Fosrenol Chewable Tablets
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Fosrenol Chewable Tablets - Scientific Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Hyperphosphatemia of Renal Failure
Class: Phosphate binders
Form: Tablets
Ingredients: lanthanum carbonate hydrate, colloidal silicon dioxide, dextrates (hydrated), magnesium stearate

Pharmaceutical Information

Drug Substance

Proper name:lanthanum carbonate hydrate
Chemical name:lanthanum (III) carbonate hydrate
Molecular formula and molecular mass:
FOSRENOL contains lanthanum carbonate (2:3) hydrate with molecular formula La2(CO3)3•qH2O (on average q=4 to 5 moles of water) and a molecular mass of 457.8 (anhydrous).
Physicochemical properties:
Lanthanum carbonate hydrate, a white to almost white powder, is a basic carbonate consisting primarily of carbonate tetrahydrate, La2(CO3)3•4H2O, although other lanthanum hydrates may be present with on average 4 to 5 moles of bound water. A macromolecular structure is formed from the association of water molecules across the crystal lattice. The pKa values for its salt, carbonic acid, are 10.33 and 6.35. Lanthanum carbonate is insoluble in organic solvents. Aqueous solubility at a pH of 1.2 is between 5 and 10mg/mL, and is poor at alkaline pHs.

Clinical Trials

Study Demographics and Trial Design

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, active-controlled, open-label studies in both hemodialysis and peritoneal dialysis (PD) patients.

Double-Blind, Placebo-Controlled Studies

One-hundred-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 225mg (n=27), 675mg (n=29), 1350mg (n=30) or 2250mg (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.

Fifty-four subjects [37 (33%) patients on FOSRENOL and 17 (53%) patients on placebo] withdrew from the study after randomization. The reasons for discontinuation are described in Table 1 below.

Table 1. Reasons for Discontinuation in Study LAM-204
Reason for DiscontinuationFOSRENOL
(n=112 randomized)
Placebo
(n=32 randomized)
Total withdrawn37 (33%)17 (53%)
Adverse events, including death10 (9%)3 (9%)
Outside pre-specified safety criteria19 (17%)13 (41%)
Administrative or other8 (7%)1 (3%)

Including efficacy-related criteria such as PO4 >10mg/dL, PO4XCa >80mg2/dL2, and change in PTH >500pg/mL.

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)

One-hundred-eighty-five patients with ESRD 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 a four- to six-week titration of lanthanum carbonate to achieve a goal phosphate level between 4.2 and 5.6mg/dL in one study (doses up to 2250mg/day) or ≤5.9mg/dL in the second study (doses up to 3000mg/day) and maintenance through 6 weeks, patients were randomized to lanthanum or placebo.

Fifty (27%) of the subjects taking lanthanum in the titration phase withdrew (unplanned) from the studies prior to randomization. The reasons for discontinuation were: adverse event including 1 death (16; 8.6%), outside pre-specified safety criteria (14; 7.6%), and protocol violation or other (20; 10.8%).

During the placebo-controlled, randomized withdrawal phase (four weeks), the phosphorus concentration rose in the placebo group by 1.9mg/dL in both studies 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 2159 patients with ESRD undergoing hemodialysis. In Study LAM-301, 800 patients completed a washout period off phosphate binders (Part 1) and were then randomized 2:1 to receive either FOSRENOL or calcium carbonate. These patients were then dose-titrated to a target phosphate level of ≤1.8mmol/L over a five-week period (Part 2). On completion of titration, remaining patients remained on their randomized phosphate binder and were followed for six months (Part 3). After the six-month maintenance phase, all subjects who had been randomized were eligible to take part in a longer-term extension on FOSRENOL only. The purpose of the extension was primarily to assess safety and long-term tolerability of FOSRENOL.

