SUMMARY OF PRODUCT CHARACTERISTICS

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 tablet for oral administration (tablet).

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

The tablets can be divided into equal halves.

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.

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 at least one hour before or one hour after food. 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.

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 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.

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.

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.

Each Loron tablet contains 3.6 mmol (83.4 mg) of sodium. To be taken into consideration by patients on a controlled sodium diet.

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 Fertility, Pregnancy and lactation

No clinical data on the effect of clodronate on fertility in humans are available. 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. Women of childbearing potential should use effective contraception during treatment.

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 (>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)

Isolated cases of osteonecrosis of the jaw, primarily in patients who were previously treated with amino-bisphosphonates like zoledronate and pamidronate (postmarketing experience).

Very rare:

Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction). 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.

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.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

RIEMSER Pharma GmbH An der Wiek 7

17493 Greifswald - Insel Riems Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 42336/0002

28/10/2004

10 DATE OF REVISION OF THE TEXT

01/12/2015