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
   1.7 Presentation, Formulation
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance Colour State/Form Description
      3.3.2 Properties of the locally available formulation(s)
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation(s)
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
   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
   5.1 Oral
   5.2 Inhalational
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
   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
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data Adults 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
   8.1 Methods
   8.2 Therapeutic and toxic concentration
   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 contact
      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 Central nervous system (CNS) Peripheral nervous system Autonomic nervous system Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary Renal 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 Acid-base disturbances Fluid and electrolyte disturbances Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
   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 and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
    1.  NAME
        1.1  Substance 
             Colchicine (USAN) 
        1.2  Group
              ATC classification index 
             Antigout preparations (M04) 
             Preparations with no effect on uric acid metabolism (M04AC) 
             (WHO, 1992) 
        1.3  Synonyms
             Colchicina (Italian)
             Colchicin (German)
             Colchique (French)
             NSC 757
             (To be completed by each Centre using local data) 
        1.4  Identification numbers
             1.4.1  CAS number
             1.4.2  Other numbers
                    UPDT                  8211
                    NIOSH/RTECS           GH 0700000
                    NSC                   757
        1.5  Brand names, Trade names
              Colchicine (monocomponent)
             Australia       Colgout (Protea); Colchicine (Medical
                             Research); Colcin (Knoll); Coluric (Nelson).
             Canada          Colchicine (Abbott).
             France          Colchicine (Houde ISH); Colchineos
                             (Houde ISH).
             Germany         Colchicum-Dispert (Kali-Chemie).
             South Africa    Colchicine Houdse (Roussel).
             USA             Colchicine (Abbott, Barr Lab., Danbury,
                             Lilly, Rugby, Towne, United Research
              Colchicine plus probenecid
             UK              ColBenemid (Merck Sharpe & Dohme)
             USA             ColBenemid (Merck Sharpe & Dohme);
                             Col-Probencid (Danbury, Goldline, Interstate,
                             Parmed, United Research Lab.,) Proben-C
              Colchicine associated with other compounds
             France          Colchimax - contains colchicine,
                             phenobarbitone and opium tincture
                             (Houde ISH).
             Generic products are also available.
             (To be completed by each Centre using local data)
        1.6  Manufacturers, Importers
             Biogen Laboratories, Columbia, Ethical Pharmaceuticals, 
             Fisher Scientific, Purepac, Regal Laboratories, Rondex, 
             Schein, Tourne- Paulsen, Westward, Zenith.
             (To be completed by each Centre using local data)
        1.7  Presentation, Formulation
             Colchicine is available as tablets and, in some 
             countries, as injectable solutions.
             Tablets contain mostly 0.5 to 0.65 mg.  Formulations with 1 
             mg per tablet are also available.
             Sterile solutions containing 0.5 mg/ml are also available for 
             intravenous injection.
             (To be completed by each Centre using local data)
    2.  SUMMARY
        2.1  Main risks and target organs
             Colchicine exerts a multiorgan toxicity.  The main toxic 
             effects are related to the effects of colchicine on cellular 
             division and account for diarrhoea, bone marrow depression, 
             alopecia.  Other acute effects are hypovolaemia, shock, and 
             coagulation disturbances, which may lead to death.
        2.2  Summary of clinical effects
             Toxic manifestations appear after a delay of 2 to 12 
             hours following ingestion or parenteral administration. 
             Symptomatology progresses in three stages:
              Stage I (Day 1 to 3) gastrointestinal and circulatory phase
             Severe gastrointestinal irritation: Nausea, vomiting, 
             abdominal cramps, severe diarrhoea.
             Dehydration, hypovolaemia, shock.  Cardiogenic shock may 
             occur and may result in death within the first 72 hours.
             Hypoventilation, acute respiratory distress syndrome.
              Stage II (Day 3 to 10) bone marrow aplasia phase
             Bone marrow aplasia with agranulocytosis.
             Coagulation disorders with diffuse haemorrhages.
             Polyneuritis, myopathy.
             Acute renal failure.
             Infectious complications.
              Stage III: (After 10 day) recovery phase
        2.3  Diagnosis
             Clinical diagnosis is difficult because of the 
             multiorgan toxicity.
             Colchicine levels are not clinically useful.
             Note: Biological samples must be stored in airtight 
             conditions and protected from light.
             Monitor the following: 
             Electrolytes, particularly potassium, calcium.
             Acid-base balance.
             Full blood count and platelets.
             Coagulation profile and fibrin/fibrinogen degradation 
             Creatinine phosphokinase and transaminases.
        2.4  First aid measures and management principles
             Patients with colchicine overdose should always be 
             admitted as soon as possible to an intensive care unit for a 
             minimum of 48 hours.
             Monitor vital signs (ECG, blood pressure, respiration, 
             central venous pressure), fluid and electrolyte balance, and 
             blood cells.
             Treatment may include the following:
             Rehydration, plasma expander infusion, inotropic and 
             vasopressor drugs,
             Artificial ventilation.
             Early gastric lavage.
             Correction of electrolytes and acid-base disorders.
             Early forced diuresis.
             Correction of coagulation disorders.
             Prevention of infectious complications.
        3.1  Origin of the substance
             Colchicine is an alkaloid of Colchicum autumnale (autumn 
             crocus, meadow saffron).  It was isolated in 1820 by 
             Pelletier and Caventou. Colchicum is also present in Gloriosa 
             superba (Glory Lily) (Gooneratne, 1966; Nagaratnam et al., 
             1973).  For more information see the PIM on Colchicum 
             The chemical structured was described by Dewar in 1945.  The 
             chemical synthesis was first realised by Woodward.
        3.2  Chemical structure
              Structural formula
             Molecular formula
             Molecular weight
             Structural Chemical names
             [alpha] heptalen-7-yl)acetamide.
             (Budavari, 1989; Reynolds, 1993)
             Different compounds have been isolated from Colchicum 
             autumnal. Colchicine has the most important biological 
             activity which is related to the tropolonic cycle (C).
