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Clofazimine

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
   1.7 Presentation, Formulation
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.3 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. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
      8.1.2 Storage of laboratory samples and specimens
      8.1.3 Transport of laboratory samples and specimens
   8.2 Toxicological analyses and their interpretation
      8.2.1 Tests on active ingredient(s) of material
         8.2.1.1 Simple qualitative test(s)
         8.2.1.2 Advanced qualitative confirmation test(s)
         8.2.1.3 Simple quantitative method(s)
         8.2.1.4 Advanced quantitative method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple qualitative test(s)
         8.2.2.2 Advanced qualitative confirmation test(s)
         8.2.2.3 Simple quantitative method(s)
         8.2.2.4 Advanced qualitative method(s)
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematologic analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 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. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    1. NAME

       1.1 Substance

           Clofazimine (INN)

           (WHO, 1992)

       1.2 Group

           ATC classification index

           Antimycobacterials (JO4)/Drugs for treatment of lepra (JO4B)
           
           (WHO, 1992)

       1.3 Synonyms

           Riminophenazine
           B-663
           G-30320

           (Budavari, 1989; Reynolds, 1989).

           (To be completed by each Centre using local data)

       1.4 Identification numbers

           1.4.1 CAS number

                 2030-63-9

           1.4.2 Other numbers

                 RTECS

                 SG1578000

       1.5 Brand names, Trade names

           Lamprene
           
           (To be completed by each Centre using local data)

       1.6 Manufacturers, Importers

           Ciba-Geigy
           
           (To be completed by each Centre using local data)

       1.7 Presentation, Formulation

           Capsule containing 50 mg
           Capsule containing 100 mg

           (To be completed by each Centre using local data)

    2. SUMMARY

       2.1 Main risks and target organs

           Acute poisoning
           
           No reports are available on acute toxicity.
           
           Chronic poisoning
           
           One report mentioned abdominal disposition of clofazamine
           crystals and one report of splenic infarction.
           
           Target organs
           
           CNS; gastrointestinal; ocular effects.
           
       2.2 Summary of clinical effects

           Dermal
           
           Pink to brownish-black discolouration of the skin; dryness;
           ichthyosis; pruritus; acneform eruptions, skin rashes; and
           photosensitivity reactions.
           
           Eye
           
           Reddish-brown discolouration of the cornea, conjunctiva and 
           lacrimal fluid.  Occasionally there could be dryness, 
           itchiness, irritation, burning and watering of the eyes.
           
           Gastrointestinal tract

           Nausea, vomiting, abdominal pain and diarrhoea, 
           discolouration of faeces.  There was even note of splenic 
           infarction seen in a patient receiving clofazimine for the 
           treatment of pyoderma gangrenosum.
           
           Nervous system

           Headache, dizziness, drowsiness, fatigue, and taste disorder. 
           Some patients became depressed because of skin discolouration.
           
           Haematopoietic system
           
           Eosinophilia; elevated ESR.
           
           Liver
           
           Elevated albumin, bilirubin and SGOT.

           Others
           
           Discolouration of the sweat, sputum and urine.
           
                        (McEvoy, 1990; Reynolds, 1989; PDR, 1990)

       2.3 Diagnosis

           By exclusion: If the patient taking clofazimine presents with 
           symptoms and signs as above in 2.2., it may be caused by 
           chronic clofazimine poisoning. Other causes that have these 
           symptoms and signs such as rifampicin toxicity may have to be 
           excluded.
           
           Clofazimine may be measured in biological fluids by Thin-
           Layer Chromatographic method (Hauffe et al., 1986), or High 
           Pressure Liquid Chromatography can also be used (Moffat, 
           1986). However, these methods are usually of no value in the 
           diagnosis in the acute stage. 

       2.4 First aid measures and management principles

           Control for hypokalaemia and its effects on ECG.

    3. PHYSICO-CHEMICAL PROPERTIES

       3.1 Origin of the substance

           Substituted iminophenazine derivative (synthetic)

       3.2 Chemical structure

           Structural formula
           
           Molecular formula
           
           C27H22C12N4
           
           Molecular weight
           
           473.41
           
           Chemical names
           
           3-(4-Chloroanilino)-10-(4-chlorophenyl)-2,10-dihydro-2-
           phenazin-2-ylideneisopropylamine
           
           N,5-Bis(4-Chlorophenyl)-3,5-dihydro-3-[(1-methylethyl)imino]-
           2-phenazinamine
           
           3-(p-Chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-
           (isopropylimino)-phenazine
           
           2-(4-Chloroanilino)-3-isopropylimino-5-(4-chlorophenyl)-3,5-
           dihydrophenazine
           
           2-p-Chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-
           isopropyliminophenazine
           
           (Budavari, 1989; Reynolds, 1993)
           
       3.3 Physical properties

           3.3.1 Properties of the substance

                 3.3.1.1 Colour

                         Reddish-brown

                 3.3.1.2 State/Form

                         Fine powder

                 3.3.1.3 Description

                         Melting point about 215 C
                         Odourless
                         Readily soluble in benzene, soluble in 
                         chloroform, slightly soluble in methanol and 
                         ethanol, very slightly soluble in ether, poorly 
                         soluble in acetone and ethyl acetate, 
                         practically insoluble in water (Reynolds, 1989; 
                         PDR, 1990).
    
