Animal NDC 54771-9847-2 Advocin

Danofloxacin Mesylate

Animal NDC Product Code 54771-9847-2

Field Name Field Value
Animal NDC Code 54771-9847-2
Proprietary Name Advocin What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.
Non-Proprietary Name Danofloxacin Mesylate What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.
Labeler Name Zoetis Inc.
Product Type Prescription Animal Drug
Active Ingredient(s)
  • Danofloxacin Mesylate
Inactive Ingredient(s)
  • PYRROLIDONE (KKL5D39EOL)
  • POVIDONE (FZ989GH94E)
  • MAGNESIUM OXIDE (3A3U0GI71G)
  • PHENOL (339NCG44TV)
  • MONOTHIOGLYCEROL (AAO1P0WSXJ)
  • WATER (059QF0KO0R)
  • PYRROLIDONE (KKL5D39EOL)
  • POVIDONE (FZ989GH94E)
  • MAGNESIUM OXIDE (3A3U0GI71G)
  • PHENOL (339NCG44TV)
  • MONOTHIOGLYCEROL (AAO1P0WSXJ)
  • WATER (059QF0KO0R)
Marketing Category NADA - NEW ANIMAL DRUG APPLICATION What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.
FDA Application Number NADA141207 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Advocin Animal Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Caution

Federal law restricts this drug to use by or on the order of a licensed veterinarian.Federal law prohibits the extra-label use of this drug in food-producing animals.

Description

ADVOCIN is a sterile injectable solution containing danofloxacin mesylate, a synthetic fluoroquinolone antimicrobial agent. Danofloxacin mesylate is the non-proprietary designation for (1S)-1cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl)-4-oxo-3-quinolone carboxylic acid monomethanesulfonate. The empirical formula is C19H20FN3O3 • CH3SO3H and the molecular weight is 453.49.Figure 1. The chemical structure of danofloxacin mesylate.Each mL contains 180 mg of danofloxacin as the mesylate salt, 200 mg 2-pyrrolidone, 50 mg polyvinyl pyrrolidone, 20.3 mg heavy magnesium oxide, 2.5 mg phenol, 5 mg monothioglycerol, hydrochloric acid or sodium hydroxide as needed to adjust pH, nitrogen headspace and water for injection, q.s.

Indications

For the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica and Pasteurella multocida in beef cattle and for the control of BRD in beef cattle at high risk of developing BRD associated with Mannheimia haemolytica and Pasteurella multocida.

Dosage And Administration

Care should be taken to dose accurately. Administered dose volume should not exceed 15 mL per injection site.Single-Dose Therapy (BRD Treatment and Control in Cattle at High Risk):Administer subcutaneously at 8 mg/kg of body weight (2 mL/100 lb) as a one-time injection.Multi-Day Therapy (BRD Treatment): Administer subcutaneously at 6 mg/kg of body weight (1.5 mL/100 lb) with this treatment repeated once approximately 48 hours following the first injection.ADVOCIN Dosage and Treatment Schedule Dose Volume (mL) Cattle Weight(lb) 6 mg/kg, given twice,48 hours apart (treatment) 8 mg/kg given once (treatment and control in cattle at high risk)  50 0.75 1 100 1.5 2 150 2.25 3 200 3 4 250 3.75 5 300 4.5 6 400 6 8 500 7.5 10 600 9 12 700 10.5 14 800 12 16Administered dose volume should not exceed 15 mL per injection site. 900 13.5 18 1000 15 20

Residue Warnings

Animals intended for human consumption must not be slaughtered within 4 days from the last treatment. Do not use in cattle intended for dairy production. A withdrawal period has not been established for this product in preruminating calves. Do not use in calves to be processed for veal.

Human Warnings

For use in animals only. Keep out of reach of children. Avoid contact with eyes. In case of contact, immediately flush eyes with copious amounts of water for 15 minutes. In case of dermal contact, wash skin with soap and water. Consult a physician if irritation persists following ocular or dermal exposures. Individuals with a history of hypersensitivity to quinolones should avoid this product. In humans, there is a risk of user photosensitization within a few hours after excessive exposure to quinolones. If excessive accidental exposure occurs, avoid direct sunlight. To report adverse reactions or to obtain a copy of the Material Safety Data Sheet (MSDS), call 1-888-963-8471.

Precautions

The effects of danofloxacin on bovine reproductive performance, pregnancy, and lactation have not been determined. Subcutaneous injection can cause a transient local tissue reaction that may result in trim loss of edible tissue at slaughter.Quinolone-class drugs should be used with caution in animals with known or suspected central nervous system (CNS) disorders. In such animals, quinolones have, in rare instances, been associated with CNS stimulation, which may lead to convulsive seizures.Quinolone-class drugs have been shown to produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature, rapidly growing animals of various species. Refer to Animal Safety for information specific to danofloxacin.

