1. Name Of The Medicinal Product
Fosrenol 500 mg chewable tablets
Fosrenol 750 mg chewable tablets
Fosrenol 1000 mg chewable tablets
2. Qualitative And Quantitative Composition
Each chewable tablet contains lanthanum carbonate hydrate corresponding to 500 mg lanthanum.
Each chewable tablet contains lanthanum carbonate hydrate corresponding to 750 mg lanthanum.
Each chewable tablet contains lanthanum carbonate hydrate corresponding to 1000 mg lanthanum.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Chewable tablet.
500 mg: White, round, beveled-edge flat tablets embossed with 'S405/500' on one side.
750 mg: White, round, beveled-edge flat tablets embossed with 'S405/750' on one side.
1000 mg: White, round, beveled-edge flat tablets embossed with 'S405/1000' on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
Fosrenol is indicated 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
4.2 Posology And Method Of Administration
Fosrenol is for oral administration.
Tablets must be chewed and not swallowed whole. To aid with chewing the tablets may be crushed.
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 a chewable tablet therefore avoiding the need to take additional fluid. Serum phosphate levels should be monitored and the dose of Fosrenol titrated every 2-3 weeks until an acceptable serum phosphate level is reached, with regular monitoring thereafter.
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 3750mg. Patients who respond to lanthanum therapy, usually achieve acceptable serum phosphate levels at doses of 1500 – 3000 mg lanthanum per day.
Children and Adolescents
The safety and efficacy of Fosrenol has not been established in patients below the age of 18 years (see section 4.4).
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 lanthanum carbonate hydrate or to any of the excipients.
Hypophosphataemia.
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). No clinical data are available on deposition of lanthanum in other human tissues. 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.
Patients with acute peptic ulcer, ulcerative colitis, Crohn's disease or bowel obstruction were not included in clinical studies with Fosrenol. Fosrenol should be used in these patients following careful assessment of benefit and risk. Fosrenol is known to cause constipation (see section 4.8) and therefore caution should be exercised in patients predisposed to bowel obstruction (e.g. previous abdominal surgery, peritonitis).
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.
Safety and efficacy of Fosrenol have not been established in children and adolescents; use in children and adolescents is not recommended (see section 4.2).
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.
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 Pregnancy And Lactation
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.
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 breast feeding or to continue/discontinue therapy with Fosrenol, taking into account the potential benefit of breast feeding to the child and the potential benefit of Fosrenol therapy to the nursing mother.
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 machinery.
4.8 Undesirable Effects
The safety of Fosrenol for use in patients with end-stage renal failure (ESRF) on maintenance haemodialysis and peritoneal dialysis has been examined in three short-term, placebo-controlled, double-blind studies, three long-term, comparator-controlled studies, and three long-term open-label studies. These studies have provided a total safety database of 1754 patients treated with lanthanum carbonate hydrate with 495 patients with more than 1 year of treatment and 130 patients with more than 2 years of treatment and represents a mean exposure of 272.1 days (median 184.0 days, range 1-1123 days).
Approximately 24% of all ESRF patients who participated in these clinical studies, reported a drug related adverse reaction, as determined by the investigator. No individual ADR was reported at a frequency greater than 10%. The most commonly reported adverse drug reactions, with the exception of hypocalcaemia, are gastrointestinal in nature; these are minimized by taking Fosrenol with food and generally abated with time with continued dosing (see section 4.2).
Organ System
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Common Reactions
(
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Uncommon Reactions
(
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Infections and Infestations
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Gastroenteritis, laryngitis
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Blood and lymphatic system disorders
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Eosinophilia
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Endocrine disorders
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Hyperparathyroidism
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Metabolism and nutrition disorders
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Hypocalcaemia
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Hypercalcaemia, hyperglycaemia, hyperphosphataemia, hypophosphataemia, anorexia, appetite increased
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Nervous system disorders
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Dizziness, headache, taste alteration
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Ear and Labyrinth disorders
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Vertigo
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Gastrointestinal disorders
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Abdominal pain, constipation, diarrhoea, dyspepsia, flatulence, nausea, vomiting
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Eructation, indigestion, irritable bowel syndrome, dry mouth, oesophagitis, stomatitis, loose stools, tooth disorder, gastro-intestinal disorder NOS*
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Skin and subcutaneous tissue disorders
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Alopecia, itching, pruritus, erythematous rash, sweating increased
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Musculoskeletal and connective tissue disorders
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Arthralgia, myalgia, osteoporosis
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General disorders
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Asthenia, chest pain, fatigue, malaise, peripheral oedema, pain, thirst.
