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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, mean baseline values and changes in transaminases were similar to those observed in the earlier comparative studies, with little change during treatment. The safety of FOSRENOL was studied in two long-term, open-labeled clinical trials, which included 1215 patients treated with FOSRENOL and 944 with alternative therapy. Fourteen percent (14%) of FOSRENOL treated patients discontinued treatment due to adverse events. Gastrointestinal adverse reactions, such as nausea, diarrhea and vomiting were the most common types of event leading to discontinuation. In pooled active comparator controlled clinical trials, hypocalcemia was noted with an incidence of approximately 5% in both lanthanum and active comparator groups. A nonclinical study and a phase 1 study have shown reduced absorption of calcium in the intestine with lanthanum carbonate treatment. In a crossover study in 72 healthy individuals comparing Fosrenol chewable tablets to Fosrenol oral powder, gastrointestinal adverse reactions such as nausea, diarrhea and vomiting were more common for the oral powder formulation (18%) than for the chewable tablets (7%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of FOSRENOL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: constipation, intestinal perforation, intestinal obstruction, ileus, subileus, dyspepsia, allergic skin reactions, hypophosphatemia, and tooth injury while chewing the tablet. 7 DRUG INTERACTIONS Lanthanum in FOSRENOL has the potential to bind to drugs with anionic (e.g., carboxyl, carbonyl and hydroxyl) groups. FOSRENOL may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism. There are no empirical data on avoiding drug interactions between FOSRENOL and most concomitant oral drugs. For oral medications where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, consider separation of the timing of the administration of the two drugs. The duration of separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product. Consider monitoring clinical responses or blood levels of concomitant medications that have a narrow therapeutic range. 7.1 Drugs Binding to Antacids There is a potential for FOSRENOL to interact with compounds which bind to cationic antacids (i.e., aluminum-, magnesium-, or calcium-based). Therefore, do not administer such compounds within 2 hours of dosing with FOSRENOL. Examples of relevant classes of compounds where antacids have been demonstrated to reduce bioavailability include antibiotics (such as quinolones, ampicillin and tetracyclines), thyroid hormones, ACE-inhibitors, statin lipid regulators and anti-malarials. 7.2 Quinolone Antibiotics Co-administration of FOSRENOL with quinolone antibiotics may reduce the extent of their absorption. The bioavailability of oral ciprofloxacin was decreased by approximately 50% when taken with FOSRENOL in a single dose study in healthy volunteers. Administer oral quinolone antibiotics at least 1 hour before or 4 hours after FOSRENOL. When oral quinolones are given for short courses, consider eliminating the doses of FOSRENOL that would be normally scheduled near the time of quinolone intake to improve quinolone absorption [see Clinical Pharmacology (12.3)] . 7.3 Levothyroxine The bioavailability of levothyroxine was decreased by approximately 40% when taken together with FOSRENOL. Administer thyroid hormone replacement therapy at least 2 hours before or 2 hours after dosing with FOSRENOL and monitor thyroid stimulating hormone (TSH) levels [see Clinical Pharmacology (12.3)] . 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. No adequate and well-controlled studies have been conducted in pregnant women. The effect of FOSRENOL on the absorption of vitamins and other nutrients has not been studied in pregnant women. FOSRENOL is not recommended for use during pregnancy. Studies in pregnant rabbits showed that oral administration of lanthanum carbonate at 1500 mg/kg/day (5 times the maximum recommended daily human dose (MRHD) of 5725 mg, on a mg/m 2 basis, assuming a 60 kg patient) was associated with increased post-implantation loss, reduced fetal weights, and delayed fetal ossification [see Nonclinical Toxicology (13.3)] . 8.2 Labor and Delivery No FOSRENOL treatment-related effects on labor and delivery were seen in animal studies. The effects of FOSRENOL on labor and delivery in humans is unknown. 8.3 Nursing Mothers It is not known whether lanthanum carbonate is excreted in human milk. As many drugs are excreted in human milk, consider the possibility of infant exposure when FOSRENOL is administered to a nursing woman. 8.4 Pediatric Use The safety and efficacy of FOSRENOL in pediatric patients have not been established. While growth abnormalities were not identified in long-term animal studies, lanthanum was deposited into developing bone including growth plate. The consequences of such deposition in developing bone in pediatric patients are unknown. Therefore, the use of FOSRENOL in this population is not recommended. 8.5 Geriatric Use Of the total number of patients in clinical studies of FOSRENOL, 32% (538) were ≥65, while 9.3% (159) were ≥75. No overall differences in safety or effectiveness were observed between patients ≥65 years of age and younger patients. 