Adverse Reactions

A hypersensitivity reaction was noted in 2 healthy calves treated with ADVOCIN in a laboratory study. In one location of a multi-site field trial, one out of the 41 calves treated with 6 mg/kg q 48 hours showed lameness on Day 6 only. In this same field trial location one of 38 calves treated with 8 mg/kg once became lame 4 days after treatment and remained lame on the last day of the study (Day 10). Another calf in the same treatment group developed lameness on the last day of the study.

(A) Pharmacokinetics

Danofloxacin distributes extensively throughout the body, as evidenced by a steady state volume of distribution (VDss) in cattle exceeding 1 L/kg. Danofloxacin concentrations in the lung homogenates markedly exceed those observed in plasma, further suggesting extensive distribution to the indicated site of infection. Danofloxacin is rapidly eliminated from the body (apparent terminal elimination T. ranging from 3–6 hours), and negligible accumulation was observed when animals were dosed twice, 48 hours apart.Danofloxacin is rapidly absorbed and is highly bioavailable when administered as a subcutaneous injection in the neck. Linear pharmacokinetics has been demonstrated when danofloxacin is administered to cattle by subcutaneous injection at doses between 1.25 to 10 mg/kg.No statistically significant gender difference was observed in peak or total systemic exposure following a single subcutaneous administration of danofloxacin to heifers and steers at a dose of 6 mg/kg body weight (Table 1).Table 1. Danofloxacin pharmacokinetic values in male and female cattle (n=6/group) after a single subcutaneous injection into the lateral neck region at a dose of 6 mg danofloxacin/kg body weight Steers Heifers Mean %CVCoefficient of variation % Mean %CV AUC0-24 = area under the plasma concentration versus time curve from hr zero to hr 24 postdose. Cmax = maximum observed concentration. Tmax = time to Cmax.AUC0-24 µg × hr/mL 9.4 10 8.8 9 Bioavailability (F%) = extent of drug absorption following subcutaneous administration. Within subject F values were determined as the ratio of AUC0-inf values estimated following a 6 mg/kg dose administered by either a subcutaneous or intravenous injection.F%  92 5 87 3 Cmax µg/mL 1.25 16 1.27 13 ,Statistically significant differences in Tmax were detected between genders. Given the similarity in Cmax values, these differences are not expected to have any clinical relevance.Tmax hr 3.2 42 1.7 31 Clearance (CL) and Volume of distribution at steady state (VDss) were determined from data obtained after intravenous administration of a 6 mg/kg dose.CL L/hr 0.54 12 0.62 9 VDss L/kg 2.7 7 2.6 4 T½ hr 4.8 18 4.2 7

(B) Microbiology

Danofloxacin exerts its activity by inhibiting the bacterial DNA gyrase enzyme, thereby blocking DNA replication. Inhibition of DNA gyrase is lethal to bacteria and danofloxacin has been shown to be rapidly bactericidal. Danofloxacin is active against gramnegative and gram-positive bacteria.The Minimum Inhibitory Concentrations (MIC) of danofloxacin for pathogens isolated in natural infections from various clinical studies in North America, 1996–1997, were determined using the standardized microdilution technique (Sensititre/Alamar, Accumed International), and are shown in Table 2.. Table 2. Danofloxacin minimum inhibitory concentration (MIC) values* of indicated pathogens isolated from 1996-1997 pivotal BRD treatment field studies in the U.S.Indicated PathogenNumber of IsolatesMIC50†(μg/ mL)MIC90†(μg/ mL)MIC Range (μg/ mL)Mannheimia haemolytica1060.060.06≤0.015 to 0.12Pasteurella multocida94≤0.0150.06≤0.015 to 0.12Table 3. Danofloxacin minimum inhibitory concentration (MIC) values* of indicated pathogens isolated from 2013 pivotal field studies in the U.S. and Canada for the control of BRD in cattle at high risk of developing BRD.Indicated PathogenNumber of IsolatesMIC50†(μg/ mL)MIC90†(μg/ mL)MIC Range (μg/ mL)Mannheimia haemolytica5070.030.06≤0.008 to >8Pasteurella multocida324≤0.0080.12≤0.008 to 1.0

