Colchicine Medication

Colchicine Medication Identity

1.1 Substance

Colchicine (USAN) (Fleeger,1993)

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)
• Colchicum
• Colchique (French)
• NSC 757

1.4 Identification numbers

1.4.1 CAS number: 64-86-8
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 Laboratories)

Colchicine plus probenecid

UK

ColBenemid (Merck Sharpe & Dohme)

USA

ColBenemid (Merck Sharpe & Dohme); Col-Probencid (Danbury, Goldline, Interstate, Parmed, United Research Lab.,); Proben-C (Rugby)

Colchicine associated with other compounds

France

Colchimax – contains colchicine, phenobarbitone and opium tincture (Houde ISH).

Generic products are also available.

1.6 Manufacturers, Importers

Biogen Laboratories, Columbia, Ethical Pharmaceuticals, Fisher Scientific, Purepac, Regal Laboratories, Rondex, Schein, Tourne- Paulsen, Westward, Zenith.

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.

Colchicine Medication 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.
Rhabdomyolyis.
Polyneuritis, myopathy.
Acute renal failure.
Infectious complications.

Stage III: (After 10 day) recovery phase

Alopecia.

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 products.
• 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.

Colchicine Medication Physico-Chemical Properties

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 autumnale.

The chemical structured was described by Dewar in 1945. The chemical synthesis was first realised by Woodward.

3.2 Chemical structure

Molecular formula

C22H25NO6

Molecular weight

399.4

Structural Chemical names

(S)-N-(5,6,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[alpha]heptalen-7-yl)acetamide.
N-(5,5,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[alpha]heptalen-7-yl)acetamide.
(Budavari, 1989; Reynolds, 1993)

Derivatives

Different compounds have been isolated from Colchicum autumnal. Colchicine has the most important biological activity which is related to the tropolonic cycle (C).

Biological activity	Substance name	R1	R2	R3	R3
+++	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

3.3.1.1 Colour

Pale yellow. It darkens on exposure to light.

3.3.1.2 State/Form

Odourless powder or scales.

3.3.1.3 Description

• 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.

Colchicine Medication Uses

4.1 Indications

4.1.1 Indications

Not relevant

4.1.2 Description

Gout

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 attacks.

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 symptoms.

Other

Colchicine has been used in the treatment of scleroderma and sarcoidosis.

4.2 Therapeutic dosage

4.2.1 Adults

Acute Gout Attack

Oral: 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 days. A course should not be repeated within three days. Tolerance is usually 4 to 8 mg.
Parenteral: Intravenous injection. Initial dose is 1 to 2 mg. The total dose is 4 mg in 24 hours or in an attack.

Prophylaxis of recurrent gout

Oral: 0.5 mg to 0.65 mg once weekly or up to three times daily, depending on the frequency of prior acute attacks. (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).

Colchicine Medication Routes Of Entry

5.1 Oral

Oral absorption is the most frequent cause of intoxication.

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).

Colchicine Medication Kinetics

6.1 Absorption by route of exposure

Oral

• 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

Parenteral: 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).
Oral: 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.
Oral:

• Kidney: 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).
• Bile: 10 to 25% of colchicine is excreted in the bile (Heaney et al., 1976).
• Faeces: Large amounts of the drug are excreted in the faeces.
• Breast Milk:Colchicine may be eliminated in breast milk (White & White, 1980).

Intravenous:

• Faeces: After intravenous administration 10 to 56% is excreted in the faeces within the first 48 hours (Walaszek et al., 1960).
• Breast Milk: Colchicine may be eliminated in breast milk.

Colchicine Medication Pharmacology & Toxicology

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, phagocytosis.

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 neutrophils.

Colchicine has other properties such as antipyretic effects, respiratory depression, vasoconstriction and hypertension.

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

Oral

• 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 absorbed Rate mg/kg	Symptoms	Mortality
<0.5	Gastrointestinal symptoms decrease of coagulation factors	0%
0.5-0.8	-Bone marrow aplasia -Alopecia	10-50%
>0.8	-Circulatory failure	100%

Intravenous

• 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., 1978).
• The enhanced toxicity of intravenous colchicine is probably due to the higher bioavailability of colchicine after parenteral administration.

7.2.1.2 Children

Oral: 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 metabolism.

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 7.2.1.1).
• The following adverse reactions have been reported during colchicine treatment (Dukes, 1983):
• Gastrointestinal: Vomiting, diarrhoea, abdominal discomfort, paralytic ileus, malabsorption syndrome with steatorrhoea.
• Haematological: Bone marrow depression with agranulocytosis, acute myelomonocytic leukaemia, multiple myeloma, thrombocytopenia.
• Neurological: Peripheral neuritis, myopathy, rhabdomyolysis (Riggs et al., 1986).
• Dermatological: 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 1972).
• Metabolic: Colchicine is capable of producing a reversible impairment of vitamin B12 absorption (Webb et al, 1968). Porphyria cutanea tarda has been reported (Gossweiler, 1985).

