PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC: 86101-032-42 20 mL

Carprofen

** Injectable 50 mg/mL**

** Non-steroidal**

** anti-inflammatory drug**

For subcutaneous use in dogs only

** Caution:** Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Approved by FDA under ANADA # 200-777

INDICATIONS

Carprofen is indicated for the relief of pain and inflammation associated with osteoarthritis and for the control of postoperative pain associated with soft tissue and orthopedic surgeries in dogs.

CONTRAINDICATIONS

Carprofen should not be used in dogs exhibiting previous hypersensitivity to carprofen.

ADVERSE REACTIONS

During investigational studies for the caplet formulation, no clinically significant adverse reactions were reported. Some clinical signs were observed during field studies (n=297) which were similar for carprofen- and placebo- treated dogs. Incidences of the following were observed in both groups:

vomiting (4%), diarrhea (4%), changes in appetite (3%), lethargy (1 .4%), behavioral changes (1 %), and constipation (0.3%). The product vehicle served as control. There were no serious adverse events reported during clinical field studies with once daily oral administration of 2 mg/lb. The following categories of abnormal health observations were reported. The product vehicle served as control.

Percentage of Dogs with Abnormal Health Observations
****Reported in Clinical Field Study (2 mg/lb once daily)

Clinical pathology parameters listed represent reports of increases from pre- treatment values; the use of clinical judgement is necessary to determine clinical relevance (refers also to table below).

There were no serious adverse events reported during clinical field studies for the injectable formulation. The following categories of abnormal health observations were reported. Saline served as placebo control.

Percentage of Dogs with Abnormal Health Observations
****Reported in Clinical Field Studies with the Injectable

*A single dog may have experienced more than one occurrence of an event.

Post-Approval Experience

Although not all adverse reactions are reported, the following adverse reactions are based on voluntary post-approval adverse drug experience reporting. The categories of adverse reactions are listed by body system.

Gastrointestinal: Vomiting, diarrhea, constipation, inappetence, melena, hematemesis, gastrointestinal ulceration, gastrointestinal bleeding, pancreatitis.

Hepatic: lnappetence, vomiting, jaundice, acute hepatic toxicity, hepatic enzyme elevation, abnormal liver function test(s), hyperbilirubinemia, bilirubinuria, hypoalbuminemia. Approximately one-fourth of hepatic reports were in Labrador Retrievers.

Neurologic: Ataxia, paresis, paralysis, seizures, vestibular signs, disorientation.

Urinary: Hematuria, polyuria, polydipsia, urinary incontinence, urinary tract infection, azotemia, acute renal failure, tubular abnormalities including acute tubular necrosis, renal tubular acidosis, glucosuria.

Behavioral: Sedation, lethargy, hyperactivity, restlessness, aggressiveness.

Hematologic: Immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, blood loss anemia, epistaxis.

Dermatologic: Pruritus, increased shedding, alopecia, pyotraumatic moist dermatitis (hot spots), necrotizing panniculitis/vasculitis, ventral ecchymosis. In rare situations, injection site reactions including necrosis, abscess and seroma formation, and granulomas have been reported with the injectable formulation.

Immunologic or hypersensitivity: Facial swelling, hives, erythema.

In rare situations, death has been associated with some of the adverse reactions listed above.

To report suspected adverse drug events, for technical assistance or to obtain a copy of the Safety Data Sheet, contact Felix Pharmaceuticals Private Limited at 1-833-571-1525. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/reporlanimalae

SPL UNCLASSIFIED SECTION

To report suspected adverse drug events, for technical assistance or to obtain a copy of the Safety Data Sheet, contact Felix Pharmaceuticals Private Limited at 1-833-571-1525. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/reportanimalae

Approved by FDA under ANADA # 200-777

Distributed by:

Felixvet Inc.,

1300 NW Briarcliff Parkway, Suite 100,

Kansas City, Missouri 64150

Manufactured in India

Neutral Code No. PON/DRUGS/08 22 2288

Rev. November 2024

DESCRIPTION

Carprofen Injectable is a sterile solution containing carprofen, a non- steroidal anti-inflammatory drug (NSAID) of the propionic acid class that includes ibuprofen, naproxen, and ketoprofen. Carprofen is the non-proprietary designation for a substituted carbazole, 6-chloro-α- methyl-9H-carbazole-2-acetic acid. The empirical formula is C15H12ClNO2 and molecular weight 273.72.

