Fosrenol (Tablets) Instructions for Use

Marketing Authorization Holder

Shire Pharmaceuticals Ireland Limited (Ireland)

Manufactured By

Hamol, Limited (United Kingdom)

ATC Code

V03AE03 (Lanthanum carbonate)

Active Substance

Lanthanum carbonate

Dosage Forms

	Fosrenol	Chewable tablets 500 mg: 90 pcs.
		Chewable tablets 750 mg: 90 pcs.
		Chewable tablets 1000 mg: 90 pcs.

Dosage Form, Packaging, and Composition

Chewable tablets white or almost white, round, flat, with beveled edges and an engraving “S405” above “500”.

Excipients: dextrates (hydrated), colloidal silicon dioxide, magnesium stearate.

45 pcs. – high-density polyethylene bottles (2) – cardboard packs.

Chewable tablets white or almost white, round, flat, with beveled edges and an engraving “S405” above “750”.

Excipients: dextrates (hydrated), colloidal silicon dioxide, magnesium stearate.

15 pcs. – high-density polyethylene bottles (6) – cardboard packs.

Chewable tablets white or almost white, round, flat, with beveled edges and an engraving “S405” above “1000”.

Excipients: dextrates (hydrated), colloidal silicon dioxide, magnesium stearate.

15 pcs. – high-density polyethylene bottles (6) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of hyperphosphatemia

Pharmacotherapeutic Group

Hyperphosphatemia treatment agent

Pharmacological Action

A drug for the treatment of hyperphosphatemia.

The activity of lanthanum carbonate as a phosphate-binding substance is determined by the high affinity of lanthanum ions, which are released from the bond with the carbonate anion in the acidic environment of the stomach, for food phosphates. Insoluble lanthanum phosphate is formed, which reduces the absorption of phosphate from the gastrointestinal tract.

Pharmacokinetics

Since the binding of lanthanum to dietary phosphate occurs in the lumen of the stomach and upper small intestine, the therapeutic effect of Fosrenol does not depend on the concentration of lanthanum in the blood plasma.

Lanthanum is present in the environment. In phase III clinical studies, the background concentration of the active substance in patients with chronic renal failure not receiving lanthanum carbonate ranged from <0.05 to 0.9 ng/ml in plasma and from < 0.006 to 1 µg/kg in bone biopsy samples.

Absorption

Lanthanum carbonate is poorly soluble in water (< 0.01 mg/ml at pH 7.5) and is minimally absorbed after oral administration. The absolute bioavailability in humans after oral administration is <0.002%.

After oral administration in healthy individuals, the AUC and C_max of lanthanum in plasma increase more slowly than in direct proportion to the dose in the range of 250-1000 mg of lanthanum, which corresponds to solubility-limited absorption.

Distribution

The small fraction of lanthanum that is absorbed after oral administration is almost completely (> 99.7%) bound to plasma proteins.

In animal studies, after absorption, lanthanum was widely distributed throughout the body tissues, mainly in bones, liver, gastrointestinal tract, and mesenteric lymph nodes. In long-term animal studies, the concentration of lanthanum in some tissues, including the gastrointestinal tract, bones, and liver, was found to increase over time to a value several orders of magnitude higher than the concentration of the substance in plasma. In some tissues, such as liver cells, the C_ss of lanthanum was gradually reached, and in the gastrointestinal tract, the concentration of the substance increased throughout the entire period of drug use. After drug withdrawal, the concentration of lanthanum in different tissues changed differently, with a relatively high proportion of accumulated lanthanum in the tissues remaining for more than 6 months after withdrawal (median proportion of remaining lanthanum in bones: < 100% (rats), < 87% (dogs); in liver: <6% (rats), <82% (dogs)).

With repeated oral administration of lanthanum carbonate, lanthanum does not accumulate in the plasma of humans and animals. In long-term animal studies, the accumulation of lanthanum in tissues with oral administration of lanthanum carbonate in high doses was not accompanied by any adverse effects.

Metabolism

Lanthanum is not metabolized.

Excretion

T_1/2 in healthy individuals is 36 hours.

In healthy individuals, lanthanum is excreted mainly in the feces, and only about 0.000031% of the orally administered dose is excreted in the urine (renal clearance is about 1 ml/min, which corresponds to < 2% of the total plasma clearance).

After intravenous administration to animals, lanthanum was excreted mainly in the feces (74% of the dose) – both with bile and by direct penetration through the intestinal wall. Renal excretion was insignificant.

Pharmacokinetics in special clinical cases

No clinical studies of the drug in patients with renal failure and impaired liver function have been conducted. In patients who had concomitant liver diseases at the time of inclusion in phase III clinical studies, there were no signs of increased lanthanum concentration in plasma or worsening of liver function impairment when using Fosrenol for up to 2 years.

The effect of impaired liver function on the pharmacokinetics of Fosrenol has not been studied.

In patients on hemodialysis receiving 1000 mg of lanthanum 3 times/day for 10 days, the mean plasma concentration of the substance was 1.06 (±1.04) ng/ml, and the mean AUC_0-∞ was 31.1 (± 40.5) ng × h/ml. Regular monitoring of lanthanum blood concentration in 1707 patients on hemodialysis receiving lanthanum carbonate for up to 2 years did not reveal an increase in plasma concentration of the substance during this period.

Indications

• Hyperphosphatemia in patients with chronic renal failure receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD);
• Patients with chronic kidney disease not on hemodialysis, with plasma phosphate concentration >1.78 mmol/L, when a low-phosphate diet is insufficient to control plasma phosphate concentration.

ICD codes

Dosage Regimen

The drug is prescribed orally to adults, including elderly patients (> 65 years).

