November 26, 2019

Dear Veterinarian:

The U.S. Food and Drug Administration (FDA) has approved Kindred Biosciences, Inc.’s Zimeta (dipyrone injection) for the control of pyrexia in horses. Zimeta belongs to the pyrazolone class of non-steroidal anti-inflammatory (NSAID) drugs and is the first injectable dipyrone product to receive FDA approval for use in horses. Zimeta is for use in horses only. Zimeta has not been evaluated for use in horses intended for human consumption or food-producing animals, including lactating dairy animals. 

Zimeta is not for use in humans. Direct contact with the skin should be avoided. Precautions should be employed by practitioners when handling and using loaded syringes to prevent accidental self-injection, as epidemiological studies have indicated that dipyrone can cause agranulocytosis in humans.

In 1977, the FDA formally withdrew the approval of all dipyrone-containing drugs intended for use in humans, after becoming aware of reports of agranulocytosis in treated patients. Dipyrone is now prohibited for use in humans in several countries.   However, the data generated to support the approval of Zimeta did not indicate that agranulocytosis occurred in horses treated with the drug.

Following the removal of the human drug product from the U.S. market, sales of an unapproved equine dipyrone product continued. However, in 1996, the FDA removed the unapproved equine dipyrone product from the market due to concerns about its use in food-producing animals. Subsequently, the FDA noted increased distribution of compounded dipyrone sold for use in horses.

The FDA emphasizes the benefits of using FDA-approved drugs in your practice. FDA-approved drugs have been demonstrated to be safe and effective for their intended use and have been consistently manufactured to preserve the drugs’ identity, strength, quality and purity. The FDA strongly encourages use of an FDA-approved dipyrone animal drug product, when dipyrone is indicated, for use in horses for the control of pyrexia.

As with all approved animal drugs, the FDA will monitor and evaluate submitted adverse event reports for Zimeta, which would include monitoring for potential human safety risks associated with dipyrone and indications that the product is being used in an extra label manner in food-producing animals.

Zimeta is a prescription animal drug product containing 500 mg dipyrone/mL and is intended for intravenous injection. The recommended dose in horses is once or twice daily, at 12-hour intervals, for up to three days, at a dosage of 30 mg/kg of body weight (13.6 mg/lb). The overall number of doses and duration of treatment with Zimeta is dependent on the response observed (fever reduction). Zimeta may be re-administered based on recurrence of fever for up to 3 days. Do not exceed twice a day dosing. Zimeta is provided in a multi-dose vial. Please refer to the package insert for Zimeta before using this product. Additional information can be accessed at the Freedom of Information Summary.

Benefits of FDA Approval

The FDA rigorously evaluates an animal drug before determining whether to issue an approval. As part of the approval process, the drug company must prove to the FDA that:

• There is evidence that the drug product is safe and effective for a specific use in the intended species;
• The manufacturing process is adequate to preserve the drug product’s identity, strength, quality, and purity; and
• The drug product’s labeling is truthful and not misleading.

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

• The drug product’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 that the identity, strength, quality and purity of the drug product are maintained;
• The drug product’s labeling to make sure the information remains truthful and not misleading; and
• The company’s marketing communications related to the drug product to make sure the information is truthful and not misleading.

Adverse Drug Events and Drug Interactions Associated with Zimeta

Zimeta is contraindicated in horses with a known sensitivity to dipyrone. Concurrent administration of potentially nephrotoxic drugs should be carefully approached or avoided. Since many NSAIDs have the potential to produce gastrointestinal ulcerations and/or gastrointestinal perforation, concomitant use of Zimeta with other anti-inflammatory drugs, such as NSAIDs or corticosteroids, should be avoided. Treatment administrators and caregivers should be aware of the potential for adverse reactions and the clinical signs associated with NSAID intolerance, which may include colic, diarrhea, and decreased appetite. Zimeta has been shown to cause prolongation of coagulation parameters in horses. Caution should be used in horses at risk for hemorrhage. The safe use of Zimeta in horses less than 3 years of age, horses used for breeding, or in pregnant or lactating mares has not been evaluated.

In a clinical field study, 138 horses of various breeds, ranging in age from 1 to 32 years of age, were treated with one or more doses of Zimeta. The most common adverse reactions were elevated serum sorbitol dehydrogenase (SDH), hypoalbuminemia, gastric ulcers, hyperemic mucosa of the right dorsal colon, and prolonged activated partial thromboplastin time (APTT). Please see Table II.3 of the Freedom of Information Summary.

Safety and Effectiveness of Zimeta Compared to Compounded Forms of Injectable Dipyrone

Compounded animal drug preparations are not FDA-approved drugs, nor are they FDA-approved generic drug products. Unlike FDA-approved Zimeta, compounded formulations of dipyrone have not been evaluated by the FDA for safety or effectiveness and may vary in quality, potency, and bioavailability. The absorption and effectiveness of Zimeta has been established. In contrast, the absorption and bioavailability of compounded formulations of injectable dipyrone are unknown and may be inadequate or variable. Further, while there are many post-approval requirements for sponsors of FDA-approved animal drug products, including the mandatory reporting of adverse drug experience reports, there are no such requirements for compounded preparations. The FDA encourages veterinarians and animal owners to report adverse drug experiences and product defects associated with animal drug products or animal devices. More information about how to report information about animal drugs and devices can be found at our website.

The effectiveness of Zimeta was demonstrated in an adequate and well-controlled clinical field study in 138 horses, followed by an extended use field safety phase in 87 horses. One hundred thirty-seven horses (103 administered Zimeta and 34 administered an inactive control) were included in the statistical analysis for effectiveness. Horses over one year of age with naturally occurring fevers (rectal temperature ≥102.0°F) were administered Zimeta intravenously at 30 mg/kg. A horse was considered a treatment success if 6 hours following the administration of a single dose of study drug, the rectal temperature decreased ≥2.0°F from hour 0, or the temperature decreased to normal (≤101.0°F). Based on this definition, the success rate was 74.8% (77/103) Zimeta-treated horses and 20.6% (7/34) control-treated horses.

The FDA’s Center for Veterinary Medicine (CVM) is committed to promoting and protecting animal health by ensuring safe and effective drugs are available for animals. For more information, please contact CVM’s Education & Outreach Staff at 240-402-7002 or [email protected].

Sincerely,

FDA’s Center for Veterinary Medicine