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Investigations
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Blood aluminium increased, increase in GGT, increases in hepatic transaminases, alkaline phosphatase increased, weight decrease.
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* Not otherwise specified
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.
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 4718mg given for 3 days. The adverse events seen were mild to moderate and included nausea and headache.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphataemia.
ATC code: V03A E03
Fosrenol contains lanthanum carbonate hydrate. The activity of lanthanum carbonate hydrate as a phosphate binder is dependent on the high affinity of lanthanum ions, which are released from the carbonate salt in the acid environment of the stomach, for dietary phosphate. Insoluble lanthanum phosphate is formed which reduces the absorption of phosphate from the gastro-intestinal tract.
A total of 1130 patients with chronic renal failure treated with maintenance haemodialysis or CAPD were studied in two phase II and two phase III studies. Three studies were placebo controlled (1 fixed dose and 2 titrated dose designs) and one included calcium carbonate as an active comparator. During these studies, 1016 patients received lanthanum carbonate, 267 received calcium carbonate and 176 received placebo.
Two placebo-controlled, randomised studies enrolled patients on dialysis after a washout from previous phosphate binders. After titration of lanthanum carbonate to achieve a serum phosphate level between 1.3 and 1.8mmol/L in one study (doses up to 2250mg/day), or
The active comparator study demonstrated that serum phosphate levels were reduced to target levels of 1.8mmol/l at the end of the 5 week titration period, in 51% of the lanthanum group compared with 57% of the calcium carbonate group. At week 25 the percentage of randomised patients showing controlled serum phosphate levels was similar in the two treatment groups, 29% on lanthanum and 30% on calcium carbonate (using a missing=failure approach). Mean serum phosphate levels were reduced by a similar amount in both treatment groups.
Further long-term extension studies have demonstrated maintenance of phosphate reduction for some patients following continued administration of at least 2 years of lanthanum carbonate.
Hypercalcaemia was reported in 0.4% of patients with Fosrenol compared with 20.2% on calcium-based binders in comparative studies. Serum PTH concentrations may fluctuate depending on a patient's serum calcium, phosphate and vitamin D status. Fosrenol has not been shown to have any direct effects on serum PTH concentrations.
In the long-term bone studies a trend towards increasing bone lanthanum concentrations with time in the control population was observed from the averaged data, the median rising 3-fold from a baseline of 53 μg/kg at 24 months. In patients treated with lanthanum carbonate, the bone lanthanum concentration increased during the first 12 months of lanthanum carbonate treatment up to a median of 1328μg/kg (range 122-5513μg/kg). Median and range concentrations at 18 and 24 months were similar to 12 months. The median at 54 months was 4246μg/kg (range 1673-9792μg/kg).
Paired bone biopsies (at baseline and at one or two years) in patients randomised to either Fosrenol or calcium carbonate in one study and patients randomised to either Fosrenol or alternative therapy in a second study, showed no differences in the development of mineralization defects between the groups.
5.2 Pharmacokinetic Properties
As binding between lanthanum and dietary phosphorus occurs in the lumen of the stomach and upper small intestine, the therapeutic effectiveness of Fosrenol is not dependent on levels of lanthanum in the plasma.
Lanthanum is present in the environment. Measurement of background levels in non-lanthanum carbonate hydrate-treated chronic renal failure patients during Phase III clinical trials revealed concentrations of <0.05 to 0.90 ng/mL in plasma, and <0.006 to 1.0 μg/g in bone biopsy samples.
Absorption
Lanthanum carbonate hydrate has low aqueous solubility (<0.01 mg/mL at pH 7.5) and is minimally absorbed following oral administration. Absolute oral bioavailability is estimated to be <0.002% in humans.