The tablets should be chewed, not swallowed whole. The chewable tablet dosage form avoids the need for additional fluid intake. Patients should follow the recommended diet to control phosphate concentration and water balance.

Experience with the drug for more than 2 years is limited. The risk/benefit ratio should be carefully assessed when using the drug for more than 2 years.

Fosrenol should be taken during or immediately after meals. The daily dose should be divided between meals. Serum phosphate concentration should be monitored, and the dose of Fosrenol should be increased every 2-3 weeks until an acceptable phosphate concentration is achieved, after which phosphate concentration should continue to be regularly monitored.

There is evidence that control of blood phosphate concentration is achieved with an initial dose of 750 mg/day. In clinical studies, the maximum dose of the drug (in a limited number of patients) was 3750 mg. In patients sensitive to lanthanum use, an acceptable serum phosphate concentration is usually achieved at a lanthanum dose of 1500-3000 mg/day.

Due to the peculiarities of the mechanism of action and the absence of hepatic metabolism, in impaired liver function, dose adjustment of the drug is not required, but patients should be carefully monitored.

Adverse Reactions

Adverse reactions associated with the use of the drug (as assessed by the investigator) were recorded in approximately 24% of study participants with end-stage chronic renal failure. The frequency of no adverse reaction exceeded 10%. Most often hypocalcemia and disorders of the digestive system were observed (they were minimized when Fosrenol was taken with meals and decreased with continued treatment).

A transient change in the QT interval was observed, but it was not accompanied by an increase in the frequency of cardiac adverse reactions.

Contraindications

• Hypophosphatemia;
• Childhood and adolescence under 18 years;
• Hypersensitivity to the components of the drug.

With caution the drug should be used in conditions associated with severe impairment of bile outflow; with gastric ulcer in the acute phase, ulcerative colitis, Crohn’s disease, intestinal obstruction.

Use in Pregnancy and Lactation

Data on the use of Fosrenol in pregnant women are insufficient. The possible risk to humans is unknown. Fosrenol is not recommended for use during pregnancy.

It is not known whether lanthanum is excreted in breast milk. The decision to continue breastfeeding or continue treatment with the drug should be made based on the risk/benefit ratio for the mother and child.

In one experimental study, fetal toxicity (delayed eye opening and puberty) and reduced offspring body weight were found in rats at high doses of the drug. In animal studies, the excretion of lanthanum in breast milk was not studied.

Use in Hepatic Impairment

Due to the peculiarities of the mechanism of action and the absence of hepatic metabolism, in impaired liver function, dose adjustment of the drug is not required, but patients should be carefully monitored.

Pediatric Use

Contraindicated in childhood and adolescence under 18 years.

Special Precautions

When using Fosrenol in animals, accumulation of lanthanum in tissues was shown. In the analysis of 105 bone biopsy samples from patients receiving Fosrenol (some for up to 4.5 years), an increase in lanthanum concentration was observed over time. There are no clinical data on the accumulation of lanthanum in other human tissues. Currently, data on the safety of using the drug for more than 24 months are limited.

Clinical studies of Fosrenol did not include patients with acute gastric ulcer, ulcerative colitis, Crohn’s disease, or intestinal obstruction. In such patients, Fosrenol should be used only after a careful assessment of the risk/benefit ratio.

In patients with renal failure, hypocalcemia may develop. Fosrenol does not contain calcium. Therefore, in this category of patients, serum calcium concentration should be regularly monitored, and calcium supplements should be prescribed if necessary.

Lanthanum is not metabolized by liver enzymes but is most likely excreted in bile. Conditions associated with severe impairment of bile outflow may be accompanied by a slowdown in the excretion of lanthanum, which may lead to an increase in its plasma concentration and increased deposition of lanthanum in tissues. Since the liver is the main organ for the excretion of absorbed lanthanum, monitoring of liver function is recommended.

If hypophosphatemia develops, Fosrenol should be discontinued.

In patients taking Lanthanum carbonate, during abdominal X-ray, radiation absorption typical of contrast agents may be observed.

Effect on ability to drive vehicles and mechanisms

Fosrenol can cause dizziness and vertigo, and as a result, the ability to drive vehicles and moving mechanisms may be impaired. If such symptoms occur, patients are advised to refrain from driving a car and other potentially hazardous activities.

Overdose

No cases of overdose have been described. The highest daily dose of lanthanum for healthy volunteers was 4718 mg for 3 days. Symptoms were mild or moderate and included nausea and headache.

Drug Interactions

Lanthanum carbonate can increase the pH of gastric juice. It is not recommended to take drugs that interact with antacids (for example, chloroquine, hydroxychloroquine, ketoconazole) within 2 hours before and after taking Fosrenol.

In healthy individuals, simultaneous intake of citrate does not affect the absorption and pharmacokinetics of lanthanum.

In clinical studies, the use of Fosrenol did not affect the serum content of fat-soluble vitamins A, D, E, and K.

In studies involving healthy volunteers, taking Fosrenol together with digoxin, warfarin, or metoprolol did not lead to a clinically significant change in the pharmacokinetics of these drugs.

In a solution simulating gastric juice, lanthanum carbonate did not form insoluble complexes with warfarin, digoxin, furosemide, phenytoin, metoprolol, or enalapril, suggesting a weak ability to affect the absorption of these substances.

However, interaction with tetracycline, doxycycline, and fluoroquinolone derivatives is theoretically possible, and if these drugs need to be used simultaneously, it is recommended to take them 2 hours before or 2 hours after taking Fosrenol.

Lanthanum carbonate is not a substrate of cytochrome P450 and does not significantly inhibit in vitro the activity of the main isoenzymes of the human cytochrome P450 system, including CYP1A2, CYP2D6, CYP3A4, CYP2C9, and CYP2C19.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.