    Biological   Substance                    R1        R2       R3      R3
    activity     name
    +++          Colchicine                   CH3       COCH3    0       OCH3
    ++           Desacetyl                    CH3       CH3      0       OCH3
                 methylcolchicine             CH3       H        0       SCH3
    ++           Desacetylthiocolchicine      C6H1105   COCH3            OCH3
    ++           Colchicoside                 CH3       H        0       OH
    +            Trimethylcolchicinic acid    CH3       COCH3    0       0
    0            Colchiceine                                     0H
        3.3  Physical properties
             3.3.1  Properties of the substance
                             Pale yellow. It darkens on exposure to light.
                             Odourless powder or scales. 
                             Melting point 153-157°C
                             pH of 0.5% solution is 5.9
                             Freely soluble in alcohol or chloroform, 
                             slightly soluble in ether (1/220) and 
                             insoluble in petroleum ether.  Solubility in 
                             water is 1/25.
             3.3.2  Properties of the locally available formulation(s)
                    To be completed by each Centre using local 
        3.4  Other characteristics
             3.4.1  Shelf-life of the substance
                    Shelf-life of the substance is three to five years.
             3.4.2  Shelf-life of the locally available formulation(s)
                    To be completed by each Centre using local data.
             3.4.3  Storage conditions
                    Store in airtight conditions and protect from light.
             3.4.4  Bioavailability
                    To be completed by each Centre using local data.
             3.4.5  Specific properties and composition
                    To be completed by each Centre using local data.
    4.  USES
        4.1  Indications
             4.1.1  Indications
                    Not relevant
             4.1.2  Description
                    Colchicine is used for acute gout attacks to reduce 
                    pain and inflammation.  It may be used on long-term 
                    basis to prevent or reduce the frequency of 
                    Familial Mediterranean Fever
                    Colchicine is used on long-term basis to prevent fever 
                    and recurrent polyserositis.  Colchicine is effective 
                    in preventing the amyloidosis in this condition.
                    Behcet's disease
                    Colchicine has been showed to be effective in the 
                    treatment of articular, cutaneous and mucosal 
                    Colchicine has been used in the treatment of 
                    scleroderma and sarcoidosis.
        4.2  Therapeutic dosage
             4.2.1  Adults
                    Acute Gout Attack
                    1 or 1.3 mg initial dose, followed by 0.5 to 0.65 mg 
                    every 1 to 2 hours (or 1 to 1.3 mg every 2 hours) 
                    until the pain is relieved or nausea and diarrhoea 
                    appear. The total dose should not exceed 10 mg over 3 
                    A course should not be repeated within three days.
                    Tolerance is usually 4 to 8 mg.
                    Intravenous injection.   Initial dose is 1 to 2 mg. 
                    The total dose is 4 mg in 24 hours or in an 
                    Prophylaxis of recurrent gout
                    0.5 mg to 0.65 mg once weekly or up to three times 
                    daily, depending on the frequency of prior acute 
                    (Reynolds 1993)
             4.2.2  Children
                    No dosage is available for use in young 
                    children (Levy, 1977).
                    A dose of 0.5 mg daily has been used in children  with 
                    familial mediterranean fever from the age of 5 years 
                    of age or under, and 1 mg daily for older children 
                    (Reynolds 1993).
        4.3  Contraindications
             Underlying disease.
             Pregnancy: There is a risk of foetal chromosomal damage 
             (Reynolds, 1989).
        5.1  Oral
             Oral absorption is the most frequent cause of 
        5.2  Inhalational
             Not relevant.
        5.3  Dermal
             Not relevant.
        5.4  Eye
             Not relevant.
        5.5  Parenteral
             Intoxications after parenteral administration are rare, 
             (Benoit et al., 1974, Jaeger et al., 1980, Liu et al., 1978), 
             however, the toxic dose appears to be lower than the oral 
             toxic dose.
             Five fatal outcomes after intravenous colchicine: the daily 
             dose was 3 to 6 mg and the total dose was 9 to 21 mg over 2 
             to 8 days.(Jaeger et al., 1980)
             A fatal bone marrow aplasia in a 70 year-old man after 10 mg 
             intravenous colchicine over 5 days (Liu et al., 1978).
        5.6  Other
             Intoxication with multisystemic reactions after 
             instillation of 50 mg colchicine into the penile urethra for 
             treatment of condyloma acuminata (Naidus et al., 1977).
    6.  KINETICS
        6.1  Absorption by route of exposure
             Rapidly absorbed from the gastro-intestinal tract.  Peak 
             plasma concentration is reached 0.5 to 2 hours after 
             ingestion (Wallace & Ertel, 1973).
             Half time of absorption is 15 minutes (Galliot, 1979).
             Absorption may be modified by pH, gastric contents, 
             intestinal motility (Wallace et al., 1970).
             Colchicine is not totally absorbed. There is an important 
             hepatic first pass effect.
        6.2  Distribution by route of exposure
             Protein binding is 10 to 20% (Bennett et al., 1980).
             Colchicine distributes in a space larger than that of the 
             body. The apparent volume of distribution is 2.2 L/kg 
             (Wallace et al., 1970). In severe renal or liver diseases the 
             volume of distribution is smaller (1.8 L/kg).
             Colchicine accumulates in kidney, liver, spleen, gastro- 
             intestinal wall and leucocytes and is apparently excluded in 
             heart, brain, skeletal muscle.
             Colchicine crosses the placenta and has also been found in 
             maternal milk.
        6.3  Biological half-life by route of exposure
             After a single 2 mg intravenous dose the average plasma half- 
             life is 20 minutes (Wallace et al., 1970).  Plasma half-life 
             is increased in severe renal disease (40 min) and decreased 
             in severe hepatic disease (9 min) (Wallace et al., 1970).