Of the 767 subjects who entered the titration period (ITT population), 101 [FOSRENOL: 60 (11.8%); Calcium: 41 (16.0%)] withdrew before entering the maintenance phase of the study. Two-hundred and ninety-one subjects [FOSRENOL: 188 (41.8%); Calcium: 103 (49.8%)] withdrew during the maintenance phase (to end of Part 3). A total of 375 subjects (including those who re-entered the study at the beginning of the extension) completed the six-month randomized therapy and additional six-month open-label safety extension. The reasons for discontinuation are shown in Table 2.

Table 2. Reasons for Discontinuation in Study LAM-301
Reason for DiscontinuationFOSRENOL
(n=533 randomized)
Calcium
(n=267 randomized)
Total withdrawn271 (50.8%)154 (57.7%)
Death19 (3.6%)11 (4.1%)
Adverse event82 (15.4%)47 (17.6%)
Serious adverse event12 (2.3%)4 (1.5%)
Protocol violation24 (4.5%)11 (4.1%)
Withdrew consent43 (8.1%)29 (10.9%)
Received kidney transplant23 (4.3%)16 (6.0%)
Lost to follow-up5 (0.9%)1 (0.4%)
Other (including 1 missing)64 (12.0%)34 (12.7%)

At the end of the maintenance phase of the study, the mean phosphate level was 1.73mmol/L (representing -0.74mmol/L from baseline) in the FOSRENOL group (doses up to 3000mg/day), and 1.73mmol/L (representing -0.75mmol/L from baseline in the Calcium group (doses up to 9000mg/day) in patients who completed the maintenance period.

In Study LAM-307, 1359 patients were randomized to receive either FOSRENOL or Standard Therapy. Subjects completed a three-week washout period (Part 1) off all phosphate binders. After a subsequent titration period of six weeks (Part 2), the patients were maintained on their randomized treatment for 24 months (Part 3). A total of 682 patients were randomized to FOSRENOL therapy, and 677 were randomized to Standard Therapy.

Standard Therapy: Patients randomized to Standard Therapy continued to take their prescribed binder at the optimal dose required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders throughout the study and could also take a combination of binders in order to achieve optimal phosphate control.

Of the 1359 patients who entered the titration period, 842 (62%) withdrew prior to completion of the two-year study. Of these, 486 (71.3%) were in the FOSRENOL group and 356 (52.6%) were in the Standard Therapygroup.

The reasons for discontinuation are shown in Table 3.

Table 3. Reasons for Discontinuation in Study LAM-307
Reason for DiscontinuationFOSRENOL
(n=682 randomized)
Standard Therapy
(n=677 randomized)
Total withdrawn486 (71.3%)356 (52.6%)
Death⚹⚹42 (6.2%)96 (14.2%)
Adverse event98 (14.4%)29 (4.3%)
Exceeded pre-specified safety criteria:
Two PO4 > 10mg/dL32 (4.7%)22 (3.3%)
Two PO4 < 2.0mg/dL02 (0.3%)
Two CaXPO4 > 90mg2/dL214 (2.1%)7 (1.0%)
Calcium > 11.5mg/dL2 (0.3%)1 (0.1%)
Increase PTH > 500pg/mL5 (0.7%)1 (0.1%)
Protocol violation13 (1.9%)5 (0.7%)
Withdrew consent107 (15.7%)34 (5.0%)
Patient received kidney transplant55 (8.1%)75 (11.1%)
Lost to follow-up10 (1.5%)12 (1.8%)
Other109 (16.0%)73 (10.8%)

Standard Therapy: Patients randomized to Standard Therapy continued to take their prescribed binder at the optimal dose required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders throughout the study and could also take a combination of binders in order to achieve optimal phosphate control.

⚹⚹Represents End of Study entry as the investigator-determined reason for study withdrawal. There were patients who died after study termination (13 FOSRENOL; 19 Standard Therapy). As a result, the total number of patients who died whether during the study or within 30 days after the last dose of study drug was 178, who are not represented all on this table.

Study LAM-307 was primarily a safety and tolerability study; phosphate control was a secondary objective.

