Didronel 200mg Tablets

D

1. Name Of The Medicinal Product

Didronel 200mg Tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 200mg of Etidronate Disodium, USP.

3. Pharmaceutical Form

White rectangular tablets marked with 'P&G' on one face and '402' on the other.

4. Clinical Particulars 4.1 Therapeutic Indications

Paget's disease of bone:

Effectiveness has been demonstrated primarily in patients with polyostotic Paget's disease with symptoms of pain and with clinically significant elevations of urinary hydroxyproline and serum alkaline phosphatase. In other circumstances in which there is extensive involvement of the skull or the spine with the prospect of irreversible neurological damage, or when a weight-bearing bone may be involved, the use of Didronel may also be considered.

4.2 Posology And Method Of Administration

5mg/kg/day to 20mg/kg/day as detailed below.

Didronel should be given on an empty stomach. It is recommended that patients take the therapy with water, at the mid point of a four hour fast (ie. two hours before and two after food).

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of risedronate on an individual patient basis, particularly after 5 or more years of use.

Adults and Elderly:

The recommended initial dose of Didronel for most patients is 5mg/kg body weight/day, for a period not exceeding six months. Doses above 10mg/kg should be reserved for use when there is an overriding requirement for suppression of increased bone turnover associated with Paget's disease or when the patient requires more prompt reduction of elevated cardiac output. Treatment with doses above 10mg/kg/day should be approached cautiously and should not exceed three months duration. Doses in excess of 20mg/kg/day are not recommended.

Re-treatment should be undertaken only after a drug-free period of at least three months and after it is evident that reactivation of the disease has occurred and biochemical indices of the disease have become substantially re-elevated or approach pretreatment values (approximately twice the upper limit of normal or 75% of pre-treatment value). In no case should duration of treatment exceed the maximum duration of the initial treatment. Premature re-treatment should be avoided. In clinical trials the biochemical improvements obtained during drug therapy have generally persisted for a period of three months to 2 years after drug withdrawal.

Daily Dosage Guide

Body Weight

Required Daily Regimen of 200mg Tablets

     

Kilogrames

Stones

5mg/kg*

10mg/kg*

20mg/kg+

50

8

1

3

5

60

9.5

2

3

6

70

11

2

4

7

80

12.5

2

4

8

90

14

2

5

9

*Course of therapy - 6 months

+Course of therapy - 3 months

Children:

Disorders of bone in children, referred to as juvenile Paget's disease, have been reported rarely. The relationship to adult Paget's disease has not been established. Didronel has not been studied in children for Paget's disease.

4.3 Contraindications

Known hypersensitivity to etidronate disodium or any of the other ingredients in the product (see Section 6.1 List of Excipients). Clinically overt osteomalacia.

4.4 Special Warnings And Precautions For Use

In Pagetic patients the physician should adhere to the recommended dose regimen in order to avoid over- treatment with Didronel. The response to therapy may be of slow onset and may continue even for months after treatment with the drug has been discontinued. Dosage should not be increased prematurely nor should treatment be resumed before there is clear evidence of reactivation of the disease process. Re-treatment should not be initiated until the patient has had at least a three-month drug-free interval.

Etidronate disodium is not metabolized and is excreted intact via the kidney. Due to the lack of clinical experience the treatment of patients with impaired renal function should be undertaken with due caution. The use of etidronate disodium is discouraged in patients with severely impaired kidney function.

Caution should be taken in patients with a history of renal stone formation. In patients with impaired renal function or a history of renal stone formation, serum and urinary calcium should be monitored regularly.

It is recommended that serum phosphate, serum alkaline phosphatase and urinary hydroxyproline be measured before commencing medication and at three month intervals during treatment. If after three months of medication the pre-treatment levels have not been reduced by at least 25%, the patient may be relatively resistant to therapy. If the serum phosphate level is unchanged in the "resistant" patient, consideration should be given to increasing the dose since the absorption of pharmacologically active amounts of Didronel is typically accompanied by a rise in serum phosphate. This rise usually correlates with reductions in the biochemical indices of disease activity. If after three or more months of medication elevations of serum phosphate above the upper limit of normal are not accompanied by clinical or biochemical evidence of reduced activity, resistance of the disease to the action of Didronel is probable and termination of Didronel medication should be considered. Etidronate disodium suppresses bone turnover and may retard mineralisation of osteoid laid down during the bone accretion process. These effects are dose and time dependent. Osteoid, which may accumulate noticeably at doses of 10-20 mg/kg/day, mineralises normally post-therapy. Patients in whom serum phosphate elevations are high and reductions of disease activity are low may be particularly prone to retarded mineralisation of new osteoid. In those cases where 200mg per day (a single tablet) may be excessive, doses may be administered less frequently.

Patients with Paget's disease of bone should maintain an adequate intake of calcium and vitamin D. Patients with low vitamin D and calcium intake may be particularly sensitive to drugs that affect calcium homeostasis and should be closely monitored during Didronel therapy.

Etidronate disodium does not adversely affect serum levels of parathyroid hormone or calcium.

Hyperphosphataemia has been observed in patients receiving etidronate disodium, usually in association with doses of 10-20mg/kg/day. No adverse effects have been traced to this, and it does not constitute grounds for discontinuing therapy. It is apparently due to a drug-related increase in renal tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2-4 weeks post therapy.

