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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 25C)
                    (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 25C 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 g/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.

    13. REFERENCES

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        role of redox cycling in mediating the toxicity of paraquat and
        nitrofurantoin. Envir. Health Pres, 85: 113
    
        American Society of Hospital Pharmacists (1995). AHFS Drug
        Information
    
        Averbuch SD & Yungbluth P (1990) Fatal pulmonary haemorrhage due
        to nitrofurantoin. Arch Intern Med 140: 271
    
        Ben David S. et al., (1995) The safety of nitrofurantoin during
        the first trimester of pregnancy: meta analysis. Fundamental and
        Clinical Pharmacology 9 (5): 503-7
    
        Briggs GG, Freeman RK, Yaffe SJ (1994) Drugs in pregnancy and
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        Bucknall CE. et al., (1987) Non-fatal pulmonary haemorrhage
        associated with nitrofurantoin. Thorax 42: 475
    
        Budavari S. (editor) (1985) The Merck Index An Encyclopedia of
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        N.J., U.S.A
    
        Clarke CJ (1986) Clarke's: Identification and isolation of Drugs.
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        D'Arcy PF (1985) Nitrofurantoin. Drug Intelligence and Clinical
        Pharmacy, 19: 540-6
    
        Ellenhorn M (1997) Medical Toxicology. Diagnosis and treatment of
        human poisoning, New York, Elsevier Publishing
    
        Gennaro A.R. (editor) 1985) Remington Pharmaceutical Science 17th.
        ed Mack Publishing Co. Pennsylvania, U.S.A
    
        Hautekeete M.L (1995) Hepatotoxicity of antibiotics. Acta
        Gastroenterlogica Belg. 58 (3-4): 290-6
    
        Hebert M.F & Roberts J. (1993) Endstage liver disease associated
        with nitrofurantoin requiring liver transplantation. Ann
        pharmacotherapy, 27(10): 1193-4
    

        Holmberg L. et al., (1980) Adverse reaction to nitrofurantoin:
        Analysis of 921 reports. Am. J. Med. 69: 733
    
        Koch-Weser J. et al., (1971) Adverse reactions to sulfisoxamoles,
        Sulfamethoxazole and nitrofurantoin: manifestations and specific
        reaction rates during 2,118 courses of therapy. Arch. Intern. Med
        128: 399-404
    
        Kurtis D. Klaassen (edit)(1996). Casarett & Doull's Toxicology;
        The Basic Science of Poisoning. (5th.ed) The McGraw-Hill
        Companies, Inc. U.S.A
    
        Korzets A et al., (1988) Pseudo-tumor cerebri and nitrofurantoin.
        Drug Intelligence and Clinical Pharmacy  22: 345
    
        Lenci G., Muller-Quernhiem J., Loernz J., Ferlinz R. (1993)
        Pulmonary Toxicity of nitrofurantoin. Pneumologie  47 (9): 518-23
    
        Macdonald B & Macdonald T (1976) Nitrofurantoin crystaluria. Brit
        Med J 2: 1044-5
    
        Martin WJ (1983) Evidence for the oxidant injury of lung
        parenchymal cells. Amer Rev Respir Dis. 127: 482
    
        Meyer M.M. & Meyer R.J.(1994) Nitrofurantoin-induced pulmonary
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        immunosuppressive therapy: case report and review of literature.
        Journal of Urology, 152 (3): 938-40
    
        New Ethicals Catalogue (1996) Vol.33, no.1 (May 1996). Adis
        International (New Zealand)
    
        Philpot J.et al., (1995) Congenital symmetrical weakness of upper
        limbs resembling brachial plexus palsy: a possible sequel of drug
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        Reynolds J.E (editor) (1985) Martindale, The Extra Pharmacopea.
        28Th.ed. The Pharmaceutical Press. London
    
        Reynolds J.E (editor) (1993) Martindale, The Extra Pharmacopea.
        30Th.ed. The Pharmaceutical Press. London
    
        Selroos O. & Edgren J. (1975) Lupus-Like Syndrome associated with
        pulmonary reaction to nitrofurantoin. Acta Med. Scand. 197: 125-8
    
        Stefanini M. (1972) A case of haemolytic anaemia associated with
        nitrofurantoin use. American J Clin Path  58:408
    
        Stricker BHC et al., (1988) Hepatic injury associated with the use
        of nitrofurantoin: a clinicopathological study of 52 reported
        cases. Hepatology  8:599-606
    

        White WT, Harrison L & Dumas J (1984) Nitrofurantoin unmasking
        peripheral neuropathy in type2 diabetic patient. Arch Intern Med
        18: 680-7
    
        WHO (1995): Anatomical Therapeutic Chemical Clasification System
        (ATC) the WHO Collaborating Centre for Drug Statistics
        Methodology, Norwegian Medicinal Depot), Norway
    
        Witten CM. (1989) Pulmonary toxicity of nitrofurantoin. Arch Phys
        Med Rehab 70: 55-7
    
        Woodruff M.W, Malvin R.L & Thompson I.M.(1961) The renal transport
        of nitrofurantoin: Effect of acid-base balance on excretion. JAMA:
        175: 1132-5

    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
    



    See Also:
       Toxicological Abbreviations
       Nitrofurantoin (IARC Summary & Evaluation, Volume 50, 1990)