EQUIOXX: Product Information

EQUIOXX- firocoxib tablet, chewable
Merial, Inc.

CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Description:

EQUIOXX (firocoxib) Tablets belongs to the coxib class of non-narcotic, non-steroidal anti-inflammatory drugs (NSAIDs). Firocoxib is a white crystalline compound described chemically as 3 (cyclopropylmethoxy)-4-(4-methylsulfonyl)phenyl)-5,5-dimethylfuranone. The empirical formula is C17H20O5S, and the molecular weight is 336.4 g/mol. The structural formula is shown below:

Chemical StructureChemical Structure

Indications:

EQUIOXX Tablets are administered once daily for up to 14 days for the control of pain and inflammation associated with osteoarthritis in horses.

Dosage and Administration:

Always provide the Client Information Sheet with the prescription. The recommended dosage of EQUIOXX Tablets is one 57 mg tablet administered orally to horses weighing 800 – 1300 lbs, once daily for up to 14 days. For ease of administration, EQUIOXX Tablets may be given with food.

The overall duration of treatment with any firocoxib formulation in horses, including EQUIOXX Tablets, Injection or Oral Paste, should not exceed 14 days. Please see the package insert for EQUIOXX Injection or Oral Paste for appropriate prescribing information for those formulations.

Contraindications:

Horses with a hypersensitivity to firocoxib should not receive EQUIOXX® Tablets.

Warnings:

For use in horses only. Do not use in horses intended for human consumption. Store EQUIOXX Tablets out of the reach of dogs and other pets in a secured location in order to prevent accidental ingestion or overdose.

Human Warnings: Not for use in humans. Keep this and all medications out of the reach of children. Consult a physician in case of accidental ingestion by humans.

Precautions:

Horses should undergo a thorough history and physical examination before initiation of NSAID therapy. Appropriate laboratory tests should be conducted to establish hematological and serum biochemical baseline data before and periodically during administration of any NSAID. Clients should be advised to observe for signs of potential drug toxicity and be given a Client Information Sheet with each prescription. See Information for Owner or Person Treating Horse section of this package insert.

Treatment with EQUIOXX Tablets should be terminated if signs such as inappetence, colic, abnormal feces, or lethargy are observed.

As a class, cyclooxygenase inhibitory NSAIDs may be associated with gastrointestinal, renal, and hepatic toxicity. Sensitivity to drug-associated adverse events varies with the individual patient. Horses that have experienced adverse reactions from one NSAID may experience adverse reactions from another NSAID. Patients at greatest risk for adverse events are those that are dehydrated, on diuretic therapy, or those with existing renal, cardiovascular, and/or hepatic dysfunction. Concurrent administration of potentially nephrotoxic drugs should be carefully approached or avoided. NSAIDs may inhibit the prostaglandins that maintain normal homeostatic function. Such anti-prostaglandin effects may result in clinically significant disease in patients with underlying or pre-existing disease that has not been previously diagnosed. Since many NSAIDs possess the potential to produce gastrointestinal ulcerations and/or gastrointestinal perforation, concomitant use of EQUIOXX Tablets with other anti-inflammatory drugs, such as NSAIDs or corticosteroids, should be avoided.

The concomitant use of protein bound drugs with EQUIOXX Tablets has not been studied in horses. The influence of concomitant drugs that may inhibit the metabolism of EQUIOXX Tablets has not been evaluated. Drug compatibility should be monitored in patients requiring adjunctive therapy.

The safe use of EQUIOXX Tablets in horses less than one year in age, horses used for breeding, or in pregnant or lactating mares has not been evaluated.

Consider appropriate washout times when switching from one NSAID to another NSAID or corticosteroid.

Adverse Reactions:

The safety and effectiveness of EQUIOXX Tablets was established in a relative bioavailability study comparing EQUIOXX Tablets and EQUIOXX (firocoxib) Oral Paste. Therefore, additional field studies were not performed to support the effectiveness of EQUIOXX Tablets.

In controlled field studies, 127 horses (ages 3 to 37 years) were evaluated for safety when given EQUIOXX Oral Paste at a dose of 0.045 mg/lb (0.1 mg/kg) orally once daily for up to 14 days. The following adverse reactions were observed. Horses may have experienced more than one of the observed adverse reactions during the study.

Table 1: Adverse Reactions Seen in U.S. Field Studies with EQUIOXX Oral Paste:
Adverse Reactions EQUIOXX n = 127 Active Control n = 125

Abdominal pain

0

1

Diarrhea

2

0

Excitation

1

0

Lethargy

0

1

Loose stool

1

0

Polydipsia

0

1

Urticaria

0

1

In these field trials, EQUIOXX Oral Paste was safely used concomitantly with other therapies, including vaccines, anthelmintics, and antibiotics. The safety data sheet (SDS) contains more detailed occupational safety information.

To report suspected adverse events, for technical assistance, or to obtain a copy of the SDS, contact Merial at 1-888-217-3543. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth.

