IPCS INCHEM Home

Warfarin

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 Brand names, 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
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
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. TOXICOLOGY
   7.1 Mode of Action
   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
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI) and other guideline levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
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 Others
      9.4.7 Endocrine & reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, 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 & 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 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER (S), DATE (S) (INCLUDING UPDATES), COMPLETE ADDRESS (ES)
    1.  NAME

        1.1  Substance

             Warfarin

        1.2  Group

             Coumarin derivative

        1.3  Synonyms

             Coumadin; Coumafene; Zoocoumarin

        1.4  Identification numbers

             1.4.1  CAS number

                    81-81-2 (unstated stereochemistry)

             1.4.2  Other numbers

                    (R)-(+)-isomer  CAS number: 5543-58-8

                    NIOSH RTECS GN4550000

        1.5  Brand names, Trade names

        1.6  Manufacturers, Importers

    2.  SUMMARY

        2.1  Main risks and target organs

             The target system is the haematological system, with
             impairment of clotting. The main risks are associated with
             potentially fatal gastrointestinal and intracerebral
             haemorrhage.

        2.2  Summary of clinical effects

             If toxic amounts have been ingested, coagulation will be
             impaired, with gum bleeding, epistaxis, ecchymosis,
             haematomata, haematemesis, melenae, haematuria.

        2.3  Diagnosis

             The diagnosis is based on history of exposure (generally
             by ingestion of a rodenticide); clinical evidence of
             bleeding, which may appear 1 to 2 days post ingestion; and
             abnormal prothrombin time.
             

             A sample of the rodenticide should be kept for toxicological
             analysis (if feasible). The most relevant biomedical analysis
             is coagulation studies including:
             
             Determination of clotting factors
             Prothrombin time (PT)
             Activated partial thromboplastin time (PTT)

        2.4  First-aid measures and management principles

             All cases of warfarin ingestion should be taken to a
             hospital for initial clinical and laboratory evaluation. If
             ingestion was recent administer activated charcoal. Gastric
             emptying is not necessary if activated charcoal can be given
             promptly, and should be avoided in patients who are already
             anticoagulated.
             
             If more than 24 hours have elapsed since ingestion,
             decontamination measures are not effective and the patient
             should be monitored closely using prothrombin time (PT) and
             plasma thromboplastin time (PTT).
             
             Treatment is based on the administration of  vitamin K1
             (phytomenadione) as indicated by the prothrombin time.
             
             Fresh frozen plasma or whole blood are indicated in cases of
             acute bleeding.
             
             Close clinical observation is essential to detect occult
             bleeding or life-threatening haemorrhage.
             
             In cases of suspected serious ingestion, vitamin K1  is
             indicated before signs and symptoms of haemorrhage
             appear.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             It may be synthesised naturally from coumarins present
             in many plants, such as sweet clover. It is usually prepared
             synthetically by the Michael condensation of benzylidene-
             acetone with 4- hydroxy-coumarin (Budavari, 1996).

        3.2  Chemical structure

             (RS)-4-hydroxy-3-(3-oxo-1-phenylbutyl)coumarin (IUPAC
             name)
             4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (CA
             name)
             
             Relative molecular mass = 308.3
             
             Molecular Formula C19H16O4
             
             Warfarin is a racemic mixture of the two optical isomers
             (Tomlin, 1994).

        3.3  Physical properties

             3.3.1  Colour

                    The racemate forms colourless crystals.

             3.3.2  State/Form

                    Solid at room temperature.

             3.3.3  Description

                    Solubility in water:    17 mg/L (20C)
                                            Sodium salt, up to 400 mg/L
                    
                    Dissolves in aqueous alkalis with the formation of
                    water soluble salts.
                    
                    Moderately soluble in metanol, ethanol, and
                    isopropanol. Acetone 65 g/L, dioxane 100 g/L (Tomlin,
                    1994).
                    
                    Melting Point 161 to 162C (Tomlin, 1994).

