Nitrofurantoin
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Main brand names, main trade names |
| 1.6 Manufacturers, Importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Colour |
| 3.3.2 State/Form |
| 3.3.3 Description |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Storage conditions |
| 4. USES |
| 4.1 Indications |
| 4.1.1 Indications |
| 4.1.2 Description |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF EXPOSURE |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL ANALYSES & BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples & specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples & specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological Analyses and Their Interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple Qualitative Test(s) |
| 8.2.1.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.1.3 Simple Quantitative Method(s) |
| 8.2.1.4 Advanced Quantitative Method(s) |
| 8.2.2 Tests for biological specimens |
| 8.2.2.1 Simple Qualitative Test(s) |
| 8.2.2.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.2.3 Simple Quantitative Method(s) |
| 8.2.2.4 Advanced Quantitative Method(s) |
| 8.2.2.5 Other Dedicated Method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations & their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical investigations |
| 8.5 Overall Interpretation |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central Nervous System (CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Life supportive procedures and symptomatic/specific treatment |
| 10.3 Decontamination |
| 10.4 Elimination |
| 10.5 Antidote treatment |
| 10.5.1 Adults |
| 10.5.2 Children |
| 10.6 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 12. ADDITIONAL INFORMATION |
| 12.1 Specific preventive measures |
| 12.2 Other |
| 13. REFERENCES |
| 14. AUTHOR (S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESSES |
NITROFURANTOIN
International Programme on Chemical Safety
Poisons Information Monograph 377
Pharmaceutical
1. NAME
1.1 Substance
Nitrofurantoin
1.2 Group
Urological (GO4) / Urinary Antiseptic and
Antiinfective (GO4A)/ Nitrofuran-derivative
(GO4AC)
1.3 Synonyms
F-30; Furadonin; Furadonium;
1-(5-Nitro-2-furfurylideneamino)hydantoin
1.4 Identification numbers
1.4.1 CAS number
67-20-9 (anhydrous form)
1.4.2 Other numbers
CAS numbers: 17140-81-7 (monohydrate)
54-87-5 (sodium salt)
NSC 2107
1.5 Main brand names, main trade names
Furadantin, Macrodantin (Australia); Apo-Nitrofurantoin,
Macrodantin, Nephronex (Canada); Furadantine, Microdoin
(France); Cystit, Ifuran, Furadantin, Nitrofurantoin Comp.,
Nieofa, Phenurin, Spasma Nierofu, Spasma Uroclear, Uro-
Fablinen, Urospasmon, Urospasmon Sine, Urolong (Germany);
Cistofuran, Furedan, Furil, Furadantin, Neofuradantin
(Italy); Furadantin, Macrodantin (S.Africa); Furadantin MC,
Europhen TC (Netherland); Furadantin, Nifuran (New Zealand);
Chemiofuran, Furobactina, Uro-Hubber, Urogobens Antispasma
(Spain); Furadantine, Trocurine Urospasmon (Switzerland);
Furadantin (Sweden); Berkfurin, Furadantin, Macrobid,
Macrodantin, Urantoin (U.K); Furadantin, Macrodantin
(U.S.A)
1.6 Manufacturers, Importers
Apotex Inc.: Apo-Nitrofurantoin; Bamford: Nifuram; Eaton
Laboratories: Macrodantin; Hoyer: Niero; Norwich Eaton:
Furadantin; Norwich Pharmacal Company: Furadantine; Procter &
Gamble Pharm.: Furadantin, Macrobid, Macrodantin; Ratiopharm:
Nitrofurantoin Comp.; SKF: Furadantin
2. SUMMARY
2.1 Main risks and target organs
The most frequent adverse effects include anorexia,
nausea and vomiting. Nitrofurantoin has also been associated
with neurological and central nervous system, hepatic,
haematological, pulmonary and dermatological toxicity.
2.2 Summary of clinical effects
Apart from G.I.T symptoms, acute reactions as a result
of overdosage of nitrofurantoin have not been reported.
