patients with hepatic impairment have not been conducted. In patientswith co-existing hepatic disorders at the time of entry into Phase III clinical studies, there was noevidence 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 thedose), both via the bile and direct transfer across the gut wall. Renal excretion was a minor route.
5.3

Preclinical safety dataNon-clinical 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 bodyweight 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 gastricglandular adenomas was seen in the high-dose group (1500 mg/kg/day). The neoplastic response in themouse is considered to be related to an exacerbation of spontaneous pathological stomach changes andto 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.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Dextrates (hydrated)
Colloidal silicon dioxide
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 resistantpolypropylene 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.

REGISTRATION HOLDER AND IMPORTER

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

8.

REGISTRATION NUMBERS:

Fosrenol 500 mg chewable tablets: 140 50 31968
Fosrenol 750 mg chewable tablets: 140 51 31998
Fosrenol 1000 mg chewable tablets: 140 52 31969

Revised in January 2024.