Microsoft word - metronidazole final 2007 2-column.doc

METRONIDAZOLE (Veterinary—Systemic)

Some commonly used brand names for human-labeled products are:
ELUS,CANHelicobacter species infections (treatment)EL—Cats and dogs: Apo-Metronidazole; Flagyl; Novonidazol; and PMS- Although the treatment of Helicobacter pylori in human gastrointestinal disease has had major clinical impact, the relationship of Helicobacter species or Helicobacter-like Note: For a listing of dosage forms and brand names by country organisms to gastric disease in cats and dogs has not been availability, see the Dosage Forms section(s). established. When evidence of infection with these organisms is found in a patient, a clinician may make a decision to treat with Category: Antibacterial (systemic); antiprotozoal.
metronidazole, in combination with other drugs, such as bismuth-containing compounds, a proton-pump inhibitor, and another antibiotic, based on the data available.{R-22-26}
Indications
ELUS,CANInfections, bacterial (treatment)EL, including Note: Metronidazole is not specifically approved for veterinary use. In ELUS,CANBone and joint infections (treatment)EL; other USP information monographs the ELUS and ELCAN ELUS,CANCentral nervous system infections (treatment)EL; designations refer to uses that are not included in U.S. and ELUS,CANIntra-abdominal infections (treatment)EL; Canadian product labeling; however, in this monograph they ELUS,CANPerioperative infections, colorectal (prophylaxis)EL; reflect the lack of veterinary products and, therefore, product ELUS,CANRespiratory tract infections, lower (treatment)EL; ELUS,CANSepticemia, bacterial (treatment)EL; or ELUS,CANSkin and soft tissue infections (treatment)EL—Cats, dogs, and General considerations
horses: Although there are insufficient clinical research data to Metronidazole is effective in the treatment of systemic and enteric establish efficacy, metronidazole is used in the treatment of many obligate anaerobic bacterial infections, including Clostridium types of anaerobic bacterial infections in animals. In human species, Fusobacterium species,{R-1} and penicillinase-producing
patients, metronidazole is indicated, usually in combination with strains of Bacteroides.{R-2; 3} Surgical therapy may be necessary to
other antibiotics, in the prevention of perioperative infections completely resolve isolated infections.{R-3}
during colorectal surgery and in the treatment of bone and joint Metronidazole is not clinically effective against facultative anaerobes infections; central nervous system infections; intra-abdominal or obligate aerobes.{R-1; 4} However, it is often combined with
infections; lower respiratory tract infections, including another antibiotic or antibiotics effective against aerobes to treat pleuropneumonia and lung abscess; septicemia; and skin and soft mixed bacterial infections.{R-2}
tissue infections caused by susceptible species, including Metronidazole is considered effective in the treatment of some Bacteroides and Clostridium species.{R-1; 4} There are limited
pharmacokinetic data and case reports available pertaining to the use of metronidazole in the treatment of these types of infections Accepted
in animals, when caused by susceptible organisms.{R-8; 9; 12; 14; 16; 19-
ELUS,CANGiardiasis (treatment)EL—Cats and dogs: Metronidazole is used to eliminate shedding of giardial cysts and treat associated ELUS,CANPeriodontal infections (treatment)EL—Cats and dogs: diarrhea in cats and dogs.{R-6; 7; 36} Environmental eradication is
Metronidazole is used in the treatment of periodontal infections in necessary for effective treatment. The infection may not be cats and dogs.{R-15; 17; 18} It may be administered for destructive
completely cleared in all animals.{R-7}
periodontal diseases as part of a treatment plan that also includes one or more of the following: dental scaling, gingival crevicular Potentially effective
lavage, periodontal surgery, or regular teeth cleaning.{R-17}
ELUS,CANAmebiasis, intestinal (treatment)EL; ELUS,CANBalantidiasis, intestinal (treatment)EL; or Regulatory Considerations
ELUS,CANTrichomoniasis, intestinal (treatment)EL—Cats and dogs: In human patients, metronidazole is used in the treatment of The Food and Drug Administration has not approved the use of susceptible Balantidium coli, Entamoeba histolytica, and me-tronidazole in animals. Federal law prohibits the extra-
Trichomonas species.{R-1; 4; 5} Metronidazole is also recommended
label use of nitroimidazoles in food-producing animals.{R-
in the treatment of enteric protozoal infections in cats and dogs, although the relationship between infection and clinical signs can Metronidazole is not approved for use in food-producing animals. ELUS,CANBowel disease, inflammatory (treatment)EL—Cats and dogs: There are no established withdrawal times. Although there are insufficient data to establish efficacy, metronidazole is used in the treatment of inflammatory bowel Chemistry
ELUS,CANColitis, antibiotic-associated (treatment)EL; or Chemical group: Nitroimidazoles.
