4.1. Therapeutic indications

Fosrenol is indicated in adult patients as a phosphate binding agent for use in the control of hyperphosphataemia in chronic renal failure patients on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Fosrenol is also indicated in adult patients with chronic kidney disease not on dialysis with serum phosphate levels ≥ 1.78 mmol/L in whom a low phosphate diet alone is insufficient to control serum phosphate levels.

4.2. Posology and method of administration

Fosrenol is for oral administration.

Fosrenol oral powder is intended to be mixed with a small quantity of soft food (e.g. applesauce or other similar food product) and consumed immediately (within 15 minutes). The sachet must not be opened until ready to use. Once mixed with food, Fosrenol oral powder must not be stored for future use. Fosrenol oral powder is insoluble and must not be dissolved in liquid for administration.

Adults, including elderly (> 65 years)

Fosrenol should be taken with or immediately after food, with the daily dose divided between meals. Patients should adhere to recommended diets in order to control phosphate and fluid intake. Fosrenol is presented as an oral powder intended to be mixed with soft food, therefore avoiding the need to take additional fluid. Serum phosphate levels should be monitored and the dose of Fosrenol titrated every 2 to3 weeks until an acceptable serum phosphate level is reached, with regular monitoring thereafter. Dose titration may be performed with the chewable tablet presentation as these are available in a number of strengths allowing for smaller increases in dose.

Control of serum phosphate level has been demonstrated at doses starting from 750 mg per day. The maximum dose studied in clinical trials, in a limited number of patients, is 3750 mg. Patients who respond to lanthanum therapy, usually achieve acceptable serum phosphate levels at doses of 1500-3000 mg lanthanum per day.

Paediatric population

The safety and efficacy of Fosrenol in children and adolescents below the age of 18 years have not been established (see section 4.8 and 5.1). Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

Hepatic impairment

The effect of hepatic impairment on Fosrenol pharmacokinetics has not been assessed. Due to its mechanism of action and the lack of liver metabolism doses in hepatic impairment should not be modified, but patients should be monitored carefully (see sections 4.4 and 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypophosphataemia

Bowel obstruction.

4.4. Special warnings and precautions for use

Tissue deposition of lanthanum has been shown with Fosrenol in animal studies. In 105 bone biopsies from patients treated with Fosrenol, some for up to 4.5 years, rising levels of lanthanum were noted over time (see section 5.1). Cases of lanthanum deposition in gastrointestinal mucosa, mainly after long term use, have been reported. Lanthanum deposition in gastroduodenal mucosa is demonstrated endoscopically as whitish lesions of different sizes and shapes. Also, various pathological features were identified in gastroduodenal mucosa with lanthanum deposition, such as chronic or active inflammation, glandular atrophy, regenerative changes, foveolar hyperplasia, intestinal metaplasia and neoplasia.

The use of Fosrenol in clinical studies beyond 2 years is currently limited. However, treatment of subjects with Fosrenol for up to 6 years has not demonstrated a change in the benefit/risk profile.

There have been cases of gastrointestinal obstruction, ileus, subileus, and gastrointestinal perforation reported in association with lanthanum, some requiring surgery or hospitalisation (see section 4.8).

Lanthanum treatment in patients predisposed to gastrointestinal obstruction, ileus, subileus and perforation; for example, those with altered gastrointestinal anatomy (e.g., diverticular disease, peritonitis, history of gastrointestinal surgery, gastrointestinal cancer and gastrointestinal ulceration), hypomotility disorders (e.g., constipation, diabetic gastroparesis) and in subjects with medications known to potentiate these effects, should only be used after careful consideration. In subjects with ongoing bowel obstruction, lanthanum treatment is contraindicated (see section 4.3).

For all subjects, physicians and patients should remain alert for signs and symptoms of gastrointestinal disorders, especially constipation and abdominal pain/distension which may indicate bowel obstruction, ileus or subileus during treatment with lanthanum carbonate.

Withdrawal of lanthanum carbonate is recommended in patients who develop severe constipation or other severe gastrointestinal signs and symptoms, irrespective of predisposing conditions.

Patients with acute peptic ulcer, ulcerative colitis, Crohn's disease or bowel obstruction were not included in clinical studies with Fosrenol.

Patients with renal insufficiency may develop hypocalcaemia. Fosrenol does not contain calcium. Serum calcium levels should therefore be monitored at regular time intervals for this patient population and appropriate supplements given.

Lanthanum is not metabolised by liver enzymes but it is most likely excreted in the bile. Conditions resulting in a marked reduction of bile flow may be associated with incrementally slower elimination of lanthanum, which may result in higher plasma levels and increased tissue deposition of lanthanum (see sections 5.2 and 5.3). As the liver is the principal organ of elimination of absorbed lanthanum monitoring of liver function tests is recommended.

Fosrenol should be discontinued if hypophosphataemia develops.

Abdominal X-rays of patients taking lanthanum carbonate may have a radio-opaque appearance typical of an imaging agent.

Patients with rare glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Lanthanum carbonate hydrate may increase gastric pH. It is recommended that compounds, which are known to interact with antacids, should not be taken within 2 hours of dosing with Fosrenol (e.g. chloroquine, hydroxychloroquine, and ketoconazole).

In healthy subjects, the absorption and pharmacokinetics of lanthanum were not affected by co-administration of citrate.

