Fosrenol

Name: Fosrenol

Pharmacology

Mechanism of Action

Lanthanum forms strong complexes with PO4 that inhibits GI absorption and results in a decrease of serum phosphate and calcium levels

Pharmacokinetics

Half-Life, elimination: 53 hr (plasma); 2-3.6 years (bond)

Peak Plasma: 1 ng/mL

Bioavailability: 0.002%

Protein bound: 99%

Metabolism: Not metabolized

Excretion: Predominantly feces

Clinical pharmacology

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.

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, FOSRENOL must be administered with or immediately after meals.

In five Phase I pharmacodynamic studies comparing the reduction frombaseline 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 FOSRENOL Oral Powder was found to be similar to FOSRENOL Chewable Tablets, based on urinary phosphate excretion.

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.

Systemic exposure to lanthanum was approximately 30% higher following administration of FOSRENOL Oral Powder when compared to FOSRENOL 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 ofmagnitude 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 lanthanumremained 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.

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 1000mg 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].

Levothyroxine

In a single-dose crossover study of levothyroxine (1mg) with or without simultaneous administration of a single dose of FOSRENOL (500mg) in six euthyroid normal healthy volunteers, the area under the serum T4 concentration-time curve was decreased by 40% [see DRUG INTERACTIONS].

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].

Citrate

Citrate did not increase the absorption of lanthanum.

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. Lanthanumcarbonate administered to rats fromimplantation 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

The effectiveness of FOSRENOL in reducing serum phosphorus in ESRD patients was demonstrated in one short-term, placebo-controlled, double-blind dose-ranging study, two placebo-controlled randomized withdrawal studies and two long-term, activecontrolled, open-label studies in both hemodialysis and peritoneal dialysis (PD) patients.

Double-Blind Placebo-Controlled Studies

One hundred and forty-four patients with chronic renal failure undergoing hemodialysis and with elevated phosphate levels were randomized to double-blind treatment at a fixed dose of lanthanum carbonate of 225 mg (n=27), 675 mg (n=29), 1350 mg (n=30) or 2250 mg (n=26) or placebo (n=32) in divided doses with meals. Fifty-five percent of subjects were male, 71% black, 25% white and 4% of other races. The mean age was 56 years and the duration of dialysis ranged from 0.5 to 15.3 years. Steady-state effects were achieved after two weeks. The effect after six weeks of treatment is shown in Figure 1.

Figure 1: Difference in Phosphate Reduction in the FOSRENOL and Placebo Group in a 6-Week, Dose-Ranging, Double-Blind Study in ESRD Patients (with 95% Confidence Intervals)

One-hundred and eighty-five patients with end stage renal disease undergoing either hemodialysis (n=146) or peritoneal dialysis (n=39) were enrolled in two placebo-controlled, randomized withdrawal studies. Sixty-four percent of subjects were male, 28% black, 62% white and 10% of other races. The mean age was 58.4 years and the duration of dialysis ranged from 0.2 to 21.4 years. After titration of lanthanum carbonate to achieve a phosphate level between 4.0 and 5.6 mg/dL in one study (doses up to 2250 mg/day) or ≤ 5.9 mg/dL in the second study (doses up to 3000 mg/day) and maintenance through 6 weeks, patients were randomized to lanthanum or placebo. During the placebo-controlled, randomized withdrawal phase (four weeks), the phosphorus concentration rose in the placebo group by 1.7 mg/Dl in one study and 1.9 mg/dL in the other study relative to patients who remained on lanthanum carbonate therapy.

Open-Label Active-Controlled Studies

Two long-term open-label studies were conducted, involving a total of 2028 patients with ESRD undergoing hemodialysis. Patients were randomized to receive FOSRENOL or alternative phosphate binders for up to sixmonths in one study and two years in the other. The daily FOSRENOL doses, divided and taken with meals, ranged from 375 mg to 3000mg. Doses were titrated to reduce serumphosphate levels to a target level. The daily doses of the alternative therapy were based on current prescribing information or those commonly utilized. Both treatment groups had similar reductions in serum phosphate of about 1.8mg/dL. Maintenance of reduction was observed for up to three years in patients treated with FOSRENOL in long-term, open-label extensions.

No effects of FOSRENOL on serum levels of 25-dihydroxy vitamin D3, vitamin A, vitamin B12, vitamin E and vitamin K were observed in patients who were monitored for 6 months.

Paired bone biopsies (at baseline and at one or two years) in 69 patients randomized to either FOSRENOL or calcium carbonate in one study and 99 patients randomized to either FOSRENOL or alternative therapy in a second study showed no differences in the development of mineralization defects between the groups.

Vital status was known for over 2000 patients, 97% of those participating in the clinical program during and after receiving treatment. The adjusted yearly mortality rate (rate/years of observation) for patients treated with FOSRENOL or alternative therapy was 6.6%.

Fosrenol Usage

  • Take Fosrenol exactly as prescribed by your healthcare provider.
  • Your healthcare provider will tell you how much Fosrenol to take.
  • Your healthcare provider may change your dose if needed.
  • Do not swallow tablets whole. Chew tablets completely before swallowing. If you cannot chew tablets completely, or if you have tooth disease, you may crush the tablets thoroughly before swallowing.
  • Take Fosrenol with or right after meals.
  • If you take an antacid medicine, take the antacid 2 hours before or 2 hours after you take Fosrenol.
  • If you take medicine for your thyroid (levothyroxine), take the thyroid medicine 2 hours before or 2 hours after you take Fosrenol.
  • If you take an antibiotic medicine, take the antibiotic 1 hour before or 4 hours after you take Fosrenol.