             After oral administration plasma concentrations reach a peak 
             within 0.5 to 2 hours and afterwards decrease rapidly within 
             2 hours (Wallace & Ertel, 1973).  The plasma half-life is 60 
             minutes (Galliot, 1979). Colchicine may remain in tissues for 
             as long as 10 days.
        6.4  Metabolism
             Colchicine undergoes some hepatic metabolism. 
             Colchicine is partially deacetylated in the liver (Naidus et 
             al., 1977).  Large amounts of colchicine and of its 
             metabolites undergo enterohepatic circulation.  This may 
             explain the occurrence of a second plasma peak concentration 
             observed 5 to 6 hours after ingestion (Galliot, 1979; 
             Walaszek et al., 1960).
        6.5  Elimination by route of exposure
             Colchicine is excreted unchanged (10 to 20 percent) or 
             as metabolites.
             Urinary excretion amount to 16 to 47% of an administered dose 
             (Heaney et al., 1976).  50 to 70% of colchicine is excreted 
             unchanged and 30 to 50% as metabolites.  20% of the dose 
             administered is excreted in urine in the first 24 hours and 
             27.5% in the first 48 hours.  Colchicine is detected in urine 
             up to 7 to 10 days after ingestion.  Urinary excretion is 
             increased in patients with impaired hepatic function ( 
             Wallace et al., 1970).
             10 to 25% of colchicine is excreted in the bile (Heaney et 
             al., 1976).
             Large amounts of the drug are excreted in the faeces.
              Breast Milk
             Colchicine may be eliminated in breast milk (White & White, 
             After intravenous administration 10 to 56% is excreted in the 
             faeces within the first 48 hours (Walaczek et al., 1960).
              Breast Milk
             Colchicine may be eliminated in breast milk.
        7.1  Mode of action
             7.1.1  Toxicodynamics
                    Colchicine binds to tubulin and this prevents 
                    its polymerization into microtubules.  The binding is 
                    reversible and the half-life of the colchicine-tubulin 
                    complex is 36 hours. Colchicine impairs the different 
                    cellular functions of the microtubule: separation of 
                    chromosome pairs during mitosis (because colchicine 
                    arrests mitosis in metaphase), amoeboid movements, 
                    Mitosis blockade accounts for diarrhoea, bone marrow 
                    depression and alopecia.  Colchicine may have a direct 
                    toxic effect on muscle, peripheral nervous system and 
                    liver. Inhibition of cellular function does not, 
                    however, account for all the organ failures seen in 
                    severe overdose.
             7.1.2  Pharmacodynamics
                    Gout inflammation is initiated by urate 
                    crystals within tissues. The crystals are ingested by 
                    neutrophils but this leads to the release of enzymes 
                    and the destruction of the cells. Chemotactic factors 
                    are released and attract more neutrophils. Colchicine 
                    may act by preventing phagocytosis, the release of 
                    chemotactic factors and the response of 
                    Colchicine has other properties such as antipyretic 
                    effects, respiratory depression, vasoconstriction and 
        7.2  Toxicity
             7.2.1  Human data
                             Fatalities have been reported after ingestion 
                             of 7 to 12 mg (Stapczynski et al., 1981).
                             The severity and the mortality rate of the 
                             poisoning is directly related to the dose 
                             ingested (Gaultier & Bismuth, 1978; Bismuth 
                             et al., 1977; Lambert et al., 1981).
            Dose              Symptoms                       Mortality
            absorbed                                         Rate
            <0.5             Gastrointestinal symptoms      0%
                              decrease of coagulation
            0.5-0.8           + Bone marrow aplasia          10-50%
                              + alopecia
            > 0.8            + circulatory failure          100%
                             Fatal outcomes in five patients who had 
                             received a total dose of 9 to 21 mg over two 
                             to eight days (daily dose 3 to 6 mg) (Jaeger 
                             et al., 1980).
                             A fatal bone marrow aplasia in a 70-year-old 
                             patient who had received 10 mg of intravenous 
                             colchicine over 5 days (Liu et al., 
                             The enhanced toxicity of intravenous 
                             colchicine is probably due to the higher 
                             bioavailability of colchicine after 
                             parenteral administration.
                             The toxic dose is about 0.1 mg/kg and the 
                             lethal dose is between 0.5 and 0.8 mg/kg 
                             (Besson-Leaud et al., 1977).
             7.2.2  Relevant animal data
             Species      Route              Effect    Dose (mg/kg)
             Rat          Intravenous        LD 50         1.6
             Rat          Intraperitoneal    LD 50         6.1
             Rat          Subcutaneous       LD Lo         4
             Mouse        Intravenous        LD 50         4.13
             Mouse        Intraperitoneal    LD 50         2
             Dog          Oral               LD Lo         0.125
             Dog          Subcutaneous       LD Lo         0.571
             Cat          Oral               LD Lo         0.125
             Cat          Subcutaneous       LD Lo         0.5
             Cat          Intravenous        LD 50         0.25
             (RTECS, 1979)
             7.2.3  Relevant in vitro data
                    No data available.
        7.3  Carcinogenicity
             No data available.
        7.4  Teratogenicity
             Colchicine is contraindicated in pregnancy as Down's 
             syndrome and spontaneous abortion have been reported. 
             Colchicine should be discontinued three months prior to 
             conception (Drugdex, 1989).
        7.5  Mutagenicity
             See section 9.4.7.
        7.6  Interactions
             Menta et al. (1987) reported a case of acute cyclosporin 
             nephrotoxicity induced by colchicine administration. 
             Colchicine may interfere with cyclosporin pharmacokinetics by 
             increasing cyclosporin plasma levels either by enhancing 
             cyclosporin absorption or by reducing its hepatic 
        7.7  Main adverse effects
             Gastrointestinal symptoms are a common complication of 
             chronic colchicine therapy.  Thus the dose of colchicine is 
             usually limited by gastrointestinal toxicity. 
             About 80 per cent of the patients treated with colchicine at 
             a dose of 3 to 4 mg per day develop gastrointestinal 
             disturbances (Wallace, 1980).
