SKELID 200mg Tablet

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1. NAME OF THE MEDICINAL PRODUCT

SKELID 200mg Tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Disodium tiludronate 240.00 mg

Quantity corresponding to tiludronic acid 200.00 mg for one tablet

For full list of excipients see section 6.1

3. PHARMACEUTICAL FORM

Tablet :Round, biconvex, white tablets with “SW” engraved on one side and “200” on the other.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of Paget's disease

4.2 Posology and method of administration

Oral route

For adults only

Daily dosage: 400 mg (i.e. 2 tablets) as a single dose for three months (i.e. 12 weeks).

Most patients respond to treatment during the first three months regardless of whether or not they were previously treated with another bisphosphonate.

Serum alkaline phosphatase levels can continue to improve 18 months after withdrawal of treatment.

Treatment can be repeated if the biochemical markers (increase in serum alkaline phosphatase levels with or without elevated hydroxyprolinuria) or pain indicate a recurrence of the condition.

Allow a period of at least 6 months to elapse before administering a second course of treatment.

The tablets should be taken with the help of a glass of water on an empty stomach (at least two hours) before / after meals.

Foodstuffs, particularly those with a high calcium contents (e.g. milk and dairy products) and antacids providing gastric protection should be avoided for two hours pre and post-dose (see Interactions).

4.3 Contraindications

History of allergy to bisphosphonates

Severe kidney failure (creatinine clearance less than 30 ml/min)

Juvenile Paget's disease

Pregnancy and lactation (see 4.6 pregnancy and lactation)

Hypersensitivity to any of the excipients

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.

4.4 Special warnings and precautions for use

Tiludronate is not metabolised and is excreted unchanged via the kidneys. Tiludronate must be administered with caution to patients suffering from mild (creatinine clearance ranging from 60 to 90 ml/min) and moderately severe kidney failure (creatinine clearance between 30 and 60 ml/min) (kidney function should be monitored on a regular basis).

Patients must have an adequate calcium and vitamin D intake. calcium metabolism disorders (hypocalcaemia, vitamin D deficiency) must be controlled before instituting treatment.

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 bisphophonates 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.

4.5 Interaction with other medicinal products and other forms of interaction

Combination therapy warranting precautions in use:

Allow over two hours between administration of tiludronate and consumption of:

calcium salts, topical gastro-intestinal agents, oral antacids (reduced gastro-intestinal absorption of bisphosphonates).

indomethacin (increased bioavailability of tiludronic acid).

The pharmacokinetic parameters of tiludronate are not significantly changed by concomitant administration of aspirin or diclofenac.

The pharmacokinetic parameters of digoxin are not significantly changed by concurrent administration of tiludronate.

Tiludronate should not be combined with products likely to induce mineralisation disorders.

4.6 Pregnancy and lactation

Pregnancy

Administration is contraindicated during pregnancy (lack of data).

 

Although there is no evidence of any deleterious effects with tiludronate in reproduction studies, delayed skeletal and bone development in the fetus has been reported in animals experiments conducted with other bisphosphonates. The passage of tiludronate through human placenta has not been documented.

Lactation

Administration is contraindicated during lactation (lack of data).

4.7 Effects on ability to drive and use machines

Drivers and machine operators are not required to take any specific precautions.

4.8 Undesirable effects

Adverse reactions are listed according the following categories:

“Very common ( 1/10); common ( 1/100 to 1/10); uncommon ( 1/1,000 to 1/100); rare ( 1/10,000 to 1/1,000); very rare ( 1/10,000), not known (can not be estimated from available data)”

Gastro-intestinal disorders:

Common: abdominal pain, nausea, and diarrhoea. These events are of slight to moderate severity and their incidence is dose-related.

Skin and subcutaneous tissue disorders:

Uncommon: rash

Nervous system disorders:

Rare : dizziness, headache.

