FURAZOLIDONE
DESCRIPTION:
Furoxone (furazolidone) is one of the synthetic antimicrobial nitrofurans. It is
a stable, yellow, crystalline compound.
3-(5-nitrofurfurylideneamino)-2-oxazolidinone
ACTIONS/CLINICAL PHARMACOLOGY:
Furoxone has a broad antibacterial spectrum covering the majority of
gastrointestinal tract pathogens including E. Coli, staphylococci, Salmonella,
Shigella, Proteus, Aerobacter Aerogenes, Vibrio Cholerae (REF. 9,10,11) and
Giardia Lamblia. (REF. 5,6) Its bactericidal activity is based upon its
interference with several bacterial enzyme systems; this antimicrobial action
minimizes the development of resistant organisms. It neither significantly
alters the normal bowel flora nor results in fungal overgrowth. The brown color
found in the urine with adequate dosage is of no clinical significance.
INDICATIONS AND USAGE:
Indicated in the specific and symptomatic treatment of bacterial or protozoal
diarrhea and enteritis caused by susceptible organisms. Furoxone products are
well tolerated, have a very low incidence of adverse reactions.
CONTRAINDICATIONS:
1. To obviate an Antabuse(R) (disulfiram)-like reaction which may occur in some
patients, the ingestion of alcohol should be avoided during or within four days
after Furoxone therapy (see ADVERSE REACTIONS).
2. IN GENERAL, MAOI DRUGS, TYRAMINE-CONTAINING FOODS AND INDIRECTLY-ACTING
SYMPATHOMIMETIC AMINES ARE CONTRAINDICATED OR SHOULD BE USED WITH CAUTION IN
PATIENTS RECEIVING FUROXONE (SEE PRECAUTIONS).
3. INFANTS UNDER 1 MONTH SHOULD NOT RECEIVE FUROXONE (SEE ADVERSE REACTIONS AND
DOSAGE FOR CHILDREN). (REF. 4) THE FUROXONE CONCENTRATION IN THE BREAST MILK OF
LACTATING WOMEN HAS NOT BEEN DETERMINED. THEREFORE THE SAFETY IN THIS
CIRCUMSTANCE HAS NOT BEEN ESTABLISHED.
4. Prior sensitivity to Furoxone is a contraindication.
WARNINGS:
(See CONTRAINDICATIONS listed above.)
USE IN PREGNANCY: The safety of Furoxone during the childbearing age has not
been established; as with any potent antibacterial, Furoxone must be
administered with caution during the childbearing age. However, animal breeding
studies have revealed no evidence of teratogenicity following the administration
of Furoxone for long periods of time and at doses far in excess of those
recommended for the human. There have been no clinical reports regarding this
possible adverse effect on the fetus or the newborn infant.
PRECAUTIONS:
MONOAMINE OXIDASE INHIBITION: (REF. 7) Effective inhibition of monoamine oxidase
by furazolidone has been demonstrated experimentally in humans by the
enhancement of tyramine and amphetamine sensitivity and by the directly measured
monoamine oxidase inhibition.
A period of five days of furazolidone administration in the recommended doses in
these patients was required to give an enhancement of the tyramine and
amphetamine sensitivities by two to threefold. Administration of furazolidone in
the recommended dose of 400 mg/day for a period of five days should not subject
the adult patient to an undue hazard of hypertensive crisis due to monoamine
oxidase inhibition. Hypertensive crises have never been reported even after the
peroral administration of larger doses and/or for doses given over longer
periods of time. Controlled studies reveal no signs or symptoms of hypertensive
crisis even after the peroral administration of Furoxone in doses of 400 mg/day
in excess of 48 consecutive months. (REF. 8)
If administered in doses larger than recommended or in excess of five days, the
indications must be weighed against the possible hazards of hypertensive crisis
related to the accumulation of monoamine oxidase inhibition. If indications are
sufficient, the patients should be informed of drugs and foods which predispose
to hypertensive crises:
(A) Other known MAOI drugs; however, when indicated they should be prescribed
with caution and at a reduced dosage.
(B) Tyramine-containing foods such as broad beans, yeast extracts, strong
unpasteurized cheeses, beer, wine, pickled herring, chicken livers, and
fermented products are contraindicated.
(C) Indirectly-acting sympathomimetic amines such as those found in nasal
decongestants (phenylephrine, ephedrine) and anorectics (amphetamines) are
contraindicated.