The chemical structure of carprofen is:

Each mL of Carprofen Injectable contains 50.0 mg carprofen, 30.0 mg arginine, 88.5 mg glycocholic acid, 169.0 mg lecithin, 10.0 mg benzyl alcohol, 6.17 mg sodium hydroxide, with additional sodium hydroxide and hydrochloric acid as needed to adjust pH, and water for injection.

CLINICAL PHARMACOLOGY

Carprofen is a non-narcotic, non-steroidal anti-inflammatory agent with characteristic analgesic and antipyretic activity approximately equipotent to indomethacin in animal models.1

The mechanism of action of carprofen, like that of other NSAIDs, is believed to be associated with the inhibition of cyclooxygenase activity. Two unique cyclooxygenases have been described in mammals.2 The constitutive cyclooxygenase, COX-1, synthesizes prostaglandins necessary for normal gastrointestinal and renal function. The inducible cyclooxygenase, COX-2, generates prostaglandins involved in inflammation. Inhibition of COX-1 is thought to be associated with gastrointestinal and renal toxicity while inhibition of COX-2 provides anti-inflammatory activity. The specificity of a particular NSAID for COX-2 versus COX-1 may vary from species to species.3 ln an in vitro study using canine cell cultures, carprofen demonstrated selective inhibition of COX-2 versus COX-1.4 Clinical relevance of these data has not been shown. Carprofen has also been shown to inhibit the release of several prostaglandins in two inflammatory cell systems: rat polymorphonuclear leukocytes (PMN) and human rheumatoid synovial cells, indicating inhibition of acute (PMN system) and chronic (synovial cell system) inflammatory reactions.1

Several studies have demonstrated that carprofen has modulatory effects on both humoral and cellular immune responses.5-9 Data also indicate that carprofen inhibits the production of osteoclast-activating factor (OAF), PGE1, and PGE2 by its inhibitory effects on prostaglandin biosynthesis.1

Based upon comparison with data obtained from intravenous administration, carprofen is rapidly and nearly completely absorbed (more than 90% bioavailable) when administered orally.10 Peak blood plasma concentrations are achieved in 1-3 hours after oral administration of 1, 5, and 25 mg/kg to dogs. The mean terminal half-life of carprofen is approximately 8 hours (range 4.5-9.8 hours) after single oral doses varying from 1-35 mg/kg of body weight. After a 100 mg single intravenous bolus dose, the mean elimination half-life was approximately 11.7 hours in the dog. Carprofen is more than 99% bound to plasma protein and exhibits a very small volume of distribution. Comparison of a single 25 mg dose in Beagle dogs after subcutaneous and oral administration demonstrated that the dorsoscapular subcutaneous administration results in a slower rate of drug input (as reflected by mean peak observed concentrations) but comparable total drug absorption within a 12 hour dosing interval (as reflected by area under the curve from hours zero to 12 postdose). Carprofen is eliminated in the dog primarily by biotransformation in the liver followed by rapid excretion of the resulting metabolites (the ester glucuronide of carprofen and the ether glucuronides of 2 phenolic metabolites, 7-hydroxy carprofen and 8-hydroxy carprofen) in the feces (70-80%) and urine (10-20%). Some enterohepatic circulation of the drug is observed.

WARNINGS

Keep out of reach of children. Not for human use. Consult a physician in cases of accidental human exposure.For use in dogs only. Do not use in cats.

All dogs should undergo a thorough history and physical examination before initiation of NSAID therapy. Appropriate laboratory tests to establish hematological and serum biochemical baseline data prior to, and periodically during, administration of any NSAID should be considered.Owners should be advised to observe for signs of potential drug toxicity (seeAdverse Reactions,Animal Safely and Post-Approval Experience).

PRECAUTIONS

As a class, cyclooxygenase inhibitory NSAIDs may be associated with gastrointestinal, renal and hepatic toxicity. Effects may result from decreased prostaglandin production and inhibition of the enzyme cyclooxygenase which is responsible for the formation of prostaglandins from arachidonic acid.11-14 When NSAIDs inhibit prostaglandins that cause inflammation they may also inhibit those prostaglandins which maintain normal homeostatic function. These anti-prostaglandin effects may result in clinically significant disease in patients with underlying or pre-existing disease more often than in healthy patients.12,14 NSAID therapy could unmask occult disease which has previously been undiagnosed due to the absence of apparent clinical signs. Patients with underlying renal disease for example, may experience exacerbation or decompensation of their renal disease while on NSAID therapy.11-14 The use of parenteral fluids during surgery should be considered to reduce the potential risk of renal complications when using NSAIDs perioperatively.