Patients with significant chronic diarrhoeal disease may experience increased frequency of bowel movements and diarrhoea, particularly at higher doses.

Increased or recurrent bone pain at existing Pagetic sites and/or the appearance of pain at sites previously asymptomatic have been reported at a dose of 5mg/kg/day.At higher doses, the incidence rises to approximately 20%. When therapy continues, pain resolves in some patients but persists in others.

Fractures are recognised as a common feature in patients with Paget's disease. There has been no evidence of increased risk of fractures at the recommended dose of 5mg/kg/day for six months. At doses of 20mg/kg/day in excess of three months' duration, mineralisation of newly formed osteoid may be impaired and the risk of fracture may be increased. The risk of fracture may also be greater in patients with extensive and severe disease, a history of multiple fractures, and/or rapidly advancing osteolytic lesions. It is therefore recommended that the drug is discontinued when fractures occur and therapy not reinstated until the fracture healing is complete.

Patients with predominantly lytic lesions should be monitored radiographically and biochemically to permit termination of etidronate disodium in those patients unresponsive to treatment.The incidence of osteogenic sarcoma is known to be increased in Paget's disease. Pagetic lesions, with or without therapy, may appear by X-ray to progress markedly, possibly with some loss of definition of periosteal margins. Such lesions should be evaluated carefully to differentiate these from osteogenic sarcoma.

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 bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patient with concominant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avod 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 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.

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

Food in the stomach or upper portions of the small intestine, particularly materials with a high calcium content such as milk, may reduce absorption of etidronate disodium. Vitamins with mineral supplements such as iron, calcium supplements, laxatives containing magnesium, or antacids containing calcium or aluminium should not be taken within two hours of dosing etidronate disodium.

The diagnostic utility of bone-imaging agents may be impaired by current or recent etidronate use.

There have been isolated reports of patients experiencing changes in their prothrombin times when etidronate was added to warfarin therapy. The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae. Although the relevance of these reports and any mechanism of coagulation alterations is unclear, patients on warfarin should have their prothrombin time monitored.

4.6 Pregnancy And Lactation

The safety of this medicinal product for use in human pregnancy has not been established. Reproductive studies have shown skeletal abnormalities in rats. It is therefore recommended that Didronel should not be used in women of childbearing potential unless adequate contraceptive measures are taken.

It is not known whether this drug passes into breast milk. It should therefore not be used during lactation period.

4.7 Effects On Ability To Drive And Use Machines

Etidronate disodium does not interfere with the ability to drive or use machines.

4.8 Undesirable Effects

Gastro-intestinal

The most common effects reported are diarrhoea and nausea. Reports of exacerbation of peptic ulcer with complications in a few patients.

Dermatological/hypersensitivity

Hypersensitivity reactions, including angio-oedema/urticaria, rash and/or pruritus, have been reported rarely.

Nervous System

Paresthesia, peripheral neuropathy , confusion, have been reported rarely.

Haematological

In patients receiving etidronate disodium, there have been rare reports of leucopenia, agranulocytosis and pancytopenia.

Musculoskeletal and connective tissue disorders

osteonecrosis of the jaw (see section 4.4 special warnings and precautions of use)

Other

Less common effects believed to be related to therapy include arthropathies (arthralgia and arthritis), and rarely burning of the tongue, alopecia, erythema multiforme and exacerbation of asthma.

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

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

4.9 Overdose

Overdose would manifest as the signs and symptoms of hypocalcaemia. Treatment should involve cessation of therapy and correction of hypocalcaemia with administration of Ca2+ intravenously.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Etidronate acts primarily on bone. It can inhibit the formation, growth and dissolution of hydroxyapatite crystals and amorphous precursors by chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required for the inhibition of crystal growth. Both effects increase as dose increases.

5.2 Pharmacokinetic Properties

Etidronate is not metabolised. Absorption averages about 1% of an oral dose of 5mg/kg body weight/day. This increases to about 1.5% at 10mg/kg/day and 6% at 20mg/kg/day. Most of the drug is cleared from the blood within 6 hours. Within 24 hours about half of the absorbed dose is excreted in the urine. The remainder is chemically absorbed to bone, especially to areas of elevated osteogenesis, and is slowly eliminated. Unabsorbed drug is excreted in the faeces.

5.3 Preclinical Safety Data

In long term studies in mice and rats, there was no evidence of carcinogenicity with etidronate disodium. All in vitro and in vivo assays conducted to assess the mutagenic potential of etidronate disodium have been negative.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Starch, magnesium stearate and microcrystalline cellulose.

6.2 Incompatibilities

See section 4.5 Interactions with other medicaments and other forms of interaction.

6.3 Shelf Life

Four years.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Supplied in high density polypropylene bottles or blister packs of 60 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Warner Chilcott UK Limited

Old Belfast Road,

Millbrook,

Larne,

County Antrim,

BT40 2SH

8. Marketing Authorisation Number(S)

PL 10947/0018

9. Date Of First Authorisation/Renewal Of The Authorisation

26th November 1987

10. Date Of Revision Of The Text

September 2011

Didronel 200mg Tablets

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