Dosage and administration

1 mg of tiludronic acid per kg of bodyweight, corresponding to 5 ml of reconstituted solution per 100 kg, via intravenous infusion.

The method of administration below should be followed:

1. Using a sterile needle and a suitable sterile disposable syringe, remove 25 ml of 0.9% sodium chloride solution or 5% glucose solution from a 1 litre to 3 litre infusion container.

2. Add the 25 ml of isotonic sodium chloride or glucose solution to the vial of powder.

3. Shake until the powder is completely dissolved.

4. Adhering to strict aseptic technique, inject the reconstituted solution into the infusion container.

5. Gently invert the container several times.

6. Administer through a suitable needle or catheter inserted into the jugular vein and connected to the infusion container with sterile disposable infusion tubing.

The product should be infused over 30 minutes.

Do not shorten the time of infusion as this could increase the risk of the horse showing signs of colic during or after infusion.

Do not exceed the recommended dosage.

Contra-indications, warnings, etc

In the absence of any data relating to the adverse effects of tiludronic acid on the skeleton of young animals, do not administer to a horse less than 3 years old.

Do not administer to a horse with known impaired renal function.

Special precautions for use in animals

The clinical effect of the product depends on the presence of osteolytic processes causing pain and leading to lameness. The product should be used only after a proper diagnosis combining a complete orthopaedic clinical examination including local analgesia and appropriate imaging techniques in order to identify the cause of pain and the nature of bone lesions.

It is advisable for an experienced horse person to observe the horse for the first four hours following the infusion due to the possible onset of side effects.

The product should be administered with caution in a hypocalcaemic horse. In this case, it is advised to slow down the rate of the infusion, as the risk of side effects might be increased under these circumstances. Also, these animals should be the subject of particularly close surveillance.

Because of its mild hypocalcaemic effect, the product should be administered with caution in animals with heart disorders. In this case, it is advisable to slow down the rate of infusion.

Special precautions to be taken by the person administering the veterinary medicinal product to animals

Avoid contact with skin and eyes.

Avoid accidental self-injection. It is recommended to insert the intravenous infusion needle into the vein before the reservoir containing the product is connected.

In the case of self injection, seek medical advice immediately and show the package leaflet or the label to the physician.

Wear suitable gloves when preparing the solution for injection. Wash hands after use.

Use during pregnancy, lactation or lay

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.

Interaction with other medicinal products and other forms of interaction

Do not mix or concomitantly administer intravenously the reconstituted solution with solutions containing divalent metal ions (Ca2+ or Mg2+) such as lactated Ringers. A solution of tiludronic acid may form complexes with these ions.

Avoid concomitant intravenous administration with drugs that can reduce serum calcium (such as tetracyclines) or whose toxicity can be exacerbated by a reduction in serum calcium (such as aminoglycosides).

Regarding other medicinal products, no data is available.

Adverse reactions (frequency and seriousness)

The main adverse reactions related to treatment with tiludronic acid are signs of discomfort or signs of colic (expressed as belly watching, yawning, pawing or kicking, stretching, light bruxism, often combined with restlessness), softening of faeces and sweating. These side effects were observed in less than 11% of horses treated with the recommended therapeutic regime.

The signs of colic appear within a few hours following treatment, are mild and transient and generally resolve spontaneously without requiring any specific treatment. If the signs persist, conventional treatments should be administered. Interactions with these treatments have not been assessed.

As recumbency can be experienced post infusion, be aware that the horse should be free to lie down in a comfortable unrestricted area.

An increase in frequency of signs of discomfort and restlessness is observed when the infusion duration is less than 15 minutes.

Withdrawal periods

Meat and offal: Zero days

Not permitted for use in lactating animals producing milk for human consumption.

Keep out of reach and sight of children. For animal treatment only.

Pharmaceutical precautions

Keep the vial in the outer carton in order to protect from light.

After reconstitution, the product may be stored at 2 to 8°C for no longer than 24 hours.

Legal category

POM-V

Packaging Quantities

Box containing 1 vial.

Further information

The pharmacodynamic effects of tiludronic acid have been investigated in-vitro, in laboratory animals and in horses.

Tiludronic acid exerts its inhibitory effect on bone resorption by blocking some of the osteoclast metabolic pathways (production of non-hydrolysable, cytotoxic, ATP-analogue metabolites, inhibition of the organisation of the cytoskeleton required for the activation of the osteoclast and inhibition of the osteoclastic proton pumps).

Tiludronic acid helps in regulating bone remodelling in every situation where excessive bone resorption (i.e. increased osteoclastic activity) is occurring. Osteolysis is a painful process. In the horse, bone spavin is a condition where osteolytic lesions develop in tarsal bones, which contributes to the clinical symptoms.

In laboratory animals the regulatory effect on bone remodelling is not accompanied by negative effects on the formation and mineralisation of bone at doses sufficient to significantly inhibit bone resorption.

Pharmacodynamic data in horses free of lameness have shown that, after intravenous administration at the dose 1 mg/kg, tiludronic acid produces immediate inhibitory effects on bone resorption, as shown by the sharp decrease of a serum marker of bone resorption (CTX-1) 12 to 24 hours after dosing. Tiludronic acid was also shown to prevent the loss of bone density after a period of immobilisation by casting.

At therapeutic doses, bone formation was not impaired as shown by the absence of significant changes in the blood concentrations of a marker of bone formation (Bone alkaline phosphatase).

Tiludronic acid has also been shown to have anti-arthritic properties in a polyarthritis model in rats. 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.

The pharmacokinetic profile of tiludronic acid in plasma after intravenous administration by infusion over 30 minutes in the horse at a dose of 1 mg/kg/day is characterised by a rapid decrease in plasma concentrations. Cmax is about 8 ± 2 mg/l, plasma t1/2 is short, about 37 ± 20 hours, and total clearance is about 0.03 ± 0.01 l/h/kg.

There is no plasma accumulation of tiludronic acid when infusions are repeated 3 times at 14 day intervals. The pharmacokinetic profile of tiludronic acid is dose-proportional and time-independent. Binding to plasma proteins is about 80% - 85%.

Tiludronic acid is rapidly cleared from blood and stored in the bone where it preferentially binds to the active remodelling sites, by binding to hydroxyapatite crystals. The bound quantity corresponds to 30 - 50% of the total administered dose. The distribution of tiludronic acid in the bone is not uniform. Binding is greater in cancellous bone than in cortical bone.

The distribution of the drug in all other body tissues is limited. It is not metabolised. Consequently, tiludronic acid is mainly eliminated via the urine, in an unchanged form.