Fosrenol (Lanthanum carbonate): Uses, Dosage, Side Effects & Warnings

Uses

1 INDICATIONS AND USAGE 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 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. FOSRENOL is a phosphate binder indicated to reduce serum phosphate in patients with end-stage renal disease (ESRD). ( 1 )

Dosage and administration

Divide the total daily dose of FOSRENOL and take with or immediately after meals. The recommended initial total daily dose of FOSRENOL 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. FOSRENOL 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, FOSRENOL 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. The recommended initial total daily dose of FOSRENOL is 1,500 mg in divided doses. Titrate every 2 to 3 weeks based on serum phosphate level. ( 2 ) Take FOSRENOL with or immediately after meals. ( 2 ) FOSRENOL Chewable Tablets: Chew or crush tablet completely before swallowing. ( 2 ) FOSRENOL Oral Powder: Sprinkle powder on a small quantity of applesauce or other similar food and consume immediately. Consider powder formulation in patients with poor dentition or who have difficulty chewing tablets. ( 2 ) Information for FOSRENOL Chewable Tablets Chew or crush FOSRENOL Chewable Tablets completely before swallowing. Do not swallow intact FOSRENOL Chewable Tablets. Information for FOSRENOL Oral Powder Sprinkle FOSRENOL Oral Powder on a small quantity of applesauce or other similar food and consume immediately. Do not open until ready to use. Do not store FOSRENOL Oral Powder for future use once mixed with food. Because FOSRENOL Oral Powder is insoluble, do not attempt to dissolve in liquid for administration. Consider using the oral powder formulation in patients with poor dentition or who have difficulty chewing tablets.

Dosage forms and strengths

Chewable Tablets: 500 mg, 750 mg, and 1,000 mg. FOSRENOL Oral Powder: 750 mg and 1,000 mg. FOSRENOL Chewable Tablets: 500 mg, 750 mg, and 1,000 mg. ( 3 ) FOSRENOL Oral Powder: 750 mg and 1,000 mg. ( 3 )

Contraindications

Contraindicated in patients with: - hypersensitivity to FOSRENOL or to any ingredient in the formulation. - bowel obstruction, including ileus and fecal impaction. Hypersensitivity to FOSRENOL or to any ingredient in the formulation. ( 4 ) Bowel obstruction, ileus, and fecal impaction. ( 4 )

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 ) FOSRENOL 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 FOSRENOL 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 FOSRENOL 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 FOSRENOL clinical studies [see Contraindications (4) ] . Advise patients who are prescribed FOSRENOL 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 FOSRENOL 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.

Side effects

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 FOSRENOL were nausea, vomiting, and abdominal pain. ( 6.1 ) The following adverse reactions have been identified during post-approval use of FOSRENOL: constipation, dyspepsia, allergic skin reactions, and tooth injury while chewing the tablet. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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 FOSRENOL has been studied in over 5,200 subjects in completed clinical trials. The most common adverse reactions for FOSRENOL 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 FOSRENOL chewable tablet and placebo, respectively, for 4 to 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). Table 1. Adverse Reactions Expressed as the event rate for each term That Were More Common on FOSRENOL in Placebo-Controlled, Double-Blind Studies with Treatment Periods of 4 to 6 Weeks FOSRENOL % (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 FOSRENOL was studied in two long-term, open-label clinical trials, which included 1,215 patients treated with FOSRENOL and 944 with alternative therapy. Fourteen percent (14%) of patients treated with FOSRENOL 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. Cases of constipation, intestinal perforation, intestinal obstruction, ileus, subileus, dyspepsia, allergic skin reactions, hypophosphatemia, and tooth injury while chewing the tablet have been reported.

Drug interactions

There is a potential for FOSRENOL 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 FOSRENOL. ( 7.1 ) Oral quinolone antibiotics must be taken at least 1 hour before or 4 hours after FOSRENOL. ( 7.2 ) 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. ( 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 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 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 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) ] . 7.4 Use with Other Oral Medications 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.