             Fatal outcomes have been reported after intravenous 
             colchicine therapy (see section
             The following adverse reactions have been reported during 
             colchicine treatment (Dukes, 1983):
             Vomiting, diarrhoea, abdominal discomfort, paralytic ileus, 
             malabsorption syndrome with steatorrhoea.
             Bone marrow depression with agranulocytosis, acute 
             myelomonocytic leukaemia, multiple myeloma, 
             Peripheral neuritis, myopathy, rhabdomyolysis (Riggs et al., 
             Allergic reactions are rare urticaria; oedema may be seen. 
             Alopecia has been reported after chronic treatment.
             Reproductive system
             A reversible, complete azoospermia has been reported (Merlin 
             Colchicine is capable of producing a reversible impairment of 
             vitamin B12 absorption (Webb et al, 1968).  Porphyria cutanea 
             tarda has been reported (Gossweiler, 1985).
        8.1  Methods
             Colchicine may be analysed in biological fluids by 
             different methods:
             Fluorometric method:  Fluorescence of organometallic 
             (Gallium) complexes (Bourdon & Galliot, 1976).
             Radioimmunoassay:  (Ertel et al., 1979; Scherrman et al., 
             High performance liquid chromatography: (Jarvie et al, 1979, 
             Caplan et al., 1980; Harzer, 1984; Lhermitte et al., 
             Liquid chromatography (Thompson, 1985).
        8.2  Therapeutic and toxic concentration
             Colchicine may be measured in biological fluids but 
             levels are not useful or necessary for the management of 
             colchicine poisoning.
             Plasma levels lower than 20 ng/ml at the 6th hour in severe 
             intoxications have been reported (Bourdon & Galliot 
             In an overdose with 7.5 mg, plasma levels of 21 ng/ml at the 
             6th hour and below 5 mg/ml at the 24th hour were noted 
             (Jarvie et al., 1979).
             In severe intoxications plasma levels usually range between 
             20 to 50 ng/ml during the 24 first hours.  After the 24th 
             hour only small amounts of colchicine (< 20 ng/ml) are 
             detected in plasma (Bismuth et al., 1977; Lambert et al., 
             1981; Jaeger et al., 1985).
             Post-mortem serum blood levels of 170 and 240 ng/mL (at the 
             4th and 8th hour) in 2 heroin addicts following intravenous 
             injection were reported (Harzer, 1984) .
             The following plasma levels were noted in an overdose with 31 
             mg orally: 720, 212, 132 and 120 ng/mL at the 20, 125, 305, 
             605 minutes respectively (Lhermitte et al., 1985).
             Colchicine levels in blood are higher than those in 
             In an overdose with 20 mg colchicine orally a blood level of 
             250 ng/ml at the second hour was noted (Caplan et al. 1980). 
             No colchicine could be detected at the 40th hour.
             Colchicine levels in urine range between 200 and 2500 ng/ml 
             over the first 24 hours (Bismuth et al., 1977; Lambert et al, 
             1981, Jaeger et al. 1985).
             Information was available on urinary excretion in 5 cases. 
             Concentrations in urine are 10 to 80 fold higher than those 
             in plasma. Four to 25 per cent of the dose ingested was 
             excreted in urine over three to ten days.  Excretion was 
             specially high during the first 24 hours following ingestion. 
             Colchicine is eliminated in urine up to the tenth day (Jaeger 
             et al., 1985).
              Gastric lavage fluid
             In four cases, gastric lavage performed 3 to 6 hours post 
             ingestion removed 7 to 25 per cent of the dose ingested 
             (Jaeger et al., 1985).
             In an overdose with 25 mg colchicine orally, 1.4 mg were 
             eliminated in diarrhoea on the 2nd day (Jaeger et al., 
        9.1  Acute poisoning
             9.1.1  Ingestion
                    Toxic manifestations appear after a delay of 2 
                    to 12 hours following ingestion.  The delay may be 
                    increased if other drugs decreasing gastro-intestinal 
                    motility have also been ingested (phenobarbitone, 
                    psychotropic drugs, opium derivatives). Symptomatology 
                    progresses in three stages and may include:
                    Stage I (Day 1 to 3) Gastrointestinal and circulatory 
                    Severe gastrointestinal irritation: Nausea, vomiting, 
                    abdominal cramps, severe diarrhoea.
                    Dehydration, hypovolemia, shock.  Cardiogenic shock 
                    may occur and may result in death within the first 72 
                    Hypoventilation, acute respiratory distress 
                    Stage II (Day 3 to 10) Bone marrow aplasia phase:
                    Bone marrow aplasia with agranulocytosis.
                    Coagulation disorders with diffuse haemorrhages.
                    Polyneuritis, myopathy.
                    Acute renal failure.
                    Infectious complications.
                    Stage III: (After ten days) Recovery phase:
                    (Gaultier & Bismuth, 1978, Ellenhorn & Barceloux, 
                    1988, Stapczynski et al., 1981).
             9.1.2  Inhalation
                    Not relevant.
             9.1.3  Skin exposure
                    Not relevant.
             9.1.4  Eye contact
                    Not relevant.
             9.1.5  Parenteral exposure
                    The clinical course after intravenous injection 
                    is similar to that observed after ingestion.  The time 
                    to onset of symptoms depends on the dose and rate of 
                    injection but gastro-intestinal symptoms usually 
                    appear two to six days after the beginning of 
                    colchicine therapy.
                    Two cases of lethal overdose after a single 
                    intravenous injection of 30 mg colchicine were 
                    reported; gastro-intestinal symptoms appeared 2 hours 
                    after injection (Michaux et al., 1972) .