        3.4  Other characteristics

             Very stable, even to strong acids

    4.  USES/CIRCUMSTANCES OF POISONING

        4.1  Uses

             4.1.1  Uses

                    Anticoagulant rodenticide.
                    Therapeutic anticoagulant.

             4.1.2  Description

                    Control of rats and mice. Commercial baits are
                    usually in a concentration of 0.02% warfarin. They may
                    be formulated as corn-meal or oats, or other grains.
                    There is no tendency to bait shyness. Warfarin is no
                    longer popular as a rodenticide because rats and mice
                    have become resistant (Tomlin, 1994).
                    
                    It is available as the sodium salt of the racemic
                    mixture for use as an anticoagulant, in oral doses of
                    2 to 25 mg daily.

        4.2  High risk circumstance of poisoning

             Children may ingest baits, but single ingestions rarely
             lead to symptoms.
             
             Mislabelled warfarinised grains and flours used as food are
             likely to lead to haemorrhagic syndromes.
             
             The therapeutic use of warfarin may produce adverse effects
             and in overdose a haemorrhagic syndrome.

        4.3  Occupationally exposed populations

             Poisoning may occur in occupations involving chronic
             exposure to warfarin, eg  people manufacturing warfarin,
             formulating baits or applying the rodenticide (WHO,
             1995).

    5.  ROUTES OF ENTRY

        5.1  Oral

             This is the commonest route of entry.

        5.2  Inhalation

             Absorption occurs via the respiratory system.

        5.3  Dermal

             Moderately absorbed through intact skin.

        5.4  Eye

             No data available.

        5.5  Parenteral

             Warfarin as the sodium salt has been administered
             intravenously as a therapeutic agent.

        5.6  Others

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Gastrointestinal absorption of warfarin is rapid and
             complete.
             
             Significant transcutaneous uptake of warfarin caused many
             cases of a hemorrhagic syndrome in infants (Martin-Bouyer et
             al., 1984).

        6.2  Distribution by route of exposure

             Data from its use as a therapeutic agent show the the
             volume of distribution to be very small (0.1 to 0.2 L/kg). It
             is predominantly bound (99%) to serum albumin and other
             plasma proteins (Baselt & Cravey, 1994)

        6.3  Biological half-life by route of exposure

             The average half-life of warfarin was found to be 36
             hours in healthy volunteers; a range of 20 to 80 hours has
             been reported in volunteers (Hackett et al., 1985; O'Reilly
             et al., 1980).
             
             The half-life of warfarin after a massive overdose of 2000 mg
             in an adult was 21.7 hours (Hackett et al., 1985).  The half-
             life in another patient who overdosed on an unknown amount
             was 53 hours (Renowden et al., 1985).

        6.4  Metabolism

             Warfarin is metabolized by oxidation to 6-
             hydroxywarfarin and 7-hydroxywarfarin (both inactive
             anticoagulants), and by reduction to a pair of
             diastereoisomeric alcohols (active) (Trager et al.,
             1970).

        6.5  Elimination by route of exposure

             Less than 1% of a dose is excreted unchanged in urine,
             and essentially no unchanged warfarin is found in the faeces
             (O'Reilly et al., 1962). Urinary excretion accounted for 16
             to 43% of a single dose of the drug over a 6 day period,
             apparently as the 7-hydroxy metabolite (O'Reilly et al.,
             1963).

    7.  TOXICOLOGY

        7.1  Mode of Action

             Warfarin acts by blocking liver prothrombin production
             and by causing vascular injury at the capillary level 
             (Baselt & Cravey, 1994).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Precise toxic doses are difficult to
                             determine since there is considerable
                             interindividual variation in response.
                             Toxicity has resulted from ingesting amounts
                             ranging from 500 to 1000mg over several days
                             (Baselt & Cravey, 1994).
                             
                             The lowest toxic dose in humans ranges from
                             10 mg/kg to 15 mg/kg (RTECS, 1991).
                             