Symptoms of toxicity are generally due to hypersensitivity to
the drug.
2.3 Diagnosis
The diagnosis is based primarily on a history of
nitrofurantoin ingestion.
2.4 First aid measures and management principles
There is no specific antidote to nitrofurantoin.
Symptomatic treatment and supportive measures for airway,
breathing and circulation. Activated charcoal should be
considered for large ingestions and in patients with renal
impairment.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Nitrofurantoin is a synthetic nitrofuran derivative
which is produced by the condensation of 5-Nitro-2-
furaldehyde with 1-aminohydantoin (Gennaro, 1985).
3.2 Chemical structure
Molecular formula: C8H6N4O5
Molecular weight: 238.2
Structural name: 1-(5-nitrofurfurylideneamino) hydantoin
(Budavari, 1985; Reynolds, 1993)
3.3 Physical properties
3.3.1 Colour
Lemon yellow
3.3.2 State/Form
Solid-crystals
3.3.3 Description
Very slightly soluble in water (1 in 5000) and
alcohol (1 in 2000 in ethanol). It is soluble 1 in 16
of diethylformamide.
PKa 7.2 (at 25°C)
(British Pharmacopeia, 1993).
3.4 Other characteristics
3.4.1 Shelf-life of the substance
As a dry powder it is stable for at least 5
years. It is decomposed upon contact with metals other
than stainless steel or aluminium.
3.4.2 Storage conditions
Should be stored in air-tight containers at or
below 25°C and protected from light (Reynolds, 1993;
AFHS Drug Information, 1995).
4. USES
4.1 Indications
4.1.1 Indications
Urological
Urinary Antiseptic and Antiinfective
Nitrofuran-derivative
4.1.2 Description
In the treatment of initial or recurrent
urinary tract infections caused by susceptible gram
positive and gram negative bacteria including most
strains of E.Coli. Enterobacter and Klebsiella
spp. are less susceptible and Pseudomonas and most
strains of Proteus are resistant to
nitrofurantoin(Reynolds 1993). Nitrofurantoin is
ineffective in systemic bacterial infections in blood
or tissues outside the urinary tract (AHFS Drug
Information, 1995).
4.2 Therapeutic dosage
4.2.1 Adults
50 mg to 100 mg 4 times a day (administered
with food or milk to minimise anorexia, nausea, and
vomiting).
A usual prophylactic dose is 50 to 100 mg at bed time
(Reynolds, 1993).
4.2.2 Children
Children and infants older than 1 month of age
may receive 5 to 7 mg/ kg daily in 4 divided doses
with food or milk to minimize anorexia, nausea, and
vomiting (AFHS Drug Information, 1995).
4.3 Contraindications
Nitrofurantoin is contraindicated in patients who are
hypersensitive to the drug or to furan derivatives. It is
also relatively contraindicated in renal impairment
(creatinine clearance < 40 mL/minute), diabetes mellitus,
electrolyte imbalance, vit.B deficiency as there is an
increased risk of developing peripheral neuropathy in these
situations (AFHS Drug Information, 1995; Reynolds, 1993;
White et al., 1984). If it has to be used in these cases,
extreme care should be taken and treatment stopped at the
first sign of toxicity. Haemolysis frequently occurs in
Glucose-6-phosphate dehydrogenase deficient patients who take
nitrofurantoin. Discontinuation of the drug will often
reverse this effect. Nitrofurantoin is contraindicated in
pregnant women at term (38-42 weeks gestation) and it should
not be administered during labour or just prior to labour to
avoid precipitation of haemolytic anaemia in the neonate
(AFHS Drug Information, 1995). There is a theoretical risk of
nitrofurantoin-induced haemolytic anaemia in the newborn of
mothers with G-6-PD deficiency (D'Arcy, 1985). Neonates are
at high risk of haemolysis induced by nitrofurantoin due to
their immature enzyme systems (New Ethicals Catalogue, 1996).
5. ROUTES OF EXPOSURE
5.1 Oral
This is the most common route of entry.