           3.3.2 Properties of the locally available formulation(s) 

                 To be completed by each Centre using local data.

       3.4 Other characteristics

           3.4.1 Shelf-life of the substance

                 Five years (Weber & Kop, 1987).
             
           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

                 With the storage condition at 23C, the physical 
                 properties and rate of disintegration of the capsules 
                 remained the same.  If stored at higher temperature, 
                 they became useless and would stick together.  The 
                 capsules should be protected from heat and moisture 
                 (Weber & Kop, 1987). 

           3.4.4 Bioavailability

                 Clofazimine has a variable absorption rate ranging from 
                 45% to 62% after oral administration. Absorption is 

                 influenced by particle size. Food increases its 
                 bioavailability.  Its half-life is approximately 70 
                 days.
                 
                 (To be completed by each Centre using local data)

           3.4.5 Specific properties and composition

                 To be completed by the local centre.

    4. USES

       4.1 Indications

           4.1.1 Indications

                 As an antileprotic in association with other agents.
                 
                 Has anti-inflammatory properties in erythema nodosum 
                 leprosum reactions. 
                 
                 For use in the treatment of Lobo's disease (a chronic 
                 topical mycosis), Crohn's disease, Leishmaniasis.
                 
                 It has been used in the treatment of cutaneous 
                 elastolytic lymphoma (von den Driesch P et al., 
                 1994).
                 
                 Chronic skin ulcers (Buruli ulcer) (Gilman et al., 
                 1990) 

           4.1.2 Description

                 Not relevant

       4.2 Therapeutic dosage

           4.2.1 Adults

                 Clofazimine, 50 to 100 mg daily. WHO recommends a 
                 regimen in which rifampicin 600mg and clofazimine 300 
                 mg are given once monthly, together with Dapsone 100 mg 
                 daily, self-administered (for at least 2 years) 
                 (Reynolds, 1993).
                 
                 The treatment of erythema nodosum leprosum reactions 
                 depends on the severity of symptoms. In general, the 
                 basic antileprosy treatment should be continued. Dosage 
                 of clofazimine above 200 mg daily is not recommended, 
                 and the dosage should be tapered to 100 mg daily as 
                 quickly as possible after the reactive episode is 
                 controlled (PDR, 1990).
                 
                 (Note: Antileprotic regimen is in accordance with the 
                 recommendation of the World Health Organization (WHO). 
                 Depending on the indication, dosage regimen varies. 

                 Because adverse effects on the gastrointestinal tract 
                 are dose related, it has been recommended that daily 
                 doses of 300 mg or more should not be administered for 
                 more than three months). 

           4.2.2 Children
                         
                 10-14 years old
                 
                 Clofazimine 200 mg once monthly, supervised; and 50 mg 
                 on alternate days, self-administered (Reynolds, 1993).
                 
                 Note: The dose should be adjusted for children with low 
                 bodyweight as follows:
                 
                 over 35 kg    50 mg daily and 300 mg monthly
                 20 to 35 kg   50 mg every 2nd day and 200 mg monthly
                 12 to 20 kg   50 mg every 2nd day and 100 mg monthly
                 12 kg or less 50 mg twice weekly and 100 mg monthly 
                 
                 (Dollery, 1991)
                 
                 (Note: The optimum effective dose has not yet been 
                 established.  The dose recommended above for children 
                 is half the adult dose, adjusted for operational 
                 suitability, since clofazimine is marketed in capsules 
                 of 100 mg and 50 mg). 

       4.3 Contraindications

           Use of clofazimine should be avoided during pregnancy or 
           lactation unless absolutely necessary.
           
           Administration of the drug should be modified or discontinued 
           in the presence of liver and kidney function disorder.
           
           It should be used with caution together with diuretics to 
           avoid hypokalaemia. 

    5. ROUTES OF ENTRY

       5.1 Oral

           This is the usual route of administration for therapeutic 
           use. 

       5.2 Inhalation

           Not relevant.

       5.3 Dermal

           Not relevant.

       5.4 Eye

           Not relevant.

       5.5 Parenteral

           Not relevant.

       5.6 Others

           Not relevant.

