Lanthanum Carbonate (Page 2 of 4)

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.

8 USE IN SPECIFIC POPULATIONS

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/m2 for a 60-kg patient. The 2,000-mg/kg/day dose in the rat is equivalent to 12,000 mg/m2 , 3 times the MRHD. In pregnant rabbits, oral administration of lanthanum carbonate at 1,500 mg/kg/day (18,000 mg/m2 ; 5 times the daily MRHD) during organogenesis was associated with increased postimplantation 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/m2 ; 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/m2 /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)].

8.2 Lactation

Risk Summary

There are no data on the presence of lanthanum carbonate from LANTHANUM CARBONATE in human milk, the effects on the breastfed infant, or the effects on milk production. 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 lactating woman.

8.4 Pediatric Use

The safety and efficacy of LANTHANUM CARBONATE 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 LANTHANUM CARBONATE in this population is not recommended.

8.5 Geriatric Use

Of the total number of patients in clinical studies of LANTHANUM CARBONATE, 32% (538) were ≥65 years of age, while 9.3% (159) were ≥75 years of age. 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, gastrointestinal (GI) symptoms were reported with daily doses up to 6,000 mg/day of lanthanum carbonate administered with food. Given the topical activity of lanthanum in the gut, and the excretion of the majority of the dose in feces, 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 2,000 mg/kg (1.7, 3.4, and 11.3 times the MRHD, respectively, on a mg/m2 basis).

11 DESCRIPTION

LANTHANUM CARBONATE contains lanthanum carbonate with molecular formula La2 (CO3 )3 xH2 O (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 mineral acids with effervescence.

Each LANTHANUM CARBONATE white to off-white, chewable tablet contains lanthanum carbonate hydrate equivalent to 500, 750, or 1,000 mg of elemental lanthanum and the following inactive ingredients: colloidal silicon dioxide, dextrates (hydrated), magnesium stearate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

LANTHANUM CARBONATE is a phosphate binder that reduces absorption of phosphate by forming insoluble lanthanum phosphate complexes that pass through the 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, LANTHANUM CARBONATE must be administered with or immediately after meals.

In five phase 1 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, LANTHANUM CARBONATE Oral Powder and LANTHANUM CARBONATE Chewable Tablets produce similar effects on urinary phosphate excretion.

12.3 Pharmacokinetics

Absorption and Distribution — Following single- or multiple-dose oral administration of LANTHANUM CARBONATE 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 patients with ESRD, the mean lanthanum concentration in plasma was approximately 0.6 ng/mL. There was a 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 LANTHANUM CARBONATE Oral Powder when compared to LANTHANUM CARBONATE 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 LANTHANUM CARBONATE 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 (IV) lanthanum as the soluble chloride salt (120 mcg), renal clearance was less than 2% of total plasma clearance.

Drug Interactions

LANTHANUM CARBONATE 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).

LANTHANUM CARBONATE does not alter gastric pH; therefore, LANTHANUM CARBONATE 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 LANTHANUM CARBONATE (three doses of 1,000 mg on the day prior to exposure and one dose of 1,000 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 three times a day), 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-hour urinary recovery of ciprofloxacin was reduced 52% by LANTHANUM CARBONATE [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 LANTHANUM CARBONATE (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

LANTHANUM CARBONATE 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.

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