Effectiveness

The effectiveness of 8 mg/kg administered once and the 6 mg/kg BW alternate day regimen was confirmed in 4 well-controlled studies of naturally acquired bacterial respiratory infections in feedlot age cattle. These studies were conducted under commercial conditions at 4 locations in North America. Bacterial pathogens isolated in the clinical field trial are provided in the Microbiology section. The effectiveness of ADVOCIN for the control of BRD in cattle at high risk of developing BRD associated with Mannheimia haemolytica and Pasteurella multocida was demonstrated in a multi-site study conducted in North America. The study enrolled a total of 1,480 commercial, crossbred-beef, Holstein and Holstein-cross steer calves at high risk of developing BRD associated with M. haemolytica and P. multocida. At enrollment, calves were randomly administered a one-time subcutaneous injection of either ADVOCIN at a dosage rate of 8 mg/kg of body weight or an equivalent volume of sterile saline. Cattle were observed daily for clinical signs of BRD and were evaluated for clinical success on Day 10 posttreatment. The treatment success rate of ADVOCIN-treated calves (86.0%) was statistically significantly (p=0.0068) greater than that of saline-treated calves (76.3%) (based on back-transformed least squares means). No adverse events associated with ADVOCIN administration were reported in the study

Animal Safety

Safety studies were conducted in feeder calves using single doses of 10, 20, or 30 mg/kg for 6 consecutive days and 18, 24, or 60 mg/kg for 3 consecutive days. No clinical signs of toxicity were observed at doses of 10 and 20 mg/kg when administered for 6 days, nor at doses of 18 and 24 mg/kg when administered for 3 days. Articular cartilage lesions, consistent with fluoroquinolone chondropathy, were observed after examination of joints from animals as follows: one of 5 animals administered 18 mg/kg for 3 days; one of 6 animals administered 20 mg/kg or 6 days; 5 of 6 animals administered 0 mg/kg for 6 days; and in all 4 animals administered 60 mg/kg for 3 days. Clinical signs of inappetence, transient lameness (2/6), ataxia (2/6), tremors (2/6), nystagmus (1/6), exophthalmos (1/6), and recumbency (2/6) were observed when a dose of 30 mg/kg was administered for 6 consecutive days. Recumbency and depression were seen in one out of 4 animals administered 60 mg/kg for 3 days. Swelling at the injection site was noted at each dose level.Safety was also evaluated in 21-day-old calves. In one group, these immature animals were given injections of 6 mg/kg on study days 0, 2, 3, 5, 6, and 8. A second group of animals received injections of 18 mg/kg for a total of 2 injections 48 hours apart. The only treatment-related sign was erythema of the nasal pad in 3 of 6 calves that received 18 mg/kg. One calf in the 6 mg/kg group had pretreatment scleral erythema, and developed nasal erythema after treatment that may or may not have been treatment-related. No changes in clinical pathology parameters were observed. No articular cartilage lesions were observed in the joints at any dosage.An injection site study conducted in feeder calves demonstrated that the product can induce a transient local reaction in the subcutaneous tissue and underlying tissue.

Toxicology

Ninety-day oral toxicity studies in dogs and rats established a no observable effect level (NOEL) of 2.5 mg/ kg bw/day and 2.4 mg/kg bw/day, respectively. Higher doses in juvenile dogs produced arthropathy, a typical quinolone-associated side effect. In chronic rodent bioassays, no evidence of carcinogenicity was associated with long-term danofloxacin administration in rats and mice. No teratogenic effects were observed in rodents at doses up to 50 mg/kg bw/day (mice) or 100 mg/kg bw/ day (rats) or in rabbits at the highest dose tested of 15 mg/kg bw/day. A three-generation rat reproductive toxicity study established a NOEL of 6.25 mg/kg bw/day. Microbial safety analyses indicate that danofloxacin residues present in edible tissues of treated animals under the current use conditions would most likely not cause adverse effects on the human intestinal microflora of the consumer.

Storage Information

Store at or below 30°C (86°F). Protect from light. Protect from freezing. The color is yellow to amber and does not affect potency.

How Supplied

ADVOCIN (180 mg danofloxacin/mL) is supplied in 100- and 250-mL, amber-glass, sterile, multi-dose vials.

Contact Information

NADA #141-207, Approved by FDADistributed by:Zoetis Inc.Kalamazoo, MI 49007Use Only as DirectedCONTACT INFORMATION: To reportsuspected adverse effects and/or obtaina copy of the MSDS or for technicalassistance, call Zoetis Inc. at1-888-963-8471.For additional information about adversedrug experience reporting for animaldrugs, contact FDA at 1-888-FDA-VETSor online at http://www.fda.gov/AnimalVeterinary/SafetyHealth. TAKE TIME  OBSERVE LABELDIRECTIONS Revised: May 2014Made in France8713833

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