Carprofen is an NSAID, and as with others in that class, adverse reactions may occur with its use. The most frequently reported effects have been gastrointestinal signs. Events involving suspected renal, hematologic, neurologic, dermatologic, and hepatic effects have also been reported. Patients at greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with renal, cardiovascular, and/or hepatic dysfunction. Concurrent administration of potentially nephrotoxic drugs should be approached cautiously, with appropriate monitoring. Concomitant use of Carprofen with other anti-inflammatory drugs, such as other NSAIDs or corticosteroids should be avoided because of the potential increase of adverse reactions, including gastrointestinal ulcerations and/or perforations. Sensitivity to drug-associated adverse reactions varies with the individual patient. Dogs that have experienced adverse reactions from one NSAID may experience adverse reactions from another NSAID. Carprofen treatment was not associated with renal toxicity or gastrointestinal ulceration in well- controlled safety studies of up to ten times the dose in healthy dogs. As with any parenterally injected product, good hygienic procedures should be used when administering Carprofen Injectable. It is suggested to use different sites for additional injections.

Carprofen is not recommended for use in dogs with bleeding disorders (e.g., Von Willebrand's disease), as safety has not been established in dogs with these disorders. The safe use of Carprofen in animals less than 6 weeks of age, pregnant dogs, dogs used for breeding purposes, or in lactating bitches has not been established. Safety has not been established for IV or IM administration. Studies to determine the activity of Carprofen when administered concomitantly with other protein-bound or similarly metabolized drugs have not been conducted. Drug compatibility should be monitored closely in patients requiring additional therapy. Such drugs commonly used include cardiac, anticonvulsant and behavioral medications. It has been suggested that treatment with carprofen may reduce the level of inhalant anesthetics needed.15 If additional pain medication is warranted after administration of the total daily dose of Carprofen, alternative analgesia should be considered. The use of another NSAID is not recommended. Consider appropriate washout times when switching from one NSAID to another or when switching from corticosteroid use to NSAID use.

HOW SUPPLIED

Carprofen Injectable is supplied in 20-mL, amber, glass, sterile, multi-dose vials.

REFERENCES

1. Baruth H, et al: In Anti-Inflammatory and Anti-Rheumatic Drugs, Vol. II, Newer Anti-Inflammatory Drugs, Rainsford KD, ed. CRC Press, Boca Raton, pp. 33-47, 1986.
2. Vane JR, Botting RM: Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol 25:102, pp. 9-21.
3. Grossman CJ, Wiseman J, Lucas FS, et al: Inhibition of constitutive and inducible cyclooxygenase activity in human platelets and mononuclear cells by NSAIDs and COX-2 inhibitors. Inflammation Research 44:253-257, 1995.
4. Ricketts AP, Lundy KM, Seibel SB: Evaluation of selective inhibition of canine cyclooxgenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J Vet Res 59:11, pp. 1441- 1446, November 1998.
5. Ceuppens JL, et al: Non-steroidal anti-inflammatory agents inhibit the synthesis of lgM rheumatoid factor in vitro. Lancet 1:528, 1982.
6. Ceuppens JL, et al: Endogenous prostaglandin E2 enhances polyclonal immunoglobulin production by ionically inhibiting T suppressor cell activity. Cell lmmunol 70:41, 1982.
7. Schleimer RP, et al: The effects of prostaglandin synthesis inhibition on the immune response. Immunopharmacology 3:205, 1981.
8. Leung KH, et al: Modulation of the development of cell mediated immunity: possible roles of the products of cyclooxgenase and lipoxygenase pathways of arachidonic acid metabolism. Int J lmmunopharmacology 4:195, 1982.
9. Veit BC: lmmunoregulatory activity of cultured-induced suppressor macrophages. Cell lmmunol 72:14, 1982.
10. Schmitt M, et al: Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs. Biopharm Drug Dispos 11 (7):585-94, 1990.
11. Kore AM: Toxicology of nonsteroidal anti-inflammatory drugs. Veterinary Clinics of North America, Small Animal Practice 20, March 1990.
12. Binns SH: Pathogenesis and pathophysiology of ischemic injury in cases of acute renal failure. Compend for Cont Ed 16: 1, January 1994.
13. Boothe DM: Prostaglandins: Physiology and clinical implications. Compend for Cont Ed 6: 11, November 1984.
14. Rubin SI: Nonsteroidal anti-inflammatory drugs, prostaglandins, and the kidney. JAVMA 188:9, May 1986.
15. Ko CH, Lange DN, Mandsager RE, et al: Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs. JAVMA217:1025-1028, 2000.