Advocin

Zoetis Inc.

ADVOCIN™(danofloxacin mesylate)

FULL PRESCRIBING INFORMATION: CONTENTS*

• CAUTION
• ADVOCIN DESCRIPTION
• INDICATIONS
• ADVOCIN DOSAGE AND ADMINISTRATION
• WARNINGS
• ANTIBACTERIAL WARNINGS
• HUMAN WARNINGS
• PRECAUTIONS
• ADVOCIN ADVERSE REACTIONS
• CLINICAL PHARMACOLOGY
  • (a) Pharmacokinetics
  • (b) Microbiology
• EFFECTIVENESS
• ANIMAL SAFETY
• TOXICOLOGY
• STORAGE INFORMATION
• HOW SUPPLIED
• CONTACT INFORMATION
• PRINCIPAL DISPLAY PANEL - 100 mL Bottle Label
• PRINCIPAL DISPLAY PANEL - 250 mL Bottle Label

FULL PRESCRIBING INFORMATION

Sterile Injectable Solution

180 mg of danofloxacin as the mesylate salt/mL

For subcutaneous use in cattle for treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica and Pasteurella multocida.

Not for use in cattle intended for dairy production or in calves to be processed for veal.

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.

ADVOCIN 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

ADVOCIN (danofloxacin) injectable solution is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica and Pasteurella multocida.

ADVOCIN DOSAGE AND ADMINISTRATION

ADVOCIN is administered subcutaneously at either 8 mg/kg of body weight (2 mL/100 lb) as a one time injection, or at 6 mg/kg of body weight (1.5 mL/100 lb) with this treatment repeated once approximately 48 hours following the first injection. Care should be taken to dose accurately. Administered dose volume should not exceed 15 mL per injection site.

ADVOCIN Dosage and Treatment Schedule

	Dose Volume (mL)
Cattle Weight (lb)	6 mg/kg, given twice, 48 hours apart	8 mg/kg given once
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	18Administered dose volume should not exceed 15 mL per injection site.
1000	15	20Administered dose volume should not exceed 15 mL per injection site.

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.

ANTIBACTERIAL WARNINGS

Use of antibacterial drugs in the absence of a susceptible bacterial infection is unlikely to provide benefit to treated animals and may increase the risk of the development of drug-resistant bacteria.

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 1-800-366-5288.

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.

ADVOCIN 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.

CLINICAL PHARMACOLOGY

(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_½ 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
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.Cmax	µg/mL	1.25	16	1.27	13
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. , 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
Clearance (CL) and Volume of distribution at steady state (VDss) were determined from data obtained after intravenous administration of a 6 mg/kg dose.VDss	L/kg	2.7	7	2.6	4
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.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 gram-negative 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) valuesThe correlation between in vitro susceptibility data and clinical effectiveness is unknown. of indicated pathogens isolated from 1996-1997 pivotal BRD treatment field studies in the U.S.

Indicated Pathogen	Number of Isolates	MIC50 The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively.(μg/ mL)	MIC90 The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively.(μg/ mL)	MIC Range (μg/ mL)
Mannheimia haemolytica	106	0.06	0.06	≤0.015 to 0.12
Pasteurella multocida	94	≤0.015	0.06	≤0.015 to 0.12

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.

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 for 6 days; 5 of 6 animals administered 30 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 treatmentrelated 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 pre-treatment 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.

NADA #141-207, Approved by FDA

Distributed by:
Zoetis Inc.
Kalamazoo, MI 49007

Use Only as Directed

CONTACT INFORMATION

To report suspected adverse effects and/or obtain a copy of the MSDS or for technical assistance, call Zoetis Inc. at 1-888-963-8471.

For a complete listing of adverse reactions for ADVOCIN Sterile Injectable Solution reported to CVM see: http://www.fda.gov/AnimalVeterinary/SafetyHealth

TAKE TIME

OBSERVE LABEL DIRECTIONS

Revised: January 2013
Made in France

8713831

PRINCIPAL DISPLAY PANEL - 100 mL Bottle Label

ADVOCIN™
(danofloxacin mesylate)

Sterile Injectable Solution

180 mg of danofloxacin as the mesylate salt/mL

For subcutaneous use in cattle for treatment of
bovine respiratory disease (BRD) associated with
Mannheimia haemolytica and Pasteurella multocida.

Not for use in cattle intended for dairy production or
in calves to be processed for veal.

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.

Net Contents: 100 mL

NADA #141-207,
Approved by FDA

zoetis

PRINCIPAL DISPLAY PANEL - 250 mL Bottle Label

ADVOCIN™
(danofloxacin mesylate)

Sterile Injectable Solution

180 mg of danofloxacin as the mesylate salt/mL

For subcutaneous use in cattle for treatment of
bovine respiratory disease (BRD) associated
with Mannheimia haemolytica and Pasteurella
multocida.

Not for use in cattle intended for dairy production or
in calves to be processed for veal.

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.

Net Contents: 250 mL

NADA #141-207,
Approved by FDA

zoetis