One-hundred and sixty-one patients entered a further 12-month extension of Study LAM-301, taking FOSRENOL only, to a total of three years. Maintenance of phosphate reduction was observed in patients treated with FOSRENOL for up to 3 years of which 62% received daily doses of either 2250mg or 3000mg at Week 58. There were minimal dose changes throughout the remainder of the study. Of the 90 patients who completed the third year of therapy, 49 (54.4%) had a phosphate level better than the target of 1.8mmol/L.

In an open-label long-term 2-year extension study in 93 patients who had transitioned from other studies, resulting in a total of up to 6 years treatment, maintenance of reduction in serum phosphate level was observed. There was no evidence of adverse safety concerns after long-term lanthanum carbonate treatment in any body system, including the hepatic system, bone and central nervous system in the small number of patients remaining in their sixth year of treatment.

No effects of FOSRENOL on serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D, vitamin A, vitamin B12, vitamin E and vitamin K were observed in patients who were monitored for 6 months.

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%.

Bone Safety

Lanthanum Deposition in Bone

In the comparative bone studies, a trend towards increasing bone lanthanum concentrations with time in the Standard Therapy group was observed from averaged data, the median rising 3-fold from a baseline of 53µg/kg (wet weight) at 24 months. In patients treated with lanthanum carbonate, the bone lanthanum concentrations increased during the first 12 months of lanthanum carbonate treatment up to a median of 1328µg/kg (range 122-5513µg/kg). Median and range concentrations at 18 and 24 months were similar to 12 months. The median at 54 months was 4246µg/kg (range 1673-9792µg/kg), a 3-fold increase from that at 12 months. Steady-state bone concentrations were not reached during the period.

Bone Histology

Paired bone biopsies (at baseline and at one year) were collected from 63 patients randomized to either FOSRENOL (n=33) or calcium carbonate (n=30) in one study. In a second randomized study 99 patients had both a baseline and follow up biopsy after 1 or 2 years of treatment; 63 patients had bone biopsies at baseline and 1 year (FOSRENOL: n=31, Standard Therapy: n=32), and 52 patients had biopsies at baseline and 2 years (FOSRENOL: n=31, Standard Therapy: n=21). Histomorphometric analysis showed no differences in the development of mineralization defects between the groups up to 2 years. However, long-term effects of lanthanum on bone quality are unknown.

Standard Therapy: Patients randomized to Standard Therapy continued to take their prescribed binder at the optimal dose required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders throughout the study and could also take a combination of binders in order to achieve optimal phosphate control.

Detailed Pharmacology

Preclinical

Pharmacodynamics

In vitro studies have shown that lanthanum binds phosphate in the physiologically relevant pH range of 3 to 7. In normal rats, lanthanum carbonate (1000mg/kg p.o.) increased fecal excretion of co-administered [32P]-phosphate and decreased urinary [32P]-phosphate excretion compared to vehicle-treated controls, indicative of effective dietary phosphate binding. In partially nephrectomised rats, lanthanum carbonate treatment (≥1000mg/kg) reduced, but not significantly, the hyperphosphataemia and hyperparathyroidism associated with chronic renal failure.

Pharmacokinetics

The absolute oral bioavailability of lanthanum (from lanthanum carbonate) was estimated from oral and intravenous studies in rats to be 0.0007%. 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. In bile-duct cannulated rats, biliary excretion of intravenous lanthanum (administered as the soluble lanthanum chloride) was the predominant route of elimination.

Long-term studies in animals have shown deposition of lanthanum in tissues, mainly the gastrointestinal tract, mesenteric lymph nodes, liver and bone (see also Action and Clinical Pharmacology –Pharmacokinetics, Distribution). There is no evidence from animal studies that lanthanum crosses the blood brain barrier.

