SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Bonefos 800 mg tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 1000 mg of disodium clodronate tetrahydrate, equivalent to 800 mg of anhydrous disodium clodronate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Pale white, oval-shaped, film-coated tablets for oral use.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Bonefos tablets are indicated in the management of osteolytic lesions, hypercalcaemia and bone pain associated with skeletal metastases in patients with carcinoma of the breast or multiple myeloma.

Bonefos tablets are also indicated for the maintenance of clinically acceptable serum calcium levels in patients with hypercalcaemia of malignancy initially treated with an intravenous bisphosphonate.

4.2    Posology and method of administration

Posology

Adults

A daily dose of 1600 mg should be taken as a single dose. When higher daily doses are used, the part of the dose exceeding 1600 mg should be taken separately (as a second dose) as recommended below.

Paediatric population

Bonefos has not been evaluated in children.

Elderly

There are no special dosage recommendations in the elderly. Clinical trials have included patients over 65 years and no adverse reactions specific to this age group have been reported.

Renal Impairment

Clodronate is eliminated mainly via the kidneys. Therefore, it should be used with caution in patients with renal failure; daily doses exceeding 1600mg should not be used continuously.

It is recommended that the clodronate dosage be reduced as follows:

Degree of renal failure	Creatinine Clearance, ml/min	Dose
Mild	50-80 ml/min	1600 mg daily (no dose reduction recommended)
Moderate	30- <50 ml/min	1200 mg/daily
Severe	10 - D30 ml/min	800 mg/daily

Method of administration

Adequate fluid intake should be maintained during treatment. A Bonefos 800mg tablet may be divided into two to ease swallowing, but the halves have to be taken at the same time of administration. Bonefos tablets should not be crushed or dissolved before intake.

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 sodium clodronate, as well as marked inter- and intra-patient variability. Dose adjustment may be required if the formulation is changed.

Dose adjustment is not recommended when switching between Bonefos capsule and tablet formulations (please refer to section 5.2 below for additional information).

4.3 Contraindications

Bonefos tablets are contraindicated in patients with severe renal failure where creatinine clearance is below 10ml/min, hypersensitivity to the active substance or to any of the excipients listed in section 6.1 and in patients receiving concomitant treatment with other bisphosphonates.

4.4 Special warnings and precautions for use

Adequate fluid intake should be maintained during treatment.

Patients with renal impairment

Bonefos tablets should be administered with care to patients with renal impairment (see dose adjustment under “Posology 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 impairment.

Renal function with serum creatinine, serum calcium and phosphate levels should be monitored before and during treatment.

Dental conditions and 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 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.

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.

4.5    Interaction with other medicinal products and other forms of interaction

Concomitant use with other bisphosphonates is contraindicated. Patients receiving NSAIDs in addition to sodium clodronate have developed renal dysfunction. However, a synergistic action has not been established. As aminoglycosides can cause hypocalcaemia, concomitant clodronate should be administered with caution.

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

Bonefos forms complexes with divalent metal ions, and therefore simultaneous administration with food, antacids and mineral supplements may impair absorption.

4.6    Fertility, pregnancy and lactation

Pregnancy

There is a limited amount of data from the use of clodronate in pregnant women. Bonefos 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. Studies in animals have shown reproductive toxicity (see section 5.3).

Breast-feeding

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 Bonefos.

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.

4.7    Effects on ability to drive and use machines

None known.

4.8    Undesirable 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 Bonefos:

System Organ Class	Common > 1/100 to < 1/10	Rare > 1/10,000 to < 1/1,000	Very rare < 1/10,000	Frequency unknown
Metabolism and nutrition disorders	Asymptomatic hypocalcemia	Symptomatic hypocalcemia. Increased levels of serum parathyroid hormone associated with decreased serum calcium levels. Increased levels of serum alkaline phosphatase*
Gastrointestinal disorders	Diarrhoea** Nausea** Vomiting**
Hepatobiliary disorders	Levels of transaminases increased - usually within normal range	Levels of transaminases increased to more than twice the normal range without associated abnormal hepatic function
Skin and subcutaneous tissue disorders		Hypersensitivity reaction manifesting as skin reaction e.g. pruritus, urticaria, exfoliative dermatitis
Respiratory, thoracic and mediastinal disorders		Bronchospasm in patients with and without a previous history of		Impairment of respiratory function in

System Organ Class	Common > 1/100 to < 1/10	Rare > 1/10,000 to < 1/1,000	Very rare < 1/10,000	Frequency unknown
		asthma.		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. Single cases of renal failure, in rare cases with fatal outcome, especially with concomitant use of NSAIDs, most often diclofenac.
Musculoskeletal and connective tissue disorders		Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction) (see Section 4.4)	Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction).	Isolated cases of osteonecrosis of the jaw, primarily in patients previously treated with amino- bisphosphonates such as zoledronate and pamidronate (see Section 4.4). Severe bone, joint and/or muscle pain has been reported in patients taking Bonefos. However, such reports have been infrequent and in randomised placebo controlled studies no differences are apparent between placebo and Bonefos treated patients.

System Organ Class	Common > 1/100 to < 1/10	Rare > 1/10,000 to < 1/1,000	Very rare < 1/10,000	Frequency unknown
				The onset of symptoms varied from days to several months after starting Bonefos.
Eye disorders				Uveitis has been reported with Bonefos during post-marketing experience. Although the following reactions have been reported with other biphosphonates; conjunctivitis, episcleritis and scleritis, only conjunctivitis has been reported for Bonefos. This was in one patient concomitantly treated with another bisphosphonate. To date, episcleritis and scleritis (bisphosphonate class adverse reactions ) have not been reported with Bonefos

* 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.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

Increases in serum creatinine and renal dysfunction have been reported with high intravenous doses of clodronate. One case of acute renal failure and liver injury has been reported after accidental ingestion of 20,000 mg (50x400 mg) clodronate. It is theoretically possible that hypocalcaemia may develop up to 2 or 3 days following the overdose.

