Didronel PMO

1. Name Of The Medicinal Product

Didronel PMO

2. Qualitative And Quantitative Composition

A two component therapy consisting of 14 Didronel 400mg tablets and 76 Cacit 500mg effervescent tablets (equivalent to 500mg elemental calcium).

Each Didronel tablet contains 400mg of etidronate disodium, USP. Each Cacit 500mg effervescent tablet contains 1250mg of calcium carbonate, Ph.Eur., which when dispersed in water provides 500mg of elemental calcium as calcium citrate.

3. Pharmaceutical Form

Each Didronel 400mg tablet is white, capsule-shaped and marked with "NE" on one face and '406' on the other. The Cacit 500mg effervescent tablet is round, flat, white with pink speckles and has a distinctive orange flavour.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of osteoporosis and prevention of bone loss in postmenopausal women considered at risk of developing osteoporosis. Didronel PMO is particularly indicated in patients who are unable or unwilling to take oestrogen replacement therapy.

Didronel PMO is also indicated for the prevention and treatment of corticosteroid induced osteoporosis.

4.2 Posology And Method Of Administration

Didronel PMO therapy is a long-term cyclical regimen administered in 90-day cycles. Each cycle consists of Didronel 400mg tablets for the first 14 days, followed by Cacit 500mg tablets for the remaining 76 days.

The majority of patients have been treated for 3 years, with a small number of patients treated for up to 7 years, with no clinical safety concerns. The optimum duration of treatment has not been established.

*Didronel 400mg component:

One tablet should be taken each day for 14 consecutive days on an empty stomach. It is recommended that patients take the tablet with water at the midpoint of a four hour fast (i.e. two hours before and two hours after food).

*Cacit 500mg component:

Following 14 days treatment with Didronel 400mg tablets, one Cacit tablet should be taken on a daily basis. The Cacit tablet should be dissolved in water and drunk immediately after complete dissolution.

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.

Adult and elderly:

The patient should adhere to the prescribed regimen above. Modification of the dosage for the elderly is not required.

Children:

No data exists on the use of this therapy in juvenile osteoporosis.

4.3 Contraindications

Known hypersensitivity to any of the ingredients. Treatment of patients with severe renal impairment. Patients with hypercalcaemia or hypercalciuria.

Clinically overt osteomalacia. Use in pregnancy and lactation.

4.4 Special Warnings And Precautions For Use

Clinicians should advise patients to adhere to the recommended treatment regimen, and compliance pack.

In long-term trials no clinical osteomalacia was observed in patients receiving cyclical etidronate. Following long-term therapy in excess of 4 years, analysis of bone biopsies showed an increased prevalence of peritrabecular fibrosis and histologically defined atypical and focal osteomalacia (not to be confused with the syndrome associated with "clinical osteomalacia" due to vitamin D deficiency). In addition, these laboratory findings were not associated with any clinical consequences. Osteoid, which may accumulate at high doses of continuous etidronate therapy (10-20mg/kg/day) mineralises normally after discontinuation of therapy. Continuous administration of etidronate should be avoided.

Patients with significant chronic diarrhoeal disease may experience increased frequency of bowel movements and diarrhoea. Therapy should be withheld from patients with enterocolitis because of increased frequency of bowel movements.

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.

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

Etidronate disodium does not adversely effect 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 re absorption of phosphate. Serum phosphate levels generally return to normal 2-4 weeks post therapy.

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 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 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.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

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.

In patients with Paget's disease the excretion of hydroxyproline and serum levels for alkaline phosphatase should be regularly monitored.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Food in the stomach or upper gastrointestinal tract, 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.

A small number of patients in clinical trials (involving more than 600 patients) received either thiazide diuretics or intravaginal oestrogen while on this treatment. The concomitant use of either of these agents did not interfere with the positive effects of the therapy on vertebral bone mass or fracture rates.

Calcium salts may reduce the absorption of some drugs, e.g. tetracyclines. It is therefore suggested that administration of Cacit tablets be separated from these products by at least three hours.

Vitamin D causes an increase in calcium absorption and plasma calcium levels may continue to rise after stopping vitamin D therapy. Concomitant administration of Cacit tablets and vitamin D should therefore be carried out with caution.

