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Summary of Product Characteristics
1. Name
TILDREN ® 5mg/ml powder and solvent for solution for injection
2. Qualitative and quantitative composition
Powder vial:
Active substance:
Tiludronic acid (as disodium salt) 50 mg
Excipient q.s. 1 vial
Solvent vial
Water for injections 10 ml
Solution after reconstitution
Active substance:
Tiludronic acid (as disodium salt) 5 mg / ml
3. Pharmaceutical form
Powder and solvent for solution for injection.
Appearance:
White powder and clear colourless solvent.
After reconstitution, the product is a clear colourless solution.
4. Pharmacological properties
Tiludronic acid is an active ingredient which belongs to the therapeutic class of bisphosphonates (ATCvet: QM05BA) whose main pharmacological property is the inhibition of bone resorption.
Pharmacodynamic properties
The pharmacodynamic effects of Tiludronate have been mostly investigated in vitro and in laboratory animals.
Tiludronic acid exerts its inhibitory effect on bone resorption by blocking some of the osteoclast's metabolic pathways (production of non-hydrolysable, cytotoxic, ATP-analog metabolites, inhibition of the organisation of the cytoskeleton required for the activation of the osteoclast and inhibition of the osteoclastic proton pumps).
As bone resorption and bone formation are two coupled processes responsible for bone remodelling, the control of bone resorption by tiludronate is followed by a control in bone formation. As a consequence, tiludronate helps in regulating bone remodelling in every situations where excessive bone resorption (i.e. increased osteoclastic activity) is occurring. In laboratory animals this regulator effect is not accompanied by negative effects on the formation and mineralisation of bone at the recommended therapeutic doses.
Pharmacodynamic data in horses free of lameness have shown that, after IV administration at the dose 1 mg/kg, tiludronate produces immediate inhibitory effects on bone resorption, as shown by the sharp decrease of a serum marker of bone resorption 24 hours after dosing. In an other study over 4 months post treatment, tiludronate prevents the increase of bone porosity consecutive to a reduced physical activity.
Osteolysis is a painful process. In the horse, bone spavin and navicular syndrome are 2 conditions where osteolytic lesions develop in bones, which process contributes to the clinical symptoms.
Tiludronic acid has also been shown to have anti-arthritic properties in a polyarthritis model in the rat. In vitro studies have revealed that the product has inhibitory effects on the secretion of enzymes degrading the cartilaginous matrix produced by the chondrocytes and the synovial cells.
Pharmacokinetic properties
The pharmacokinetic profile of tiludronic acid (as the disodium salt) after intravenous administrations to the horse at a dose of 0.1 mg/kg/day is characterised by:
- A rapid decrease in plasma concentrations during the first 24 hours after each injection. During the course of a 10-day treatment with daily doses of 0.1 mg/kg by the intravenous route, Cmax are about 0.9 mg/L, plasma t1/2 is short (about 4.5 hours) and total clearance is about 0.040 to 0.050 L/h/kg. There is no plasma accumulation of tiludronate during repeated administrations.
- A degree of binding to plasma proteins of about 80% - 85%,
- A fast and widespread distribution in the bone, the storage compartment where tiludronic acid preferentially binds to the active remodelling sites, by binding to hydroxyapatite crystals. After a treatment with single daily injections for 10 days, the bound quantity corresponds to 30 to 50% of the total administered dose. The distribution of the tiludronate in the bone is not uniform ; binding is greater in cancellous bone than in cortical bone,
- A low distribution in all other body tissues,
- No biotransformation,
- An elimination mainly via the urine, in unchanged form. After a single injection, the dose excreted via the urine over a period of 96 hours corresponds to 25 to 50 % of the injected dose. The dose excreted via the faeces corresponds to less than 1% of the injected dose.
Environmental properties
Not relevant.
5. Clinical particulars
5.0 Target species
Horses over 3 years of age.
5.1 Indications for use
To aid in the treatment of lameness associated with osteolytic processes observed in bone spavin and in navicular syndrome of less than 6 months.
5.2 Contra indications
In the absence of any data relating to the adverse effects of tiludronic acid on the skeleton of young animals, do not administer to horses less than 3 years old.
Do not use in horses producing milk for human consumption.
Do not administer to horses with renal dysfunction
5.3 Undesirable effects
The main adverse reactions related to treatment with tiludronic acid are signs of colic (expressed as loss of appetite, abdominal discomfort, scratching the ground, restlessness and pawing), muscle tremor and sweating. These side effects were observed in less than 5 % of horses treated with the recommended therapeutic scheme and could be related to a mild hypocalcemic effect.