Information for Owner or Person Treating Horse:

A Client Information Sheet should be provided to the person treating the horse. Treatment administrators and caretakers should be aware of the potential for adverse reactions and the clinical signs associated with NSAID intolerance. Adverse reactions may include erosions and ulcers of the gums, tongue, lips and face, weight loss, colic, diarrhea, or icterus. Serious adverse reactions associated with this drug class can occur without warning and, in some situations, result in death. Clients should be advised to discontinue NSAID therapy and contact their veterinarian immediately if any of these signs of intolerance are observed. The majority of patients with drug-related adverse reactions recover when the signs are recognized, drug administration is stopped, and veterinary care is initiated.

Clinical Pharmacology:

Relative Bioavailability Study

A pharmacokinetic study was conducted to compare the relative bioavailability of an oral firocoxib tablet containing 57 mg firocoxib (EQUIOXX Tablets) to the approved paste formulation (EQUIOXX Oral Paste; NADA 141-253). The criteria for the Test/Reference (T/R) ratios and the 90% Confidence Intervals (CI) of EQUIOXX Tablets (test product) were adjusted on the basis of the safety and effectiveness data for EQUIOXX Oral Paste (reference product). The lower bound of the 90% CI for effectiveness was defined by the minimal effective plasma concentration in the study used to support the dosage characterization of EQUIOXX Oral Paste. Effectiveness was based upon the area under the plasma drug concentration-time curve to the last quantifiable concentration (AUClast), with the effectiveness criteria set at a T/R ratio of greater than or equal to 0.77 and a corresponding lower bound for the 90% CI set at 0.71. The upper bound of the 90% CI for safety was defined by the maximum safe plasma concentration (Cmax) in the study used to establish a margin of safety for EQUIOXX Oral Paste Based upon that margin of safety, product safety was defined as a T/R of less than or equal to 1.53, with a corresponding upper bound for the 90% CI of 1.71.

The relative bioavailability study was a randomized, two period, two sequence crossover study in thirty horses. Each horse received a single tablet (57 mg firocoxib) and a single tube of paste (56.7 mg firocoxib). Blood samples were collected at 15 minutes, 45 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, 96 and 120 hours following each treatment. Samples were analyzed by LC-MS/MS for firocoxib concentrations. The results of the relative bioavailability study are summarized in Table 2. The Cmax and AUClast of EQUIOXX Tablets were within the adjusted 90% CI for safety and effectiveness and met the criteria established for successfully demonstrating that EQUIOXX Tablets will be safe and effective. Therefore, EQUIOXX Tablets and EQUIOXX Oral Paste are acceptable as pharmaceutical alternatives.

There was a substantial difference in the Tmax (time to maximum plasma concentration) between EQUIOXX Oral Paste and EQUIOXX Tablets. The Tmax ranged from 0.25-4 hours for EQUIOXX Oral Paste and 0.25-12 hours for EQUIOXX Tablets. The difference in the rate and extent of absorption was greatest within the first three hours after administration. The mean terminal elimination half-life of EQUIOXX Oral Paste (45.45 hours) was similar to that of EQUIOXX Tablet (44.49 hours).

Table 2: Relative Bioavailability Results for EQUIOXX Oral Paste (Reference) and EQUIOXX Tablets (Test) (n=30 horses)
Parameter Units Reference Geometric Mean Test Geometric Mean Test/Reference Lower 90% CI Upper 90% CI
Cmax= maximum observed plasma concentrationAUClast = Area Under the Curve to the last quantifiable time pointCI= Confidence Interval

Cmax

ng/mL

78.44

58.85

0.75

67.92

82.88

AUC last

hr*ng/mL

2515.77

2336.32

0.93

86.37

99.85

The major metabolism mechanism of firocoxib in the horse is decyclopropylmethylation followed by glucuronidation of that metabolite. Based upon radiolabel studies done for the firocoxib paste formulation, the majority of firocoxib is eliminated in the urine as the decyclopropylmethylated metabolite. Despite a high degree of plasma protein binding (98%), firocoxib exhibits a large volume of distribution (mean Vd(ss) = 1652 mL/kg). The terminal elimination half-life (T1/2) in plasma averages 30-40 hours after IV, oral paste or tablet dosing. Therefore, drug accumulation occurs with repeated dose administrations and steady state concentrations are achieved beyond 6-8 daily oral doses in the horse.

Mode of Action

EQUIOXX (firocoxib) Tablets is a cyclooxygenase-inhibiting (coxib) class, non-narcotic, non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic activity1 in animal models. Based on in vitro horse data, firocoxib is a selective inhibitor of prostaglandin biosynthesis through inhibition of the inducible cyclooxygenase-2-isoenzyme (COX-2)2,3. Firocoxib selectivity for the constitutive isoenzyme, cyclooxygenase-1 (COX-1) is relatively low. However, the clinical significance of these in vitro selectivity findings has not been established.

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