                             Large amounts of warfarin containing grain
                             bait do not usually produce significant
                             toxicity because of the small concentration
                             of the warfarin and poor absorption in large
                             amounts of grain. However, fourteen reported
                             cases of accidental poisoning in Korea
                             involved eating cornmeal containing 0.25%
                             warfarin included in rat bait. The corn meal
                             was eaten over a period of 15 days.  All 14
                             became severely ill with  hemorrhage; two of
                             the 14 died.  The estimated dosage was 1 to 2
                             mg/kg/day (Baselt & Cravey, 1994)
                             
                             Persons with a history of blood disorders
                             with bleeding tendencies would be expected to
                             be at increased risk from exposure.
                             

                             The minimum lethal exposure would depend in
                             part on whether or not an individual is on
                             anticoagulant therapy; individuals on therapy
                             would be expected to react to lower exposures
                             than non-treated persons.

                    7.2.1.2  Children

                             Extrapolation from the amount needed
                             in adults to acutely and reliably prolong the
                             PT (40 milligrams) predicts a dose of about
                             0.5 milligram/kilogram in children that would
                             be considered potentially toxic. This dose
                             resulted in PTs between 18 and 30 seconds in
                             children receiving a single loading dose
                             after heart valve surgery (Carpentieri et
                             al., 1976).
                             
                             A 20-month-old child ingested approximately
                             50 milligrams (4 milligrams/ kilogram) of
                             warfarin sodium and subsequently developed
                             prolonged PT.  The child, however, remained
                             asymptomatic with no signs of bleeding or
                             bruising (Montanio et al., 1993).
                             
                             Death can occur from significant
                             transcutaneous uptake of warfarin. In August,
                             1981, paediatric hospitals in Ho Chi Minh
                             City (formerly Saigon), Vietnam, reported 741
                             cases of a haemorrhagic syndrome in infants. 
                             The cause of this phenomenon was identified
                             as talcum powder contaminated with warfarin
                             in concentrations between 1.7 and 6.5 %.  One
                             hundred seventy-seven (177) of the 741 
                             reported cases died (Martin-Bouyer et al.,
                             1984).

             7.2.2  Relevant animal data

                    Acute oral LD50 for rats is 186 mg/kg, mice 374
                    mg/kg. Oral LD50 for rats 1, pigs 1, cats 3, dogs 3,
                    cattle 200 (all mg/kg daily for 5 days) (Tomlin,
                    1994).

             7.2.3  Relevant in vitro data

                    No data available

             7.2.4  Workplace standards

                    TLV-TWA (Threshold limit value-Time weighted
                    average) 0.1 mg/m3  in air  (ACGIH, 1992).

             7.2.5  Acceptable daily intake (ADI) and other guideline
                    levels

                    No ADI has been established for warfarin.

        7.3  Carcinogenicity

             No data available.

        7.4  Teratogenicity

             Developmental effects have been reported when warfarin
             has been administered as a therapeutic agent during
             pregnancy. There are two types of defects dependent upon the
             time of administration during pregnancy. The first, a
             characteristic embryopathy decribed by the terms "warfarin
             embryopathy" or "fetal warfarin syndrome", occurs from early,
             first-trimester use. Fetal wastage and other abnormalities,
             especially Central Nervous System anomalies, result from
             treatment later during gestation (usually the second or third
             trimesters) (WHO, 1995).
             
             Nasal hypoplasia is the most consistant feature of warfarin
             embryopathy. The other common feature is bone abnormalities
             of the axial and appendicular skeleton. Other non-skeletal
             abnormalities reported include opthalmological malformations,
             low birth weight, mental retardation, hypotonia and ear
             abnormalities (WHO, 1995)
             
             Wafarin was found to be embryotoxic and teratogenic to Wistar
             rats when administered by gavage in single doses or
             repeatedly throughout the periods of pre-implantation (1 to 7
             days of gestation) and organogenesis (8 to 16 days), and also
             throughout the whole gestation (1 to 21 days) at a wide range
             of dose levels (0.04 to 8 mg/kg body weight) (WHO,
             1995).