    6. KINETICS

       6.1 Absorption by route of exposure

           Clofazimine has a variable absorption rate ranging from 45 to 
           62% after oral administration. About 20% of a dose is 
           absorbed from the gastrointestinal tract when clofazimine is 
           administered as coarse crystals, but 45 to 70% of a dose may 
           be absorbed when the drug is administered as capsules 
           containing a microcrystalline (micronized) suspension of the 
           drug in an oil-wax base.  Presence of food in the GIT may 
           increase the rate and extent of absorption of Clofazimine 
           (McEvoy, 1990).  According to Alford (1989) absorption is 
           variable with 9 to 74% of an administered dose appearing in 
           faeces. 

       6.2 Distribution by route of exposure

           Clofazimine is highly lipophilic and is distributed 
           principally to fatty tissue and cells of the 
           reticuloendothelial system; the drug is taken up by 
           macrophages throughout the body.  It accumulates in high 
           concentrations in the mesenteric lymph nodes, adipose tissue, 
           adrenals, liver, lungs, gallbladder, bile, and spleen and in 
           lower concentrations in the skin, small intestine, lungs, 
           heart, kidneys, pancreas, muscle, omentum, and bone. 
           Clofazimine crystals have also been found in bone marrow, 
           sputum, sebum, and sweat, and in the iris, conjunctiva, 
           macula, sclera, and cornea.  The drug does not appear to 
           distribute into the brain or CSF (McEvoy, 1990).  It crosses 
           the placental barrier and is distributed into breast milk. 

       6.3 Biological half-life by route of exposure

           At least 70 days after repeated therapeutic dose (AHFS, 1990; 
           Alford, 1989).
           
           Repeated therapeutic doses result with a biological half life 
           of approximately 70 days with a plasma concentration of 
           0.4-3_g/ml (McEvoy, 1990; Alford R, 1989). 

       6.4 Metabolism

           The metabolic fate of clofazimine has not been fully 
           elucidated, but the drug appears to accumulate in the body 
           and to be excreted principally unchanged.  Clofazimine 
           appears to be partially metabolized and at least 3 
           metabolites have been found in urine of patients receiving 
           the drug.  Metabolite I is formed by hydrolytic 
           dehalogenation of clofazimine, metabolite II presumably is 
           formed by a hydrolytic deamination reaction followed by 
           glucuronidation, and metabolite III appears to be a hydrated 
           clofazimine glucuronide (McEvoy, 1990). 

       6.5 Elimination  by route of exposure

           Clofazimine is excreted principally in faeces, both as 
           unabsorbed drug and via biliary elimination. Faecal 
           elimination of clofazimine exhibits considerable 
           interindividual variation, and 35% to 74% of a single oral 
           dose may be excreted unchanged in faeces over the first 72 
           hours after the dose. Following oral administration of a 
           single 200 mg or 300 mg dose, elimination of unchanged 
           clofazimine and its metabolites in urine is negligible during 
           the first 24 hours. Following multiple doses of the drug, 
           less than 1% of the daily dose is excreted in urine over a 
           24-hour period. Small amounts of the drug also are excreted 
           via sebaceous and sweat glands. (McEvoy, 1990)

    7. PHARMACOLOGY AND TOXICOLOGY

       7.1 Mode of action
                         
           7.1.1 Toxicodynamics

                 No data available.

           7.1.2 Pharmacodynamics

                 The precise mechanism of the drug's antimycobacterial 
                 effect has not been fully elucidated just like its 
                 anti-inflammatory and immunosuppressive effects. The 
                 drug binds preferentially to mycobacterial DNA at base 
                 sequences containing guanine resulting to inhibition of 
                 mycobacterial replication and growth.  The inhibitory 
                 concentration of clofazimine in tissue is between 0.1 
                 and 1_g/kg (Alford R, 1989).
                 
                 Studies in vivo and in vitro showed that clofazimine 
                 causes a progressive, dose-dependent inhibition of 
                 neutrophil motility and mitogen-induced lymphocyte 
                 transformation.  Clofazimine also increases synthesis 
                 of prostaglandin E2 by the polymorphonuclear leucocytes 
                 in vitro.  However, most of the studies done showed 
                 that clofazimine increases the phagocytic activity and 
                 oxidative metabolism of the polymorphonuclear cells and 

                 macrophages in vitro and in vivo (McEvoy, 1990; 
                 Reynolds, 1989,  Alford, 1989). 

       7.2 Toxicity

           7.2.1 Human data

                 7.2.1.1 Adults

                         Severe abdominal symptoms have necessitated 
                         exploratory laparotomies in some patients on 
                         clofazimine therapy. Rare reports have included 
                         splenic infarction, bowel obstruction, and 
                         gastrointestinal bleeding. Deaths have been 
                         reported, following severe abdominal symptoms. 
                         Autopsies revealed crystalline deposits of 
                         clofazimine in various tissues including the 
                         intestinal mucosa, liver, spleen and mesenteric 
                         lymph nodes (PDR, 1992).
                         
