WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Overview
Lanthanum carbonate is a phosphate binder that is FDA approved for the treatment of reduce serum phosphate in patients with end stage renal disease (ESRD). Common adverse reactions include Abdominal pain, Nausea and Vomiting..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
FOSRENOL is a phosphate binder indicated to reduce serum phosphate in patients with end stage renal disease (ESRD).
Management of elevated serum phosphorus levels in end stage renal disease patients 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.
Dosage
Divide the daily dose of FOSRENOL and take with or immediately after food. The recommended initial total daily dose of FOSRENOL is 1500 mg. Titrate the dose every 2-3 weeks until an acceptable serum phosphate level is reached. Monitor serum phosphate levels as needed during dose titration and on a regular basis thereafter.
In clinical studies of ESRD patients, FOSRENOL doses up to 4500 mg were evaluated. Most patients required a total daily dose between 1500 mg and 3000 mg to reduce plasma phosphate levels to less than 6.0 mg/dL. Doses were generally titrated in increments of 750 mg/day.
Chew tablets completely before swallowing. To aid in chewing, tablets may be crushed. Do not swallow intact tablets.
Consider potential drug interactions when prescribing FOSRENOL
DOSAGE FORMS AND STRENGTHS
Chewable Tablets: 500 mg, 750 mg, and 1000 mg.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lanthanum carbonate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lanthanum carbonate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lanthanum carbonate in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lanthanum carbonate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lanthanum carbonate in pediatric patients.
Contraindications
Bowel obstruction, ileus, and fecal impaction.
Warnings
Gastrointestinal Adverse Effects
There have been reports of serious cases of gastrointestinal obstruction, ileus, and fecal impaction reported in association with lanthanum, some requiring surgery or hospitalization.
Risk factors for gastrointestinal obstruction identified from post-marketing reports include alteration in gastrointestinal anatomy (e.g., history of gastrointestinal surgery, colon cancer), hypomotility disorders (e.g., constipation, ileus, diabetes) and concomitant medications (e.g., calcium channel blockers). Some cases were reported in patients with no history of gastrointestinal disease.
Advise patients to chew the tablet thoroughly to reduce the risk of adverse gastrointestinal events.
Patients with acute peptic ulcer, ulcerative colitis, Crohn's disease or bowel obstruction were not included in FOSRENOL clinical studies [SEE CONTRAINDICATIONS (4)].
5.2 Diagnostic Tests
FOSRENOL has radio-opaque properties and therefore may give the appearance typical of an imaging agent during abdominal X-ray procedures.
Adverse Reactions
Clinical Trials Experience
Overall, the safety profile of FOSRENOL has been studied in over 5200 subjects in completed clinical trials. The most common adverse reactions for FOSRENOL were gastrointestinal events, such as nausea and vomiting and they generally abated over time with continued dosing.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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.
In double-blind, placebo-controlled studies where a total of 180 and 95 ESRD patients were randomized to FOSRENOL and placebo, respectively, for 4-6 weeks of treatment, the most common reactions that were more frequent (>5% difference) in the FOSRENOL group were nausea, vomiting, and abdominal pain (Table 1).
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.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of FOSRENOL: constipation, dyspepsia, allergic skin reactions, hypophosphatemia, and tooth injury.
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 drugs. When administering an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug at least one hour before or three hours after FOSRENOL. Monitor blood levels of the concomitant drugs 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. aluminium-, 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 PHARMACOKINETICS (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
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/m2 basis, assuming a 60 kg patient) was associated with increased post-implantation loss, reduced fetal weights, and delayed fetal ossification
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lanthanum carbonate in women who are pregnant.
Labor and Delivery
No lanthanum carbonate treatment-related effects on labor and delivery were seen in animal studies. The effects of lanthanum carbonate on labor and delivery in humans is unknown.
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.
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.
Geriatic 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.
Gender
There is no FDA guidance on the use of Lanthanum carbonate with respect to specific gender populations.
Race
There is no FDA guidance on the use of Lanthanum carbonate with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Lanthanum carbonate in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Lanthanum carbonate in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lanthanum carbonate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Lanthanum carbonate in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
Titrate the dose every 2-3 weeks until an acceptable serum phosphate level is reached. Monitor serum phosphate levels as needed during dose titration and on a regular basis thereafter.
Do not take thyroid hormone replacement therapy within 2 hours of dosing with FOSRENOL. Monitoring of TSH levels is recommended in patients receiving both medicinal agents.
Monitor blood levels of the concomitant drugs that have a narrow therapeutic range.
IV Compatibility
There is limited information regarding IV Compatibility of Lanthanum carbonate in the drug label.
Overdosage
The symptoms associated with overdose are adverse reactions such as headache, nausea and vomiting. In clinical trials, daily doses up to 6000 mg/day of lanthanum carbonate were well tolerated in healthy adults when administered with food, with the exception of GI symptoms. 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/m2 basis).
Pharmacology
There is limited information regarding Lanthanum carbonate Pharmacology in the drug label.
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.
Structure
FOSRENOL contains lanthanum carbonate (2:3) hydrate with molecular formula La2(CO3)3 xH2O (on average x=4-5 moles of water) and molecular weight 457.8 (anhydrous mass). Lanthanum (La) is a naturally occurring rare earth element. Lanthanum carbonate is practically insoluble in water.
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: dextrates (hydrated) NF, colloidal silicon dioxide NF, magnesium stearate NF.
In vitro studies have shown that lanthanum effectively 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 efficiently, FOSRENOL must be administered with or immediately after food.
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.
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 Cmax 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.
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. Quantifiable amounts of lanthanum were not measured in the dialysate of treated ESRD patients.
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.
Nonclinical Toxicology
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/m2 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.
13.2 Animal Toxicology and/or Pharmacology
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.
Clinical Studies
There is limited information regarding Clinical Studies of Lanthanum carbonate in the drug label.
How Supplied
Storage
There is limited information regarding Lanthanum carbonate Storage in the drug label.
Images
Drug Images
{{#ask: Page Name::Lanthanum carbonate
|?Pill Name
|?Drug Name
|?Pill Ingred
|?Pill Imprint
|?Pill Dosage
|?Pill Color
|?Pill Shape
|?Pill Size (mm)
|?Pill Scoring
|?NDC
|?Drug Author
|format=template
|template=DrugPageImages
|mainlabel=-
|sort=Pill Name
}}