ELUS,CANColitis, clostridial (treatment)EL—Horses: Although there are Chemical name:
insufficient data to establish efficacy, metronidazole is used in the Metronidazole—1H-Imidazole-1-ethanol, 2-methyl-5-nitro-.{R-29}
treatment of bacterial colitis caused by susceptible organisms, Metronidazole hydrochloride—1H-Imidazole-1-ethanol, 2- including Clostridium difficile.{R-10-12}
methyl-5-nitro-, hydrochloride.{R-29}
ELUS,CANEncephalopathy, hepatic (treatment)EL—Cats and dogs: Molecular formula:
Although there are insufficient data to establish efficacy, Metronidazole—C6H9N3O3.{R-29}
metronidazole is used to reduce gastrointestinal bacterial Metronidazole hydrochloride—C6H9N3O3·HCl.{R-29}
production of ammonia thought to contribute to clinical signs in Molecular weight:
Metronidazole—171.15.{R-29}
ELUS,CANEndometritis (treatment)EL—Horses: Although there are Metronidazole hydrochloride—207.61.{R-29}
insufficient data to establish efficacy, metronidazole is used in Description: Metronidazole USP—White to pale yellow, odorless
combination with other antibiotics in the treatment of crystals or crystalline powder. Is stable in air, but darkens on endometritis, including infections caused by penicillinase- exposure to light.{R-30}
producing anaerobic bacteria.{R-13}
Solubility: Metronidazole USP—Sparingly soluble in water and in
2007 The United States Pharmacopeial Convention All rights reserved. alcohol; slightly soluble in ether and in chloroform.{R-30}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance Pharmacology/Pharmacokinetics
(possible mechanism in parentheses where appropriate)—not Mechanism of action/Effect: Metronidazole is reduced as it enters
the target cell where it interacts with bacterial or protozoal DNA, Note: Combinations containing any of the following medications, causing a loss of helical structure and strand breakage in the depending on the amount present, may also interact with DNA; these effects inhibit nucleic acid synthesis and cause death (hepatic metabolism of metronidazole may be decreased when Absorption: Metronidazole is moderately well absorbed from the
metronidazole and cimetidine are used concurrently, possibly gastrointestinal tract.{R-21; 33; 37}
resulting in delayed elimination and increased serum metronidazole concentrations;{R-5} dosage of metronidazole
Distribution: Horses—In one pharmacokinetic study of horses, peak
metronidazole concentrations in peritoneal fluid, synovial fluid, and cerebrospinal fluid were 65%, 92%, and 30% of peak serum (phenobarbital may induce microsomal liver enzymes, concentrations.{R-21} With an oral dose of 7.5 mg/kg every 6
increasing metronidazole’s metabolism and resulting in a hours, endometrial penetration was poor.{R-21}
decrease in half-life and plasma concentration;{R-5} dosage of
Biotransformation: Hepatic, metabolized primarily by side-chain
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of Pharmacokinetic data:
their potential clinical significance (possible signs and, for humans, symptoms in parentheses where appropriate)—not Those indicating need for medical attention
Neurologic disturbances (ataxia, nystagmus, seizures, tremors,
Dogs{R-37}
weakness)—usually with high dosage in cats, dogs, and horses,{R-31;
32} although signs have been reported with doses as low as 30
Horses{R-33}
mg/kg.{R-41}
Those indicating need for medical attention only if they
continue or are bothersome
Anorexia; neutropenia; vomiting
Those not indicating need for medical attention
Reddish brown urine
Human side/adverse effects{R-5}
In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are included in the human monograph Metronidazole (Systemic) in USP DI Volume I; these side/adverse effects are intended for Dogs{R-37}
informational purposes only and may or may not be applicable to Horses{R-33} 25
the use of metronidazole in the treatment of animals: {R-21}† 15
Central nervous system (CNS) effects; gastrointestinal
disturbance
† Two horses with pleuropneumonia yielded similar kinetic results to Change in taste sensation; CNS toxicity, including ataxia
and encephalopathy; dark urine; dryness of mouth;
hypersensitivity; leukopenia; pancreatitis; peripheral
Precautions to Consider
neuropathy—usually with high doses or prolonged use;
Carcinogenicity/Mutagenicity
seizures—usually with high doses; thrombocytopenia—
Metronidazole has been shown to be a carcinogen in mice and rats reversible; thrombophlebitis; unpleasant or sharp metallic
with chronic oral administration. It has also been shown to be taste; urinary tract effects, including frequent or painful
mutagenic in in vitro assays.{R-1; 4}
urination and inability to control urine flow; vaginal
candidiasis
Pregnancy/Reproduction
Pregnancy—Metronidazole readily crosses the placenta and enters the Overdose
fetal circulation.{R-1} No teratogenic effects were seen in the pups
For information in cases of overdose or unintentional ingestion, of rats that had received 250 mg per kg of body weight (mg/kg) a contact the American Society for the Prevention of Cruelty to
day for 1 to 12 days, or 100 mg/kg a day for 40 days. However, Animals (ASPCA) National Animal Poison Control Center
spermatogenesis in male rats was affected by the administration of (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer.