(D) Likewise, sedatives, antihistamines, tranquilizers, and narcotics should be
used in reduced dosages and with caution.
Orthostatic hypotension and hypoglycemia may occur.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Furazolidone has shown
evidence of tumorigenic activity in several studies involving chronic, high-dose
oral administration to rodents. Promotion of the development of mammary
neoplasia has been demonstrated in rats of two strains. Prominent among the
findings in mice was that furazolidone caused significant increases in malignant
lung tumors. The relevance of these animal findings, particularly in
relationship to short-term therapy in humans, is not established.
DRUG INTERACTIONS:
MONOAMINE OXIDASE INHIBITION: (REF. 7) Effective inhibition of monoamine oxidase
by furazolidone has been demonstrated experimentally in man by the enhancement
of tyramine and amphetamine sensitivity and by the directly measured monoamine
oxidase inhibition.
A period of five days of furazolidone administration in the recommended doses in
these patients was required to give an enhancement of the tyramine and
amphetamine sensitivities by two to threefold. Administration of furazolidone in
the recommended dose of 400 mg/day for a period of five days should not subject
the adult patient to an undue hazard of hypertensive crisis due to monoamine
oxidase inhibition. Hypertensive crises have never been reported even after the
peroral administration of larger doses and/or for doses given over longer
periods of time. Controlled studies reveal no signs or symptoms of hypertensive
crisis even after the peroral administration of Furoxone in doses of 400 mg/day
in excess of 48 consecutive months. (REF. 8)
If administered in doses larger than recommended or in excess of five days, the
indications must be weighed against the possible hazards of hypertensive crisis
related to the accumulation of monoamine oxidase inhibition. If indications are
sufficient, the patients should be informed of drugs and foods which predispose
to hypertensive crises:
(A) Other known MAOI drugs; however, when indicated they should be prescribed
with caution and at a reduced dosage.
(B) Tyramine-containing foods such as broad beans, yeast extracts, strong
unpasteurized cheeses, beer, wine, pickled herring, chicken livers, and
fermented products are contraindicated.
(C) Indirectly-acting sympathomimetic amines such as those found in nasal
decongestants (phenylephrine, ephedrine) and anorectics (amphetamines) are
contraindicated.
(D) Likewise, sedatives, antihistamines, tranquilizers, and narcotics should be
used in reduced dosages and with caution.
Orthostatic hypotension and hypoglycemia may occur.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
A few hypersensitivity reactions to Furoxone have been reported including a fall
in blood pressure, urticaria, fever, arthralgia, and a vesicular morbilliform
rash. These reactions subsided following withdrawal of the drug.
Nausea, emesis, headache, or malaise occur occasionally and may be minimized or
eliminated by reduction in dosage or withdrawal of the drug.
Rarely, individuals receiving Furoxone have exhibited an Antabuse(R)
(disulfiram)-like reaction to alcohol characterized by flushing, slight
temperature elevation, dyspnea, and in some instances, a sense of constriction
within the chest. All symptomatology disappeared within 24 hours with no lasting
ill effects. During nine years of clinical use and approximately 3.5 million
courses of therapy (in the U.S.A. alone) in the published literature and
documented case reports 43 cases have been reported--of which 14 were produced
under experimental conditions with planned doses of the compound in excess of
those recommended.
Three of these experienced a fall in blood pressure necessitating active
therapy. Indications are that levarterenol (Levophed(R)) may be used to combat
such hypotensive episodes since human studies show that this drug is not
potentiated in patients treated with Furoxone. (Indirectly acting pressor agents
should be avoided.) The ingestion of alcohol in any form should be avoided
during Furoxone therapy and for four days thereafter to prevent this reaction.
Furoxone may cause mild reversible intravascular hemolysis in certain ethnic
groups of Mediterranean and Near-Eastern origin, and blacks. (REF. 1,3) This is
due to an intrinsic defect of red blood cell metabolism in a small percentage of
these ethnic groups, making them unusually susceptible to hemolysis by numerous
compounds. (REF. 2) It is necessary to observe such patients closely while
receiving Furoxone and to discontinue its use if there is any indication of
hemolysis.
