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 23°C, 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_µg/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_µg/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 -20°C 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 -20°C
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
Alford R (1989) Antimycobacterial agents, principles and
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