General Information

Fosrenol is a chewable tablet formulation which delivers the carbonate salt of the element lanthanum. This salt dissolves freely in the acid of the digestive tract, yielding ionic lanthanum, which has been shown to bind dietary phosphate released from food during digestion. This binding actvity prevents the dietary absorption of phosphate in the intestines.

Fosrenol is indicated to reduce serum phosphate levels in patients with kidney dysfunction due to end-stage renal disease (ESRD) when taken with or immediately following meals. By preventing absorption of gastric phosphate, the burden of phosphate regulation on the kindeys is lowered. In addition, because only a very small percentage of Fosrenol is absorbed into the blood stream, it does not place significant additional burden on metabolic systems of the liver or elimination systems in the kidneys.

Fosrenol is supplied as a chewable tablet of two dosage strengths (250 mg and 500 mg), and is designed to be taken with or immediately following meals. The recommended initial total daily dose is 750-1500 mg, and dosing should be titrated every 2-3 weeks until optimum serum phosphate levels are achieved. Most in clinical trials patients needed total daily doses of 1500-3000mg.

Clinical Results

FDA approval of Fosrenol for the treatment of hyperphosphatemia in ESRD was based on a total of 5 clinical trials: 3 were placebo controlled, including 1 short-term, double-blind dose-ranging study and 2 randomized withdrawal studies; and 2 were active-controlled, both long-term, open-label studies in both hemodialysis and peritoneal dialysis (PD) patients.
Placebo Controlled Studies
Short-Term Study
144 hyperphosphatemic patients with chronic renal failure undergoing hemodialysis were randomized to double-blind treatment at a fixed dose of lanthanum carbonate of 225 mg (n=27), 675 mg (n=29), 1350 mg (n=30) or 2250 mg (n=26) or placebo (n=32) in divided doses with meals for 6 weeks. Mean age was 56 years, and the duration of dialysis experience ranged from 0.5 to 15.3 years. Results indicated that the drug reduced serum phosphate levels in a dose-dependent manner, with steady state levels achieved after 2 weeks.

Long Term Withdrawal Studies
185 patients with ESRD undergoing either hemodialysis (n=146) or peritoneal dialysis (n=39) were enrolled in 2 randomized withdrawal studies. Mean age was 58.4 years and the duration of dialysis ranged from 0.2 to 21.4 years. All subjects receved titrated doses of Fosrenol until target phostphate levels were reached (4.2-5.6 mg/dl in one study or < 5.9 mg/dl in the second) and maintained for 6 weeks. Following this steady state, patients were randomized to receive Fosrenol or placebo during a 4 week withdrawal period. Results indicated that subjects receiving Fosrenol maintained steady-state serum phosphorus levels, but subjects receiving placebo experienced significant increases in serum phosphate levels (1.9 mg/dl in both studies) back to the range of hyperphosphatemia (>6.0 mg/dL).

Open Label Studies 2 long-term studies were conducted, involving a total of 2028 patients with ESRD on hemodialysis. Patients were randomized to receive Fosrenol or alternative phosphate binders to investigate the drug's efficacy in long term treatment (up to 6 months for study 1, and 2 years for study 2). Subjects receiving Fosrenol were treated with titrated regimens based on doses needed to achieve target serum phosphate levels (total daily doses: 375 mg-3000 mg). Regimens of active controll medicines followed current prescribing guides or common standards. Fosrenol demonstrated a non-inferior reduction in serum phosphate levels (roughly 1.8 mg/dL for all medications), and maintenance of these levels with Fosrenol was extablished for up to three years in long-term, open label extensions.

Safety Data
Fosrenol demonstrated an excellent safety and tollerability, due to its very low rate of systemic absorption. Preclinical animal studies indicated that 94%-99% of the drug passed completely through the intestinal tract, and clinical experience demostrated no systemic metabolism, no significant changes in liver function, no drug-related effects of on vitamin absorption (other than phosphate) in patients monitored for 6 months, and no differences in the development of mineralization defects in bone density scans between Fosrenol and placebo or approved therapies.

Mechanism of Action

Fosrenol is a carbonate salt of the rare-earth metal lanthanum. This salt dissociates in the acid of the stomach to release lanthanum ions that bind dietary phosphate released from food during digestion. Binding phosphate ions forms highly insoluble lanthanum-phosphate complexes, which are not absorbed in the rest of the GI tract. Dietary phosphate thus cannot contribute to serum phosphate levels, allowing the kidneys to reduce these levels to normal reanges. Lower serum phosphate levels also reduce the prodution of calcium phosphate, high levels of which can lead to ectopic calcification.

Literature References

Behets GJ, Dams G, Vercauteren SR, Damment SJ, Bouillon R, De Broe ME, D'Haese PC Does the phosphate binder lanthanum carbonate affect bone in rats with chronic renal failure? Journal of the American Society of Nephrology. 2004 Aug;15(8):2219-28

Hutchison AJ, Speake M, Al-Baaj F Reducing high phosphate levels in patients with chronic renal failure undergoing dialysis: a 4-week, dose-finding, open-label study with lanthanum carbonate. Nephrology Dialysis Transplantation. 2004 Jul;19(7):1902-6

Joy MS, Finn WF; LAM-302 Study Group Randomized, double-blind, placebo-controlled, dose-titration, phase III study assessing the efficacy and tolerability of lanthanum carbonate: a new phosphate binder for the treatment of hyperphosphatemia. American Journal of Kidney Diseases. 2003 Jul;42(1):96-107