[Code of Federal Regulations]
[Title 21, Volume 1]
[Revised as of April 1, 2002]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR500.27]

[Page 6-7]
 
                        TITLE 21--FOOD AND DRUGS
 
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                          SERVICES (CONTINUED)
 
PART 500--GENERAL--Table of Contents
 
        Subpart B--Specific Administrative Rulings and Decisions
 
Sec. 500.27  Methylene blue-containing drugs for use in animals.

    (a) New information requires a re- evaluation of the status of drugs 
containing methylene blue (tetramethylthionine chloride) for oral use in 
cats or dogs.
    (1)(i) It has been demonstrated that two orally administered urinary 
antiseptic-antispasmodic preparations that contained methylene blue 
cause Heinz body hemolytic anemia in cats when used according to label 
directions. The specific cause of the reaction was determined to be the 
methylene blue contained in the preparations. The reaction can be severe 
enough to cause death of treated animals.
    (ii) The Heinz body hemolytic anemia reaction to methylene blue has 
also been demonstrated in dogs under laboratory conditions. The precise 
mechanism by which methylene blue produces the characteristic 
erythrocytic inclusion bodies (Heinz bodies) and associated hemolytic 
anemia is unclear.
    (2) The effectiveness of orally administered methylene blue as a 
urinary antiseptic is open to question. It appears that following oral 
administration, methylene blue is poorly and erratically absorbed and 
also slowly and erratically excreted in the urine. Studies

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in the dog indicate it is excreted in the urine essentially as 
leukomethylene blue stabilized in some manner. Methylene blue itself is 
stepwise demethylated in alkaline solutions (alkaline urine being a 
frequent consequence of urinary infection) to Azure B, Azure A, and 
Azure C. The antiseptic efficacy of all of these excretion products is 
unsubstantiated.
    (3) In view of the foregoing, the Commissioner has concluded that 
animal drugs containing methylene blue for oral use in cats or dogs are 
neither safe nor generally recognized as effective within the meaning of 
section 201(v) of the act and are therefore considered new animal drugs. 
Accordingly, all prior formal and informal opinions expressed by the 
Food and Drug Administration that such drugs are ``not new drugs'' or 
``no longer new drugs'' are hereby revoked.
    (b) Animal drugs that contain methylene blue for oral use in cats or 
dogs and not the subject of an approved new animal drug application 
(NADA) are deemed to be adulterated under the provisions of section 
501(a) (5) and/or (6) and/or misbranded under section 502(a) of the act 
and subject to regulatory action as of April 10, 1978.
    (c) Sponsors of animal drugs that contain methylene blue for oral 
use in cats or dogs and not the subject of an approved new animal drug 
application (NADA) may submit an application in conformity with 
Sec. 514.1 of this chapter. Such applications will be processed in 
accordance with section 512 of the act. Submission of an NADA will not 
constitute grounds for continued marketing of this drug substance until 
such application is approved.
    (d) New animal drug applications required by this regulation 
pursuant to section 512 of the act shall be submitted to the Food and 
Drug Administration. Center for Veterinary Medicine, Office of New 
Animal Drug Evaluation (HFV-100), 7500 Standish Pl., Rockville, MD 
20855.

[43 FR 9803, Mar. 10, 1978; 43 FR 12310, Mar. 24, 1978, as amended at 54 
FR 18279, Apr. 28, 1989; 57 FR 6475, Feb. 25, 1992; 60 FR 38480, July 
27, 1995]