Fosrenol 250 mg

Fosrenol 250 mg 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 250 mg 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.

Fosrenol 250 mg is for oral administration.

The tablets must be chewed completely and not swallowed whole. To aid with chewing the tablets may be crushed. Fosrenol 250 mg oral powder can be used in patients who have difficulty chewing the tablets.

Adults, including elderly (> 65 years)

Fosrenol 250 mg 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 250 mg 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 250 mg 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 3750mg 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 250 mg in children and adolescents below the age of 18 years has not been established.

Hepatic impairment

The effect of hepatic impairment on Fosrenol 250 mg 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.

Hypophosphataemia.

Tissue deposition of lanthanum has been shown with Fosrenol 250 mg in animal studies. In 105 bone biopsies from patients treated with Fosrenol 250 mg, some for up to 4.5 years, rising levels of lanthanum were noted over time. No clinical data are available on deposition of lanthanum in other human tissues.

The use of Fosrenol 250 mg in clinical studies beyond 2 years is currently limited. However, treatment of subjects with Fosrenol 250 mg 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.

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). Patients with acute peptic ulcer, ulcerative colitis, Crohn's disease or bowel obstruction were not included in clinical studies with Fosrenol 250 mg.

Fosrenol 250 mg tablets must be chewed completely and not swallowed whole to reduce the risk of serious adverse gastrointestinal complications .

Patients with renal insufficiency may develop hypocalcaemia. Fosrenol 250 mg 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. 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 250 mg have not been established in children and adolescents; use in children and adolescents is not recommended.

Fosrenol 250 mg 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.

Fosrenol 250 mg 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 250 mg with food and generally abated with time with continued dosing.

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).

Post marketing experience: During post-approval use of Fosrenol 250 mg, 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 250 mg 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 Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard).

No case of overdose has been reported. The highest daily dose of lanthanum administered to healthy volunteers during Phase I studies was 4718mg given for 3 days. The adverse events seen were mild to moderate and included nausea and headache.

Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphataemia.

ATC code: V03A E03.

Fosrenol 250 mg 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 250 mg 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 250 mg 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 μg/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 1328μg/kg (range 122-5513 μg/kg). Median and range concentrations at 18 and 24 months were similar to 12 months. The median at 54 months was 4246 μg/kg (range 1673-9792 μg/kg).

Paired bone biopsies (at baseline and at one or two years) in patients randomised to either Fosrenol 250 mg or calcium carbonate in one study and patients randomised to either Fosrenol 250 mg 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 250 mg in one or more subsets of the paediatric population in treatment of hyperphosphataemia. See 4.2 for information on paediatric use.

As binding between lanthanum and dietary phosphorus occurs in the lumen of the stomach and upper small intestine, the therapeutic effectiveness of Fosrenol 250 mg 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 μg/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_max 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 (± sd) 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.).

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 250 mg 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.

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. However, life-time studies in healthy animals do not indicate a hazard for man from the use of Fosrenol 250 mg. Specific immunotoxicity studies have not been performed.

Not applicable.

No special requirements.