5.2 Inhalation
Not applicable
5.3 Dermal
Not applicable
5.4 Eye
Not applicable
5.5 Parenteral
Not applicable
5.6 Other
No data available
6. KINETICS
6.1 Absorption by route of exposure
Nitrofurantoin is readily absorbed from the
gastrointestinal tract. Absorption occurs mainly in the small
intestine. The microcrystalline form of the drug (in
suspension, tablets or capsules) is absorbed faster than the
macrocrystalline form (in capsules). Presence of food in the
gastrointestinal tract or delayed gastric emptying increases
the extent of absorption (enhancing the dissolution rate of
the drug). Bioavailability is a mean of 87% when taken on an
empty stomach, and increases to a mean of 94% when ingested
with food (Shah & Wade, 1989). Peak plasma concentrations
following a single oral dose of 100 mg are usually attained
at 1 to 2 hours after ingestion and are a mean of 1 µg/mL
(Shah & Wade, 1989).
6.2 Distribution by route of exposure
Nitrofurantoin is 25 to 90% bound to plasma protein. It
crosses the placenta and is excreted in the milk (Reynolds,
1993). The volume of distribution is 0,6 L/kg (Ellenhorn,
1997).
6.3 Biological half-life by route of exposure
The plasma half life is approximately 20 to 60 minutes
in adults with normal renal function after a therapeutic oral
dose (D'Arcy, 1985). The half-life is prolonged in patients
with impaired renal function.
6.4 Metabolism
Approximately 2/3 of a dose is metabolized in the liver.
A small fraction is reduced to aminofurantoin (Reynolds,
1993; AFHS Drug Information, 1995).
6.5 Elimination by route of exposure
20 to 44% of an oral dose is excreted unchanged in the
urine within 24 hours. 1% is excreted as aminofurantoin.
Nitrofurantoin is dialyzable (AHFS Drug Information, 1995).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Nitrofurantoin causes hepatic injury (acute and
chronic) through an immunological or metabolic
mechanism. Cholestatic jaundice and hepatocellular
damage result in elevation of alkaline phosphatase and
aspartate transaminase levels (Hebert & Roberts,
1993). Development of antinuclear antibodies and
antismooth muscle antibodies has also been reported.
(AHFS Drug Information, 1995).
Pulmonary toxicity is attributed to nitrofurantoin
production of superoxide anion free radicals with
subsequent chain reactions and uncontrolled
destructive oxidation (Adam et al., 1990; Kurtis,
1996). Martin (1983) suggested that nitrofurantoin
mediated oxidant injury to the lung may be due to
direct cytotoxicity or indirectly through recruitment
of activated neutrophils.
Nitrofurantoin can cause an acute non-cardiogenic
pulmonary oedema, or subacute interstitial pneumonitis
which may progress to interstitial fibrosis. The acute
reaction is generally considered to be a
hypersensitivity reaction. There is evidence pointing
to an immunological mechanism for injury and an
increase in T-Lymphocytes in broncheo-alveolar lavage
(Witten, 1989).
Peripheral neuropathy is a complication of
nitrofurantoin therapy especially in patients with
pre-existing renal impairment or diabetes mellitus.
Nitrofurantoin triggers a degenerative process in the
nerve cell axon with subsequent impairment of
sensation and motor strength in the distal extent of
the axonal process (Kurtis, 1996).
7.1.2 Pharmacodynamics
Nitrofurantoin is bacteriostatic or
bacteriocidal depending on the concentration and the
susceptibility of the microorganism. Its antibacterial
activity is enhanced in an acidic pH (Reynolds, 1993;
AFHS Drug Information, 1995). It is thought that
nitrofurantoin is reduced by bacterial flavoprotein
enzymes to an active intermediate which inhibits the
microorganism's proteins, DNA, RNA and cell wall
synthesis (AHFS Drug Information, 1995).
