Animal & Veterinary

FDA Provides Equine Veterinarians with Important Information about TILDREN and OSPHOS for Navicular Syndrome in Horses

In the first half of 2014, FDA approved two new equine drugs—TILDREN distributed by Ceva Sante Animale and OSPHOS distributed by Dechra, Ltd.—intended to control the clinical signs of navicular syndrome, a common cause of forelimb lameness in horses. Below is a brief reference guide for equine veterinarians on both drugs.


What are the active ingredients in TILDREN and OSPHOS and how do they work?
What are bisphosphonates?
What are the precautions for bisphosphonates?
How do you administer TILDREN and OSPHOS?
What are the contraindications for TILDREN?
What are the contraindications for OSPHOS?
What adverse reactions are caused by TILDREN?
What adverse reactions are caused by OSPHOS?
What should you do if a horse experiences an adverse reaction related to TILDREN or OSPHOS?
Important information for your client
What are the benefits of using an FDA-approved equine drug?
For more information
References


What are the active ingredients in TILDREN and OSPHOS and how do they work?

The active ingredient in TILDREN is tiludronate disodium, and the active ingredient in OSPHOS is clodronate disodium. Both belong in the bisphosphonate drug class and the exact mechanism of action in horses with navicular syndrome is unknown.

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What are bisphosphonates?

Bisphosphonates are a class of drugs commonly prescribed to prevent bone loss in people. While TILDREN and OSPHOS are not used for this purpose in horses, knowing how bisphosphonates work in people will help you better understand this drug class overall and especially the adverse reactions seen in horses.

Bones undergo constant turnover, with osteoblasts forming bone and osteoclasts resorbing it. In normal bone tissue, there is a balance between bone formation and bone resorption. But in diseased bone tissue, this balance is disrupted. Bisphosphonates inhibit bone resorption by encouraging osteoclasts to undergo cell death, leading to a decrease in the breakdown of bone.

Bisphosphonates preferentially “stick” to calcium and bind to it. Because most of the body’s calcium is stored in bones, these drugs accumulate to a high concentration only in bones. Bisphosphonates are incorporated into the bone matrix and are gradually released over months to years.

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What are the precautions for bisphosphonates?

As a class, bisphosphonates can cause gastrointestinal and renal toxicity. Higher blood plasma levels may increase the risk of toxicity. Because bisphosphonates are excreted by the kidneys, conditions that impair renal function may increase the blood plasma level and lead to more adverse reactions. It is not recommended to use bisphosphonates in horses with impaired renal function. Use caution if you give bisphosphonates along with other potentially nephrotoxic drugs, and be sure to monitor renal function.

Bisphosphonates can cause signs of colic in horses, including abdominal pain, discomfort, and agitation. These colic signs usually occur shortly after the drug is given and may be associated with altered intestinal motility.

Bisphosphonates affect the blood plasma levels of some minerals and electrolytes, such as calcium, magnesium and potassium. The effects are immediate and can last up to several hours. Use caution when you give bisphosphonates to horses with conditions affecting mineral or electrolyte homeostasis (for example, hyperkalemic periodic paralysis or hypocalcemia) or conditions which may be worsened by hypocalcemia (for example, cardiac disease).

The safe use of either TILDREN or OSPHOS has not been evaluated in horses less than 4 years of age. The effect of bisphosphonates on the skeleton of growing horses has not been studied. Because bisphosphonates inhibit osteoclast activity and decrease bone turnover, these drugs may affect bone growth.

The safe use of either TILDREN or OSPHOS has not been evaluated in breeding horses or pregnant or lactating mares. Bisphosphonates have been shown to cause abnormal fetal development in laboratory animals. The uptake of bisphosphonates into fetal bone may be greater than into maternal bone, creating a possible risk of skeletal or other abnormalities in the fetus. Bisphosphonates may be excreted in milk and absorbed by nursing animals.

Increased bone fragility has been seen in animals given bisphosphonates at high doses or for long periods of time. Because bisphosphonates inhibit bone resorption and decrease bone turnover, the body may be unable to repair microdamage within a bone.

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How do you administer TILDREN and OSPHOS?

TILDREN and OSPHOS are prescription animal drugs and federal law restricts them to use by or on the order of a licensed veterinarian. Although both drugs are in the same drug class, they have different routes of administration.

After reconstituting TILDREN with sterile 0.9% sodium chloride, you administer the drug by intravenous infusion into a jugular catheter slowly and evenly over 90 minutes to minimize the risk of adverse reactions. It may take two months to see the maximum effect.

You administer OSPHOS by intramuscular injection. The total volume should be divided equally into three injection sites. Similar to TILDREN, it may take two months to see the most clinical improvement.

For horses that initially respond to OSPHOS but don’t maintain their clinical improvement for 6 months, you may re-administer the drug at 3- to 6-month intervals based on clinical signs. For horses that respond to OSPHOS and maintain their clinical improvement for 6 months, you should re-administer after clinical signs recur.