The signs of colic appear within a few hours following treatment, are mild and transient and generally resolve spontaneously without requiring any specific treatment. In case where signs persist, conventional treatments should be administered. Interactions with these treatments have not been assessed.
Muscle tremors may be stopped by the administration of calcium gluconate or any other calcium solution.
Phlebitis may occur in less than 9% of horses due to local reaction at the injection site. It is mostly seen from the 5th injection onwards.
Excitation, hypertonia of the tail and salivation are other possible side effects.
Fatigue, sometimes expressed by recumbency, can be experienced post injection. This side effect could also be related to a mild hypocalcemic effect. Be aware that the horse should be free to lie down in a comfortable unrestricted area.
5.4 Special precautions for use
The clinical effect of TILDREN depends on the presence of osteolytic processes causing pain and leading to lameness. TILDREN should be used only after a proper diagnosis combining a complete orthopaedic clinical examination including local anaesthesia and appropriate imaging techniques in order to identify the cause of pain and the nature of bone lesions.
It is advisable that an experienced horse keeper should observe the horse for the first four hours following the injection due to the possible onset of side effects.
TILDREN® should be administered with caution in hypocalcemic horses. In this case, is advised to slower the speed of injection. As the risk of appearance of side effects might in these animals be increased, these animals should be the subject of particular surveillance.
Because of its mild hypocalcemie effect, TILDREN® should be administered with caution in horses with disorders of heart function. In this case, it is advised to slower the speed of injection.
5.5 Use during pregnancy and lactation
Studies conducted on laboratory animals (mice, rats, rabbits) did not reveal any embryotoxic, foetotoxic or teratogenic effects nor effects on peri- or post-natal development. Particularly, no adverse effects have been observed on the skeleton.
The safety of the product has not been studied in pregnant or lactating mares. The use of the product during pregnancy or lactation in mares is not recommended.
5.6 Interaction with other medicaments
Do not administer concomitantly by intravenous route the reconstituted solution TILDREN® with solutions based on divalent metal ions such as Ca2+ or Mg2+ ; a solution of tiludronic acid may form complexes with these ions.
Regarding other medicinal products, no data are available.
5.7 Posology and method of administration
- 0.1 mg of tiludronic acid per kg of body weight per day for 10 days by slow intravenous route, i.e. 1 ml per 50 kg of body weight per day of a reconstituted solution containing 5 mg/ml of tiludronic acid.
The reconstituted solution is obtained by adding under aseptic conditions the solvent to the powder and gently mixing them.
- The product should be administered over 20 to 30 seconds for 10 ml.
- The side of the site of injection must be alternated from day to day.
- The product should be used immediately and not stored after reconstitution
- Do not exceed the recommended dosage.
5.8 Overdose
At 3 times the recommended dosage, an increase in frequency of the side effects, in particular signs of colic and muscle tremor, is observed.
The signs of colic appear within a few hours following the treatment, are mild and transient and generally resolve spontaneously without requiring any specific treatment. In case where signs persist, conventional treatments should be administered.
Muscle tremors may be stopped by the administration of calcium gluconate or any other calcium solution.
5.9 Special warnings for each target species
See point 5.11. Withdrawal period.
5.10 Withdrawal periods
Meat and offal: zero days
Not permitted for use in lactating animals producing milk for human consumption.
5.11 Special precautions to be taken by the person administering the product to animals
- Avoid contact with skin and eyes.
- Wear suitable gloves when preparing the solution for injection
- Wash hands after use.
- In the case of self injection, seek medical advice immediately and show the package insert or the label to the physician.
6. Pharmaceutical particulars
6.1 Incompatibilities
Do not mix the reconstituted solution with solutions based on divalent metal ions such as Ca2+ or Mg2+ ; a solution of tiludronic acid may form complexes with these ions.
6.2 Shelf-life
3 years.
To be used immediately after reconstitution, any remaining product should be discarded.
6.3 Special precautions for storage
Keep the container in the outer carton.
6.4 Nature and contents of container
Material of the primary container
Glass, type-II vial,
Chlorobutyl stopper,
Aluminium cap.
Pack sizes
- Box containing one vial of 50 mg of Tiludronic acid and one vial of 10 ml solvent
- Box containing five vials of 50 mg of Tiludronic acid and five vials of 10 ml solvent
- Box containing ten vials of 50 mg of Tiludronic acid and ten vials of 10 ml solvent
6.5 Name or style and permanent address or registred place of business of the marketing authorisation holder
6.6 Special precautions for the disposal of unused product or waste material if any
Any unused product or waste material should be disposed of in accordance with national requirements.
7.0 Additional informations
This SPC has been generated by the on the 09/05/04 at 19:22:28
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