Nitrofurantoin is active against most strains of Gram-
positive and Gram-negative urinary tract pathogens but
generally less active against most strains of
Klebsiella, Enterobacter, Pseudomonas and Proteus
(Reynolds, 1993).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Acute toxic exposures to
nitrofurantoin have not been reported and
there have been no acute ingestions causing
fatalities. No toxic or lethal levels have
been determined for nitrofurantoin. However
there are a number of adverse effects and
hypersensitivity reactions reported which
have included fatalities (Shah & Wade, 1989).
The duration of exposure before the onset of
symptoms of acute pulmonary toxicity varies
from two or three days to several weeks
(Witten, 1989).
7.2.1.2 Children
No data on acute toxicity.
7.2.2 Relevant animal data
LD50 (Intraperitoneal) mouse: 150mg/kg
LD50 (Oral) mouse: 360mg/kg
LD50 (Intraperitoneal) rat: 112 mg/kg
LD50 (Oral) rat: 604 mg/kg
Chronic low and high dose administration results in
ovarian atrophy and sterility (Kurtis, 1996).
7.2.3 Relevant in vitro data
No relevant data
7.3 Carcinogenicity
Nitrofurantoin does not appear to be carcinogenic. There
is increased ovarian cancer in mice with chronic, high dose
administration (Kurtis, 1996). It was found to be
carcinogenic in B6C3F female mice and in F344/N male rats
(Shah & Wade, 1989; AHFS Drug Inform, 1995). This should be
considered in light of the fact that other nitrofurans have
carcinogenic potential.
7.4 Teratogenicity
There is no evidence to link nitrofurantoin to birth
defects in animals or humans. However, the case of a 14 month
old girl with asymmetrical paralysis limited to the upper
limbs with signs suggesting an early prenatal onset was
reported. Nitrofurantoin - and bendectin - taken during early
pregnancy were suspected to be the cause (Shah & Wade, 1989;
Briggs et al., 1994; Ben David et al., 1995; Philpot et al.,
1995).
7.5 Mutagenicity
There is data demonstrating mutagenicity in human cells
(Shah & Wade, 1989).
7.6 Interactions
Food significantly enhances the bioavailability and
duration of the therapeutic concentration of nitrofurantoin
(D'Arcy, 1985).
Uricosuric agents (probenecid or sulfinpyrazone) may inhibit
renal excretion of nitrofurantoin and hence increase its
plasma level, reduce its effectiveness, and increase its
toxicity (AFHS Drug Information, 1995).
Antacids - specifically magnesium trisilicate - were reported
to decrease the rate and extent of nitrofurantoin absorption
through an adsorption mechanism (D'Arcy, 1985).
Quinolones antibacterial activity in vitro is antagonized
by nitrofurantoin. It is possible that this interaction could
occur in vivo as well (AFHS Drug Information 1995).
Drugs which acidify the urine decreases the excretion of
nitrofurantoin (Woodruff et al., 1961).
7.7 Main adverse effects
The most frequent adverse effects of nitrofurantoin are
anorexia, nausea, and vomiting, which are dose related (Koch-
Weser et al., 1971; Holmberg et al., 1980; Shah & Wade,
1989).
Peripheral polyneuropathy and optic neuritis are serious
adverse effects of nitrofurantoin and call for immediate
withdrawal of the drug. They occur especially in pre-existing
renal impairment and the presence of vit.B deficiency. (White
et al., 1984; D'Arcy, 1985).
Peripheral neuropathy was reported in 10 month to 18 year old
children (Corraggio, 1989).
Hepatic damage with nitrofurantoin is reversible on
discontinuation of the drug. Hepatic reactions range from
acute self-limiting hepatitis to chronic active hepatitis and
necrosis associated with long term use (Stricker et al.,
1988; Shah & Wade, 1989; Hebert & Roberts, 1993).
Pulmonary hypersensitivity reactions to nitrofurantoin can be
life threatening and nitrofurantoin should be stopped
immediately on occurance of symptoms. Impaired pulmonary
function may remain even after cessation of therapy. Deaths
as a result of cardiopulmonary collapse and of alveolar
haemorrhage have been reported (Witten, 1989; Meyer & Mayer,
1994).
