LANTHANUM CARBONATE

Lanthanum carbonate chewable tablet contains lanthanum carbonate dihydrate with molecular formula La 2 (CO 3 ) 3 .2H 2 O and molecular weight 457.8 (anhydrous mass). Lanthanum carbonate is described as white to off-white powder. Lanthanum carbonate is soluble in dilute hydrochloric acid and practically insoluble in water. Each lanthanum carbonate chewable tablets, white to off-white, chewable tablet contains lanthanum carbonate dihydrate equivalent to 500, 750 or 1,000 mg of elemental lanthanum and the following inactive ingredients: colloidal silicon dioxide, dextrates, hydroxy propyl cellulose, magnesium stearate and talc. lanthanum-carbonate-structure

Lanthanum carbonate chewable tablet 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 chewable tablet is a phosphate binder indicated to reduce serum phosphate in patients with end-stage renal disease (ESRD). ( 1 )

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 carbonate chewable tablets have 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 chewable tablets 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 powder formulation in patients with poor dentition or who have difficulty chewing tablets ( 2 )

Contraindicated in patients with: hypersensitivity to lanthanum carbonate 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 )

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 (≥ 5% difference vs. placebo) in lanthanum carbonate chewable tablets were nausea, vomiting, and abdominal pain. ( 6.1 ) The following adverse reactions have been identified during post-approval use of lanthanum carbonate chewable tablets: constipation, dyspepsia, allergic skin reactions, and tooth injury while chewing the tablet. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 chewable tablets have been studied in over 5,200 subjects in completed clinical trials. The most common adverse reactions for lanthanum carbonate chewable tablets 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 tablets and placebo, respectively, for 4 to 6 weeks of treatment, the most common reactions that were more frequent (≥5% difference) in the lanthanum carbonate chewable tablets group were nausea, vomiting, and abdominal pain (Table 1). Table 1: Adverse Reactions* That Were More Common on Lanthanum Carbonate Chewable Tablets in Placebo-Controlled, Double-Blind Studies with Treatment Periods of 4 to 6 Weeks * Expressed as the event rate for each term Lanthanum Carbonate Chewable Tablets % (N=180) Placebo % (N=95) Nausea 11 5 Vomiting 9 4 Abdominal pain 5 0 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 chewable tablets was studied in two long-term, open-label clinical trials, which included 1,215 patients treated with lanthanum carbonate chewable tablets and 944 with alternative therapy. Fourteen percent (14%) of patients treated with lanthanum carbonate chewable tablets 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 chewable tablets to lanthanum 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 chewable tablets. 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.

There is a potential for lanthanum carbonate chewable tablets 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 chewable tablets. ( 7.1 ) Oral quinolone antibiotics must be taken at least 1 hour before or 4 hours after lanthanum carbonate chewable tablets. ( 7.2 ) Do not take thyroid hormone replacement therapy within 2 hours of dosing with lanthanum carbonate chewable tablets. 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 chewable tablets 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 chewable tablets. 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 chewable tablets 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 chewable tablets in a single-dose study in healthy volunteers. Administer oral quinolone antibiotics at least 1 hour before or 4 hours after lanthanum carbonate chewable tablets. When oral quinolones are given for short courses, consider eliminating the doses of lanthanum carbonate chewable tablets 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 chewable tablets. Administer thyroid hormone replacement therapy at least 2 hours before or 2 hours after dosing with lanthanum carbonate chewable tablets 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 chewable tablets 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.