Underlined text has been added, text with strike through deleted:

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.

Atypical fractures of the femur – atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis.   These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare.  These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture.   Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture.   Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.   During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

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.

4.8      Undesirable effects

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention:

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)

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)

Musculoskeletal and connective tissue disorders:

Rare:

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction reported during post-marketing experience)

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

10       DATE OF REVISION OF THE TEXT

19 OctoberNovember 2011

Underlined text has been added, text with strike through deleted

1         NAME OF THE MEDICINAL PRODUCT

Loron 520 mg Film-coated Tablets.

2         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Loron 520 tablet contains 520 mg disodium 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.

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 520 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 disodium clodronate disodium.

4.2      Posology and method of administration

Adults

The recommended dose is 2 tablets (1040 mg disodium clodronate disodium) daily.  If necessary, the dosage may be increased but should not exceed a maximum of 4 tablets (2080 mg disodium 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 disodium 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.  Disodium cClodronate disodium is contra-indicated in patients with creatinine clearance below 10ml/min.

4.3      Contraindications

Hypersensitivity to disodium 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

[…]

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 disodium clodronate disodium have developed renal dysfunction.  However, a synergistic action has not been established.  There is no evidence from clinical experience that sodium 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 disodium clodronate disodium on the embryo and foetus.  No studies have been conducted on excretion in breast milk.  Consequently, disodium clodronate disodium is contraindicated in pregnancy and lactation.

4.7      Effects on ability to drive and use machines

No known effects which would impair alertness.Clodronate disodium has no influence on the ability to drive and use machines.

4.8      Undesirable effects

Patients may experience a mild gastrointestinal upset, usually in the form of nausea or mild diarrhoea. The symptoms may respond to the use of a twice daily dosage regime rather than a single dose.  It is not normally required to withdraw therapy or to provide medication to control these effects.  Asymptomatic hypocalcaemia has been noted rarely.  A reversible elevation of serum parathyroid hormone may occur.  In a small proportion of patients, a mild, reversible increase in serum lactate dehydrogenase and a modest transient leucopenia have been reported although these may have been associated with concurrent chemotherapy.  Renal dysfunction, including renal failure has been reported.  Hypersensitivity reactions have been mainly confined to the skin: pruritus, urticaria and rarely exfoliative dermatitis.  However, bronchospasm has been precipitated in patients with or without a previous history of asthma. Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention:

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)

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

5.1      Pharmacodynamic properties

Pharmacotherapeutic group: Bisphosphonates, ATC code: M05BA02.

Disodium cClodronate 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 disodium 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%.

Disodium cClodronate 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

Disodium cClodronate 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 disodium clodronate disodium passes into the mother's milk or through the placenta.

6.1      List of excipients

Loron 520 tablets also contain:

Tablet Core

Disodium clodronate, tTalc,

 mMaize starch,

Cellulose microcrystalline cellulose,

mMagnesium stearate,

sSodium starch glycollate.

Film Coating

MethylhydroxypropylcelluloseHypromellose,

poly(meth) acrylic acid esters (Eudragit NE 30D)Polyacrylate dispersion 30%,

polyoxyethylene alkyl ether (Macrogol 10000),

lLactose monohydrate,

tTalc,

tTitanium dioxide (E171),

pPolysorbate 80,

sSodium citrate.

6.3      Shelf life

PVC/aluminium blister packs:  5 years.

6.4      Special precautions for storage

None.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

No special instructionsrequirements.

9         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:       1 July 1999

Date of last renewal:                11 November 2003

10       DATE OF REVISION OF THE TEXT

16 July 200919 October 2011

4.2       Posology and method of administration

Adults

The recommended dose is 2 tablets (1040mg disodium clodronate) daily.  If necessary, the dosage may be increased but should not exceed a maximum of 4 tablets (2080mg disodium clodronate) 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.

When changing therapy from Loron capsules (400mg) to Loron 520 tablets (520mg), it should be noted that two Loron capsules are equivalent to one Loron 520 tablet.  This is due to greater bioavailability of the tablet formulation.The oral bioavailability of bisphosphonates is poor.  Bioequivalence studies have shown appreciable differences in bioavailability between different oral formulations of disodium clodronate, as well as marked inter and intra patient variability.  Dose adjustment may be required if the formulation is changed.

4.4       Special warnings and precautions for use

The following text has been added:

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.

10.       DATE OF REVISION OF THE TEXT

Updated to: October 2006