Haematological disorders - and of special significance,
haemolytic anaemia associated with use in patients with G-6-
PD deficiency - have been reported in association with
nitrofurantoin use (D'Arcy, 1985). Additional haematologic
effects include leukopenia, granulocytopenia,
agranulocytosis, thrombocytopenia, and aplastic anemia (Shah
& wade, 1989).
Dermatologic reactions include Stevens Johnson syndrome and
other rashes.
8. TOXICOLOGICAL ANALYSES & BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples & specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples & specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
To 1 mL of a 0.1% w/v solution in
dimethylformamide add 0.1 mL of 0.5
methanolic potassium hydroxide. A brown
colour developes (British Pharmacopeia
1993).
8.2.1.2 Advanced Qualitative Confirmation Test(s)
The procedure is carried out
protected from bright light: Dissolve 0.12 g
nitrofurantoin in 50 mL of dimethylformamide.
Add sufficient water to produce 1000 mL and
dilute 5 mL in 100 mL with a solution
containing 1.8% w/v sodium acetate and 0.14%
v/v of glacial acetic acid . The light
absorption of the solution obtained in the
range 220 to 400 nm exhibits two maxima, at
266 nm and at 367 nm. The ratio of the
absorbance at the maximum at 367 nm to that
at the maximum at 266 nm is 1.36 to 1.42
(British Pharmacopeia, 1993).
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
The procedure is carried out
protected from bright light: Dissolve 0.12 g
nitrofurantoin in 50 mL of dimethylformamide
. Add sufficient water to produce 1000 mL and
dilute 5 mL in 100 mL with a solution
containing 1.8% w/v sodium acetate and 0.14%
v/v of glacial acetic acid. Measure the
absorbance of the resulting solution a the
maximum at 367 nm, B.P, using the sodium
acetate -acetic acid solution in the
reference cell. Calculate the content of
C8H6N4O5 taking 765 as the value of a (1%,
1cm) at the maximum at 367 nm (British
Pharmacopeia 1993).
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
Colour test: Reagent: 20% solution
of potassium hydroxide in methanol. Method:
Add few drops of the reagent to a solution of
the sample in methanol and heat to develop
the colour, if nessecary heat to boiling
point. Colour changes to yellow-orange
(British Pharmacopeia 1993).
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
Fluorescent assay of nitrofurantoin:
Dilute a sample of urine with eightfolds
distilled water. Place in a test tube and add
1 mL 0.001% sod. nitrate and 2 mL
hydrochloric acid. Add 1 mL 0.1% o-
aminothiophenol HCl. Heat at 70 C in a water
bath for 10 minutes. Cool to room temprature.
Carry out ultralight irradiation for 3
minutes. Measure the relative fluorescence
intensity with excitation and emission at 375
and 422 nm (Clark'es Isolation and
Identification of Drugs 1986).
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations & their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
Nitrofurantoin colours the urine
brown. Urine examination for red blood cells
(specially in G-6-PD defficient patients), as
haemolysis is possible in these patients.
Urine examination for crystals. Therapeutic
nitrofurantoin level in the urine is 50 to
250 mg/L after a therapeutic dose in a
patient with normal renal function. Levels
exceeding these may indicate possibility of
systemic toxicity.
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical investigations
8.5 Overall Interpretation
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
There are no reports on acute poisoning due to
overdosages. However, the most reported effects are
the gastrointestinal symptoms which are dose related.
The most frequent of the gastrointestinal effects are
anorexia, nausea and vomiting (D'Arcy, 1985).
9.1.2 Inhalation
No data available
9.1.3 Skin exposure
No data available
9.1.4 Eye contact
No data available
9.1.5 Parenteral exposure
No data available
9.1.6 Other
No data available
9.2 Chronic poisoning
9.2.1 Ingestion
Chronic ingestion of nitrofurantoin is
associated with liver reactions in susceptible
individuals in the first six months of therapy,
resulting in both acute and chronic hepatitis. It has
also been associated with allergic pneumonitis and
interstitial pulmonary fibrosis especially in the
elderly and in those who have taken the drug
previously (Stricker et al., 1988; Hebert & Roberts,
1993). Peripheral neuropathy has been reported
especially in patients with pre-existing renal
impairment (White et al., 1984). Haemolytic anemia can
result with nitrofurantoin therapy in patients with
G6-PD deficiency.