10 OVERDOSAGE The symptoms associated with overdose are adverse reactions such as headache, nausea and vomiting. In clinical trials in healthy adults, GI symptoms were reported with daily doses up to 6000 mg/day of lanthanum carbonate administered with food. Given the topical activity of lanthanum in the gut, and the excretion in feces of the majority of the dose, supportive therapy is recommended for overdosage. Lanthanum carbonate was not acutely toxic in animals by the oral route. No deaths and no adverse effects occurred in mice, rats or dogs after single oral doses of 2000 mg/kg (1.7, 3.4, and 11.3 times the MRHD, respectively, on a mg/m 2 basis). 11 DESCRIPTION FOSRENOL contains lanthanum carbonate with molecular formula La 2(CO 3) 3 xH 2O (on average x=4-5 moles of water) and molecular weight 457.8 (anhydrous mass). Lanthanum carbonate is described as white to almost white powder. Lanthanum carbonate is practically insoluble in water and is insoluble in organic solvents; it dissolves in dilute minral acids with effervescence. Each FOSRENOL, white to off-white, chewable tablet contains lanthanum carbonate hydrate equivalent to 500, 750, or 1000 mg of elemental lanthanum and the following inactive ingredients: colloidal silicon dioxide NF, dextrates (hydrated) NF, magnesium stearate NF. FOSRENOL Oral Powder is a white to off-white powder containing lanthanum carbonate hydrate equivalent to 750 or 1000 mg of elemental lanthanum and the following inactive ingredients: colloidal silicon dioxide NF, dextrates (hydrated) NF, magnesium stearate NF. 12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 Pharmacodynamics 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 from baseline 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. 12.3 Pharmacokinetics 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 C max 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 of magnitude 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 lanthanum remained 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 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 1000 mg 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. Ciprofloxacin 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 (7.2)] . Levothyroxine In a single-dose crossover study of levothyroxine (1 mg) with or without simultaneous administration of a single dose of FOSRENOL (500 mg) in six euthyroid normal healthy volunteers, the area under the serum T4 concentration-time curve was decreased by 40% [see Drug Interactions (7.3)] . 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 (14.2)] . Citrate Citrate did not increase the absorption of lanthanum. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Oral administration of lanthanum carbonate to rats for up to 104 weeks, at doses up to 1500 mg of the salt per kg/day [2.5 times the MRHD of 5725 mg, on a mg/m 2 basis, assuming a 60-kg patient] revealed no evidence of carcinogenic potential. In the mouse, oral administration of lanthanum carbonate for up to 99 weeks, at a dose of 1500 mg/kg/day (1.3 times the MRHD) was associated with an increased incidence of glandular stomach adenomas in male mice. Lanthanum carbonate tested negative for mutagenic activity in an in vitro Ames assay using Salmonella typhimurium and Escherichia coli strains and in vitro HGPRT gene mutation and chromosomal aberration assays in Chinese hamster ovary cells. Lanthanum carbonate also tested negative in an oral mouse micronucleus assay at doses up to 2000 mg/kg (1.7 times the MRHD), and in micronucleus and unscheduled DNA synthesis assays in rats given IV lanthanum chloride at doses up to 0.1 mg/kg, a dose that produced plasma lanthanum concentrations >2000 times the peak human plasma concentration. Lanthanum carbonate, at doses up to 2000 mg/kg/day (3.4 times the MRHD), did not affect fertility or mating performance of male or female rats. 13.3 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. Lanthanum carbonate administered to rats from implantation 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. 14 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, active-controlled, open-label studies in both hemodialysis and peritoneal dialysis (PD) patients. 14.1 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)
[See USP controlled room temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labelling (Medication Guide). Advise patients to take FOSRENOL with or immediately after meals [see Dosage and Administration (2)] . Instruct patients on concomitant medications that should be dosed apart from FOSRENOL [see Drug Interactions (7)] Instruct patients who are prescribed FOSRENOL Chewable Tablets to chew or crush tablets completely before swallowing. Emphasize that FOSRENOL Chewable Tablets should not be swallowed intact. Consider crushing FOSRENOL Chewable Tablets completely or prescribing the oral powder formulation for patients with poor dentition or who have difficulty chewing tablets [see Dosage and Administration (2)]. Instruct patients who are prescribed FOSRENOL Oral Powder to sprinkle powder on a small quantity of applesauce or other similar food. Patients should be instructed to consume the entire dose immediately. FOSRENOL Oral Powder is insoluble so no attempt should be made to dissolve the powder in liquid for administration [see Dosage and Administration (2)] . Advise patients who are taking an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy to separate the dosing of FOSRENOL from the dosing of the affected drug by several hours [see Drug Interactions (7)]. Advise patients to notify their physician that they are taking FOSRENOL prior to an abdominal X-ray or if they have a history of gastrointestinal disease [see Warnings and Precautions (5.1, 5.2)].
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