TILDREN and OSPHOS for Navicular Syndrome in Horses—Information for Equine Veterinarians
Two equine drugs—TILDREN distributed by Bimeda Animal Health Limited and OSPHOS distributed by Dechra, Ltd. — are FDA-approved 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 and OSPHOS?
What adverse reactions are caused by TILDREN?
What adverse reactions are caused by OSPHOS?
Should you report problems 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.
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 causing 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.
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 negatively affect bone growth and bone health.
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, which can increase the 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. The horse racing industry has concerns about the negative effects of bisphosphonates on the bone health of horses. In March 2019, a coalition of 29 Mid-Atlantic Thoroughbred organizations, representing 7 U.S. states, banned the use of bisphosphonates in racehorses under the age of 4 (this is an extra-label use of the drugs, as both are approved only for horses 4 years of age and older). In October 2019, the Maryland Racing Commission went even further, ruling horses of any age treated with bisphosphonates are ineligible to run in any race, and a veterinarian found to have given bisphosphonates to a horse will be suspended for one year.
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 only when clinical signs recur.
What are the contraindications for TILDREN and OSPHOS?
Do not give TILDREN to horses with a known hypersensitivity to the active ingredient, tiludronate disodium, or to mannitol. Do not give OSPHOS to horses with a known sensitivity to clodronate sodium. Both drugs have the same contraindication regarding use 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 or OSPHOS 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 or OSPHOS has been determined, it may be especially risky to give an NSAID from 48 hours before to 48 hours after treatment. Make sure you observe an appropriate wash-out period between administering an NSAID and administering TILDREN or OSPHOS and monitor blood urea nitrogen and creatinine values. The length of the wash-out period will vary depending on the age, condition, and renal status of the horse.
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.
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 other signs of colic. In the safety study, several horses treated with OSPHOS developed soft or firm injection site swellings, which resolved within 10 days.
Since 2014, when FDA originally approved OSPHOS, end-users of the drug (veterinarians and horse owners) have submitted voluntary reports of adverse drug experiences to Dechra, Ltd., and the drug company then forwarded these reports to the agency. Based on this information, FDA asked the company to include additional adverse reactions on the drug’s label in the “Post-Approval Experience” section. The following adverse reactions are listed in decreasing order of reported frequency (most frequent at the top):
- Renal failure;
- Polyuria;
- Polydipsia;
- Abdominal pain;
- Anorexia;
- Lethargy;
- Hypercalcemia;
- Abnormal behavior, such as head shaking, flehmen response, and lip licking;
- Discomfort;
- Hyperkalemia;
- Hyperactivity;
- Recumbency;
- Hyperthermia;
- Injection site reactions, such as pain, edema, and inflammation;
- Muscle tremors;
- Urticaria;
- Hyperglycemia; and
- Bone fractures.
In some cases, horses have died as a result of the adverse reactions listed above.
Read the package inserts for TILDREN and OSPHOS for a complete description of the contraindications, warnings, and precautions for each drug.
Should you report problems related to TILDREN or OSPHOS?
Yes. FDA encourages veterinarians to report all problems related to TILDREN or OSPHOS. Problems include adverse drug experiences and product defects. Adverse drug experiences are adverse reactions associated with a drug, a lack of effectiveness, and reactions in people who handle the drug. Product defects are problems such as defective packaging (like a broken seal) or the drug is off-color. Please see How to Report Animal Drug and Device Side Effects and Product Problems.
Bimeda Animal Health Limited (for TILDREN) and Dechra, Ltd. (for OSPHOS) are required to submit to FDA all reports of adverse drug experiences and product defects that they receive. FDA reviews the reports to identify potential safety and effectiveness concerns that may not have been apparent at the time the drug was approved. Sometimes, as with OSPHOS, FDA works with the drug company to add important post-approval information to the drug’s label. FDA conducts this post-approval monitoring to make sure that TILDREN and OSPHOS continue to be safe and effective when used according to the label.
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, especially the adverse reactions to watch for in the hours and days after treatment and what to do if they occur. Importantly, you should advise owners to not give their horse any NSAID after treatment with either TILDREN or OSPHOS without first consulting you.
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 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.
For more information
If you have questions or want more information, please contact the FDA Center for Veterinary Medicine at 240-402-7002 or AskCVM@fda.hhs.gov.