Tissue deposition of lanthanum, particularly in bone, liver and the stomach wall, has been shown with FOSRENOL in animal studies. Deposition of lanthanum in bone has been studied (see Pharmacology: Pharmacodynamics: Clinical Studies: Effects on Bone under Actions). Results from long-term studies (Studies 301, 303 and 307) demonstrated that bone lanthanum concentration had no apparent effect on bone health or treatment outcome for up to 4.5 years. There is no clinical data examining the potential deposition of lanthanum in other tissues. 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.
The efficacy and safety of FOSRENOL has not been studied in children.
Patients with renal insufficiency may develop hypocalcaemia. FOSRENOL does not contain calcium. Serum calcium levels should therefore be monitored at the usual 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 Pharmacology: Pharmacokinetics under Actions). As the liver is the principal organ of elimination of absorbed lanthanum monitoring of liver function tests is recommended.
There have been cases of gastrointestinal obstruction, ileus, subileus, and gastrointestinal perforation reported in association with lanthanum, some requiring surgery or hospitalization. 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 vigilant for signs and symptoms of gastrointestinal disorders, especially constipation and abdominal pain/distention 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. Serious gastrointestinal complications have been reported in association with unchewed or incompletely chewed tablets (see Dosage & Administration).
Abdominal x-rays of patients taking lanthanum carbonate may have a radio-opaque appearance typical of an imaging agent.
Effects on Fertility: There are no human data on the effects of lanthanum carbonate on fertility. Lanthanum carbonate administered to female and male rats prior to and throughout mating at oral doses up to 2000 mg/kg/day (half the clinical exposure based on AUC at 3000 mg/day) did not alter mating or fertility.
Carcinogenicity: Lanthanum carbonate, at doses 13-times higher than the clinical dose of 3000 mg/day, caused a slight increase in gastric adenomas in mice. This response was considered to be an exacerbation of spontaneous stomach pathology and secondary to changes in the gastric environment caused by lanthanum carbonate administration. Gastric pathology was confined to rodents.
Genotoxicity: In vitro assays for gene mutations (bacteria and CHO cells) and in vivo studies for chromosomal or DNA damage did not provide evidence of genotoxic potential. An in vitro chromosome aberration assay in CHO cells had an equivocal outcome.
Effects on Ability to Drive and use Machines: No effects on ability to drive and use machines have been observed.
Use in Pregnancy: Pregnancy Category B3.
There was no evidence of teratogenicity in rats or rabbits following oral administration of lanthanum carbonate during the period of organogenesis at doses up to 2000 (rat) and 1500 (rabbit) mg/kg/day (0.5-1.2 times the clinical exposure based on AUC at 3000 mg/day). Increased implantation loss, and delayed skeletal ossification occurred in rabbits at ≥1500 mg/kg/day, in association with maternal toxicity. There are no adequate data from the use of FOSRENOL in pregnant women. The safety of lanthanum carbonate in human pregnancy has not been established. FOSRENOL should not be used during pregnancy unless the potential benefit justifies the potential risk.
Use in Lactation: There is some evidence that lanthanum can be excreted in human breast milk. The excretion of lanthanum in milk following oral treatment with lanthanum carbonate has not been studied in animals. Post-natal development was delayed in the offspring of rats receiving oral doses of lanthanum carbonate at 2000 mg/kg/day. Women taking FOSRENOL should stop breastfeeding.