                         To minimise toxicity it is recommended that 
                         daily doses of 300 mg or more should not be 
                         administered for more than three months and 
                         patients on doses greater than 100 mg daily 
                         should be under medical supervision (Reynolds, 
                         1993).  
     
                 7.2.1.2 Children

                         No data available.

           7.2.2 Relevant animal data

                 Oral LD 50 (rabbits)  3.3 g/kg
                 
                 Oral LD 50 (mice, rats and guinea pigs) >4 g/kg.
                 
                 (McEvoy, 1990; Budavari, 1989).

           7.2.3 Relevant in vitro data

                 No data available.

       7.3 Carcinogenicity

           No data available.

       7.4 Teratogenicity

           There is no evidence of teratogenicity.  However, clofazimine 
           crosses the human placenta.  The skin of infants born to 
           women who had received the drug during pregnancy was deeply 
           pigmented at birth. However, no evidence of teratogenicity 
           was noted.  There are no adequate and well-controlled studies 
           in pregnant women, but 3 neonatal deaths had been reported in 

           15 pregnancies in patients given clofazimine.  (McEvoy, 1990; 
           Reynolds, 1989; Farb et al., l982; PDR, 1990).

       7.5 Mutagenicity

           The drug was not mutagenic in the Ames microbial mutagen test 
           with or without metabolic activation (McEvoy, 1990).  
           However, genotoxic micronuclear testing studies in mice bone 
           marrow and spermatocytes revealed increase of chromosomal 
           aberrations.  The mechanism is not well understood but has 
           been suggested to be secondary to generation of hydroxyl 
           radicals and their effects on chromosomes (Das & Roy, 1990). 
           However, there is a significant higher incidence of 
           micronucleus in bone marrow erythrocytes and regenerated 
           hepatocytes indicating that clofazamine has a clastogenic 
           effect.  Clofazamine has been noted to have antimitotic 
           effects and the proposed mechanism is impairment of DNA 
           template or antimitochondrial activity (Roy & Das, 1990).

       7.6 Interactions

           Several studies done showed that concomitant clofazimine 
           administration does not affect the pharmacokinetics of 
           dapsone, but a few patients showed transient increase in the 
           urinary excretion of dapsone. However, there is some evidence 
           that the anti-inflammatory effects of clofazimine may be 
           decreased or nullified by dapsone; since, in vitro studies 
           showed that there is an opposite effect of both drugs on the 
           neutrophil motility and lymphocyte transformation.  But there 
           is no evidence of interference between the two drugs with 
           regard to their antimycobacterial activity.
           
           Clofazimine with rifampicin alone, or in conjunction with 
           dapsone, results in a delay in time to reach peak serum 
           rifampicin concentration, decrease in the rate of absorption 
           of rifampicin, and slight decrease in the area under the 
           plasma concentration curve (AUC) of the drug.  But, in a 
           study of lepromatous leprosy patients receiving dapsone 100 
           mg daily and rifampicin 600 mg daily, concomitant 
           administration of clofazimine 100 mg daily did not affect 
           plasma rifampicin concentrations of the AUC, plasma half-life 
           or urinary elimination of rifampicin.
           
           In a study of lepromatous leprosy patients receiving 
           clofazimine 300 mg daily, concomitant administration of 
           isoniazid 300 mg daily resulted in increased urinary and 
           plasma concentrations of clofazimine and decreased 
           concentration of the drug in the skin (McEvoy, 1990). 

       7.7 Main adverse effects

           Potentially life-threatening
           
           When clofazimine is given in high dosage for months or years, 
           crystals of the drug are deposited in the lamina propria and 

           submucosa of the small intestine, and in the mesenteric lymph 
           nodes (Dollery, 1991). The ileal wall may become thickened 
           with nodular or polypoid changes, and the mucosal pattern 
           coarsen and eosinophilic enteritis may also occur (Mason et 
           al., 1977; de Bergeyck, 1980).
           
           One patient, who received clofazimine in dosage varying 
           between 100 mg and 600 mg daily for 6 years for severe ENL, 
           after 3 years developed severe, progressive loss of weight, 
           recurring anorexia, nausea, diarrhoea and abdominal pain. She 
           died 4 months after stopping clofazimine from presumed 
           electrolyte imbalance (Jopling, 1976; Harvey et al., 1977).
           