9.2.2 Inhalation
No data available
9.2.3 Skin exposure
No data available
9.2.4 Eye contact
No data available
9.2.5 Parenteral exposure
No data available
9.2.6 Other
No data available
9.3 Course, prognosis, cause of death
There are no reports of fatalities as a result of
overdosages. However, deaths have occurred following
idiosyncractic or hypersensitivity reactions in susceptible
individuals who took the drug for various lengths of time. In
most cases of toxicity, early withdrawal of the drug reverses
the course of the reaction and improves symptoms.
A number of deaths have been reported as a result of chronic
hepatitis and as a result of acute massive hepatic necrosis
caused by nitrofurantoin (Stricker et al., 1988).
Neurological toxicity of nitrofurantoin can be severe or
irreversible but rarely fatal. Pulmonary hypersensitivity may
lead to changes in ECG and may lead to cardiopulmonary
failure resulting in collapse and death. There were reports
of fatal alveolar haemorrhage following nitrofurantoin
treatment (Meyer & Meyer, 1994).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
ECG changes may occur secondary to pulmonary
toxicity (New Ethicals Catalogue, 1996).
9.4.2 Respiratory
Acute pulmonary toxicity of nitrofurantoin is
well documented. It is characterized by the onset of
fever, dyspnea and nonproductive cough. Several
relevant laboratory abnormalities have been reported
(Meyer & Meyer, 1994). The clinical course of acute
toxicity is generally that of improvement of the
symptoms and laboratory findings within days of
withdrawing the drug (Witten, 1989).
In patients taking nitrofurantoin for at least six
months, chronic pulmonary toxicity has been
documented. Pulmonary fibrosis is the usual outcome
and presents with dyspnea and persistent nonproductive
cough. On physical examination, the respiratory rate
is often increased and there is crepitous at the lung
base. Lung biopsies show interstitial fibrosis. If the
drug is withdrawn, clinical improvement follows over
months (Witten, 1989).
Pulmonary effects present as acute, or chronic
pulmonary hypersensitivity reactions. Acute reactions
often develop within 8 hours of administration of
nitrofurantoin to patients previously sensitized to
the drug or within 3 weeks in patients on chronic
therapy. These are usually accompanied by eosinophilia
and are manifest by sudden severe dyspnea, chills,
chest pain, fever and cough (Lenci et al., 1993).
Chronic pulmonary reactions usually develop after one
month of therapy. Symptoms of acute and subacute
reactions to nitrofurantoin usually resolve within 1
week to several months after discontinuation of the
drug (D'Arcy, 1985; Witten, 1989; AHFS, 1995).
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
Neurological adverse effects of
nitrofurantoin include headache, drowsiness,
vertigo, dizziness, nystagmus and benign
intracranial hypertension (Korzets et al.,
1988; Reynolds, 1993). Optic neuritis has
been reported.
9.4.3.2 Peripheral nervous system
Rare but severe and sometimes
irreversible peripheral polyneuropathy has
been reported. Initial symptoms are sensory
loss and paresthesia, usually described as
numbness and tingling. This often affects the
lower extremities and can progress to severe
muscle weakness and atrophy. A predisposing
condition in most patients is renal impairment
(D'Arcy, 1985; Witten, 1989).
9.4.3.3 Autonomic nervous system
No relevant data available
9.4.3.4 Skeletal and smooth muscle
No relevant data available
9.4.4 Gastrointestinal
Nitrofurantoin causes anorexia, nausea,
vomiting and flatulance. Diarrhoea, dyspepsia, and
abdominal pain occur less frequently (AFHS Drug
Information, 1995). These effects are more common at
daily doses greater than 7 mg/kg. Nausea and vomiting
occur less frequently when nitrofurantoin is
administered as the macrocrystals (D'Arcy, 1985).
