Lanthanum Carbonate

1 INDICATIONS AND USAGE Lanthanum carbonate is a phosphate binder indicated to reduce serum phosphate in patients with end-stage renal disease (ESRD). Management of elevated serum phosphorus levels in patients with ESRD usually includes all of the following: reduction in dietary intake of phosphate, removal of phosphate by dialysis, and reduction of intestinal phosphate absorption with phosphate binders. Lanthanum carbonate is a phosphate binder indicated to reduce serum phosphate in patients with end-stage renal disease (ESRD). ( 1 )

2 DOSAGE AND ADMINISTRATION Divide the total daily dose of lanthanum carbonate chewable tablets and take with or immediately after meals. The recommended initial total daily dose of lanthanum carbonate chewable tablets is 1,500 mg. Titrate the dose every 2 to 3 weeks until an acceptable serum phosphate level is reached. Monitor serum phosphate levels as needed during dose titration and on a regular basis thereafter. Lanthanum has the potential to bind other orally administered drugs; consider separating the administration of other oral medications [see Drug Interactions ( 7 )] . In clinical studies of patients with ESRD, lanthanum carbonate chewable tablets doses up to 4,500 mg were evaluated. Most patients required a total daily dose between 1,500 mg and 3,000 mg to reduce plasma phosphate levels to less than 6.0 mg/dL. Doses were generally titrated in increments of 750 mg/day. Information for lanthanum carbonate Chewable Tablets Chew or crush lanthanum carbonate chewable tablets completely before swallowing. Do not swallow intact lanthanum carbonate chewable tablets. Consider using the oral powder formulation in patients with poor dentition or who have difficulty chewing tablets. The recommended initial total daily dose of lanthanum carbonate is 1,500 mg in divided doses. Titrate every 2 to 3 weeks based on serum phosphate level. ( 2 ) Take lanthanum carbonate chewable tablets with or immediately after meals. ( 2 ) Lanthanum carbonate chewable tablets: Chew or crush tablet completely before swallowing. ( 2 ) Consider using the oral powder formulation in patients with poor dentition or who have difficulty chewing tablets. ( 2 )

4 CONTRAINDICATIONS Contraindicated in patients with: - hypersensitivity to lanthanum carbonate chewable tablets or to any ingredient in the formulation. - bowel obstruction, including ileus and fecal impaction. Hypersensitivity to Lanthanum carbonate or to any ingredient in the formulation. ( 4 ) Bowel obstruction, ileus, and fecal impaction.( 4 )

5 WARNINGS AND PRECAUTIONS • Serious cases of gastrointestinal obstruction, ileus, subileus, gastrointestinal perforation, and fecal impaction. Risks include altered gastrointestinal anatomy, hypomotility disorders, and concomitant medications. Advise patients to chew or crush the tablet completely. ( 5.1 ) • Lanthanum carbonate has radio-opaque properties and, therefore, may give the appearance typical of an imaging agent during abdominal X-ray procedures. ( 5.2 ) 5.1 Gastrointestinal Adverse Effects Serious cases of gastrointestinal obstruction, ileus, subileus, gastrointestinal perforation, and fecal impaction have been reported in patients taking lanthanum, some requiring surgery or hospitalization. Consider discontinuing lanthanum carbonate chewable tablets in patients without another explanation for severe gastrointestinal symptoms. Risk factors for gastrointestinal obstruction and gastrointestinal perforation identified from post-marketing reports in patients taking lanthanum carbonate chewable tablets include abnormal gastrointestinal anatomy (e.g., diverticular disease, peritonitis, history of gastrointestinal surgery, gastrointestinal cancer, gastrointestinal ulceration), hypomotility disorders (e.g., constipation, ileus, subileus, diabetic gastroparesis), and the use of medications known to potentiate these effects. Some cases were reported in patients with no history of gastrointestinal disease. Patients with acute peptic ulcer, ulcerative colitis, Crohn’s disease, or bowel obstruction were not included in lanthanum carbonate clinical studies [see Contraindications ( 4 )] . Advise patients who are prescribed lanthanum carbonate chewable tablets to chew the tablet completely and not to swallow them whole. Serious gastrointestinal complications have been reported in association with unchewed or incompletely chewed tablets [see Adverse Reactions ( 6.2 )] . 5.2 Diagnostic Tests Lanthanum carbonate has radio-opaque properties and therefore may give the appearance typical of an imaging agent during abdominal X-ray procedures. Postmarketing reports of product residue have been reported during endoscopic imaging.