Lactation
Lethal dose
Metronidazole is distributed into milk at concentrations similar to Dogs: 250 mg per kg of body weight (mg/kg) a day induced central plasma concentrations.{R-1; 4} Risk-benefit should be considered
nervous system dysfunction within 4 to 6 days and death within a carefully when metronidazole is used in nursing animals. week of onset of signs.{R-32}
2007 The United States Pharmacopeial Convention All rights reserved. Clinical effects of overdose
Usual dose: See Metronidazole Capsules.
The following effects have been selected on the basis of their potential Note: Cats—The typical way to give 15 mg per kg of body weight clinical significance—not necessarily inclusive: to an eight- to nine-pound cat is to administer one-fourth of Dogs, with doses of 65 to 129 mg/kg a day.{R-32}
Ataxia; head tilt; nystagmus (spontaneous, positional, vertical);
seizures
Strength(s) usually available:
Note: Neurologic effects have also been reported with doses as low as 30 mg/kg.{R-41}
Ataxia and nystagmus were noted consistently in a report on five cases of toxicosis. Signs appeared within 7 to 12 days of initiating therapy. In dogs that survived complications of 250 mg (base) (Rx) [Flagyl; GENERIC]. neurologic dysfunction, signs gradually resolved over 1 to 2 500 mg (base) (Rx) [Flagyl; GENERIC]. weeks after ending metronidazole administration.{R-32}
Oral Dosage Forms
Note: The dosing and strengths of the dosage forms available are 250 mg (base) (Rx) [Apo-Metronidazole; Novonidazol expressed in terms of metronidazole base. (scored); PMS-Metronidazole; GENERIC]. Metronidazole is not specifically approved for veterinary use. In other USP information monographs the ELUS and ELCAN Packaging and storage: Store below 40 ºC (104 ºF), preferably
designations indicate uses that are not included in U.S. and between 15 and 30 ºC (59 and 86 ºF), in a well-closed container, Canadian product labeling; however, in this monograph they unless otherwise specified by manufacturer. Store in a light- reflect the lack of veterinary products and, therefore, product Additional information: For cats, tablets should not be crushed for
METRONIDAZOLE CAPSULES
administration, because metronidazole is bitter and often Usual dose:
ELUS,CANBacterial infections, anaerobicEL; or USP requirements: Preserve in well-closed, light-resistant
Cats and dogs: Oral, 15 mg (base) per kg of body weight containers. Contain the labeled amount, within ±10%. Meet the every twelve hours.{R-38}
requirements for Identification, Dissolution (85% in 60 minutes in Horses: Oral, 15 to 25 mg (base) per kg of body weight every 0.1 N hydrochloric acid in Apparatus 1 at 100 rpm), and six hours.{R-33}
Uniformity of dosage units.{R-30}
Note: Anorexia may occur in horses treated with the above dose; therefore, some clinicians recommend Parenteral Dosage Forms
use of a lower oral dose of 10 mg per kg of body
weight every twelve hours.{R-40}
Note: The dosing and strengths of the dosage forms available are expressed in terms of metronidazole base. For susceptible gram-negative anaerobic infections in horses, one study recommended an alternative Metronidazole is not specifically approved for veterinary use. In dosage regimen of 15 mg per kg of body weight as other USP information monographs the ELUS and ELCAN an initial dose, followed by 7.5 mg per kg of body designations indicate uses that are not included in U.S. and weight every six hours.{R-21}
Canadian product labeling; however, in this monograph they reflect the lack of veterinary products and, therefore, product Contents of the capsule can be mixed with molasses or administered via nasogastric tube.{R-31; 33; 34}
ELUS,CANInflammatory bowel diseaseEL—Cats and dogs: Oral, 7.5 METRONIDAZOLE INJECTION USP