           Other patients, whose clofazimine dosage was stopped at an 
           earlier stage, have usually gradually become symptom free, 
           although clofazimine crystals have been detected in a 
           mesenteric lymph node 46 months later (Jopling, 1976).  One 
           patient, who received 300 to 400 mg clofazimine daily for 
           only 11 months, developed a splenic infarct with evidence of 
           considerable accumulation of crystals in the spleen with 
           massive accumulation in a mesenteric lymph node (McDougal et 
           al., 1980).
           
           Dermal
           
           Adverse effects are usually dose-related, they include:
           
           Pink to brownish-black discolouration of the skin: dryness, 
           ichthyosis, pruritus, acneform eruptions, skin rashes and 
           photosensitivity reactions.
           
           Ocular
           
           Reddish-brown discolouration of the cornea, conjunctiva, and 
           lacrimal fluid.  Occasionally there could be dryness 
           itchiness, irritation, burning and watering of the eyes.
           
           Gastrointestinal
           
           Nausea, vomiting, abdominal pain and diarrhoea, 
           discolouration of faeces.  There was even note of splenic 
           infarction in a patient receiving clofazimine for the 
           treatment of pyoderma gangrenosum. Bowel obstruction and 
           G.I.S. bleeding in less than 1% of patients.
           
           Nervous system
           
           Headache, dizziness, drowsiness, fatigue and taste disorder. 
           Some patients developed depression because of the skin 
           discolouration.
           
           Haematopoietic effects
           
           Elevated ESR, eosinophilia.

           Liver
           
           Elevated albumin, bilirubin and SGOT.
           
           Other
           
           Discolouration of sweat, sputum, urine and breast milk, 
           hypokalaemia.
           
           (McEvoy, 1990; Reynolds, 1989; PDR, 1990). 

    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

       8.1 Material sampling plan

           8.1.1 Sampling and specimen collection

                 Blood samples are collected in heparinized tubes and 
                 these would be centrifuged.  The plasma must be 
                 separated and transferred into a plastic tube (Hauffe 
                 et al, 1986; Weber and Kop, 1987). 

           8.1.2 Storage of laboratory samples and specimens

                 The samples are to be kept frozen at -20C until 
                 required for analysis (Hauffe et al, 1986, Weber and 
                 Kop, 1987). 

           8.1.3 Transport of laboratory samples and specimens

                 Samples can be transferred in containers which could 
                 provide a temperature of -20 C (Hauffe et al., 1986; 
                 Weber and Kop, 1987). 

       8.2 Toxicological analyses and their interpretation

           8.2.1 Tests on active ingredient(s) of material

                 8.2.1.1 Simple qualitative test(s)

                 8.2.1.2 Advanced qualitative confirmation test(s)

                 8.2.1.3 Simple quantitative method(s)

                         Photometric determination alone.
                         
                         Photometric determination after TALC-separation
                         (Weber & Kop, 1987).

                 8.2.1.4 Advanced quantitative method(s)

           8.2.2 Tests for biological specimens

                 8.2.2.1 Simple qualitative test(s)

                 8.2.2.2 Advanced qualitative confirmation test(s)

                 8.2.2.3 Simple quantitative method(s)

                         Thin-layer chromatographic method.
                         
                         High pressure liquid chromatography (Moffat, 
                         1986). 

                 8.2.2.4 Advanced qualitative method(s)

       8.3 Biomedical investigations and their interpretation

           8.3.1 Biochemical analysis

                 8.3.1.1 Blood, plasma or serum

                         Use function test as ALT, AST, albumin, 
                         bilirubin, SGOT. 

                 8.3.1.2 Urine

           8.3.2 Arterial blood gas analyses

           8.3.3 Haematologic analyses

                 ESR, total eosinophile count, prothrombin time.

           8.3.4 Interpretation of biomedical investigations

       8.4 Other biomedical (diagnostic) investigations and their 
           interpretation 

           ECG.

       8.5 Overall interpretation of all toxicological analyses and
           toxicological investigations

           In view of the distribution and the lack of information on 
           therapeutic and/or toxic blood levels, measuring has no 
           practical relevance in the management of intoxication. 

       8.6 References

           See Section 13.

    9. CLINICAL EFFECTS

       9.1 Acute poisoning 

           9.1.1 Ingestion

                 No data available.

           9.1.2 Inhalation

                 No data available.

           9.1.3 Skin exposure

                 No data available.

           9.1.4 Eye contact

                 No data available.

           9.1.5 Parenteral exposure

                 No data available.

           9.1.6 Other

                 No data available.

       9.2 Chronic poisoning 
                         
           9.2.1 Ingestion

                 The only route of administration.  Dose-related adverse 
                 effects are therefore only from oral ingestion of 
                 clofazimine.
                 
                 Adverse reactions are dose-related with daily doses of 
                 300 mg or more, and more than three months of intake. 

           9.2.2 Inhalation

                 No data available.