In healthy subjects, plasma AUC and Cmax increased as a function of dose, but in a less than proportional manner, after single oral doses of 250 to 1000 mg lanthanum, consistent with dissolution-limited absorption. The apparent plasma elimination half-life in healthy subjects was 36 hours.
In renal dialysis patients dosed for 10 days with 1000 mg lanthanum 3 times daily, the mean (± sd) peak plasma concentration was 1.06 (± 1.04) ng/mL, and mean AUClast was 31.1 (± 40.5) ng.h/mL. Regular blood level monitoring in 1707 renal dialysis patients taking lanthanum carbonate hydrate for up to 2 years showed no increase in plasma lanthanum concentrations over this time period.
Distribution
Lanthanum does not accumulate in plasma in patients or in animals after repeated oral administration of lanthanum carbonate hydrate. The small fraction of orally administered lanthanum absorbed is extensively bound to plasma proteins (>99.7%) and in animal studies, was widely distributed to systemic tissues, predominantly bone, liver and the gastrointestinal tract, including the mesenteric lymph nodes. In long-term animal studies, lanthanum concentrations in several tissues, including the gastrointestinal tract, bone and liver increased over time to levels several orders of magnitude above those in plasma. An apparent steady-state level of lanthanum was attained in some tissues, e.g. the liver whereas levels in gastrointestinal tract increased with duration of treatment. Changes in tissue lanthanum levels after withdrawal of treatment varied between tissues. A relatively high proportion of lanthanum was retained in tissues for longer than 6 months after cessation of dosing (median % retained in bone
Metabolism
Lanthanum is not metabolised.
Studies in chronic renal failure patients with hepatic impairment have not been conducted. In patients with co-existing hepatic disorders at the time of entry into Phase III clinical studies, there was no evidence of increased plasma exposure to lanthanum or worsening hepatic function after treatment with Fosrenol for periods up to 2 years.
Elimination
Lanthanum is excreted mainly in the faeces with only around 0.000031% of an oral dose excreted via the urine in healthy subjects (renal clearance approximately 1mL/min, representing <2% of total plasma clearance).
After intravenous administration to animals, lanthanum is excreted mainly in the faeces (74% of the dose), both via the bile and direct transfer across the gut wall. Renal excretion was a minor route.
5.3 Preclinical Safety Data
Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated dose toxicity or genotoxicity.
Lanthanum carbonate hydrate reduced gastric acidity in the rat in a safety pharmacology study.
In rats administered high doses of lanthanum carbonate hydrate from day 6 of gestation to day 20 post partum there were no maternal effects, but reduced pup weight and delays in some developmental markers (eye and vaginal opening) were seen. In rabbits given high daily doses of lanthanum carbonate hydrate during gestation, maternal toxicity with reduced maternal food intake and body weight gain, increased pre- and post-implantation losses and decreased pup weight were seen.
Lanthanum carbonate hydrate was not carcinogenic in mice or rats. In mice, an increase in gastric glandular adenomas was seen in the high-dose group (1500 mg/kg/day). The neoplastic response in the mouse is considered to be related to an exacerbation of spontaneous pathological stomach changes and to be of little clinical significance.
Studies in animals have shown deposition of lanthanum in tissues, mainly the gastrointestinal tract, mesenteric lymph nodes, liver and bone (see section 5.2). However, life-time studies in healthy animals do not indicate a hazard for man from the use of Fosrenol. Specific immunotoxicity studies have not been performed.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Dextrates (hydrated)
Colloidal anhydrous silica
Magnesium stearate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
6.5 Nature And Contents Of Container
White cylindrical HDPE bottles containing a rayon coil fitted with a tamper evident, child resistant polypropylene screw cap.
Pack sizes
500 mg: 90 tablets
750 mg: 90 tablets
1000 mg: 90 tablets
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Shire Pharmaceutical Contracts Ltd
Hampshire International Business Park
Chineham
Basingstoke
Hampshire, RG24 8EP
United Kingdom
8. Marketing Authorisation Number(S)
PL 08081/0042
PL 08081/0043
PL 08081/0044
9. Date Of First Authorisation/Renewal Of The Authorisation
12 September 2006 / 19 March 2009
10. Date Of Revision Of The Text
31 May 2011