9.4.5 Hepatic
Hepatic toxicity following nitrofurantoin
administration can occur and could be described as
idiosyncractic hypersensitivity reactions of an
immunoallergic or metabolic origin. Nitrofurantoin-
induced hepatic reactions are often reversible on
discontinuation of the drug. Cholestatic jaundice and
hepatocellular damage have been reported as well as
chronic active hepatitis. These reactions are observed
more often with chronic use. However, acute hepatic
reactions have also been reported and presented within
one to six weeks after initiation of therapy. Symptoms
include jaundice, malaise, abdominal pain, nausea,
anorexia and abnormal liver function tests (Hebert &
Roberts, 1993; Hautekeete, 1995).
9.4.6 Urinary
9.4.6.1 Renal
There are no reports to indicate
that nitrofurantoin is nephrotoxic. However,
data suggest that underlying renal impairment
predisposes to nitrofurantoin-induced
toxicity. As nitrofurantoin is renally
excreted, renal impairment will lead to
elevated serum nitrofurantoin levels and
increase its systemic toxicity (White et al.,
1984; D'Arcy, 1985).
9.4.6.2 Other
Crystaluria has been described
(McDonald & McDonald, 1976).
9.4.7 Endocrine and reproductive systems
In humans, nitrofurantoin can decrease the
sperm count (New Ethicals Catalogue, 1996).
9.4.8 Dermatological
Exfoliative dermatitis, erythema multiforme,
Stevens-Johnson syndrome, maculopapular erythematous
or eczematous eruptions and transient alopecia may
occur (AFHS Drug Information, 1995).
9.4.9 Eye, ear, nose, throat: local effects
No data available.
9.4.10 Haematological
Haematological effects include haemolytic
anaemia which is strongly associated with glucose-6-
phosphate dehydrogenase deficiency. Methemoglobinemia,
granulocytopenia, agranulocytosis, leukopenia,
thrombocytopenia, aplastic anaemia and megaloblastic
anaemia have also been reported (D'Arcy, 1985; Shah &
Wade, 1989).
9.4.11 Immunological
No relevant data available
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No relevant data available
9.4.12.2 Fluid and electrolyte disturbances
No relevant data available
9.4.12.3 Others
No relevant data available
9.4.13 Allergic reactions
Allergic skin rashes and fever may develop
and, less frequently, serious acute pulmonary
sensitivity reactions including symptoms of asthma and
oedema. Allergic pulmonary reactions following long
term treatment with nitrofurantoin have been reported
(allergic pneumonitis and interstitial pulmonary
fibrosis) (Witten, 1989). Nitrofurantoin induced lupus
erythematous skin reactions have been reported
(Selroos & Edgren, 1975).
9.4.14 Other clinical effects
No relevant data available
9.4.15 Special risks
Patients with renal impairment, Glucose-6-
phosphate dehydrogenase deficiency, diabetics,
patients with vitamine B deficiency, and taking the
drug chronically. Neonates and pregnant women since
nitrofurantoin can pass through the placenta and cause
haemolysis in the foetus. Nitrofurantoin is unsafe in
patients with porphyria (Reynolds, 1993).
9.5 Other
No data
9.6 Summary
10. MANAGEMENT
10.1 General principles
No specific antidote available. Symptomatic treatment
and supportive measures for respiratory and cardiovascular
function should be initiated in case of suspected toxicity.
10.2 Life supportive procedures and symptomatic/specific treatment
Evaluate and support airway, breathing and circulation
as needed.
10.3 Decontamination
Activated charcoal should be considered for large
ingestions, especially in patients with renal
impairment.
10.4 Elimination
There are no known methods to enhance the elimination
of nitrofurantoin.
10.5 Antidote treatment
10.5.1 Adults
No antidote available
10.5.2 Children
No antidote available
10.6 Management discussion
Management of cases is through providing supportive
treatment as there is no antidote to nitrofurantoin. Emphasis
should be on withdrawing the drug on the first sign of
toxicity.