Colchicine Medication Toxicological Analyses & Biomedical Investigations

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., 1976; Scherrman et al., 1980).
• High performance liquid chromatography: (Jarvie et al, 1979, Caplan et al., 1980; Harzer, 1984; Lhermitte et al., 1985).
• 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.

Serum/Plasma/Blood

Plasma

• Plasma levels lower than 20 ng/ml at the 6th hour in severe intoxications have been reported (Bourdon & Galliot 1976).
• 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).

Blood

• Colchicine levels in blood are higher than those in plasma.
• 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.

Urine

• 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).

Diarrhoea

• In an overdose with 25 mg colchicine orally, 1.4 mg were eliminated in diarrhoea on the 2nd day (Jaeger et al., 1985).

Colchicine Medication Clinical Effects

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 phase:

• 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 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.
• Rhabdomyolyis.
• Polyneuritis, myopathy.
• Acute renal failure.
• Infectious complications.

Stage III: (After ten days) Recovery phase:

• Alopecia

(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

Course

• See section 9.1.1.

Prognosis

• Prognosis is related to the dose ingested (see section 7.2.1).
• 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 syndrome.
• Death due to haemorrhagic or infectious complications may occur at the stage of bone marrow aplasia (day 3 to 10).

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 1981).
• 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

9.4.3.1 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 haemorrhages.

9.4.3.2 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).

9.4.3.3 Autonomic nervous system

None described.

9.4.3.4 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 enzymes.

9.4.4 Gastrointestinal

Acute

• 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.

Chronic

• Gastrointestinal symptoms are a common feature during colchicine treatment. Paralytic ileus has been reported after intravenous colchicine treatment.

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

9.4.6.1 Renal

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.

9.4.6.2 Other

Proteinuria and haematuria have been reported.

9.4.7 Endocrine and reproductive systems

Endocrine

• 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).

Reproductive

Acute

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.

Chronic

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

Acute

• 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 punctures.

9.4.9 Eye, ear, nose, throat: local effects

• Eye: Subconjunctival haemorrhage may occur.
• Ear: Definitive unilateral deafness due to an inner ear haemorrhage has been observed (personal experience).
• Nose: Nasal haemorrhages may occur especially after local trauma due to insertion of tracheal or gastric tubes.
• Throat: Stomatitis may also occur (Wallace, 1974; Lambert et al., 1981).

9.4.10 Haematological

At toxic doses, colchicine induces marked bone marrow depression.

Leucocytes

• 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 day.

Erythrocytes
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 haemorrhages.
• 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 al.,1970)

9.4.11 Immunological

No data available.

9.4.12 Metabolic

9.4.12.1 Acid-base disturbances

Metabolic acidosis due to diarrhoea and/or shock may be seen.

9.4.12.2 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., 1972).

9.4.12.3 Others

• Hyperglycaemia: A 58-year-old woman who ingested 25 mg and developed transient diabetes mellitus has been reported (Hillemand et al., 1977).
• Hyperlipaemia: A transient hyperlipaemia has been reported (Hillemand et al. 1977).
• Hyperuricaemia: A transient hyperuricaemia has also been noted (Hillemand et al. 1977).
• Hyperthermia-fever: 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

Pregnancy
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.

Breast-feeding
As colchicine is eliminated in the breast milk breast-feeding should be avoided.

9.5 Other

No data available.

9.6 Summary

Not relevant

Colchicine Medication Management

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 occurs.

10.2.3 Toxicological analysis

Colchicine analysis in biological fluids is not necessary or useful for the management of the poisoning.

10.2.4 Other investigations

No other specific investigations are required.

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 injection.
• 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 exposure.

Diarrhoea

• 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

• 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 (PPSB).

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
Emesis may be useful in recent ingestion if there are no contraindications.

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.

Cathartics
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 available.

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.

Colchicine Medication Illustrative Cases

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 recovered.

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.

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Colchicine Medication Authors, Reviewers, Date, Address

Authors

A. Jaeger, F. Flesch, Ph. Sauder, J Kopferschmitt
Poison Control Center
Strasbourg
France
Tel: 33-88161144
Fax: 33-88161930

Date

28 March 1989

Peer Review

London, United Kingdom, March 1990
Berlin, Germany, October 1995

GoutPal changes are not included in the peer review. These are: removal of ‘To be completed by each Centre using local data.’ or change to ‘See product packaging/labeling.’; linking of references; and addition of missing Wallace1973 reference.

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