           9.2.3 Skin exposure

                 No data available.

           9.2.4 Eye contact

                 No data available.

           9.2.5 Parenteral exposure

                 No data available.

           9.2.6 Other
                                                  
                 No data available.

       9.3 Course, prognosis, cause of death

           Adverse effects of clofazimine were generally well tolerated 
           and no patient stopped treatment because of them. However, 

           there was a report of fatal syndrome of abdominal pain, 
           malabsorption, intra-abdominal deposition of clofazimine 
           crystals in one patient.  There was also noted splenic 
           infarction and tissue accumulation of clofazimine in a 
           patient receiving clofazimine for the treatment of pyoderma 
           gangrenosum (Reynolds, 1989). 

       9.4 Systematic description of clinical effects

           9.4.1 Cardiovascular

                 Arrhythmia secondary to hypokalaemia (PDR, 1990).
                 
                 Its cardiotoxicity has been postulated (Choudhri et 
                 al., 1995). 

           9.4.2 Respiratory

                 Discolouration of the sputum.

           9.4.3 Neurological

                 9.4.3.1 Central nervous system (CNS)

                         Headache, dizziness, drowsiness, fatigue, taste 
                         disorder, depression. 

                 9.4.3.2 Peripheral nervous system

                         Not relevant.

                 9.4.3.3 Autonomic nervous system

                         Not relevant.

                 9.4.3.4 Skeletal and smooth muscle

                         Not relevant.

           9.4.4 Gastrointestinal

                 Nausea, vomiting, abdominal pain, diarrhoea, 
                 discolouration of the faeces.  There was even note of 
                 splenic infarction seen in a patient receiving 
                 clofazimine for the treatment of pyoderma gangrenosum.

           9.4.5 Hepatic

                 Elevated albumin, bilirubin, SGOT.

           9.4.6 Urinary

                 9.4.6.1 Renal

                         Discolouration of urine.

                 9.4.6.2 Other

                         No data available.

           9.4.7 Endocrine and reproductive systems

                 Urinary-oestrogen excretion, which can be used as an 
                 index of foeto-placental function, was reduced in women 
                 with lepromatous leprosy receiving clofazimine 
                 (Reynolds, 1989).
                 
                 Thyroid: no data available.

           9.4.8 Dermatological

                 Bilateral pedaloedema developed in five men and one 
                 woman who were treated with clofazimine, rifampicin and 
                 dapsone for multibacillary leprosy. The bilateral 
                 pedaloedema was symmetrical, pitting, nontender and 
                 progressive and developed after about 3 month's 
                 therapy.  Symptoms developed only in patients receiving 
                 all 3 drugs and not in patients who received only 
                 rifampicin and dapsone. It appears that this oedema is 
                 due to clofazimine (Oommen T, 1990).
                 
                 Pink to brownish-black discolouration of the skin, 
                 dryness, ichthyosis, pruritus, rashes, acneform 
                 eruptions, photosensitivity reactions. 

           9.4.9 Eye, ear, nose, throat: local effects

                 Bull's eye pigmentary maculopathy and widespread 
                 retinal damage were observed in a 37-year-old man with 
                 AIDS after 8 months therapy with clofazimine 20 mg/day 
                 for disseminated Mycobacterium avium complex infection. 
                 The patient was also receiving isoniazid rifabutin, 
                 ethambutol, ganciclovir, pyrimethamine + sulfadoxine 
                 and prednisone. Clofazimine therapy was withdrawn and 
                 no change was observed after 6 weeks. Long term follow-
                 up was not possible as the patient died 3 months later. 
                 The authors suggest that all AIDS patients receiving 
                 this drug be closely followed for the development of 
                 macular pigmentary changes (Cunningham, 1990).
                 
                 Reddish-brown discolouration of the cornea conjunctiva, 
                 lacrimal fluid, occasional dryness, itchiness 
                 irritation, burning and watering of the eyes. 

          9.4.10 Haematological

                 Eosinophilia, elevated ESR.

          9.4.11 Immunological

                 No data available.

          9.4.12 Metabolic

                 9.4.12.1 Acid-base disturbances

                          No data available.

                 9.4.12.2 Fluid and electrolyte disturbances

                          Hypokalaemia (PDR, 1990).

                 9.4.12.3 Others

                          No data available.
                          
          9.4.13 Allergic reactions

                 Pruritus, skin rashes.

          9.4.14 Other clinical effects

                 No data available.