There are no reported cases of poisoning or overdose to
provide information about specific therapy. Treatment of
methemoglobinemia with methylene blue in patients with G6-PD
deficiency is contra-indicated.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Case 1: A 40-year-old woman developed hepatic failure
after receiving nitrofurantoin 200 mg twice daily for one
month for urinary tract prophylaxis. Other causes of hepatic
failure were excluded. It was suggested that she developed
hepatic failure secondary to the use of nitrofurantoin,
ultimately necessitating orthotopic liver transplantation
(Hebert & Roberts, 1993).
Case 2: A 33-year-old woman recieved a renal transplant for
focal segmental glomerulosclerosis. Nitrofurantoin urinary
prophylaxis was started on postoperative day 13. Two days
later the patient started to complain of cough and mild
hemoptysis. Open lung biopsy was done and specimen was
examined. Clinical course, culture results and pathological
examination excluded infectious etiologies and were
consistent with a drug reaction. The report argued that
although direct lung injury may develop through
nitrofurantoin mediated production of toxic oxygen radicals,
the immunosupressant regimen may have contributed to the
induced injury to the lung endothelium (Meyer & Meyer,
1994).
Case 3: A 41-old-woman with chronic pyelitis was given
nitrofurantoin 100mg four times daily for 3 days. She
developed haemolytic anaemia associated with erythrocyte
enolase deficiency (Stefanini, 1972).
Case 4: Averbuch and Yungbluth (1990) reported a case of
alcoholism treated with nitrofurantoin which subsequently
developed fatal alveolar haemorrhage in the setting of
chronic liver impairment and coagulopathy. The symptoms of
hemoptysis began within 1 -2 days of nitrofurantoin therapy.
Autopsy revealed alveolar haemorrhage, reactive type 2
pneumonocytes and no signs of infection.
Case 5: A 43-year-old woman developed cough with hemoptysis
and dyspnea after 2 days of starting nitrofurantoin
treatment for urinary tract infection. On hospitalization, a
chest X-ray revealed a bilateral alveolar filling process,
and a blood examination showed no eosinophilia but an
elevated total count. The patient was treated with
nitrofurantoin withdrawal, steroids, cyclophosphamide and
plasmapheresis. She was discharged after 27 days in hospital
with mildly restrictive lung function (Bucknall et al.,
1987).
Case 6: A 73-year-old man developed progressive peripheral
neuropathy and cerebral dysfunction during therapy with
nitrofurantoin 400 mg daily for 15 weeks (Gaebner &
Hoerskowitz, 1973).
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
Since pulmonary and hepatic toxicities of
nitrofurantoin are usually accompanied by pulmonary symptoms
or abnormal liver function tests, it is important that the
drug is withdrawn immediately in case of such symptoms or
abnormalities. It is imperative that patients are educated
about symptoms that could indicate potential toxicity and to
stop the drug and seek medical help.
Nitrofurantoin should not be prescribed or administered to
patients with renal impairment, diabetes, and vitamin B
deficiency where it might precipitate peripheral neuropathy
in these patients.
12.2 Other
No data available.
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14. AUTHOR (S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESSES
Authors: A.Nadir, M. Kheir
National Toxicology Group. PO Box 913
Dunedin School of Medicine
Dunedin. New Zealand
Fax 64-3- 4770509
Dr Wayne A Temple
National Toxicology Group
Dunedin School of Medicine
University of Otago. PO Box 913
Dunedin. New Zealand
Phone: 64-3-4797244 E-mail: wtemple@gandalf.otago.ac.nz
Dr Nerida A Smith
School of Pharmacy
University of Otago. PO Box 913
Dunedin. New Zealand
Phone: 64-3-4797239 E-mail: nerida.smith@stonebow.otago.ac.nz
Reviewer: WA Watson, Kansas City, USA
Date: August 1997
Peer review: INTOX-10 Meeetings, Rio, 2 September 1997 (Drs M
Kowalczyk, L Lubomirov, R McKeown, P Rosen, J Szajewski, W Watson)
Finalization: MO Rambourg Schepens. M Ruse
October 1997