Management

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

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Bisphosphonates, ATC Code: M05BA

Clodronate is a bisphosphonate, (formerly diphosphonates), a group of analogues of pyrophosphate, which have been shown, in vitro, to inhibit the formation and dissolution of calcium phosphate (hydroxyapatite). In vivo, they have been shown to inhibit bone resorption to a greater or lesser extent, depending on the compound, and clodronate is one of the most effective in this respect.

5.2    Pharmacokinetic properties

Absorption

As with other bisphosphonates, the gastrointestinal absorption of clodronate is low, about 2%. The absorption of clodronate is rapid, the peak serum concentration after a single oral dose is reached within 30 minutes. Due to the strong affinity of clodronate for calcium and other divalent cations, the absorption is negligible when clodronate is taken with meals or drugs containing divalent cations. In a study, where clodronate administration 2 h before breakfast was used as the reference treatment, a dose-breakfast interval of 1 h or 0.5 h decreased the bioavailability of clodronate, but the difference was not statistically significant (relative bioavailability 91% and 69%, respectively). In addition, there is large inter- and intraindividual variation in the gastrointestinal absorption of clodronate. Despite the large intraindividual variation in the absorption of clodronate, the exposure to clodronate remains constant during long-term treatment.

The plasma protein binding of clodronate is low, and the distribution volume is 20-50 1. The elimination of clodronate from serum is characterized by two clearly distinguished phases: the distribution phase with a half-life of about 2 hours, and an elimination phase which is very slow because clodronate is strongly bound to bone. Clodronate is mainly eliminated via the kidneys. About 80% of the absorbed clodronate appears in urine during a follow-up of a few days. The substance which is bound to bone (about 20% of the absorbed amount) is excreted more slowly, and the renal clearance is about 75% of the plasma clearance.

Clodronate is removed by haemodialysis. The dose studied is 300mg given by slow infusion 2 h before haemodialysis. 35% of clodronate dose collected in the 4 h dialysate. No other doses were studied. Furthermore, as stated by the authors: “Bone uptake of clodronate and presumably clinical effectivity decreased with a dose reduction of clodronate”.

Characteristics in patients

Because clodronate affects bone there is no clear relationship between plasma or blood concentrations of clodronate and the therapeutic activity or with adverse drug reactions. Apart from renal insufficiency, which decreases the renal clearance of clodronate, the pharmacokinetic profile is not affected by any known factor related to age, drug metabolism or other pathological conditions.

Data from a bioequivalence study show that, based on serum clodronate concentrations, the relative bioavailability of the tablet formulation is 91% (90% confidence interval 76-107%) of that of the capsule formulation. Urinary excretion of clodronate from one Bonefos 800 mg tablet is 92% (90% confidence interval 80107%) of that of two Bonefos 400 mg capsules.

5.3 Preclinical safety data

Systemic tolerance:

Repeated dose oral and intravenous toxicity studies in rats and mini-pigs up to 6 to 12 months duration respectively have been performed. . At oral daily doses up to 480 mg/kg in rats and 800 mg/kg in mini-pigs no test substance related mortality was noted. In these studies, the effect of clodronate was observed in the following organs (the observed changes within brackets): bone (sclerosis related to the pharmacological effects of clodronate), gastrointestinal tract (irritation), blood (lymphopenia, effects on hemostasis), kidneys (dilated tubules, proteinuria), and liver (elevation of serum transaminases).

Reproduction toxicity:

In reproductive toxicity studies in the rat, clodronate at exposures at or below clinical exposure levels caused maternal mortality around the time of parturition and is believed to be as a result of hypocalcaemia. In teratology studies in rats and rabbits at oral daily dosages of 200 mg/kg and 300mg/kg respectively (0.5 to 2 times the maximum clinical dose based on body surface area, mg/m²), no adverse or teratogenic effects were observed in the offspring. At higher doses associated with maternal

toxicity, there was reduced litter size in the rabbit and a reduction in foetal body weight, reduced ossification and renal pelvis dilation in the rat.

In fertility studies in the rat, clodronate 600 mg/kg/day in males was associated with reduced body weight, lesions in the testes and epididymides and reduced mating performance.

After one month of subcutaneous administration of clodronate to newborn rats, skeletal changes resembling osteopetrosis were found, which are related to the pharmacological effects of clodronate.

Carcin ogen icity:

Clodronate has not shown genotoxic potential. No carcinogenic effects have been observed in long term studies with rats and mice.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Croscarmellose sodium Magnesium stearate Silicified microcrystalline cellulose Stearic acid

Coating:

Opadry II white, containing:

Macrogol (PEG) 3350

Polyvinyl alcohol (partially hydrolysed)

Purified water Talc

Titanium dioxide (E171)

6.2    Incompatibilities

None stated.

6.3    Shelf life

3 years

6.4    Special precautions for storage

Do not store above 25°C.

6.5    Nature and contents of container

Bonefos tablets are supplied in clear, colourless PVC/aluminium blister packs of 10 and 60 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

None stated.

7    MARKETING AUTHORISATION HOLDER

Bayer plc Bayer House Strawberry Hill Newbury

Berkshire RG14 1JA

8    MARKETING AUTHORISATION NUMBER(S)

PL 00010/0522

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01 May 2008

10 DATE OF REVISION OF THE TEXT

16/06/2016