LORON 520 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Loron 520

520 mg, film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 film-coated tablet contains 649.7 mg clodronate disodium tetrahydrate, equivalent to 520 mg clodronate disodium.

Excipients with known effect: lactose monohydrate; sodium (3.6 mmol per film-coated tablet)

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet for oral administration.

Oblong, white, film-coated tablets, imprinted with “E9” on one side and with a break line on both sides.

The film-coated tablets can be divided into equal doses.

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

Clodronate is mainly eliminated via the kidneys. Therefore, adequate fluid intake must be maintained during clodronate treatment.

After taking Loron the patient should not lay down, but remain in an upright position to prevent upper abdominal pain.

Posology

Adults

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

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 30 ml/min, the daily dose should be reduced to one half of the recommended adult dose. Serum creatinine should be monitored during therapy. Clodronate disodium is contra-indicated in patients with creatinine clearance below 10 ml/min.

Method of administration

The film-coated tablets may be taken as a single dose or in two equally divided doses if necessary to improve gastrointestinal tolerance.

The single daily dose and the first dose of two should preferably be taken in the morning on an empty stomach together with a glass of water. The patient should then refrain from eating, drinking (other than plain water), and taking any other oral drugs for one hour.

When twice daily dosing is used, the first dose should be taken as recommended above. The second dose should be taken between meals, more than two hours after and one hour before eating, drinking (other than plain water), or taking any other oral drugs.

Clodronate should in no case be taken with milk, food or drugs containing calcium or other divalent cations because they impair the absorption of clodronate.

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.

4.3 Contraindications

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

Acute, severe inflammatory conditions of the gastrointesti­nal tract.

Pregnancy and lactation.

Renal failure with creatinine clearance below 10 ml/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.

Adequate fluid intake should be maintained during treatment.

Patients with renal insufficiency

Loron tablets should be administered with care to patients with renal insufficiency (see dose adjustment under “Dosage and method of administration”). Adequate fluid intake must be maintained during clodronate treatment. This is particularly important when administering clodronate to patients with hypercalcaemia or renal insufficiency. Renal function with serum creatinine, serum calcium and phosphate levels should be monitored before and during treatment.

In clinical trials, asymptomatic, reversible elevations of transaminases have occurred, without changes in other liver function tests. Monitoring of serum transaminases is advised (see also section 4.8).

Osteonecrosis of the jaw

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 both intravenous and oral 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.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Irritation of the upper gastrointestinal mucosa

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.

Excipients

Owing to the presence of lactose monohydrate, patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains 83.4 mg sodium per film-coated tablet, equivalent to 4 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction No other bisphosphonate drugs should be given with Loron film-coated 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.

Clodronate has been reported to be associated with renal dysfunction when used simultaneously with non-steroidal anti-inflammatory analgesics (NSAIDs), most often diclofenac.

Clodronate forms poorly soluble complexes with divalent metal ions. Therefore, clodronate should not be taken with calcium rich foods, mineral supplements and antacids as these may impair absorption.

An increase in the serum concentration of estramustine phosphate by up to 80% has been reported with concomitant use of estramustine phosphate and clodronate.

4.6 Fertility, pregnancy and lactation

Fertility

In animal studies, clodronate did not cause foetal damage, but large doses decreased male fertility. No clinical data on the effect of clodronate on fertility in humans are available.

Pregnancy

Although in animals clodronate passes through the placental barrier, it is not known if it passes into the foetus in humans. Furthermore, it is not known if clodronate can cause foetal damage or affect reproduction in humans. There are only limited amount of data from the use of clodronate in pregnant women. Clodronate is not recommended during pregnancy and in women of childbearing potential not using effective contraception.

Lactation

It is unknown whether clodronate is excreted in human milk. A risk to the suckling child cannot be excluded.

Breast-feeding should be discontinued during treatment with clodronate.

4.7 Effects on ability to drive and use machines

Clodronate disodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The most common reported drug reaction is diarrhoea which is usually mild and occurs more commonly with higher doses.

* In patients with metastatic disease, may also be due to hepatic and bone disease.

$ Usually mild

# Some severe and with complications

Post-marketing experience

Eye disorders

Uveitis has been reported with clodronate during post-marketing experience. The following reactions have been reported with other bisphosphonates: conjunctivitis, episcleritis and scleritis. Conjunctivitis was only reported with clodronate in one patient concomitantly treated with another bisphosphonate. So far, episcleritis and scleritis have not been reported with clodronate (bisphosphonate class adverse reaction).

Respiratory, thoracic and mediastinal disorders

Impairment of respiratory function in patients with aspirin-sensitive asthma. Hypersensitivity reactions manifesting as respiratory disorder.

Renal and urinary disorders

Impairment of renal function (elevation of serum creatinine and proteinuria), severe renal damage especially after rapid intravenous infusion of high doses.

Single cases of renal failure, in rare cases with fatal outcome have been reported especially with concomitant use of NSAIDs, most often diclofenac.

Musculoskeletal and connective tissue disorders

Isolated cases of osteonecrosis of the jaw have been reported, primarily in patients who were previously treated with amino-bisphosphonates like zoledronate and pamidronate (see also section 4.4). Severe bone, joint, and/or muscle pain has been reported in patients taking clodronate. However, such reports have been infrequent and in randomised placebo controlled studies no differences are apparent between placebo and verum treated patients. The onset of symptoms varied from days to several months after starting treatment with clodronate.

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

Symptoms

The development of hypocalcaemia is possible for up to 2 or 3 days following the overdosage. Acute overdosage may be associated with gastrointestinal symptoms such as nausea and vomiting.

Increases in serum creatinine and renal dysfunction have been reported with high intravenous doses of clodronate. One case of total kidney failure and liver damage has been reported after accidental ingestion of 20,000 mg (50×400 mg) of clodronate.

Treatment

Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and renal, hepatic function and serum calcium should be monitored.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Bisphosphonates, ATC code: M05BA02.

Bisphosphonates are structural analogues of inorganic pyrophosphate but resistant to enzymatic and chemical breakdown. Bisphosphonates share a high binding affinity to calcium and therefore are selectively adsorbed to mineral surfaces of bone. During the natural remodelling process of bone they are incorporated by bone-resorbing osteoclasts and finally cause a reduction of bone break down. Two groups of bisphosphonates exist based on their chemistry and their distinct molecular modes of action, non-amino-bisphosphonates and amino-bisphosphonates.

Clodronate disodium is a non-amino-bisphosphonate. It replaces a functional phosphate group leading to non-hydrolysable analogues of adenosine triphosphate (ATP) inside the osteoclasts. This process reduces the energy supply for the osteoclast which leads to a reduced activity. This may also initiate apoptosis of osteoclasts. Amino-bisphosphonates in contrast act via selective inhibition of certain enzymes for post-translational protein modification. This causes the apoptosis of osteoclastic cells.

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 Coating

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.