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Mechanism Of Action

FOSRENOL is a phosphate binder that reduces absorption of phosphate by forming insoluble lanthanum phosphate complexes that pass through the gastrointestinal (GI) tract unabsorbed. Both serum phosphate and calcium phosphate product are reduced as a consequence of the reduced dietary phosphate absorption.


In vitro studies have shown that lanthanum binds phosphate in the physiologically relevant pH range of 3 to 7. In simulated gastric fluid, lanthanum binds approximately 97% of the available phosphate at pH 3-5 and 67% at pH 7, when lanthanum is present in a two-fold molar excess to phosphate. Bile acids have not been shown to affect the phosphate binding affinity of lanthanum. In order to bind dietary phosphate, FOSRENOL must be administered with or immediately after meals.

In five Phase I pharmacodynamic studies comparing the reduction frombaseline of urinary phosphorus excretion in healthy volunteers (N=143 taking lanthanum carbonate), it was shown that the mean intestinal phosphate binding capacity of lanthanum ranged from 235 to 468 mg phosphorus/day when lanthanum was administered at a dose of 3 g per day with food. By comparison, in one study with an untreated control group (n=10) and another study with a placebo group (n=3), the corresponding mean changes from baseline were 3 mg phosphorus/day and 87 mg phosphorus/day, respectively. In healthy subjects FOSRENOL Oral Powder was found to be similar to FOSRENOL Chewable Tablets, based on urinary phosphate excretion.


Absorption And Distribution

Following single or multiple dose oral administration of FOSRENOL to healthy subjects, the concentration of lanthanum in plasma was very low (bioavailability < 0.002%). Following oral administration in patients, the mean lanthanum Cmax was 1.0 ng/mL. During long-term administration (52 weeks) in ESRD patients, the mean lanthanum concentration in plasma was approximately 0.6 ng/mL. There was minimal increase in plasma lanthanum concentrations with increasing doses within the therapeutic dose range. The timing of food intake relative to lanthanum administration (during and 30 minutes after food intake) has a negligible effect on the systemic level of lanthanum.

Systemic exposure to lanthanum was approximately 30% higher following administration of FOSRENOL Oral Powder when compared to FOSRENOL Chewable Tablets. However, systemic exposure to lanthanum from both formulations in this study was within the range seen in previous pharmacokinetic studies of Chewable Tablets in healthy individuals.

In vitro, lanthanum is highly bound ( > 99%) to human plasma proteins, including human serum albumin, α1-acid glycoprotein, and transferrin. Binding to erythrocytes in vivo is negligible in rats.

In animal studies, lanthanum concentrations in several tissues, particularly gastrointestinal tract, mesenteric lymph nodes, bone and liver, increased over time to levels several orders ofmagnitude higher than those in plasma. The level of lanthanum in the liver was higher in renally impaired rats due to higher intestinal absorption. Lanthanum was found in the lysosomes and the biliary canal consistent with transcellular transport. Steady state tissue concentrations in bone and liver were achieved in dogs between 4 and 26 weeks. Relatively high levels of lanthanumremained in these tissues for longer than 6 months after cessation of dosing in dogs. There is no evidence from animal studies that lanthanum crosses the blood-brain barrier.

In 105 bone biopsies from patients ciprofloxacin treated with FOSRENOL for up to 4.5 years, rising levels of lanthanum were noted over time. Estimates of elimination half-life from bone ranged from 2.0 to 3.6 years. Steady state bone concentrations were not reached during the period studied.

Metabolism And Elimination

Lanthanum is not metabolized. Lanthanum was cleared from plasma of patients undergoing dialysis with an elimination half-life of 53 hours following discontinuation of therapy.

No information is available regarding the mass balance of lanthanum in humans after oral administration. In rats and dogs, the mean recovery of lanthanum after an oral dose was about 99% and 94%, respectively, and was essentially all from feces. Biliary excretion is the predominant route of elimination for circulating lanthanum in rats. In healthy volunteers administered intravenous lanthanum as the soluble chloride salt (120 μg), renal clearance was less than 2% of total plasma clearance.

Drug Interactions

FOSRENOL has a low potential for systemic drug-drug interactions because of the very low bioavailability of lanthanum and because it is not a substrate or inhibitor of major cytochrome P450 enzyme groups involved in drug metabolism (CYP1A2, CYP2C9/10, CYP2C19, CYP2D6 and CYP3A4/5). FOSRENOL does not alter gastric pH. Therefore, FOSRENOL drug interactions based on altered gastric pH are not expected.

In an in vitro investigation, lanthanum did not form insoluble complexes when mixed in simulated gastric fluid with warfarin, digoxin, furosemide, phenytoin, metoprolol and enalapril. Clinical studies have shown that FOSRENOL (three doses of 1000mg on the day prior to exposure and one dose of 1000 mg on the day of co-administration) administered 30 minutes earlier did not alter the pharmacokinetics of oral warfarin (10 mg), digoxin (0.5 mg), or metoprolol (100 mg). Potential pharmacodynamic interactions between lanthanum and these drugs (e.g., bleeding time or prothrombin time) were not evaluated. None of the drug interaction studies were done with the maximum recommended therapeutic dose of lanthanum carbonate. No drug interaction studies assessed the effects of drugs on phosphate binding by lanthanum carbonate.