Toxicology

Single- and Repeat-Dose Toxicity

In single-dose oral toxicity studies in mice and rats, lanthanum carbonate at doses up to 2000mg/kg resulted in no deaths and produced no overt signs of toxicity. Single-dose intravenous toxicity studies in mice and rats were conducted using the soluble chloride salt of lanthanum to ensure delivery of high systemic lanthanum doses. The maximum non-lethal intravenous doses were 3.0mg/kg in the mouse and 6.25mg/kg in the rat. In both species, at 6.25mg/kg, histopathological changes in the liver included degeneration and necrosis of hepatocytes, with hemorrhage and inflammation 2 days post-dose.

In repeat-dose oral toxicity studies in mice (for up to 99 weeks), rats (for up to 104 weeks), and dogs (for up to 52 weeks), lanthanum carbonate was well tolerated at the maximum practicable doses of 1500mg/kg/day in rodents and 2000mg/kg/day in dogs. In a 13-week oral toxicity study in mice, lanthanum carbonate at doses up to 2000mg/kg/day was associated with a dose- dependent accumulation of lanthanum particularly in the liver and femur. Epithelial hyperplasia was observed in the gastric mucosa at doses of 500mg/kg/day or higher in rodents. No gastric pathology occurred in dogs, but there was a dose-related increase in lanthanum concentration in the femur at the end of the 52-week treatment period.

Repeat-dose intravenous toxicity studies of 4 weeks duration with lanthanum chloride exposed rats and dogs to peak plasma lanthanum concentrations that were approximately 1500 times (rats, 0.3mg/kg/day) or 20 000 times (dogs, 1.0mg/kg/day) higher than in patients (assuming a human Cmax of 1.06ng/mL after 1000mg of lanthanum carbonate hydrate TID). No adverse effects occurred in rats. Chronic hepatitis was present in all male and female dogs given 1mg/kg/day.

Pre-clinical studies also found that chronically renal impaired rats given high doses of lanthanum carbonate resulted in osteomalacia, and non-dietary phosphate supplements minimized this effect.

Mutagenicity

Lanthanum carbonate tested negative for mutagenic activity in an in vitro Ames assay using Salmonella typhimurium and Escherichia coli strains and an in vitro HGPRT gene mutation and chromosomal aberration assays in Chinese Hamster Ovary (CHO) cells. Lanthanum carbonate also tested negative in an in vivo mouse micronucleus assay at oral doses up to 2000mg/kg/day.

In addition, lanthanum chloride, administered intravenously, was shown to be non-clastogenic in a bone marrow micronucleus test and in a liver unscheduled DNA synthesis assay in rats at doses up to 0.1mg/kg/day, a dose that produced plasma lanthanum concentrations >2000 times the peak human plasma concentration.

Carcinogenicity

Oral administration of lanthanum carbonate to rats for up to 104 weeks, at doses up to 1500mg/kg/day, revealed no evidence of carcinogenic potential. In mice, oral administration of lanthanum carbonate for up to 99 weeks at a dose of 1500mg/kg/day was associated with an increased incidence of gastric glandular adenomas. There were no treatment effects on the incidences of malignant tumors.

Reproduction and Teratology

In pregnant rats, oral administration of lanthanum carbonate at doses up to 2000mg/kg/day resulted in no evidence of harm to the fetus. There was an increased incidence of observations of small pups in the group treated at 2000mg/kg/day. In pregnant rabbits, oral administration of lanthanum carbonate at a dose of 1500mg/kg/day was associated with a reduction in maternal body weight gain, food consumption, fecal production, increased pre- and post-implantation losses, reduced fetal weights, and delayed fetal ossification.

Oral administration of lanthanum carbonate to rats from implantation through lactation at 2000mg/kg/day caused delayed eye opening, reduction in body weight gain, and delayed sexual development (preputial separation and vaginal opening) of the offspring.

Lanthanum carbonate at doses up to 2000mg/kg/day did not affect fertility or mating performance of male or female rats.

Immunotoxicity

Specific immunotoxicity studies have not been performed.