What should i avoid while taking lanthanum carbonate (fosrenol)?

If you also take thyroid replacement medication, take it at least 2 hours before or after taking lanthanum carbonate. Do not take thyroid medication and lanthanum carbonate at the same time.

Avoid taking an antacid within 2 hours before or after you take lanthanum carbonate. Some antacids contain calcium, magnesium or aluminum which can make it harder for your body to absorb lanthanum carbonate.

What is lanthanum carbonate?

Lanthanum prevents the body from absorbing phosphate, allowing it to be removed from the body.

Lanthanum carbonate is used to lower phosphate levels in patients with end stage kidney disease. High levels of phosphate can make it hard for your body to absorb calcium, which can cause serious medical problems.

Lanthanum carbonate may also be used for purposes not listed in this medication guide.

How should I take lanthanum carbonate?

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Take lanthanum carbonate with food or immediately after eating.

The chewable tablet should be chewed completely before you swallow it. Do not swallow whole. Tell your doctor if you have trouble chewing the tablet.

Sprinkle the oral powder into a small amount of applesauce or other soft food (oral powder will not dissolve in liquid). Swallow right away without chewing. Do not save the mixture for later use.

While using lanthanum carbonate, you may need frequent blood tests.

Store at room temperature away from moisture and heat.

Stability

Storage

Oral

Chewable Tablets

25°C (may be exposed to 15–30°C).1 Protect from moisture.1

Uses For Fosrenol

Lanthanum is used to treat hyperphosphatemia (too much phosphate in the blood) in patients with end stage kidney disease who are on dialysis.

This medicine is available only with your doctor's prescription.

Proper Use of Fosrenol

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

It is best to take this medicine with or immediately right after meals.

Chew or crush the tablet completely before swallowing. Do not swallow the tablet whole.

Sprinkle the oral powder on a small quantity of applesauce or other similar food. Mix and take it immediately. Do not mix it with water or other liquid.

Follow carefully any diet program your doctor may recommend.

If you are taking any other medicines, take them at least 1 hour before or 2 hours after you take lanthanum. If you need help deciding the best times to take your other medicines, ask your doctor or pharmacist.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage forms (chewable tablets or powder):
    • For high phosphorus levels in the blood:
      • Adults—At first, the dose is usually 1500 milligrams (mg) per day, divided in small doses. Your dose will be determined and adjusted by your doctor depending on how high your blood phosphorus level is.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Warnings and Precautions

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.

Risk factors for gastrointestinal obstruction and gastrointestinal perforation identified from post-marketing reports in patients taking Fosrenol Chewable Tablets include altered 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 concomitant medications (e.g., calcium channel blockers). 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 to reduce the risk of serious adverse gastrointestinal events such as those described above.

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

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Gastrointestinal Adverse Effects [see Warnings and Precautions (5.1)]

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, vomiting, and abdominal pain and they generally abated over time with continued dosing.

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 chewable tablet 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).

Table 1. Adverse Reactions * That Were More Common on Fosrenol in Placebo-Controlled, Double-Blind Studies With Treatment Periods of 4-6 Weeks
Fosrenol
%
(N=180)
Placebo
%
(N=95)
* expressed as the event rate for each term
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-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.

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%).

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: constipation, intestinal perforation, intestinal obstruction, ileus, subileus, dyspepsia, allergic skin reactions, hypophosphatemia, and tooth injury while chewing the tablet.

PRINCIPAL DISPLAY PANEL - 750 mg Tablet Bottle Label

NDC 54092-253-15

Fosrenol ®
(lanthanum carbonate)
chewable tablets

750 mg

Do not swallow tablets whole.
Chew or crush tablets completely
before swallowing.
Take with or immediately after meals.

ATTENTION PHARMACIST: Each patient is required
to receive the enclosed Medication Guide.

15 TABLETS
Rx only
Shire

PRINCIPAL DISPLAY PANEL - 1000 mg Packet Carton - 10 Stick Pack

NDC 54092-257-01

Fosrenol ®
(lanthanum carbonate)
oral powder

1000 mg

Mix with small quantity of soft food
and take immediately

Shire

10 stick packs

Rx only

Before taking this medicine

You should not use Fosrenol if you are allergic to lanthanum carbonate, or if you have:

  • a bowel obstruction or severe constipation.

To make sure Fosrenol is safe for you, tell your doctor if you have:

  • a stomach ulcer;

  • any type of bowel obstruction;

  • slow digestion or severe constipation;

  • a history of surgery on your stomach or intestines;

  • ulcerative colitis, Crohn's disease, diverticulitis;

  • a history of stomach or intestinal cancer;

  • diabetes; or

  • problems with your teeth.

If you need to have any type of x-ray or CT scan of your stomach area, tell the doctor ahead of time that you are using Fosrenol.

It is not known whether Fosrenol will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether lanthanum carbonate passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

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