FOSRENOL Chewable tablet Ref.[8721] Active ingredients: Lanthanum

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. Lanthanum deposition in gastroduodenal mucosa is demonstrated endoscopically as whitish lesions of different sizes and shapes. Also, various pathological features were identified in gastroduodenal mucosa with lanthanum deposition, such as chronic or active inflammation, glandular atrophy, regenerative changes, foveolar hyperplasia, intestinal metaplasia and neoplasia.

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 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 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.

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.

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, frusemide, 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.

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.

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

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).

¹ See Lanthanum deposition in gastrointestinal mucosa warning in section 4.4 Special warnings and precautions for use

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.

Paediatric population

Frequency, type and severity of adverse reactions in children have not been fully established. In particular, uncertainty exists on the accumulation in bone and risk of growth retardation with treatment in children.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

Not applicable.