        7.5  Mutagenicity

             No data available.

        7.6  Interactions

             Multiple drug interactions are known to alter the
             anticoagulant effect of coumarins. A decreased anticoagulant
             effect has been reported for barbiturates, carbamazepine,
             cholestyramine, glutethimide, oral contraceptives and
             rifampicin.  An increased anticoagulant effect has  been
             reported with allopurinol, chloral hydrate, cimetidine,
             disulfiram, indomethacin, quinidine, salycilates and
             sulfonamides (Olson, 1994).

    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

                    Symptoms of poisoning usually occur after
                    repeated ingestions of warfarin. The degree of 
                    haemorrhage  depends on individual response, pre-
                    existing liver disease and current drug treatment.
                    After a variable period of time (between 1 and  7
                    days), external bleeding and internal haemorrhage may
                    occur from any site. Signs may include epistaxis,
                    gingival bleeding ( and in other miscellaneous
                    mucocutaneous sites), petechial rash, ecchymoses,
                    large haematomas (including intra-articular),
                    haematuria and melaena.

             9.1.2  Inhalation

                    Effects are similar to those of ingestion.

             9.1.3  Skin exposure

                    Human warfarin intoxication by dermal
                    absorption has been described after prolonged (>24
                    hours) upper extremity contact with an oil-based
                    warfarin solution. Two days post exposure, haematuria
                    and subcutaneous haematomas appeared, followed by
                    epistaxis and mucocutaneous bleeding from the mouth
                    (Fristedt & Sterner 1965)

             9.1.4  Eye contact

                    No data available.

             9.1.5  Parenteral exposure

                    Warfarin as the sodium salt has been
                    administered intravenously as a therapeutic agent and 
                    in an overdose situation would presumably produce
                    effects similar to those of ingestion.

             9.1.6  Other

                    No relevant data available.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Repeated ingestion of warfarin causes the same
                    haemorrhagic risks as acute exposure because of the
                    cumulative effects on serum concentrations of the
                    clotting factors.

             9.2.2  Inhalation

                    Poisoning by inhalation can occur and symptoms
                    are similar to those of ingestion.

             9.2.3  Skin exposure

                    Haematomas, epistaxis, punctate haemorrhages of
                    the palate and mouth, bleeding from the lower lip have
                    been reported following prolonged percutaneous
                    exposure (Proctor et al., 1988).

             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

             Symptoms of poisoning usually occur after repeated
             ingestions of warfarin. The degree of haemorrhage  depends on
             individual response, pre-existing liver disease and current
             drug treatment. After a variable period of time (between 1
             and  7 days), external bleeding and internal haemorrhage may
             occur from any site. Death is usually due to shock from
             intracranial haemorrhage or  massive gastrointestinal
             bleeding (WHO, 1995).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypotension may occur as a result of
                    haemorrhage due to warfarin therapy (Papagiannis et
                    al., 1995).

             9.4.2  Respiratory

                    Dysphonia, dysphagia, dyspneoa and inability to
                    clear secretions have been reported (Boster & Bergin,
                    1983).

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System  (CNS)

                             Weakness, confusion, or signs of
                             increased intracranial pressure secondary to
                             bleeding may occur. Cerebrovascular accidents
                             may occur in severe poisoning cases (WHO,
                             1995).

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             Haemarthrosis may occur and cause
                             joint pain.

             9.4.4  Gastrointestinal

                    Haematemesis and malena may occur (WHO, 1995).

             9.4.5  Hepatic

                    Although the liver is the site of metabolism of
                    warfarin, no observable clinical effects are apparent,
                    except coagulopathy.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Haematuria may be clinically evident
                             (WHO, 1995).

                    9.4.6.2  Others

                             No data available.

             9.4.7  Endocrine & reproductive systems

                    No data available.

             9.4.8  Dermatological

                    Petechial rashes may be seen.