             9.1.6  Other
                    An intoxication with multisystemic reactions 
                    after instillation of 50 mg colchicine into the penile 
                    urethra for treatment of condyloma acuminata has been 
                    reported. (Naidus et al., 1977)
        9.2  Chronic poisoning
             9.2.1  Ingestion
                    Chronic administration of colchicine may induce 
                    similar toxicity to that seen in acute poisoning: 
                    gastro-intestinal symptoms (vomiting, diarrhoea), 
                    agranulocytosis, aplastic anaemia, myopathy (Gilman et 
                    al., 1985)
             9.2.2  Inhalation
                    No data available.
             9.2.3  Skin contact
                    No data available.
             9.2.4  Eye contact
                    No data available.
             9.2.5  Parenteral exposure
                    Similar to acute poisoning.
             9.2.6  Other
                    No data available.
        9.3  Course, prognosis, cause of death
             See section 9.1.1.
             Prognosis is related to the dose ingested (see section 
             Occurrence of cardiogenic shock indicates a poor prognosis 
             (Sauder et al., 1983).
             If the patient has recovered from aplasia and has not 
             developed acute respiratory distress syndrome or systemic 
             infectious complications, prognosis is usually good.
              Cause of death
             At the early stage (day 1 to 3) of the intoxication, death is 
             due to cardiogenic shock and/or acute respiratory distress 
             Death due to haemorrhagic or infectious complications may 
             occur at the stage of bone marrow aplasia (day 3 to 
        9.4  Systematic description of clinical effects
             9.4.1  Cardiovascular
                    Cardiovascular shock is always present in 
                    severe intoxications. Most deaths result from shock 
                    within the first 72 hours.
                    Hypotension is usually the result of hypovolaemia due 
                    to gastrointestinal fluid loss.  Hypovolaemia with 
                    decreased central venous pressure is initially always 
                    present but some patients may develop cardiogenic 
                    shock.  (Sauder et al., 1983; Bismuth & Sebag 
                    Haemodynamic studies showed two different profiles: 
                    Patients with a hyperkinetic state (increased cardiac 
                    index and decreased systemic vascular resistances); 
                    patients with cardiogenic shock (decreased cardiac 
                    index and increased systemic vascular resistances) 
                    (Sauder et al., 1983). Occurrence of cardiogenic shock 
                    indicates a poor prognosis. Septic shock may occur 
                    during the phase of aplasia.
             9.4.2  Respiratory
                    Acute respiratory failure is usually 
                    concomitant of circulatory failure, although Murray et 
                    al 1983, reported a case with ascending paralysis 
                    occurring more than 4 hours post-exposure.
                    Acute respiratory distress syndrome due to diffuse 
                    interstitial and alveolar oedema has been reported in 
                    severe cases (Hill et al., 1975; Corbin et al., 1989; 
                    Maurizi et al., 1986; Davies et al., 1988; Hobson & 
                    Rankin, 1986).
             9.4.3  Neurological
            Central nervous system (CNS)
                             In severe cases hypotension and/or 
                             hypoxaemia can lead to confusion, agitation, 
                             and mental depression. Coma and seizures are 
                             observed.  Profound coma may be due to 
                             cerebral complications such as 
            Peripheral nervous system
                             Peripheral neuritis, neuromyopathy 
                             and myopathy have been reported (Carr, 1965; 
                             Favarel-Garrigues et al., 1975; Kuncl, 1987; 
                             Bismuth et al., 1977; Mouren et al., 1969; 
                             Kontos, 1962). Ascending paralysis may be 
                             responsible for respiratory failure (Carr, 
                             1965). Polyneuritis usually recovers within 
                             one month (Bismuth et al., 1977).
            Autonomic nervous system
                             None described.
            Skeletal and smooth muscle
                             Rhabdomyolysis may occur with an 
                             increase in muscle enzymes and myoglobinuria 
                             (Murray et al., 1983; Kontos et al., 1962; 
                             Letellier et al., 1979). A case of 
                             rhabdomyolysis was reported in a 58-year-old 
                             patient treated with 3 mg colchicine daily 
                             over 6 days (Letellier et al., 1979).  The 
                             patient developed proximal scapular weakness 
                             with muscle oedema and increase in muscle 
             9.4.4  Gastrointestinal
                    Gastrointestinal symptoms develop after a delay of 2 
                    to 12 hours following ingestion and include nausea, 
                    vomiting, abdominal pain and severe diarrhoea. 
                    Usually diarrhoea lasts for 48 hours and may induce 
                    hypovolaemia and electrolyte disturbances. 
                    Gastrointestinal symptoms also occur after colchicine 
                    overdose by the intravenous route.  Paralytic ileus 
                    may develop (Heaney et al., 1976).
                    Gastrointestinal disturbances may be lacking or 
                    decreased if drugs decreasing gastrointestinal 
                    motility (atropine, phenobarbitone, opium tincture) 
                    have also been ingested.
                    Gastrointestinal symptoms are a common feature during 
                    colchicine treatment.  Paralytic ileus has been 
                    reported after intravenous colchicine 
             9.4.5  Hepatic
                    Colchicine may exert direct hepatic toxicity. 
                    Hepatomegaly has been reported.  Hepatic damage may 
                    occur in severe poisoning and includes cytolysis and 
                    hepatocellular insufficiency, increase in glutamic 
                    pyruvic transaminase (SGOT) (alanine amino 
                    transferase, ALT) and glutamic oxaloacetic 
                    transaminase (SGOT) (aspartate amino transferase, AST) 
                    and in alkaline phosphatase, a decrease in coagulation 
                    factors.  Histological examination has shown necrosis 
                    and steatosis of hepatocytes.
             9.4.6  Urinary
                             No direct nephrotoxic effect has 
                             been reported. Functional renal insufficiency 
                             is usually observed and is secondary to fluid 
                             and electrolytes losses or hypovolaemia. 
                             Acute renal failure may occur following 
                             cardio-vascular or septic shock.
                             Proteinuria and haematuria have been 
             9.4.7  Endocrine and reproductive systems
                    Transient diabetes mellitus has been reported by 
                    Hillemand et al. 1977 in a 58-year-old woman after an 
                    overdose with 25 mg.