mg (base) per kg of body weight every twelve hours. Usual dose:
Note: Reliable dosing information is not available for the use of Strength(s) usually available:
parenteral metronidazole in animals. However, for situations in which oral administration is not a viable option, injectable forms are used by following dosing regimens similar to oral 375 mg (base) (Rx) [Flagyl; GENERIC]. Strength(s) usually available:
500 mg (base) (Rx) [Apo-Metronidazole; Flagyl; PMS- 500 mg (base) per 100 mL (Rx) [GENERIC]. Packaging and storage: Store below 40 ºC (104 ºF), preferably
between 15 and 30 ºC (59 and 86 ºF), in a well-closed container, unless otherwise specified by manufacturer. Store in a light- 500 mg (base) per 100 mL (Rx) [GENERIC]. Withdrawal times: There are no established withdrawal times since
USP requirements: Not in USP.{R-30}
metronidazole is not approved for use in food-producing animals. METRONIDAZOLE TABLETS USP
Packaging and storage: Store below 40 ºC (104 ºF), preferably
2007 The United States Pharmacopeial Convention All rights reserved. between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified 19. Chou S, Richards GK, Brown RA. A new approach to antibiotic by manufacturer. Protect from light. Protect from freezing. therapy in colon surgery based on bioassay tissue concentrations. Incompatibilities: Intravenous admixtures of metronidazole and
20. Piek CJ, Robben JH. Pyothorax in nine dogs. Vet Q 2000 Apr; other medications are not recommended.{R-35}
21. Specht TE, Brown MP, Gronwall RR, et al. Pharmacokinetics of Additional information: Metronidazole Injection USP is an
metronidazole and its concentration in body fluids and isotonic (297 to 310 mOsm per L), ready-to-use solution, endometrial tissues of mares. Am J Vet Res 1992 Oct; 53(10): requiring no dilution or buffering prior to administration.{R-35}
22. Neiger R, Seiler G, Schmassmann A. Use of a urea breath test to USP requirements: Preserve in single-dose containers of Type I or
evaluate short-term treatments for cats naturally infected with Type II glass, or in suitable plastic containers, protected from Helicobacter heilmannii. Am J Vet Res 1999 Jul; 60(7): 880-3. light. A sterile, isotonic, buffered solution of Metronidazole in 23. Perkins SE, Yan LL, Shen Z, et al. Use of PCR and culture to detect Helicobacter pylori in naturally infected cats following Water for Injection. Contains the labeled amount, within ±10%. triple antimicrobial therapy. Antimicrob Agents Chemother 1996 Meets the requirements for Identification, Bacterial endotoxins, pH (4.5–7.0), and Particulate matter, and for Injections.{R-30}
24. Happonen I, Linden J, Westermarck EJ. Effect of triple therapy on eradication of canine gastric helicobacters and gastric disease. Interim revision: 06/05/95; 06/20/96; 05/19/97; 7/21/98 25. Simpson KW, Strauss-Ayali D, McDonough PL, et al. Gastric function in dogs with naturally acquired gastric Helicobacter spp. infection. J Vet Intern Med 1999 Nov-Dec; 13(6): 507-15. References
26. Cornetta AM, Simpson KW, Strauss-Ayali D, et al. Use of a 1. Flagyl 375 (capsules) package insert (Pharmacia—US), Rev 9/01. [13C]urea breath test for detection of gastric infection with Downloaded from www.pharmacia.com on 4/15/02. Helicobacter spp in dogs. Am J Vet Res 1998 Nov; 59(11): 1364- 2. Boothe DM. Anaerobic infections in small animals. Probl Vet Med 27. Drugs prohibited for extra-label use in animals. In: Code of 3. Dow SW. Management of anaerobic infections. Vet Clin North Am Federal Regulations. Washington, D.C.: US Government Printing Small Anim Pract 1988 Nov; 18(6): 1167-82. Office. April 1, 2006. 21 CFR 530.41. Available at 4. Flagyl tablets package insert (Pharmacia—US), Rev 9/01. www.gpoaccess.gov/cfr/index.html. Accessed on March 5, 2007. Available at www.pfizer.com. Accessed on December 4, 2006. 