             9.4.9  Eye, ears, nose, throat: local effects

                    Epistaxis and  gum bleeding (WHO, 1995).

             9.4.10 Haematological

                    Coagulation is impaired after ingestion of
                    significant quantities of warfarin. The usual
                    haematological symptoms gingival bleeding, epistaxis,
                    ecchymoses, haematoma, and haematuria. There may be
                    internal bleeding (WHO, 1995).

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    No data available.

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid & electrolyte disturbances

                             No data available.

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Developmental effects have been reported when
                    warfarin has been administered as a therapeutic agent
                    during pregnancy. There are two types of defects
                    dependent upon the time of administration during
                    pregnancy. The first a characteristic embryopathy
                    decribed by the terms "warfarin embryopathy" or "fetal
                    warfarin syndrome", occurs from early, first-trimester
                    use. Fetal wastage and other abnormalities, especially
                    CNS anomalies, result from treatment later during
                    gestation (usually the second or third trimesters)
                    (WHO 1995).
                    
                    Nasal hypoplasia is the most consistant feature of
                    warfarin embryopathy. The other common feature is bone
                    abnormalities of the axial and appendicular skeleton.
                    Other non-skeletal abnormalities reported include
                    opthalmological malformations, low birth weight,
                    mental retardation, hypotonia and ear abnormalities.
                    (WHO, 1995).

        9.5  Others

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             All cases of warfarin ingestion should be taken to a
             hospital for initial clinical and laboratory evaluation. If
             ingestion was recent administer activated charcoal. Gastric
             emptying is not necessary if activated charcoal can be given
             promptly, and should be avoided in patients who are already
             anticoagulated.
             
             If more than 24 hours have elapsed since ingestion,
             decontamination measures are not effective and the patient
             should be monitored closely using prothrombin time (PT) and
             plasma thromboplastin time (PTT).
             
             Treatment is based on the administration of vitamin K1
             (phytomenadione) as indicated by the prothrombin time.
             
             Fresh frozen plasma or whole blood are indicated in cases of
             acute bleeding.
             
             Close clinical observation is essential to detect occult
             bleeding or life-threatening haemorrhage.
             

             In cases of suspected serious ingestion, vitamin K1  is
             indicated before signs and symptoms of haemorrhage appear 
             (Olson 1994)

        10.2 Relevant laboratory analyses

             10.2.1 Sample collection

                    Collect a sample of the product, blood/ urine/faeces.

             10.2.2 Biomedical analysis

                    Prothrombin time (PT) monitoring is essential.
                    For the first 5 to 6 days it should be done at least
                    daily, and repeated even if results were normal upon
                    admission. Prothrombin time may initially be normal,
                    even in a severe poisoning because vitamin K-dependent
                    clotting factors have a long half-life and are still
                    circulating several hours after warfarin starts its
                    effect.
                    
                    Activated partial thromboplastin time (PTT) is
                    abnormal.
                    
                    Coagulation tests in general may be normal (e.g.
                    coagulation time, thromboelastogram).
                    
                    Haemoglobin
                    
                    Red blood count
                    
                    Urinalysis (haematuria)
                    
                    Stools

             10.2.3 Toxicological analysis

                    Although a sensitive HPLC technique exists, it
                    is not clinically useful.

             10.2.4 Other investigations

                    Specific organ evaluation for bleeding as
                    clinically indicated.

        10.3 Life supportive procedures

             Life-saving procedures are indicated if serious
             complications arise.
             
             Symptomatic treatment for bleeding is the administration of
             fresh frozen plasma or fresh whole blood for correcting
             coagulopathy.

        10.4 Decontamination

             If more than 24 hours have elapsed since exposure,
             decontamination measures are not effective and the patient
             should be monitored closely using prothrombin time (PT) and
             plasma thromboplastin time (PTT).
             
             If ingestion was recent administer activated charcoal.
             Gastric emptying is not necessary if activated charcoal can
             be given promptly, and should be avoided in patients who are
             already anticoagulated.

