A.Menarini Pharmaceuticals Ltd

Osteofos D3 1200 mg/ 800 I.U. powder for oral suspension

Each sachet contains:

Colecalciferol (Vitamin D3) 20 micrograms (equivalent to 800 I.U.)

Calcium phosphate 3100 mg

(equivalent to 1200 mg or 30 mmol of elemental calcium per sachet)

Excipients: also contains 2mg Sunset yellow FCF (E110) per dose and not more than 8.8 mg sucrose per dose

For a full list of excipients see section 6.1.

Powder for oral suspension.

White or slightly orange, granular powder.

Correction of calcium and Vitamin D deficiency in the elderly.

Osteofos D3 may be used as an adjunct to specific therapy for osteoporosis, in patients with either established vitamin D and calcium combined deficiencies or in those patients at high risk of needing such therapeutic supplements.

Adults and elderly: 1 sachet/day for oral use

Pour the contents of the sachet into a glass of non-carbonated water. Stir with a spoon to obtain a pleasant-tasting suspension. Drink immediately.

It is advisable to take the preparation during the evening meal.

Children: The safe or effective use of Osteofos D3 in children has not been established. Therefore, it should not be used in children.

Patients with hepatic dysfunction: No dosage adjustment is required.

Patients with renal dysfunction: Osteofos D3 should not be used in patients with severe renal dysfunction.

Hypersensitivity to active substances or to excipients.

Hypercalcaemia (>10.5 mg/dl), hypercalciuria (300 mg or 7.5 mmol/24 hours), severe renal insufficiency, kidney stones, calcium lithiasis, calcification of tissues, prolonged immobilisation accompanied by hypercalciurea and/or hypercalcaemia.

Hypervitaminosis D.

Osteofos D3 is not indicated in children, pregnancy and lactation.

Osteofos D3 must be used with caution in patients with renal insufficiency or when there is an evident tendency for the formation of urinary calculi. Calcaemia and calciuria must be adequately monitored in these patients to prevent the onset of hypercalcaemia. If calciuria levels exceed 7.5 mmol/24 hours (300 mg/24 hours), treatment should be temporarily interrupted.

Special caution is also required in the treatment of patients with cardiovascular disease. The effect of cardiac glycosides may be accentuated with the oral administration of calcium combined with Vitamin D. Strict medical supervision, and if necessary, monitoring ECG and calcaemia are necessary.

All other Vitamin D compounds and their derivatives, including food-stuffs which may be fortified with Vitamin D, should be withheld during treatment with Osteofos D3.

The product should be prescribed with caution to patients with sarcoidosis because of possible increased metabolism of Vitamin D to its active form. These patients should be monitored for serum and urinary calcium.

Osteofos D3 contains the colouring agent E110 which can cause allergic-type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take Osteofos D3.

Absorption of orally administered tetracyclines can be reduced by the simultaneous oral administration of calcium. These two drugs should be taken at least 3 hours apart.

Some diuretics (furosemide, ethacrynic acid), antacids containing aluminium salts and thyroid hormones can inhibit calcium absorption and increase renal and faecal excretion. Thiazide diuretics can reduce urinary excretion of calcium and can induce hypercalcaemia, some antibiotics such as penicillin, neomycin and chloramphenicol can increase its absorption. Monitoring of the serum calcium levels during prolonged treatment is recommended.

Colestyramine, corticosteroids and mineral oils interfere with and reduce Vitamin D absorption, while phenytoin and barbiturates favour its inactivation.

The calcium/digitalis synergism on the heart may cause severe disorders of cardiac function (see section 4.4).

In case of concomitant treatment with bisphosphonate or with sodium fluoride, it is advisable to allow a minimum period of two hours before taking Osteofos D3 (risk of reduction of the gastrointestinal absorption of bisphosphonate and sodium fluoride).

Possible interactions may occur with food (e.g. foods containing phosphate, oxalic or phytinic acid) with a reduction of calcium absorption.

Due to its high vitamin D content, Osteofos D3 is not indicated for use during pregnancy and lactation as the daily dose of Vitamin D should not exceed 600 I.U. Animal studies have shown that vitamin D overdose during pregnancy leads to teratogenic effects and there are no studies on this medicinal product in human pregnancy and lactation. Vitamin D and its metabolites pass into breast milk.

Therefore Osteofos D3 should not be used during pregnancy and breast-feeding.

None

Undesirable effects are listed according to the MedRA System Organ Class.

Since the following reactions have been reported in the post-marketing experience with Osteofos D3, their frequency is not known (cannot be estimated from the available data).

