1. Name Of The Medicinal Product
Loron 520 mg Film-coated Tablets.
2. Qualitative And Quantitative Composition
Each tablet contains 520 mg clodronate disodium (as the tetrahydrate).
Excipients:
Each tablet contains:
• 4.875 mg lactose monohydrate
• 3.6 mmol (83.4 mg) sodium, as clodronate disodium, sodium starch glycolate and sodium citrate.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablets for oral administration.
4. Clinical Particulars
4.1 Therapeutic Indications
Loron is indicated for the management of osteolytic lesions, hypercalcaemia and bone pain associated with skeletal metastases in patients with carcinoma of the breast or multiple myeloma. Loron is also indicated for the maintenance of clinically acceptable serum calcium levels in patients with hypercalcaemia of malignancy initially treated with an intravenous infusion of clodronate disodium.
4.2 Posology And Method Of Administration
Adults
The recommended dose is 2 tablets (1040 mg clodronate disodium) daily. If necessary, the dosage may be increased but should not exceed a maximum of 4 tablets (2080 mg clodronate disodium) daily.
The tablets may be taken as a single dose or in two equally divided doses if necessary to improve gastrointestinal tolerance. Loron tablets should be swallowed with a little fluid, but not milk, at least one hour before or one hour after food.
The oral bioavailability of bisphosphonates is poor. Bioequivalence studies have shown appreciable differences in bioavailability between different oral formulations of clodronate disodium, as well as marked inter and intra patient variability. Dose adjustment may be required if the formulation is changed.
Elderly
No special dosage recommendations.
Children
Safety and efficacy in children has not been established.
Use in renal impairment
In patients with renal insufficiency with creatinine clearance between 10 and 30ml/min, the daily dose should be reduced to one half the recommended adult dose. Serum creatinine should be monitored during therapy. Clodronate disodium is contra-indicated in patients with creatinine clearance below 10ml/min.
4.3 Contraindications
Hypersensitivity to clodronate disodium or to any of the excipients. Acute, severe inflammatory conditions of the gastrointestinal tract. Pregnancy and lactation. Renal failure with creatinine clearance below 10ml/min, except for short term use in the presence of purely functional renal insufficiency caused by elevated serum calcium levels. Concomitant use of other bisphosphonates.
4.4 Special Warnings And Precautions For Use
No information is available on the potential carcinogenicity of clodronate disodium, but patients have been treated in clinical trials for up to 2 years. The duration of the treatment is therefore at the discretion of the physician, according to the status of the underlying malignancy.
It is recommended that appropriate monitoring of renal function with serum creatinine be carried out during treatment. Serum calcium and phosphate should be monitored periodically. Monitoring of liver enzymes and white cells is advised (see side effects).
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Orally administered, mainly nitrogen-containing, bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when clodronate disodium is given to patients with active upper gastrointestinal problems (e.g. known Barrett's oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).
Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalisation, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention and be able to comply with the dosing.
Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue clodronate disodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.
Owing to the presence of lactose monohydrate, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No other bisphosphonate drugs should be given with Loron tablets.
The calcium-lowering action of clodronate disodium can be potentiated by the administration of aminoglycosides either concomitantly or one to several weeks apart. Severe hypocalcaemia has been observed in some cases. Hypomagnesaemia may also occur simultaneously. Patients receiving NSAID's in addition to clodronate disodium have developed renal dysfunction. However, a synergistic action has not been established. There is no evidence from clinical experience that clodronate disodium interacts with other medication, such as steroids, diuretics, calcitonin, non NSAID analgesics, or chemotherapeutic agents. Calcium rich foods, mineral supplements and antacids may impair absorption.
4.6 Pregnancy And Lactation
There are insufficient data either from animal studies or from experience in humans of the effects of clodronate disodium on the embryo and foetus. No studies have been conducted on excretion in breast milk. Consequently, clodronate disodium is contraindicated in pregnancy and lactation.
4.7 Effects On Ability To Drive And Use Machines
Clodronate disodium has no influence on the ability to drive and use machines.
4.8 Undesirable Effects
Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention:
Very common (
Common (
Uncommon (
Rare (
Very rare (<1/10,000)
Immune system disorders:
Rare:
Allergic reaction
Very rare:
Bronchoconstriction
Metabolic and nutritional disorders:
Rare:
Hypocalcaemia
Gastrointestinal disorders:
Common:
Nausea and diarrhoea (especially at beginning of treatment and at higher doses)
Renal and urinary disorders:
Rare:
Deterioration of renal function
Transient proteinuria immediately after intravenous infusion
Very rare:
Acute renal failure has been reported after intravenous injection
Investigations:
Very rare:
Decreased serum phosphate
Increased serum alkaline phosphatase
Increased serum lactate dehydrogenase
Increased serum parathormone
Increased serum transaminases
4.9 Overdose
Symptoms and signs: There is no experience of acute overdosage in humans. The development of hypocalcaemia is possible for up to 2 or 3 days following the overdosage.
Treatment: Serum calcium should be monitored and oral or parenteral calcium supplementation may be required. Acute overdosage may be associated with gastrointestinal symptoms such as nausea and vomiting. Treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Bisphosphonates, ATC code: M05BA02.
Clodronate disodium is a bisphosphonate which has a high affinity to bone. It is mainly the portion of the dose adsorbed to bone which is pharmacologically active. The pharmacological effect of clodronate disodium is to suppress osteoclast mediated bone resorption as judged by bone histology and decreases in serum calcium, urine calcium and urinary excretion of hydroxyproline, without adversely affecting mineralisation.
5.2 Pharmacokinetic Properties
Oral bioavailability is in the order of 2%.
Clodronate disodium is not metabolised. The volume of distribution is approximately 0.3L/kg. Elimination from serum is rapid, 75% of the dose is recovered unchanged in urine within 24 hours.
The elimination kinetics best fit a 3 compartment model. The first two compartments have relatively short half-lives. The third compartment is probably the skeleton. Elimination half life is approximately 12 - 13 hours.
5.3 Preclinical Safety Data
Clodronate disodium shows relatively little toxicity either on single oral administration or after daily oral administration for a period of up to 6 months. In rats, a dose of 200mg/kg/day in the chronic toxicity test is at the limit of tolerability. In dogs, 40mg/kg/day chronically is within the tolerated range.
On daily administration of 500mg/kg for 6 weeks to rats, signs of renal failure with a clear rise in BUN, and initial liver parenchymal reaction with rises of SGOT, SGPT and AP occurred. No significant haematological changes were found in the toxicological investigations.
Investigations for mutagenic properties did not show any indication of mutagenic potency.
Reproduction toxicology investigations did not provide any indication of peri and post natal disorders, teratogenic damage or disorders of fertility.
It is not known if clodronate disodium passes into the mother's milk or through the placenta.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet Core
Talc
Maize starch
Cellulose microcrystalline
Magnesium stearate
Sodium starch glycolate
Film Coat
Hypromellose
Polyacrylate dispersion 30%
Macrogol 10000
Lactose monohydrate
Talc
Titanium dioxide (E171)
Polysorbate 80
Sodium citrate
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
5 years.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
6.5 Nature And Contents Of Container
PVC/aluminium blister packs containing 10 or 60 tablets.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Roche Products Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW, United Kingdom
8. Marketing Authorisation Number(S)
PL 00031/0521
9. Date Of First Authorisation/Renewal Of The Authorisation
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10. Date Of Revision Of The Text
19 October 2011
11 LEGAL CATEGORY
POM
Loron is a registered trade mark
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