Should not be administered to infants under 1 month of age because of the
possibility of producing a hemolytic anemia due to immature enzyme systems
(glutathione instability) in the early neonatal period. (REF. 4)
Colitis, proctitis, anal pruritus, staphylococcic enteritis, and renal or
hepatic toxicity have not been a significant problem with Furoxone.
DOSAGE AND ADMINISTRATION:
FUROXONE TABLETS, 100 mg each, are green and scored to facilitate adjustment of
dosage.
AVERAGE ADULT DOSAGE: One 100 mg tablet four times daily.
AVERAGE DOSAGE FOR CHILDREN: Those 5 years of age or older should receive 25 to
50 mg (1/4 to 1/2 tablet) four times daily. The tablet dosage may be crushed and
given in a spoonful of corn syrup.
FUROXONE LIQUID COMPOSITION: each 15 ml tablespoonful contains Furoxone 50 mg
per 15 ml (3.33 mg per ml) in a light-yellow aqueous vehicle. Suitable
flavoring, suspending and preservative agents complete the formulation. (See
Inactive Ingredients.) It is stable in storage. Prior to administering Furoxone
Liquid shake the bottle vigorously. It should be dispensed in amber bottles.
AVERAGE ADULT DOSAGE: Two tablespoonfuls four times daily.
AVERAGE DOSAGE FOR CHILDREN:
5 years or older--1/2 to 1 tablespoonful four times daily (7.5-15.0 ml)
1 to 4 years old--1 to 1 1/2 teaspoonfuls four times daily (5.0-7.5 ml)
1 month to 1 year--1/2 to 1 teaspoonful four times daily (2.5-5.0 ml)
This dosage is based on an average dose of 5 mg of Furoxone per Kg (2.3 mg per
lb) of body weight given in four equally divided doses during 24 hours. The
maximal dose of 8.8 mg of Furoxone perKg (4 mg per lb) of body weight per 24
hours should probably not be exceeded because of the possibility of producing
nausea or emesis. If these are severe, the dosage should be reduced.
The average case of diarrhea treated with Furoxone will respond within 2 to 5
days of therapy. Occasional patients may require a longer term of therapy. If
satisfactory clinical response is not obtained within 7 days it indicates that
the pathogen is refractory to Furoxone and the drug should be discontinued.
Adjunctive therapy with other antibacterial agents or bismuth salts is not
contraindicated. (N.B. Refer to WARNINGS.)
In order to administer furazolidone in doses larger than recommended or in
excess of five days the indications must be weighed against the possible hazards
of hypertensive crisis related to the accumulation of monoamine oxidase
inhibition. If indications are sufficient, the patient should be informed of
drugs and foods which predispose to hypertensive crises. (See PRECAUTIONS.)
REFERENCES:
1 Kellermeyer, R.S., Tarlov, A.R., Schrier, S.L., and Alving, A.S.J. Lab. Clin.
Med. 52:827-828 (Nov) 1958.
2 Tarlov et al. Arch. Int. Med. 109:209-234, 1962.
3 Kellermeyer et al. J.A.M.A. 180: No. 5, 388-394, 1962.
4 Zinkham, Pediatrics 23:18-32, 1959; Gross & Hurwitz, Pediatrics 22:453, 1958.
5 Fallas Vargas, M. Un Nuevo Tratamiento para la Giardiasis (A New Treatment for
Giardiasis). Rev. Med. Costa Rica 19:269-284 (July) 1962.
6 Webster, B. H. Furazolidone in the Treatment of Giardiasis. Amer. J. Dig.
Diseases 5:618-622 (July) 1960.
7 Oates, J.A., Pettinger, W.A. Inhibition of Monoamine Oxidase by Furazolidone
in Man. Data on file: Office of the Medical Director, Roberts Pharmaceutical
Corp. Available upon request.
8 Kirsner, Joseph B., M.D., Ph.D. Data on file: Office of the Medical Director,
Roberts Pharmaceutical Corp. Available upon request.
9 Neogy, K.N., et al. Furazolidone in Cholera, Journ. Indian Med. Assoc. 48:137,
1967.
10 Chaudhuri, R.N. et al. Furazolidone in Cholera. Lancet 2:909 (Oct 30) 1965.
11 Curlin, G. Comparison of Antibiotic Regimens in Cholera. Abstracts of papers,
Epidemiological Intelligence Service Conference, Atlanta, Ga., April 11-14,
1967, p. 11.
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