General disorders and administration site conditions:

Rare : asthenia

Musculo-skeletal disorders:

Not known: bone pain

4.9 Overdose

Some patients may present with hypocalcaemia and kidney failure following a massive overdose. Gastric lavage may prove useful in order to evacuate any as yet unabsorbed tiludronate.

Symptomatic treatment of hypocalcaemia (intravenous administration of calcium salts such as calcium gluconate) and/or kidney failure should be instituted.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Used in the treatment of bone diseases.

(M05 BA bisphosphonates).

Like other bisphosphonates, tiludronate inhibits the bone absorption of osteoclasts.

Tiludronate slows down the bone remodelling of lesions due to Paget's disease, as manifested by the fall in serum alkaline phosphatase levels. Preliminary studies of Paget's disease involving a small number of biopsies showed that tiludronate reduces excessive remodelling due to this disease.

No clinical data on potential long-term mineralisation disorders are available. However, long-term administration (6 months to 1 year) of high daily doses did not cause osteomalacia in rats or baboons.

5.2 Pharmacokinetic properties

The absolute bioavailability of tiludronate is low (averaging 6 %) and variable (2 to 11 %). Plasma concentration peaks following repeated dosing with 400 mg per day were extremely variable (generally between 1 and 5 mg/L occuring 1 to 2 hours post-dose). Bioavailability is decreased when the product is administered during or after a meal and falls considerably in the presence of calcium.

Plasma protein binding is of the order of 91 % and is constant within the therapeutic concentration range. Albumin is the protein responsible for this phenomenon. Less than 5 % binds to red blood cells. Approximately half of the dose absorbed is bound to bone.

Tiludronate is excreted unchanged via the kidneys. 3.5 ? 1.9 % of excreted unchanged tiludronate are detected 48 hours after single oral administration.

The decrease in tiludronate plasma levels following treatment withdrawal occurs in two stages, the second of which is much slower and difficult to assess accurately due to the very low plasma concentrations (half-life of over 100 hours). This last phase is due to bone remodelling and to the very slow absorption of tiludronate from the bones.

5.3 Preclinical safety data

Single dose toxicity: Acute moderate toxicity (LD50 of about 550 mg/kg) and low toxicity (LD50 1000 mg/kg) were observed in the rat and mouse respectively following oral administration. The principal target organs are the kidney, stomach and lungs.

Repeated dose toxicity: gastritis and proximal renal tubulopathies were observed mainly in the rat and baboon following repeated oral dosing with 50mg/kg/day for up to a year. These dose levels are considerably higher than the pharmacologically active daily dose levels of 5 to 10 mg/kg which lead to inhibition of bone resorption and increase the bone density of trabecular bone.

Genotoxicity and carcinogenicity: in-vitro and in-vivo studies of gene mutation, chromosomal aberration and DNA repair processes did not reveal any signs of toxicity.

No evidence of carcinogenicity was detected in mice given up to 50 mg/kg/day for 80 weeks or in rats receiving up to 25 mg/kg/day for 2 years.

Reproduction toxicity: orally administered doses of up to 375 mg/kg/day did not induce any direct teratogenic or embryotoxic effect in rats, mice or rabbits.

Neither fertility nor peri- and post-natal development were affected in the rat following administration of up to 75 mg/kg/day.

However, given the retarded skeletal and bone maturation observed in animal foetuses during studies with other bisphosphonates, and since no data are available on the passage of tiludronate through human placenta, this product is contraindicated during pregnancy.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium laurilsulfate, Hypromellose, Crospovidone, Magnesium stearate, Lactose monohydrate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

No special precautions for storage.

6.5 Nature and contents of container

28 tablets in heat-formed blister packs (polyamide - aluminium - PVC/aluminium)

More information about this product

Patient Information Leaflets (PILs):

Skelid 200mg Tablets

Medicine Guides:

Skelid
The above information is the translation of the manufacturer's insert. It is provided under the supplying company's terms and conditions and should not replace the advice of your personal physician.