          9.4.15 Special risks

                 Pregnance
                 
                 It has been found that clofazimine crosses the human 
                 placenta.  The skin of infants born to women who had 
                 received the drug during pregnancy was noted to be 
                 deeply pigmented at birth. However, no evidence of 
                 teratogenicity was noted.  There are no adequate and 
                 well controlled studies in pregnant women, but 3 
                 neonatal deaths had been reported in 15 pregnancies in 
                 patients given clofazimine.  Further evaluation of the 
                 perinatal consequences of clofazimine therapy in 
                 patients with leprosy is needed (McEvoy, 1990; 
                 Reynolds, 1989; PDR, 1990).
                 
                 Urinary oestrogen excretion, which can be used as an 
                 index of foeto-placental function, was reduced in women 
                 with lepromatous leprosy receiving Clofazimine 
                 (Reynolds, 1989).
                 
                 Breastfeeding
                 
                 Clofazimine is excreted in breastmilk.
                 
                 Enzyme deficiencies
                 
                 No data available.
                 
       9.5 Other

           No data available.

       9.6 Summary

           Not relevant

    10. MANAGEMENT

        10.1 General principles

             Acute poisoning
             
             No data are available.
             
             Chronic poisoning
             
             Symptomatic therapy.  ECG for detecting hypokalaemia.

        10.2 Relevant laboratory analyses

             10.2.1 Sample collection

                    Blood samples for levels of Clofazimine can be 
                    collected in heparinized tubes.  The volume is about 
                    1 ml.  Then the blood sample is to be centrifuges so 
                    that plasma could be separated and transferred into 
                    a plastic tube.  It will be kept frozen at -20C 
                    until required for analysis with the use of the 
                    thin-layer chromatographic method (Hauffe et al., 
                    1986).
                    
                    High pressure liquid chromatography and thin-layer 
                    chromatography can be used. 

             10.2.2 Biomedical analysis

                    No data available

             10.2.3 Toxicological analysis

                    Clofazimine concentration could be analyzed with the 
                    use of blood samples collected in heparinized tubes. 
                    The samples collected are then centrifuged and the 
                    separated plasma is analyzed with the use of thin-
                    layer chromatographic method or HPLC (Moffat, 1986). 

             10.2.4 Other investigations

                    No data available.

        10.3 Life supportive procedures and symptomatic/specific 
             treatment 

             ECG for detecting hypokalaemia.
          
        10.4 Decontamination

             Gastric lavage (preferably with activated charcoal), or 
             inducing emesis may be useful, if the patient is seen early 
             after the ingestion.  The use of a cathartic is no longer 
             recommended.

        10.5 Elimination

             No data available.

        10.6 Antidote treatment

             10.6.1 Adults

                    No antidote available.

             10.6.2 Children

                    No antidote available.

        10.7 Management discussion

                  No data available

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             A 46 year-old woman experienced weight loss, diarrhoea, and 
             abdominal pain 10 months after receiving a 6 month course 
             of clofazimine 300 mg given daily for prurigo nodularis.  
             Abdominal symptoms were initially relieved by a gluten-free 
             diet, but returned 22 months after withdrawal of 
             clofazimine.  Laparotomy showed crystal deposition in the 
             chorion of intestinal villi and in the mesenteric lymph 
             nodes (Reynolds, 1989).
             
             Splenic infarction and tissue accumulation of clofazimine 
             in a patient receiving clofazimine for the treatment of 
             pyoderma gangrenosum (Reynolds, 1989).
             
             Although 2 pregnant patients received clofazimine without 
             any adverse effects to the fetus, 2 neonatal deaths had 
             been reported in 13 pregnancies in patients given 
             clofazimine (Farb et al., 1982; Reynolds, 1989). 

        11.2 Internally extracted data on cases

             No data available.

        11.3 Internal cases

             To be completed by each Centre using local data

    12. ADDITIONAL INFORMATION

        12.1 Availability of antidotes

             To be completed by each Centre using local data

        12.2 Specific preventive measures

             Clofazimine should be stored at 23 C.  It should be 
             protected from heat and moisture.  If the capsules are 
             sticking together, then do not use them.  When the 
             preceding adverse effects are noted, discontinue the use of 
             the drug.  The drug should not be given to pregnant or 
             nursing mothers, unless absolutely necessary.  Refrain from 
             using the drug in patients with liver function 
             disturbances.  It should be used with caution with 
             diuretics.  The drug should be used with Dapsone or 
             Rifampicin in treating leprosy.  At present, it has no 
             potential of becoming a drug of abuse. 

        12.3 Other

             No data available.

    13. REFERENCES

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        practice of infectious diseases,  3rd ed., pp 358-359.
        
        de Bergeyck E, Janssens PG,  & de Muynck A (1980) Radiological 
        abnormalities of the ileum associated with the use of 
        clofazamine (Lamprene: B.663) in the treatment of skin 
        ulceration due to Mycobacterium ulcerans. Leprosy Review, 51: 
        221-228.
        
