CLASTEON^® 400mg capsules

Sodium Clodronate 400mg capsules

Each capsule contains 400mg sodium clodronate (as the tetrahydrate). For excipients, see 6.1.

Hard capsules for oral administration.

The capsules are oblong, white and blue, marked “CLASTEON^®”.

Sodium clodronate 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. Sodium clodronate capsules are also indicated for the maintenance of clinically acceptable serum calcium levels in patients with hypercalcaemia of malignancy initially treated with an intravenous infusion of sodium clodronate

Adequate fluid intake should be maintained during treatment.

Adults; The recommended dose is 4 capsules (1600mg sodium clodronate) daily. If necessary, the dosage may be increased but should not exceed a maximum of 8 capsules (3200mg sodium clodronate) daily.

The capsules may be taken as a single dose or in two equally divided doses if necessary to improve gastrointestinal tolerance. Sodium clodronate capsules should be swallowed with a little fluid, but not milk, at least one hour before or one hour after food.

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. Sodium clodronate is contra-indicated in patients with creatinine clearance below 10ml/min.

The oral bioavailability of bisphosphonates is poor. Bioequivalence studies have shown appreciable differences in bioavailability between different oral formulations of sodium clodronate, as well as marked inter and intra patient variability. Dose adjustment may be required if the formulation is changed.

Hypersensitivity to sodium clodronate 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.

Sodium clodronate should be administered with care to patients with renal insufficiency. It is recommended that appropriate monitoring of hydration status and renal function with serum creatinine measurement be carried out during treatment. Serum calcium should be monitored periodically.

No information is available on the potential carcinogenicity of sodium clodronate, 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.

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 judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

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.

Concomitant use of other bisphosphonates is contraindicated.

As aminoglycosides can cause hypocalcaemia concomitant clodronate should be administered with caution.

Patients receiving NSAID's in addition to sodium clodronate have developed renal dysfunction. However, a synergistic action has not been established.

Concomitant use of estramustine phosphate with clodronate has been reported to increase the serum concentration of estramustine phosphate by 80% at the maximum.

Calcium rich foods, mineral supplements and antacids may impair absorption as sodium clodronate forms complexes with divalent ions.

There are limited amount of data from the use of clodronate in pregnant women. Sodium clodronate is not recommended during pregnancy and in women of childbearing potential not using effective contraception. 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.

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 sodium clodronate.

No effects.

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

These adverse reactions may occur when using sodium clodronate:

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

** usually mild – use of the divided dose regimen rather than a single daily dose may improve gastro-intestinal tolerance.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

During post-marketing experience the following reactions have been reported (frequency rare):

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)

Symptoms:

Increases in serum creatinine and renal dysfunction have been reported with high intravenous doses of clodronate. It is theoretically possible that hypocalcaemia may develop up to 2 or 3 days following the overdose.

Treatment:

Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and renal function and serum calcium should be monitored. Serum calcium should be monitored and oral or parenteral calcium supplementation may be needed.

Sodium clodronate 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 sodium clodronate 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.

Oral bioavailability is in the order of 2%.

Sodium clodronate 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.

Sodium clodronate 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 sodium clodronate passes into the mother's milk or through the placenta.

Capsule content: Maize starch, Talc, Magnesium stearate, Sodium starch glycolate.

Capsule shell: Titanium dioxide (E171), Indigotin (E132), Gelatin.

Not applicable.

PVC/PVDC/aluminium blister packs:3 years.

No special precautions for storage.

PVC/PVDC/aluminium Blister Packs containing 30, 60 or 120 capsules.

No special instructions.

Beacon Pharmaceuticals Limited

85 High Street, Tunbridge Wells, Kent TN1 1YG

PL 18157/0028

15 May 2007 / 13/09/2011

04/11/2011