        10.5 Elimination

             There is no role for enhanced elimination procedures
             (Olson 1994).

        10.6 Antidote treatment

             10.6.1 Adults

                    Phytomenadione (vitamin K1) should be
                    administered. If prothrombin time is significantly
                    reduced vitamin K1 should be administered
                    intravenously starting with 10mg each 6 hours (40
                    mg/day). The intramuscular route may be chosen under
                    appropriate clinical settings. The dosage should be
                    adjusted according to the prothrombin time.

             10.6.2 Children

                    Indication and dosage is the same as in
                    adults.

        10.7 Management discussion

             There is no concensus on the appropriate administration
             schemes for vitamin K. Some authors give oral vitamin K
             prophylactically in cases where ingestion is uncertain. The
             usual route for treatment is intravenous, although in some
             cases it has been given intramuscularly or subcutaneously.
             The use of phenobarbital as an hepatic microsomal enzyme
             inducer is controversial.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             A farmer whose hands were intermittently wetted with an
             0.5% solution of warfarin over a period of 24 days developed
             gross haematuria 2 days after the last contact with the
             solution. The following day, spontaneous haematomas appeared
             on the arms and legs.  Within 4 days, other  effects included
             epistaxis, punctate haemorrhages of the palate and mouth, and
             bleeding from the lower lip. Four days later, after treatment
             for 2 days with vitamin K1, haematologic indices had returned
             to the  normal range (Proctor et al., 1988).
             
             Fourteen members of a family in the Republic of Korea were
             poisoned by eating warfarin-containing maize meal. The first
             symptoms appeared 7 to 10 days after the beginning of
             exposure and were followed by massive bruises or haemtomata
             on the buttocks in all cases (WHO, 1995).
             
             In August, 1981, paediatric hospitals in Ho Chi Minh City
             (formerly Saigon), Vietnam, reported  741 cases of a
             haemorrhagic syndrome in infants.  The cause of this
             phenomenon was identified as talcum powder contaminated with
             warfarin in concentrations between 1.7 and 6.5 percent.  One
             hundred seventy-seven (177) of the 741 reported cases died
             (Martin-Bouyer et al., 1984).
             
             A 73-year-old woman suffered from recurrent episodes of
             hypothrominaemia. Clotting tests and further investigation
             showed that this was due to a warfarin rodenticide
             intentionally mixed in the woman's cough syrup by her
             daughter-in-law (WHO, 1995).
             
             A 39-year-old female presented  with symptoms of headache,
             dyspneoa, nausea, vomiting, and double vision. She had been
             administering weekly applications of a warfarin-type rat
             poison, with her bare hands, to areas of her house.  She
             would not routinely wash her hands afterwards. The patient's
             PT and PTT were prolonged (31.1 and 59.9 seconds
             respectively). A   CT scan of her head revealed an
             intercerebellar haematoma (Abell et al., 1994).

        11.2 Internally extracted data on cases

        11.3 Internal cases

    12. ADDITIONAL INFORMATION

        12.1 Availability of antidotes

        12.2 Specific preventive measures

        12.3 Other

    13. REFERENCES

        Abell TL, Merigian KS, Lee JM et al. (1994)  Cutaneous
        exposure to warfarin-like anticoagulant  causing intracerebral
        hemorrhage:  a case report.  Clin Toxicol 32:69-73.
        
        ACGIH (1992) Documentation of the Threshold Limit Values and
        Biological Exposure Indices 6th edition volume 3, American
        Conference of Governmental Industrial Hygienists Inc.
        
        Baselt RC & Cravey RH (1994) Disposition of Toxic Drugs and
        Chemicals in Man, fourth edition, Chemical Toxicology Institute,
        Foster City, California.
        
        Boster SR & Bergin JJ (1983)  Upper airway obstruction
        complicating warfarin therapy - with a note on reversal of
        warfarin toxicity.  Ann Emerg Med 12:711-715.
        