                    Inappropriate antidiuretic syndrome has been reported 
                    (Gauthier et al., 1975).
                    A case of colchicine poisoning (40 mg) has been 
                    reported in a 18 year old pregnant woman (Lambert et 
                    al., 1981).  The patient developed severe poisoning 
                    with coagulopathy, ARDS and abortion on day 7 
                    following ingestion.  The patient recovered.
                    A reversible complete azoospermia has been reported in 
                    a 36- year-old man treated with colchicine for gout 
                    (Merlin, 1972).  2 cases of Down's syndrome babies 
                    have been reported (Ehrenfeld et al., 1987). The 
                    obstetric histories of 36 women with familial 
                    Mediterranean fever on long-term colchicine treatment 
                    between 3 and 12 years have been reported (Ehrenfeld 
                    et al., 1987).  Seven of 28 pregnancies ended in 
                    miscarriage.  13 women had periods of infertility. 
                    All 16 infants born to mothers who had taken 
                    colchicine during pregnancy were healthy.  The authors 
                    do not advise discontinuation of colchicine before 
                    planned pregnancy but recommend amniocentesis for 
                    karyotyping and reassurance.
             9.4.8  Dermatological
                    Alopecia begins at about the 12th day and is complete 
                    by 3 weeks after ingestion.  Hair regrowth begins 
                    after the first month.
                    Cutaneous and subcutaneous haemorrhages are frequent 
                    in severe poisoning.  They are due to coagulation 
                    disturbances and may be induced by venous or arterial 
             9.4.9  Eye, ear, nose, throat: local effects
                    Subconjunctival haemorrhage may occur.
                    Definitive unilateral deafness due to an inner ear 
                    haemorrhage has been observed (personal 
                    Nasal haemorrhages may occur especially after local 
                    trauma due to insertion of tracheal or gastric 
                    Stomatitis may also occur (Wallace, 1974; Lambert et 
                    al., 1981).
             9.4.10 Haematological
                    At toxic doses, colchicine induces marked bone 
                    marrow depression.
                    At the initial stage a peripheral leucocytosis occurs 
                    frequently.  a leucopenia with agranulocytosis begins 
                    at the third day and reaches a maximum at day 5 to 7. 
                    WBC return to normal values at about the 10 to 12th 
                    Anaemia is frequent in severe cases and may be due to 
                    different factors:
                    Hypoplastic anaemia due to bone marrow suppression may 
                    be observed but is rarely important.
                    Haemolytic anaemia with Heinz body has been rarely 
                    reported (Heaney et al., 1976).
                    Acute intravascular haemolysis with haemoglobinemia 
                    and haemoglobinuria has been observed in 6 severe 
                    cases (Lambert et al., 1981)
                    Severe anaemia is mostly secondary to multiple diffuse 
                    Bleeding diatheses and coagulopathy
                    A tendency toward bleeding is always present in severe 
                    cases. It appears two to three days following 
                    ingestion and may last for eight to ten days.
                    Usually the earliest indication of coagulopathy is 
                    persistent bleeding from venous or arterial puncture 
                    sites and subcutaneous haemorrhages.  Other types of 
                    bleeding include epistaxis, gingival, conjunctival and 
                    gastrointestinal haemorrhages.  Bleeding may be due to 
                    thrombocytopenia or a consumptive coagulopathy.
                    A consumptive coagulopathy with prolongation of 
                    coagulation time, hypoprothrombinaemia, a decrease in 
                    fibrinogen, elevated fibrin degradation products and 
                    thrombocytopenia is observed in severe intoxication 
                    (Bismuth et al., 1977; Lambert et al., 1981; Crabie et 
             9.4.11 Immunological
                    No data available.
             9.4.12 Metabolic
           Acid-base disturbances
                             Metabolic acidosis due to diarrhoea 
                             and/or shock may be seen.
           Fluid and electrolyte disturbances
                             The gastro-intestinal syndrome 
                             often results in marked dehydration and 
                             hypovolaemia with haemoconcentration and 
                             functional renal failure.
                             Hypokalaemia due to gastrointestinal losses 
                             is also frequent at the initial stage.
                             Hypocalcaemia may be seen and can persist for 
                             several days.  Frayha et al. (1984) reported, 
                             in a 20-year-old girl who had ingested 20 mg, 
                             convulsions and paralytic ileus which were 
                             related to a hypocalcaemia (1.25 mmol/L). 
                             Hypocalcaemia may be due to a direct toxic 
                             effect of colchicine (Heath et al., 
                             A 58-year-old woman who ingested 25 mg and 
                             developed transient diabetes mellitus has 
                             been reported (Hillemand et al., 1977).
                             A transient hyperlipaemia has been reported 
                             (Hillemand et al. 1977).
                             A transient hyperuricaemia has also been 
                             noted (Hillemand et al. 1977).
                             Occurrence of fever may be relate to an 
                             infectious complication, especially during 
                             the stage of aplasia.
             9.4.13 Allergic reactions
                    No data available.
             9.4.14 Other clinical effects
                    No data available.
             9.4.15 Special risks 
                    Two cases of Down's syndrome babies have been 
                    reported. The obstetric histories of 36 women with 
                    familial Mediterranean fever on long-term colchicine 
                    treatment between 3 and 12 years have been reported 
                    (Ehrenfeld et al. 1987).  Seven of 28 pregnancies 
                    ended in miscarriage. Thirteen women had periods of 
                    infertility.  All 16 infants born to mothers who had 
                    taken colchicine during pregnancy were healthy.  The 
                    authors do not advise discontinuation of colchicine 
                    before planned pregnancy but recommend amniocentesis 
                    for karyotyping and reassurance.
                    As colchicine is eliminated in the breast milk breast- 
                    feeding should be avoided.
        9.5  Other
             No data available.