The effects of digoxin and other cardiac glycosides may be accentuated by calcium and toxicity may be produced, especially in combination with vitamin D therapy.

There have been isolated reports of patients experiencing changes in their prothrombin times when etidronate was added to warfarin therapy. The majority ot 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

There are no adequate data from the use of Didronel in pregnant women.

Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Didronel should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

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

In clinical studies of 2-3 years duration, the incidence of these events were comparable to placebo. The most common effects reported in order of incidence were diarrhoea, nausea, flatulence, dyspepsia, abdominal pain, gastritis, constipation and vomiting. Reports of exacerbation of peptic ulcers with complications in a few patients.

Dermatological/hypersensitivity

Hypersensitivity reactions including angio-oedema, urticaria, rash and/or pruritus have been reported rarely. The colouring agent E110 can cause allergic-type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.

Nervous System

Headache, and rarely paresthesia, peripheral neuropathy and confusion.

Haematological

There have been rare reports of leucopenia, agranulocytosis and pancytopenia.

Other

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

Occasional mild leg cramps have been reported in less than 5% of patients on the Didronel PMO regimen. These cramps were transient, often nocturnal and generally associated with other underlying conditions. osteonecrosis of the jaw (see section 4.4 special warnings and precautions of use) 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

Clinical experience of acute overdosage with etidronate is limited and unlikely with this compliance kit. Theoretically it would be manifested as the signs and symptoms of hypocalcaemia and possibly paresthesia of the fingers.

Treatment would consist of gastric lavage to remove unabsorbed drug along with correction of hypocalcaemia with administration of Ca2+ intravenously.

Prolonged continuous treatment (chronic overdose) has been reported to cause nephrotic syndrome and fractures.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Etidronate in an intermittent cyclical regimen, works indirectly to increase bone mass.

By timing delivery and withdrawal, the etidronate disodium component acts to modulate osteoclasts and reduce the mean resorption depth of the affected basic multicellular units (BMU).

Calcium is an essential element which has been shown to help prevent bone loss.

Epidemiological studies have suggested that there are a number of risk factors associated with postmenopausal osteoporosis, such as early menopause, a family history of osteoporosis, prolonged exposure to corticosteroid therapy, small and thin skeletal frame and excessive cigarette smoking.

5.2 Pharmacokinetic Properties

Within 24 hours, about one half of the absorbed dose of etidronate is excreted in the urine. The remainder is chemically absorbed on bone and is slowly eliminated. Unabsorbed drug is excreted in the faeces. Etidronate disodium is not metabolised. After oral doses of up to 1600mg of the disodium salt, the amount of drug absorbed is approximately 3-4%. In normal subjects, plasma half life (T½) of etidronate, based on non-compartmental pharmacokinetics is 1-6 hours.

Calcium carbonate is converted into soluble calcium salts in the stomach under the influence of hydrochloric acid. 30-80% of orally ingested calcium is absorbed both by active transport (primarily in the upper small intestine) and by passive diffusion. The distribution of calcium in the body is subject to the mechanism of physiological regulation controlled by parathyroid hormone, calcitonin, calciferol and other hormones.

When Calcium effervescent tablets are added to water, insoluble calcium carbonate is converted into calcium citrate.

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

Etidronate disodium tablets contain microcrystalline cellulose, pregelatinised starch and magnesium stearate. Cacit tablets contain citric acid, sodium saccharin, sodium cyclamate, sunset yellow (E110) and orange flavouring.

6.2 Incompatibilities

None.

6.3 Shelf Life

The expiry date for the compliance pack should not exceed 3 years from the date of its manufacture.

6.4 Special Precautions For Storage

Store in a dry place below 30°C. Since Cacit 500mg tablets are hygroscopic, the stopper should be carefully replaced after use.

6.5 Nature And Contents Of Container

14 Didronel 400mg tablets in a blister plus four polypropylene tubes, each containing 19 Cacit 500mg tablets, all packaged in a compliance kit.

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 10947/0019

9. Date Of First Authorisation/Renewal Of The Authorisation

24/02/2009

10. Date Of Revision Of The Text

15/09/2011