Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Takeda UK Ltd, 1 Kingdom Street, London, W2 6BD, United Kingdom
Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphataemia.
ATC code: V03AE03
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.
In healthy subjects administered Fosrenol 3 times daily for 3 days as oral powder or chewable tablets, Fosrenol oral powder was found to be pharmacodynamically equivalent to Fosrenol chewable tablets, based on urinary phosphate excretion.
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 3000 mg/day), patients were randomised to lanthanum carbonate or placebo as maintenance treatment. After the 4-week randomised placebocontrolled 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 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 1328 μg/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 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.
An open-label study was conducted to investigate the efficacy and safety of Fosrenol in hyperphosphataemic paediatric patients with chronic kidney disease on dialysis. This study did not reach the originally planned sample size required for statistical non-inferiority comparison to calcium carbonate, thus only descriptive analysis was performed on the final data. Among the 52 patients in the FAS population, who were exposed to lanthanum carbonate in Parts 2b and 3 combined. 51 enrolled and 10 discontinued in Part 2b; 42 patients enrolled and 7 discontinued in Part 3; the total exposure was 26.4 patient-years; and the observation time was 36.8 patient-years.
After 8 weeks of treatment with Fosrenol, 35% of the subjects included in the primary analysis population met the Kidney Disease Outcome Quality Initiative (KDOQI) specified serum phosphorus target levels (ie. <1.94 mmol/L for age <12 years; <1.78 mmol/L for age between 12 and 18 years).
No new significant safety issues with lanthanum carbonate were identified in this study in paediatric subjects with chronic kidney disease who were on dialysis administered mean daily dose of 1,705 mg (median 1,500 mg).
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 hydratetreated 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.
In healthy subjects administered Fosrenol 3 times daily for 3 days as oral powder or chewable tablets, the systemic exposure to lanthanum (based on AUC0-48 and Cmax) was approximately 30% higher and more variable following administration of Fosrenol oral powder than Fosrenol chewable tablets. By comparison with data for the chewable tablet (see below), the systemic exposure arising from the oral powder is still consistent with an absolute bioavailability <0.002%.
In hyperphosphataemic children and adolescents with chronic kidney disease on dialysis dosed with oral powder in the morning following breakfast, lanthanum was slowly absorbed with tmax typically occurring within 3 to 8 hours after administration but occurring as late as 12 to 24 hours after a single dose. The pharmacokinetic profile of lanthanum in the paediatric patients exhibited high variability with the coefficient of variation (CV) for lanthanum Cmax and AUC being greater than 100%. The lanthanum t½ could not be estimated in all subjects, but the mean t½ was approximately 19 hours (range, 5 to 35 hours).
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 Cmax 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 AUClast 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.
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 longterm animal studies with high oral doses of lanthanum carbonate (see section 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).
The mean lanthanum Cmax and AUClast in children (<12 years) receiving a single 500-mg dose of lanthanum carbonate were approximately one third of the value of those in adolescents (≥12 years) receiving 1000 mg lanthanum carbonate (mean Cmax 0.214 ng/mL vs. 0.646 ng/mL, and mean AUClast 2.57 ng·h/mL vs. 8.31 ng·h/mL, respectively).
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.
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. L anthanum 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.
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