Serum levels of fat-soluble vitamins A, D, E and K, were not affected by Fosrenol administration in clinical studies.

Human volunteer studies have shown that co-administration of Fosrenol with digoxin, warfarin or metoprolol does not produce clinically-relevant changes in the pharmacokinetic profiles of these drugs.

In simulated gastric juice, lanthanum carbonate hydrate did not form insoluble complexes with warfarin, digoxin, furosemide, phenytoin, metoprolol or enalapril, suggesting a low potential to affect the absorption of these drugs.

However, interactions with drugs such as tetracycline and doxycycline are theoretically possible and if these compounds are to be co-administered, it is recommended that they are not to be taken within 2 hours of dosing with Fosrenol.

The bioavailability of oral ciprofloxacin was decreased by approximately 50% when taken with Fosrenol in a single dose study in healthy volunteers. It is recommended that oral floxacin formulations are taken at least 2 hours before or 4 hours after Fosrenol.

Phosphate binders (including Fosrenol) have been shown to reduce the absorption of levothyroxine. Consequently, thyroid hormone replacement therapy should not be taken within 2 hours of dosing with Fosrenol and closer monitoring of TSH levels is recommended in patients receiving both medicinal products.

Lanthanum carbonate hydrate is not a substrate for cytochrome P450 and does not significantly inhibit the activities of the major human cytochrome P450 isoenzymes, CYP1A2, CYP2D6, CYP3A4, CYP2C9, or CYP2C19 in vitro.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Fosrenol in pregnant women.

One study in rats showed reproductive foetotoxicity (delayed eye opening and sexual maturation) and reduced pup weights at high doses (see section 5.3). The potential risk for humans is unknown. Fosrenol is not recommended for use during pregnancy.

Breast-feeding

It is unknown whether lanthanum is excreted in human breast milk. The excretion of lanthanum in milk has not been studied in animals. Caution should be used in taking a decision whether to continue/discontinue breastfeeding or to continue/discontinue therapy with Fosrenol, taking into account the potential benefit of breastfeeding to the child and the potential benefit of Fosrenol therapy to the nursing mother.

Fertility

There are no fertility data available on lanthanum carbonate in humans. In rat toxicology studies, lanthanum carbonate had no adverse effects on fertility.

4.7. Effects on ability to drive and use machines

Fosrenol may induce dizziness and vertigo, which may impair the ability to drive and use machines.

4.8. Undesirable effects

The safety of lanthanum carbonate for use in patients has been examined in a number of clinical studies. The most commonly reported adverse drug reactions, with the exception of headache and allergic skin reactions, are gastrointestinal in nature; these are minimised by taking Fosrenol with food and generally abated with time with continued dosing (see section 4.2).

The following convention was used for frequency of adverse drug reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Infections and infestations

Uncommon

Gastroenteritis, laryngitis

Blood and lymphatic system disorders

Uncommon

Eosinophilia

Endocrine disorders

Uncommon

Hyperparathyroidism

Metabolism and nutrition disorders

Common

Hypocalcaemia

Uncommon

Hypercalcaemia, hyperglycaemia, hyperphosphataemia, hypophosphataemia, anorexia, appetite increased

Nervous system disorders

Very common

Headache

Uncommon

Dizziness, taste alteration

Ear and labyrinth disorders

Uncommon

Vertigo

Gastrointestinal disorders*

Very common

Abdominal pain, diarrhoea, nausea, vomiting

Common

Constipation, dyspepsia, flatulence,

Uncommon

Ileus, subileus, intestinal obstruction, irritable bowel syndrome, oesophagitis, stomatitis, loose stools, indigestion, gastrointestinal disorder (not otherwise specified), dry mouth, tooth disorder, eructation

Rare

Intestinal perforation

Skin and subcutaneous tissue disorders

Uncommon

Alopecia, sweating increased

Musculoskeletal and connective tissue disorders

Uncommon

Arthralgia, myalgia, osteoporosis

General disorders and administration site conditions

Uncommon

Asthenia, chest pain, fatigue, malaise, peripheral oedema, pain, thirst.

Investigations

Uncommon

Blood aluminium increased, increase in GGT, increases in hepatic transaminases, alkaline phosphatase increased, weight decrease.

Not known

Product residue present1

1See Lanthanum deposition in gastrointestinal mucosa warning in section 4.4

*In a clinical trial in healthy subjects, the incidence of gastrointestinal adverse events was higher after administration of the oral powder formulation of Fosrenol (13 subjects, 18.3%) than after chewable tablets (4 subjects, 6.6%).

Post-marketing experience

During post-approval use of Fosrenol, cases of allergic skin reactions (including skin rashes, urticaria and pruritus) have been reported which show a close temporal relationship to lanthanum carbonate therapy. In clinical trials, allergic skin reactions were seen in both Fosrenol and placebo/active comparator groups at a frequency of very common (≥1/10).

Although there have been a number of additional isolated reactions reported, none of these reactions are considered unexpected in this patient population.

Transient QT changes have been observed but these were not associated with an increase of cardiac adverse events.

Paediatric population

Frequency, type and severity of adverse reactions in children have not been fully established. In particular, uncertainty exists on the accumulation in bone and risk of growth retardation with treatment in children.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

No case of overdose has been reported. The highest daily dose of lanthanum administered to healthy volunteers during Phase I studies was 4718 mg given for 3 days. The adverse events seen were mild to moderate and included nausea and headache.