        9.6  Summary
             Not relevant
        10.1 General principles
             Patients with colchicine overdose should always be 
             admitted in an intensive care unit.  Treatment depends on the 
             dose ingested, the symptomatology and the delay following 
             ingestion.  It includes gastric lavage, early forced 
             diuresis, and supportive treatment with correction of the 
             shock, artificial ventilation, treatment and prevention of 
             haemorrhagic and infectious complications.  Vital signs (ECG, 
             blood pressure, central venous pressure, respiration) should 
             be monitored. Be careful about venous and arterial punctures 
             if there is a severe coagulopathy.
        10.2 Relevant laboratory analyses
             10.2.1 Sample collection
                    Blood samples for colchicine should be drawn 
                    in plastic tubes with heparin.  Colchicine may be 
                    analysed in whole blood or plasma.  Biological samples 
                    (blood, plasma, urine...) should be stored in airtight 
                    conditions and protected from light. Concentrations in 
                    whole blood are markedly higher than those in plasma. 
                    Concentration in urine are 10 to 80 fold higher than 
                    those in plasma.
             10.2.2 Biomedical analysis
                    A biochemical profile with glucose, BUN, 
                    electrolytes, creatinine, blood cells, coagulation 
                    parameters, enzymes, and blood gases should be 
                    obtained on admission and repeated every 12 hours. 
                    Samples for bacteriological analysis should be 
                    obtained at the stage of aplasia or when fever 
             10.2.3 Toxicological analysis
                    Colchicine analysis in biological fluids is 
                    not necessary or useful for the management of the 
             10.2.4 Other investigations
                    No other specific investigations are 
        10.3 Life supportive procedures and symptomatic/specific treatment
             Observation and monitoring
             Monitor systematically vital signs, ECG, blood pressure and 
             central venous pressure.  Repeated monitoring of central 
             venous pressure is essential to avoid circulatory overload 
             during plasma expander infusion.
             Insert a venous catheter for rehydration and drug 
             If shock is present, insertion of a pulmonary artery (Swan- 
             Ganz) catheter for monitoring of haemodynamic parameters may 
             be useful for guiding the treatment. 
             The patient remains at risk until at least 48 hours after 
             Diarrhoea should not be treated because some colchicine is 
             eliminated in faeces.
             Dehydration - Electrolyte disturbances - Acidosis
             Give intravenous fluids and electrolytes according to 
             clinical and biological status.  If metabolic acidosis is 
             present give intravenous bicarbonate.  Monitor potassium 
             levels and blood gases.  Maintain adequate urinary output 
             (>100 ml/hr).
             Hypotension, shock
             Hypotension should be anticipated and treated with adequate 
             fluid replacement and vasoactive drugs.  Monitor blood 
             pressure.  Early institution of hemodynamic monitoring is 
             very helpful for adequate treatment of shock.
             Hypotension and shock are due primarily to hypovolaemia. 
             Cardiogenic shock may occur.
              Plasma expanders
             Infuse plasma expander solutions (e.g. modified gelatine 
             fluids) under control of haemodynamic parameters e.g. central 
             venous pressure, pulmonary arterial pressure. Very large 
             amounts of plasma expanders may be necessary: 3 to 4 litres 
             over 24 hours (personal observation).
              Inotropic and vasoconstrictor drugs
             If the patient is unresponsive to these measures administer 
             inotropic and vasoconstrictor drugs e.g. dopamine or 
             dobutamine in doses sufficient to cause vasoconstriction (10 
             to 20 mcg/kg/min).
             Vasodilators e.g. glyceryl trinitrate may be useful in the 
             case of cardiogenic shock with increased systemic arterial 
             resistance (personal observation).
             Respiratory disturbances
             Respiratory depression or ARDS should be treated by 
             artificial ventilation.  The early institution of mechanical 
             ventilation is indicated in patients with severe intoxication 
             and shock.
             Bone Marrow Depression      
             Isolate the patient if there is evidence of bone marrow 
             depression. Infusion of white blood cell units is usually not 
             necessary because aplasia is transient.  However, it may be 
             useful in patients who develop concomitant infection 
             (Gauthier & Bismuth, 1978).
             Coagulation Disorders
             Prevent haemorrhagic complications due to local trauma: avoid 
             insertion of endotracheal tube by the nasal route, avoid 
             femoral arterial puncture.
             Coagulation disorders require specific treatment only if 
             haemorrhages develop.  According to biological parameters, 
             treatment may include infusion of fresh-frozen plasma, 
             platelet units, fibrinogen and coagulation factors 
             Prevention of Infectious Complications
             In severe cases with shock and/or aplasia a prophylactic 
             antibiotic treatment should be given. Prophylactic 
             antibiotherapy may be directed towards gram positive  (e.g. 
             staphylococcal) and negative bacteria and also anaerobic 
             bacteria. Preventative treatment for fungal infections should 
             also be given because fungal septicaemia may develop 
             (personal observation).
        10.4 Decontamination
             Gastric Lavage
             Early gastric lavage is indicated because it may remove 7 to 
             25 per cent of the dose ingested if it is performed within 6 
             hours of ingestion (Jaeger et al., 1985).
             Emesis may be useful in recent ingestion if there are no 
             Oral Activated Charcoal
             The efficacy of oral activated charcoal has not been 
             established. However, because colchicine undergoes 
             enterohepatic circulation, oral activated charcoal may be 
             indicated: one dose at the end of the gastric lavage and 
             repeated every 4 to 6 hours.
             The usefulness of cathartics has not been established and is 
             not recommended.
        10.5 Elimination
             Forced Diuresis
             Toxicokinetic studies (Jaeger et al., 1985) indicate that 
             significant amounts of colchicine are eliminated in urine, 
             especially during the first 24 hours following ingestion. 
             Thus early forced diuresis should be instituted after 
             correction of dehydration and/or shock (Jaeger et al., 1985). 
             Continue forced diuresis until the third or fourth day 
             provided there are no contraindications.