7 DRUG INTERACTIONS • There is a potential for lanthanum carbonate to interact with compounds that bind to cationic antacids (i.e., aluminum-, magnesium-, or calcium-based); therefore, do not take such compounds within 2 hours of dosing with lanthanum carbonate. ( 7.1 ) • Oral quinolone antibiotics must be taken at least 1 hour before or 4 hours after lanthanum carbonate. ( 7.2 ) • Do not take thyroid hormone replacement therapy within 2 hours of dosing with lanthanum carbonate. Monitoring of TSH levels is recommended in patients receiving both medicinal agents. ( 7.3 ) • 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. ( 7.4 ) 7.1 Drugs Binding to Antacids There is a potential for lanthanum carbonate 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 lanthanum carbonate. 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 lanthanum carbonate with quinolone antibiotics may reduce the extent of their absorption. The bioavailability of oral ciprofloxacin was decreased by approximately 50% when taken with lanthanum carbonate in a single-dose study in healthy volunteers. Administer oral quinolone antibiotics at least 1 hour before or 4 hours after lanthanum carbonate. When oral quinolones are given for short courses, consider eliminating the doses of lanthanum carbonate that would normally be 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 lanthanum carbonate. Administer thyroid hormone replacement therapy at least 2 hours before or 2 hours after dosing with lanthanum carbonate and monitor thyroid stimulating hormone (TSH) levels [see Clinical Pharmacology ( 12.3 )] . 7.4 Use with Other Oral Medications There are no empirical data on avoiding drug interactions between lanthanum carbonate 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.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Gastrointestinal Adverse Effects [see Warnings and Precautions ( 5.1 )] In controlled trials, the most common adverse reactions that were more frequent (greater than or equal to 5% difference vs. placebo) in lanthanum carbonate were nausea, vomiting, and abdominal pain. ( 6.1 ) The following adverse reactions have been identified during post- approval use of lanthanum carbonate: constipation, dyspepsia, allergic skin reactions, and tooth injury while chewing the tablet. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Overall, the safety profile of lanthanum carbonate has been studied in over 5,200 subjects in completed clinical trials. The most common adverse reactions for lanthanum carbonate were gastrointestinal events, such as nausea, vomiting, and abdominal pain and they generally abated over time with continued dosing. In double-blind, placebo-controlled studies where a total of 180 and 95 patients with ESRD were randomized to lanthanum carbonate chewable tablet and placebo, respectively, for 4 to 6 weeks of treatment, the most common reactions that were more frequent (greater than or equal to 5% difference) in the lanthanum carbonate group were nausea, vomiting, and abdominal pain (Table 1). Table 1. Adverse Reactions* That Were More Common on Lanthanum Carbonate in Placebo-Controlled, Double-Blind Studies with Treatment Periods of 4 to 6 Weeks Lanthanum Carbonate % (N=180) Placebo % (N=95) Nausea 11 5 Vomiting 9 4 Abdominal pain 5 0 * Expressed as the event rate for each term 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 lanthanum carbonate was studied in two long-term, open-label clinical trials, which included 1,215 patients treated with lanthanum carbonate and 944 with alternative therapy. Fourteen percent (14%) of patients treated with lanthanum carbonate 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 lanthanum carbonate chewable tablets to lanthanum carbonate 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 lanthanum carbonate. 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. Cases of constipation, intestinal perforation, intestinal obstruction, ileus, subileus, dyspepsia, allergic skin reactions, hypophosphatemia, and tooth injury while chewing the tablet have been reported.

8.1 Pregnancy Risk Summary Available data from case reports with use of lanthanum carbonate in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of lanthanum carbonate to pregnant rats and rabbits during organogenesis at doses 3 and 2.5 times, respectively, the maximum recommended human dose (MRHD), resulted in no adverse developmental effects. In rabbits, lanthanum carbonate doses 5 times the MRHD was associated with maternal toxicity and resulted in increased post-implantation loss, reduced fetal weights, and delayed fetal ossification (see Data) . Deposition of lanthanum into developing bone, including growth plate, was observed in juvenile animals in long-term animal studies with lanthanum carbonate [see Use in Specific Populations ( 8.4 )] . Use a non-lanthanum containing phosphate binder in a pregnant woman. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In pregnant rats, oral administration of lanthanum carbonate at doses as high as 2,000 mg/kg/day during organogenesis resulted in no evidence of harm to the fetus. The MRHD for lanthanum carbonate is 5,725 mg, representing a dose of 95.4 mg/kg, or 3,530 mg/m 2 for a 60-kg patient. The 2,000-mg/kg/day dose in the rat is equivalent to 12,000 mg/m 2 , 3 times the MRHD. In pregnant rabbits, oral administration of lanthanum carbonate at 1,500 mg/kg/day (18,000 mg/m 2 ; 5 times the daily MRHD) during organogenesis was associated with increased post-implantation loss, reduced fetal weights, and delayed fetal ossification. No effects on the pregnant rabbits or fetuses were observed at 750 mg/kg/day (9,000 mg/m 2 ; 2.5 times the MRHD). In a pre-and postnatal development study in the rat, pregnant rats were dosed at up to 2,000 mg/kg/day (12,000 mg/m 2 /day; equivalent to 3 times the MRHD) from day 6 of pregnancy through 20 days postpartum (including lactation). At 2,000 mg/kg/day, no maternal toxicity was observed, nor were any changes seen with respect to gestational length or delivery; however, piloerection/pallor, delayed eye opening, decreased body weight, and delayed sexual development were observed in the offspring at 2,000 mg/kg/day. At 200 and 600 mg/kg/day (equivalent to 0.3 and 1 time the MRHD, respectively), slight delays in sexual development (delayed vaginal opening) were observed in the female offspring [see Nonclinical Toxicology ( 13.2 )] .