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What are the contraindications for TILDREN?

Do not give TILDREN to horses with a known hypersensitivity to the active ingredient, tiludronate disodium, or to mannitol. Also do not use the drug in horses with impaired renal function or with a history of renal disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be used concurrently with TILDREN as this may increase the risk of renal toxicity and acute renal failure. While no safe window for the concurrent use of NSAIDS and TILDREN has been determined, it may be especially risky to give an NSAID from 48 hours before to 48 hours after treatment with TILDREN. Make sure you observe appropriate wash-out periods between NSAID and TILDREN administration and monitor blood urea nitrogen and creatinine values.

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What are the contraindications for OSPHOS?

Do not give OSPHOS to horses with a known hypersensitivity to clodronate disodium.

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What adverse reactions are caused by TILDREN?

In three field studies, adverse reactions in horses treated with TILDREN most commonly occurred during the 90-minute intravenous infusion or within four hours following the end of the infusion. The most common reaction was colic.

Expect about 30 to 45 percent of horses given TILDREN to show transient signs of colic. Hoses should be observed closely for four hours after treatment. Colic signs can last about 90 minutes and may be intermittent. In many cases, hand-walking may improve or resolve the colic signs. If a horse needs medical therapy, you should give non-NSAID treatments, as the concurrent use of an NSAID increases the risk of renal toxicity and acute renal failure.

In the field studies, adverse reactions occurring between four hours and one day after treatment included:

  • Increased frequency of urination with or without increased drinking;
  • Reduced appetite;
  • Sore or stiff neck;
  • Fever; and
  • Colic - this was the most common adverse reaction.

When giving TILDREN, you should advise owners of the potential for adverse reactions in the hours or days following treatment. Also tell owners to consult you before giving their horse any NSAID after treatment with TILDREN.

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What adverse reactions are caused by OSPHOS?

In the effectiveness field study, adverse reactions in horses treated with OSPHOS usually began within two hours of treatment. The most common adverse reactions were discomfort, agitation, pawing, and signs of colic. In the safety study, several horses treated with OSPHOS developed soft or firm injection site swellings, which resolved within 10 days.

When giving OSPHOS, you should advise owners to watch their horse for at least two hours after treatment for agitation, signs of colic, and other abnormal behavior, such as head shaking and lip licking. If a horse seems uncomfortable or nervous or experiences cramping, tell the owner to hand-walk the horse for 15 minutes. Advise the owner to contact you if signs don’t resolve or if the horse displays other abnormal symptoms.

Read the package inserts for TILDREN and OSPHOS for a complete description of the contraindications, warnings, and precautions for each drug.

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What should you do if a horse experiences an adverse reaction related to TILDREN or OSPHOS?

FDA encourages veterinarians to report all adverse reactions (also called adverse drug experiences, or ADEs) related to TILDREN or OSPHOS. Please see How to Report Animal Drug Side Effects and Product Problems.

Ceva Sante Animale (for TILDREN) and Dechra, Ltd. (for OSPHOS) are required to submit to FDA all reports of adverse drug experiences that they receive. FDA reviews the reports to identify potential safety and effectiveness concerns that may not have been apparent at the time of drug approval. FDA conducts this post-marketing monitoring to make sure that TILDREN and OSPHOS continue to meet the required standards for safety and effectiveness established during the approval process.

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Important information for your client

The package insert for TILDREN has a section called “Information for Owners” and the package insert for OSPHOS has a similar section called “Information for Horse Owners.” These sections may help you in your communication with clients regarding both drugs.

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What are the benefits of using an FDA-approved equine drug?

A main benefit of using an FDA-approved equine drug is that you know the drug is safe and effective in horses when used according to the label. A second benefit is that the label is written specifically for horses and includes all necessary information, including associated risks, so you can use the drug safely and effectively in your patients.

FDA rigorously evaluates an animal drug before approving it. As part of the approval process, the drug company must prove to FDA that:

  • The drug is safe and effective for a specific use in a specific animal species;
  • The manufacturing process is adequate to preserve the drug’s identity, strength, quality, and purity. The drug company must show that the drug can be consistently produced from batch to batch; and
  • The drug’s labeling is truthful, complete, and not misleading.

FDA’s role does not stop after the agency approves an animal drug. As long as the drug company markets the animal drug, the agency continues to monitor:

  • The drug’s safety and effectiveness. Sometimes, the agency’s post-approval monitoring uncovers safety and effectiveness issues that were unknown at the time of approval;
  • The manufacturing process to ensure quality and consistency are maintained from batch to batch;
  •  The drug’s labeling to make sure the information remains truthful, complete, and not misleading; and
  • The company’s marketing communications related to the drug to make sure the information is truthful and not misleading.

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For more information

If you have questions or want more information, please contact CVM’s Education & Outreach Staff at 240-402-7002 or AskCVM@fda.hhs.gov.

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References

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Page Last Updated: 12/09/2016
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