             Haemoperfusion, Haemodialysis
             No data about haemoperfusion or haemodialysis clearances have 
             been reported.  However, the low colchicine plasma 
             concentrations reported in acute poisonings and the large 
             volume of distribution indicate that haemoperfusion or 
             haemodialysis is not useful.
        10.6 Antidote treatment
             10.6.1 Adults
                    Currently no antidote for colchicine is 
             10.6.2 Children
                    No antidote available.
        10.7 Management discussion
             Gastrointestinal symptoms may be overshadowed if 
             psychotropic drugs or drugs decreasing gastrointestinal 
             motility have also been ingested.
             Institute prophylactic antibiotic therapy.
        11.1 Case reports from literature
              Case report 1
             In 69 reported cases of colchicine poisoning (Bismuth et al., 
             1977) thirty eight patients (dose ingested <0.5 mg/kg) 
             developed gastro- intestinal symptoms and coagulation 
             disturbances; all survived. Twenty patients (dose ingested 
             0.5 to 0.8 mg/kg) developed bone marrow aplasia:  mortality 
             was 10 per cent. Eleven patients (dose ingested > 0.8 mg/kg) 
             died within 72 hours from cardiovascular shock.
              Case report 2
             In another reported 22 cases (Lambert et al., 1981), 
             according to the doses ingested (DI), mortality rates were: 
             100% for DI > 1 mg/kg; 50% for DI = 0.5 to 0.9 mg/kg; 10% 
             for DI < 0.5 mg/kg.  Clinical features included: 
             gastrointestinal symptoms (22 cases), leucopenia, aplasia (11 
             cases), disseminated intravascular coagulation (9 cases), 
             shock (9 cases), acute respiratory distress syndrome (8 
             cases), polyneuropathy (4 cases).
              Case report 3
             Two cases were reported (Gaultier et al., 1969) who developed 
             inappropriate antidiuresis following ingestion of about 40 
             mg. Both patients recovered.
              Case report 4
             A 18-year-old woman developed an acute respiratory distress 
             syndrome (ARDS) following ingestion of 150 mg.  The patient 
             died at the 42nd hour (Hill et al., 1975).
              Case report 5
             An acute respiratory distress syndrome was reported in a 17- 
             year-old woman who had ingested 0.37 mg/kg (Corbin et al., 
             1989).  Pulmonary capillary wedge pressure was 7 mm Hg.  The 
             patient died (72nd hour), despite mechanical ventilation 
             (PEEP), from shock any hypoxaemia.
              Case report 6
             Two cases with ARDS have been reported (Maurizi et al., 
             1986).  A 25- year-old woman who had ingested 80 mg died on 
             the 7th day from septic shock with acute renal failure; a 21 
             year old man who had ingested 15 to 20 mg also developed 
             aplasia and recovered.
              Case report 7
             A fatal overdose in a 15-year-old boy who had ingested 18 mg 
             colchicine and developed cardiovascular shock, ARDS, 
             metabolic acidosis, hypocalcaemia, hypokalaemia, 
             hypophosphotaemia, bone marrow suppression and coagulopathy 
             has been reported (Hobson & Rankin, 1986).
              Case report 8
             Report of an overdose with about 24 mg in a 15 year old girl 
             (Murray et al., 1983). The clinical picture showed:
             *      myocardial injury with cardiogenic shock
             *      ventilatory insufficiency with ARDS
             *      rhabdomyolysis
             *      metabolic acidosis
             *      agranulocytosis
             *      coagulopathy
             *      alopecia.
             The patient recovered without sequelae.
        11.2 Internally extracted data on cases
             Jaeger et al. (1980) reported five fatal outcomes in 
             five patients after intravenous colchicine treatment for 
             gout. The total dose ranged between 9 to 21 mg administered 
             over two to eight days.  During the treatment the patients 
             developed gastro-intestinal symptoms and thereafter (on about 
             the 7th day) agranulocytosis, thrombocytopenia and shock with 
             acute renal failure.  Death occurred between the 7th and 15th 
             day after beginning of the treatment.
             Sauder et al. (1983) performed haemodynamic studies in eight 
             cases of colchicine poisoning. The doses ingested ranged 
             between 9 and 160 mg.  Haemodynamic studies performed between 
             the 6th and 72nd hour following ingestion showed:
             Hypovolemia in all cases,
             A hyperkinetic state with increased cardiac index and 
             decreased systemic vascular resistance in the 4 patients who 
             Cardiogenic shock with decreased cardiac index and increased 
             systemic vascular resistances in the 4 patients who died.
             An initial decrease of cardiac performance is an index of 
             severity and poor prognosis.
             Jaeger et al, (1985) performed a toxicokinetic study in 5 
             cases (dose ingested 19 to 60 mg).  Plasma concentrations 
             ranged between 20 and 54 ng/mL during the 24 first hours. 
             Gastric lavage removed 7.1 to 25% of the dose ingested.  In 
             one case 1.4 mg colchicine was excreted in diarrhoea on the 
             second day.  Four to 25 per cent of the dose ingested was 
             eliminated in urine over 3 to 10 days.
             Urinary colchicine excretion was especially high during the 
             first day following ingestion (2 to 10 per cent of the dose 
             ingested). Colchicine levels in urine were 10 to 80 times 
             higher than those in plasma.  This study emphasizes the 
             usefulness of early gastric lavage, of early diuresis and of 
             colchicine elimination in diarrhoea.
        11.3 Internal cases
             To be completed by each Centre using local data.
        12.1 Availability of antidotes
             Not relevant
        12.2 Specific preventive measures
             Not relevant
        12.3 Other
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        Authors     A. Jaeger, F. Flesch, Ph. Sauder, J Kopferschmitt
                    Poison Control Center
                    Tel: 33-88161144
                    Fax: 33-88161930
        Date        28 March 1989
        Peer Review          London, United Kingdom, March 1990
                             Berlin, Germany, October 1995

    See Also:
       Toxicological Abbreviations