28. Bartlett JG, Louie TJ, Gorbach SL, et al. Therapeutic efficacy of 5. Klasco RK, editor. USP DI Drug information for the healthcare 29 antimicrobial regimens in experimental intra-abdominal sepsis. professional. Volume I. Greenwood Village, CO: Rev Infect Dis 1981 May-Jun; 313: 535-42. 29. USP dictionary of USAN and international drug names, 2006 ed. 6. Zimmer JF. Treatment of feline giardiasis with metronidazole. Rockville, MD: The United States Pharmacopeial Convention, 7. Zimmer JF, Burrington DB. Comparison of four protocols for the 30. The United States pharmacopeia. The national formulary. USP treatment of canine giardiasis. J Am Anim Hosp Assoc 1986; 22: 30th revision (May 1, 2007). NF 25th ed (May 1, 2007). Rockville, MD: The United States Pharmacopeial Convention, 8. Tisdall PL, Hunt GB, Beck JA, et al. Management of perianal fistulae in five dogs using azathioprine and metronidazole prior to surgery. Aust Vet J 1999 Jun; 77(6): 374-8. 32. Dow SW, LeCouteur RA, Poss ML, et al. Central nervous system 9. Carlson GP, O'Brien MA. Anaerobic bacterial pneumonia with toxicosis associated with metronidazole treatment of dogs: five septicemia in two racehorses. J Am Vet Med Assoc 1990 Mar 15; cases (1984-1987). J Am Vet Med Assoc 1989; 195(3): 365-8. 33. Sweeny RW, Sweeney CR, Soma LR, et al. Pharmacokinetics of 10. Jones RL. Clostridial enterocolitis. Vet Clin North Am Equine metronidazole given to horses by intravenous and oral routes. Am 11. Weese JS, Parsons DA, Staempfli HR. Association of Clostridium 34. Sweeny RW, Sweeney CR, Weiher J. Clinical use of difficile with enterocolitis and lactose intolerance in a foal. J Am metronidazole in horses: 200 cases (1984-1989). J Am Vet Med Vet Med Assoc 1999 Jan 15; 214(2): 229-32, 205. 12. McGorum BC, Dixon PM, Smith DG. Use of metronidazole in 35. Flagyl IV and IV RTU package insert (SCS Pharmaceuticals— equine acute idiopathic toxaemic colitis. Vet Rec 1998 Jun 6; US), Rev 7/16/98. In: PDR Physician’s Desk Reference. 54th ed. 2000. Montvale, NJ: Medical Economics Company, 2000. p. 13. Ricketts SW, Mackintosh ME. Role of anaerobic bacteria in equine endometritis. J Reprod Fertil Suppl 1987; 35(2): 343-51. 36. Kirkpatrick CE, Farrell JP. Feline giardiasis: observations on 14. Mair TS. The medical management of eight horses with grade 3 natural and induced infections. Am J Vet Res 1984 Oct; 45(10): rectal tears. Equine Vet J Suppl 2000 Jun; 16(32): 104-7. 15. Heijl L, Lindhe J. Effect of selective antimicrobial therapy on 37. Neff-Davis CA, Davis LE, Gillette EL. Metronidazole: a method plaque and gingivitis in the dog. J Clin Periodontol 1980 Dec; for its determination in biological fluids and its disposition kinetics in the dog. J Vet Pharmacol Ther 1981; 4: 121-7. 16. Sweeney RW, Sweeney CR, Weiher J. Clinical use of metronidazole in horses: 200 cases (1984-1989). J Am Vet Med 39. Steinman A, Gips M, Lavy E, et al. Pharmacokinetics of metronidazole in horses after intravenous, rectal, and oral 17. Norris JM, Love DN. In vitro antimicrobial susceptibilities of administration. J Vet Pharmacol Ther 2000; 23: 353-7. three Porphyromonas spp and in vivo responses in the oral cavity of cats to selected antimicrobial agents. Aust Vet J 2000 Aug; 41. Evans J, Levesque D, Knowles K, et al. Diazepam as a treatment for metronidazole toxicosis in dogs: a retrospective study of 21 18. Heijl L, Lindhe J. The effect of metronidazole on established cases. J Vet Int Med 2003; 17(3): 304-10. gingivitis and plaque in beagle dogs. J Periodontol 1982 Mar; 53(3): 180-7. 2007 The United States Pharmacopeial Convention All rights reserved.

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