Immune system disorders

Anaphylactic reaction, allergic dermatitis

Metabolism and nutrition disorders

Hypercalcaemia, hypercalciuria

Gastrointestinal Disorders

Nausea, constipation, diarrhoea, epigastric pain

Skin and subcutaneous tissue disorders

Urticaria

Overdose can lead to hypervitaminosis D and hypercalcaemia. Symptoms of hypercalcaemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polidipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias. Extreme hypercalcaemia may result in coma and death. Persistently high calcium levels may lead to irreversible renal damage and soft tissue calcification.

Treatment of hypercalcaemia: the treatment with calcium and vitamin D must be discontinued. Treatment with thiazide diuretics, lithium, vitamin A and cardiac glycosides must be also discontinued. Fluid deficiency should be balanced and individual rescue measures should be decided by the doctor. Rehydration, and, according to the severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids. Serum electrolytes, renal function and diuresis must be monitored. In severe cases, ECG (electrocardiogram) and CVP (central venous pressure) should be followed.

The threshold for vitamin D intoxication is between 40,000 and 100,000 IU/day for 1-2 months in persons with normal parathyroid function, for calcium in excess of 2,000 mg per day. Symptoms of vitamin D intoxication are due to hypercalcaemia and should be treated as indicated above.

Calcium, combinations with other drugs. ATC code: A12AX

Osteofos D3 is a preparation for oral use, in which calcium phosphate is associated with colecalciferol (Vitamin D3).

Calcium and Vitamin D have a fundamental effect on “bone rebuilding” processes and it is for this reason that they are used in those conditions of the elderly patient characterised by a negative calcium balance with low levels of circulating Vitamin D and elevated serum levels of parathormone. This secondary hyperparathyroidism is effectively corrected by the combined effect of tribasic calcium phosphate and Vitamin D3, the active ingredients in Osteofos D3.

Vitamin D3 regulates calcium and phosphate metabolism, guaranteeing calcium absorption by the intestinal mucosa.

Approximately 30% of administered calcium is absorbed in the proximal part of the small intestine. Vitamin D is also quickly absorbed in the intestines after oral administration. The role of bile salts in facilitating absorption is well known. Approximately 40% of plasma calcium is bound to proteins, especially albumin, approximately 1/10 is diffusable, but bound to anions (phosphates); the remaining fraction is diffusable ionic calcium which has a physiological effect.

Vitamin D has a half-life of 19 to 25 hours, and circulates in the plasma bound to a specific protein, an alpha-globulin, and it is accumulated in the body for long periods. In the liver Vitamin D is converted into the derivative 25-hydroxylate (calcidiol) which is put back into the circulation where it binds with a specific alpha-globulin and undergoes further hydroxylation in the kidneys into 1-25 hydroxyderivative (calcitriol). Vitamin D is excreted mainly in the bile. Only a small portion of the administered dose is found in the urine.

Calcium is secreted into the gastro-intestinal tract via the saliva, bile and pancreatic secretion. Calcium from these sources, along with the calcium that is not absorbed comprises the portion excreted in the faeces. Of the portion of calcium excreted via the renal system, approximately 2/3 of the filtered calcium is reabsorbed.

Parathormone stimulates calcium reabsorption in the convoluted distal tubules, while Vitamin D increments proximal reabsorption. Part of the calcium is also excreted in perspiration.

Chronic safety evaluation studies in animals show that Vitamin D and Calcium combination is generally well tolerated.

Preclinical data revealed no specific hazard for humans, except for toxicity to reproduction (see section 4.6).

Propylene glycol

Sunset yellow FCF (E110)

Lemon flavouring (containing: natural flavourings, maltodextrin, gum arabic)

Saccharin sodium

Anhydrous citric acid

Microcrystalline cellulose and carmellose sodium

Monopalmitate sucrose

Silica colloidal anhydrous

Mannitol

α-tocopherol

Edible fats

Gelatin

Sucrose

Maize starch.

Not applicable

2 years.

Shelf life after reconstitution: use immediately.

Do not store above 25°C.

Single, paper-aluminium-polythene bonded, sealed sachets.

The sachets are packaged in cardboard boxes containing 2, 30 or 60 sachets.

Not all pack sizes may be marketed.

No special requirements

The appearance of the reconstituted product is a smooth orange opaque suspension with visible white granules.

Menarini International Operations Luxembourg S.A.

1, Avenue de la Gare

L-1611

Luxembourg

PA 865/7/1

Date of first authorisation: 28 June 2002

Date of last renewal: 23 September 2009

May 2010