        Budavari S (1996) The Merck Index, An encyclopedia of chemicals,
        drugs and biologicals, Twelfth edition, Merck & Co., Inc. Rahway,
        NJ., USA.
        
        Carpentieri U, Ngheim QX & Harris LC (1976)  Clinical experience
        with an oral anticoagulant in children.  Arch Dis Child 51:445-
        448.
        
        Fristedt B, Sterner N (1965) Warfarin intoxication from
        percutaneous absorption. Arch Environ Health 11:205- 208.
        
        Hackett LP, Ilett KF & Chester A (1985) Plasma warfarin
        concentrations after a massive overdose. Med J Aust  142:642-
        643.
        
        Martin-Bouyer G, Khanh NB, Linh PD et al (1984)  An epidemic of a
        "new" haemorrhagic disease in infants attributable to talcum
        powder contaminated with warfarin in Ho-Chi-Minh Ville (Vietnam). 
        Arch Toxicol  7(Suppl):494-498.
        
        Montanio CD, Wruk KM, Kulig KW et al (1993)  Acute pediatric
        warfarin (coumadin) ingestion:  toxic effects despite early
        treatment (Letter).  Am J Dis Child  147:609-610.
        
        Olson KR (1994) Poisoning and Drug Overdose, 2nd edition, Appleton
        & Lange,  Norwalk, Connecticut.
        

        O'Reilly RA, Aggeler MS, Hoag MS & Leong L (1962) Studies on the
        coumarin anticoagulant drugs: the assay of warfarin and its
        biologic application. Throm Diath Haemat 8:82-95
        
        O'Reilly RA, Aggeler MS,  & Leong L (1963) Studies on the coumarin
        anticoagulant drugs: the pharmacodynamics of warfarin in man  J
        Clin Invest 42:1542-1551.
        
        O'Reilly RA, Trager WF, Motley CH et al (1980) Interaction of
        secobarbital with warfarin pseudoracemates.  Clin Pharmacol Ther 
        28:187-195.
        
        Papagiannis A, Smith AP & Hebden MW (1993) Acute dyspnea, chest
        tightness, and anemia in a 33-year-old man.  Chest 107:863-
        865.
        
        Proctor NH, Hughes JP & Fischman ML (1988) Chemical Hazards of the
        Workplace, 2nd ed.  JB Lippincott Co, Philadelphia, PA, p 510.
        
        RTECS:  Registry of Toxic Effects of Chemical Substances. (1991)
        National Institute for Occupational Safety and Health, Cincinnati,
        OH
        
        Renowden S, Westmoreland D, White JP et al. (1985) Oral
        cholestyramine increases elimination of warfarin after overdose 
        Br Med J  291:513-514.
        
        Tomlin C (1994) The Pesticide Manual, Incorporating The
        Agrochemicals Handbook, Tenth edition British Crop protection
        Council and The Royal Society of Chemistry, UK.
        
        Trager WF, Lewis RJ & Garland (1970) Mass spectral analysis in the
        identification of human metabolites of warfarin. J Med Chem 13:
        1196-1204.
        
        WHO (1995)  Environmental health Criteria 175 Anticoagulant
        Rodenticides,  WHO, Geneva.

    14. AUTHOR(S), REVIEWER (S), DATE (S) (INCLUDING UPDATES),
        COMPLETE ADDRESS (ES)

        Authors:    Prof R Merad
                    Centre Anti-Poisons
                    Algiers
                    February, 1988
        
                    Steven K Galson
                    IPCS/WHO
                    Geneva
                    April, 1989
        

        Peer review:         Strasbourg, France, April 1990
                             Newcastle-upon-Tyne, January 1991
        
        Revision:   Dr W A Temple
                    National Toxicology Group
                    University of Otago
                    Dunedin
                    New Zealand
                    February, 1997
        
        Editor:              M.Ruse

        Finalised:           IPCS, Geneva, April 1997
    



    See Also:
       Toxicological Abbreviations
       Warfarin (HSG 96, 1995)
       Warfarin (ICSC)