        Budavari S ed. (1989) Merck index, an encyclopedia of chemicals, 
        drugs and biologicals ,11th ed. Rahway, New Jersey, Merck and 
        Co., Inc. pp 370-371.
        
        Choudhri SH, Harris L, Butany JW, & Keystone JS 
        (1995)Clofazimine induced cardiotoxicity: a case report. Lepr 
        Rev 66(1): 63-68.
        
        Cunningham CA, Friedberg DN, & Carr RE (1990) Clofazimine-
        induced generalized retinal degeneration.  Retina, 10: 131-134.
        
        Das RK & Roy B (1990)  Evaluation of genotoxicity of 
        Clofazamine, an antileprosy drug in mice in vivo. I. Chromosomal 
        analysis in bone marrow and spermatocytes.  Mutation Research, 
        241: 161-168.
        
        Dollery ed. (1991)  Therapeutic drugs.  Churchill & Livingstone, 
        Edinburgh.

        Farb H, West DP, & Pedvis-Leftick A (1982) Clofazimine in 
        pregnancy complicated by leprosy.  Obstetrics & Gynecology, 
        59: 122-123.
        
        Gilman AG, Rall TW, Nies AS & Taylor P eds.(1990) Goodman and 
        Gilman's the pharmacological basis of therapeutics, 8th ed. New 
        York, Pergamon Press, pp 1160-1162.
        
        Harvey RF Harman RRM, Black C, et al. (1977) Abdominal pain and 
        malabsorption due to tissue deposition of clofazimine (Lamprene) 
        crystals. Brit J of Dermatology, 97 (suppl) l5: 19
        
        Hauffe et al. (1986) CIBA-Geigy Pharma Research and Development 
        Pharmacological Chemistry.
        
        Jopling WH (1976)  Editorial.  Complications of treatment with 
        clofazimine (Lamprene: B.663).  Leprosy Review, 47: 1-3.
        
        Mason GH, Ellis-Pegler RB, Arthur JF (1977)  Clofazamine and 
        eosinophilic enteritis.  Leprosy Review, 48: 175-180.
        
        McDougal AC, Horsfall WR, Hede JE, Chaplin AJ (1980)  Splenic 
        infarction and tissue accumulation of crystals associated with 
        the use of clofazimine (Lamprene: B.663) in the treatment of 
        pyoderma gangrenosum.  Brit J of Dermatology, 102: 227-230
        
        McEvoy GK ed. (1990) American Hospital Formulary Service, Drug 
        Information. American Society of Hospital Pharmacists. Bethesda, 
        MD, American Society of Hospital Pharmacists,  pp 442-446.
        
        Moffat, AC ed. (1986) Clarke's Isolation and Identification of 
        Drugs, 2nd ed. London, The Pharmaceutical Press, pp 476-477.
        
        Oommen T (1990) Clofazimine-induced lymphoedema. Leprosy Review, 
        61: 289.
        
        PDR - Physicians' Desk Reference (1990)  44th ed., Ordell NJ, 
        Medical Economics, pp 980-981.
        
        Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia, 
        29th ed. London, The Pharmaceutical Press, pp 556-557.
        
        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 
        30th ed. London, The Pharmaceutical Press, pp 151-152.
        
        Roy B & Das RK (1990)  Evaluation of genotoxicity of 
        clofazamine, an antileprosy drug in mice in vivo.  II. 
        Micronucleus test in bone marrow and hepatocytes.  Mutation 
        Research, 241: 169-173.
        
        von den Driesch, Mielke V, Simon M Jr, Staib G, Tacke J, & 
        Sterry W (1994) "Granulomatous slack skin" - cutaneous 
        elastolytic lymphoma. Hautarzt, 45(12): 861-865.
        
        Weber & Kop (1987)  CIBA-Geigy Pharma Analytical Development, 
        Basle. Pharmaceutical Documentation.
        
        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 
        index. Oslo, WHO Collaborating Centre for Drug Statistics 
        Methodology, p 61.
        
        WHO (1988)  Guide to Leprosy Control, 2nd Edition.  World Health 
        Organization, Geneva, pp 34-36.
        
        WHO (1992) International nonproprietary names (INN) for 
        pharmaceutical substances. Geneva, World Health Organisation,  
        p 130. 
        
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
        ADDRESS(ES)

        Author        Dr Diana Jacinto Gascon
                      National Poisons Control and Information Service
                      UP, College of Medicine - Philippine General
                      Hospital
                      547 Pedro Gil Street
                      Ermita
                      Manila
                      Philippines 1000
        
        Date          January 1992
        
        Updated by 
             author   May 1992
        
        Peer Review   Newcastle-upon-Tyne, United Kingdom, February 1992
        
                           London, United Kingdom, September 1992
    
    


    See Also:
       Toxicological Abbreviations