In a randomized, two–way crossover study in healthy volunteers examining the interaction potential of a single oral dose of ciprofloxacin (750 mg) alone and with lanthanum carbonate (1 g TID), the maximum plasma concentration of ciprofloxacin was reduced by 56%and the area under the ciprofloxacin plasma concentration-time curve was reduced by 54%. The 24-h urinary recovery of ciprofloxacin was reduced 52% by FOSRENOL [see DRUG INTERACTIONS].


In a single-dose crossover study of levothyroxine (1mg) with or without simultaneous administration of a single dose of FOSRENOL (500mg) in six euthyroid normal healthy volunteers, the area under the serum T4 concentration-time curve was decreased by 40% [see DRUG INTERACTIONS].

Fat Soluble Vitamins

FOSRENOL appears not to affect the availability of fat soluble vitamins (A, D, E and K) or other nutrients [see Clinical Studies].


Citrate did not increase the absorption of lanthanum.

Developmental Toxicity

In pregnant rats, oral administration of lanthanum carbonate at doses as high as 2000 mg/kg/day (3.4 times the MRHD) resulted in no evidence of harm to the fetus. In pregnant rabbits, oral administration of lanthanum carbonate at 1500 mg/kg/day (5 times the MRHD) was associated with a reduction in maternal body weight gain and food consumption, increased post-implantation loss, reduced fetal weights, and delayed fetal ossification. Lanthanumcarbonate administered to rats fromimplantation through lactation at 2000 mg/kg/day (3.4 times the MRHD) caused delayed eye opening, reduction in body weight gain, and delayed sexual development (preputial separation and vaginal opening) of the offspring.

Clinical Studies

The effectiveness of FOSRENOL in reducing serum phosphorus in ESRD patients was demonstrated in one short-term, placebo-controlled, double-blind dose-ranging study, two placebo-controlled randomized withdrawal studies and two long-term, activecontrolled, open-label studies in both hemodialysis and peritoneal dialysis (PD) patients.

Double-Blind Placebo-Controlled Studies

One hundred and forty-four patients with chronic renal failure undergoing hemodialysis and with elevated phosphate levels 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. Fifty-five percent of subjects were male, 71% black, 25% white and 4% of other races. The mean age was 56 years and the duration of dialysis ranged from 0.5 to 15.3 years. Steady-state effects were achieved after two weeks. The effect after six weeks of treatment is shown in Figure 1.

Figure 1: Difference in Phosphate Reduction in the FOSRENOL and Placebo Group in a 6-Week, Dose-Ranging, Double-Blind Study in ESRD Patients (with 95% Confidence Intervals)

Difference in Phosphate Reduction in the FOSRENOL and Placebo Group in a 6-Week, Dose-Ranging, Double-Blind Study - Illustration

One-hundred and eighty-five patients with end stage renal disease undergoing either hemodialysis (n=146) or peritoneal dialysis (n=39) were enrolled in two placebo-controlled, randomized withdrawal studies. Sixty-four percent of subjects were male, 28% black, 62% white and 10% of other races. The mean age was 58.4 years and the duration of dialysis ranged from 0.2 to 21.4 years. After titration of lanthanum carbonate to achieve a phosphate level between 4.0 and 5.6 mg/dL in one study (doses up to 2250 mg/day) or ≤ 5.9 mg/dL in the second study (doses up to 3000 mg/day) and maintenance through 6 weeks, patients were randomized to lanthanum or placebo. During the placebo-controlled, randomized withdrawal phase (four weeks), the phosphorus concentration rose in the placebo group by 1.7 mg/Dl in one study and 1.9 mg/dL in the other study relative to patients who remained on lanthanum carbonate therapy.

Open-Label Active-Controlled Studies

Two long-term open-label studies were conducted, involving a total of 2028 patients with ESRD undergoing hemodialysis. Patients were randomized to receive FOSRENOL or alternative phosphate binders for up to sixmonths in one study and two years in the other. The daily FOSRENOL doses, divided and taken with meals, ranged from 375 mg to 3000mg. Doses were titrated to reduce serumphosphate levels to a target level. The daily doses of the alternative therapy were based on current prescribing information or those commonly utilized. Both treatment groups had similar reductions in serum phosphate of about 1.8mg/dL. Maintenance of reduction was observed for up to three years in patients treated with FOSRENOL in long-term, open-label extensions.

No effects of FOSRENOL on serum levels of 25-dihydroxy vitamin D3, vitamin A, vitamin B12, vitamin E and vitamin K were observed in patients who were monitored for 6 months.

Paired bone biopsies (at baseline and at one or two years) in 69 patients randomized to either FOSRENOL or calcium carbonate in one study and 99 patients randomized to either FOSRENOL or alternative therapy in a second study showed no differences in the development of mineralization defects between the groups.

Vital status was known for over 2000 patients, 97% of those participating in the clinical program during and after receiving treatment. The adjusted yearly mortality rate (rate/years of observation) for patients treated with FOSRENOL or alternative therapy was 6.6%.


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