Use in specific populations

8.1 Pregnancy Risk Summary Available data from case reports with use of FOSRENOL 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 FOSRENOL 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) ] . 8.2 Lactation Risk Summary There are no data on the presence of lanthanum carbonate from FOSRENOL 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 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 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.

Pregnancy

8.1 Pregnancy Risk Summary Available data from case reports with use of FOSRENOL 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 FOSRENOL 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) ] .

Pediatric use

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.

Geriatric use

8.5 Geriatric Use Of the total number of patients in clinical studies of FOSRENOL, 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.

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/m 2 basis).

Description

11 DESCRIPTION FOSRENOL contains lanthanum carbonate with molecular formula La 2 (CO 3 ) 3 xH 2 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 FOSRENOL, 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. FOSRENOL Oral Powder is a white to off-white powder containing lanthanum carbonate hydrate equivalent to 750 or 1,000 mg of elemental lanthanum and the following inactive ingredients: colloidal silicon dioxide, dextrates (hydrated), magnesium stearate.

Mechanism of action

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 GI tract unabsorbed. Both serum phosphate and calcium phosphate product are reduced as a consequence of the reduced dietary phosphate absorption.

How supplied

16.1 FOSRENOL Chewable Tablets FOSRENOL is supplied as a chewable tablet in three dosage strengths for oral administration: 500-mg tablets, 750-mg tablets, and 1,000-mg tablets. Each chewable tablet is white to off-white round, flat with a beveled edge, and debossed on one side with 'S405' above the dosage strength corresponding to the content of elemental lanthanum. 500-mg Patient Pack (2 bottles of 45 tablets, NDC 54092-252-45, per each patient pack) NDC 54092-252-90. 750-mg Patient Pack (6 bottles of 15 tablets, NDC 54092-253-15, per each patient pack) NDC 54092-253-90. 1,000-mg Patient Pack (9 bottles of 10 tablets, NDC 54092-254-10, per each patient pack) NDC 54092-254-90. 16.2 FOSRENOL Oral Powder FOSRENOL Oral Powder is supplied in two dosage strengths for oral administration: 750 mg and 1,000 mg. Each 750-mg and 1,000-mg stick pack contains 2.1 g and 2.8 g oral powder, respectively, packed in a polyethylene terephthalate/aluminum/polyethylene laminate. Strength Carton of 10 Stick Packs Patient Pack of 9 Cartons 750 mg NDC 54092-256-01 NDC 54092-256-02 1,000 mg NDC 54092-257-01 NDC 54092-257-02 Storage and Handling Store FOSRENOL Chewable Tablets and FOSRENOL Oral Powder at 25°C (77°F): excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP controlled room temperature.]

Storage

Storage and Handling Store FOSRENOL Chewable Tablets and FOSRENOL Oral Powder at 25°C (77°F): excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP controlled room temperature.]

Patient information

Advise the patient to read the FDA-approved patient labeling (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 do not attempt 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) ] .

Active ingredients

Lanthanum Carbonate in 5 products

Fosrenol NDC products (5)

NDC	Strength & form	Labeler	Type
54092-252	Lanthanum Carbonate 500 mg/1 Tablet, Chewable	Takeda Pharmaceuticals America, Inc.	NDA
54092-253	Lanthanum Carbonate 750 mg/1 Tablet, Chewable	Takeda Pharmaceuticals America, Inc.	NDA
54092-254	Lanthanum Carbonate 1000 mg/1 Tablet, Chewable	Takeda Pharmaceuticals America, Inc.	NDA
54092-256	Lanthanum Carbonate 750 mg/1 Powder	Takeda Pharmaceuticals America, Inc.	NDA
54092-257	Lanthanum Carbonate 1000 mg/1 Powder	Takeda Pharmaceuticals America, Inc.	NDA

Frequently asked questions

What is Fosrenol used for?

1 INDICATIONS AND USAGE 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 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.…

What are the side effects of Fosrenol?

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 FOSRENOL were nausea, vomiting, and abdominal pain. ( 6.1 ) The following adverse reactions have been identified… See the full label for the complete list.

Who makes Fosrenol?

Fosrenol is listed by 1 labeler in the FDA NDC directory, including Takeda Pharmaceuticals America, Inc..