Clofazimine

473.4

473.40

217-980-2

D959AE5USF

759283|141046

DTXSID7022839

C47456

J - Antiinfectives for systemic use

2933990090

40

7.1

Solid

1.3±0.1 g/cm3

210-212 °C

566.9ºC at 760mmHg

296.7±30.1 °C

1.667

H2O: 10mg/L(temperature not stated);Practically insoluble in water, soluble in methylene chloride, very slightly soluble in ethanol (96 per cent). It shows polymorphism (5.9).

LD50 orally in mice, rats, and guinea pigs: >4 g/kg (Stenger)

8.51None

8.51

216.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

NONH for all modes of transport

3

22-36/37/38

36-26

SG1578000

Xn,Xi

|Warning|H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

The reported oral LD50 of clofazimine in rats and mice is 8400 mg/kg and >5000 mg/kg, respectively. No specific data are available regarding the treatment of clofazimine overdosage. In cases of overdose consider gastrointestinal decontamination via gastric lavage or induced vomiting. Employ symptomatic and supportive measures as clinically indicated.

Therapy with clofazimine has not been associated with elevations in serum enzymes during treatment and has not been linked to cases of clinically apparent liver injury. The multidrug therapy combination of clofazimine, rifampin and dapsone, however, is associated with instances of jaundice and hepatitis, which are most likely attributable to dapsone ("dapsone syndrome") and marked by fever, rash, eosinophilia and hepatic involvement (DRESS syndrome) typically arising within 8 weeks of starting the drug regimen. Dapsone induced liver injury can be severe and the mortality rate in cases with jaundice is as high as 25% to 33%. The liver injury usually resolves with stopping therapy and most patients have later tolerated restarting of clofazimine and rifampin. Thus, clinically apparent liver injury from clofazimine must be very rare, if it occurs at all.

Clofazimine is bound primarily to beta-lipoproteins (and, to a lesser extent, alpha-lipoproteins) in the serum. This binding was saturable at concentrations of ~10 µg/mL. Binding to gamma-globulin and albumin is negligible.

Clofazimine is indicated for the treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum. To prevent the development of drug resistance, it should be used only in combination with other antimycobacterial leprosy treatments.

Clofazimine is a fat soluble, brick red dye that is used in combination with other agents in the therapy of leprosy. Clofazimine, by itself, has not been associated with serum aminotransferase elevations during therapy or to instances of clinically apparent acute liver injury.

Antiinfective Agents

Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae (Hansen's bacillus) due primarily to its action on the bacterial outer membrane, though there is some evidence that activity on the bacterial respiratory chain and ion transporters may play a role. It also exerts anti-inflammatory properties due to the suppression of T-lymphocyte activity. Clofazimine has a relatively long duration of action owing to its long residence time in the body, but is still administered daily. Approximately 75-100% of patients receiving clofazimine will experience an orange-pink to brownish-black discoloration of the skin, conjunctivae, and bodily fluids. Skin discoloration may take several months or years to reverse following the cessation of therapy. Clofazimine has also been implicated in abdominal obstruction, in some cases fatal, due to the deposition of drug and formation of crystals in the intestinal mucosa - complaints of abdominal pain and nausea/vomiting should be investigated promptly, and the doses of clofazimine should be lowered or discontinued if it is found to be the culprit. Its use should be avoided in patients with hepatic dysfunction.

Substances that suppress Mycobacterium leprae, ameliorate the clinical manifestations of leprosy, and/or reduce the incidence and severity of leprous reactions. (See all compounds classified as Leprostatic Agents.)|Substances that reduce or suppress INFLAMMATION. (See all compounds classified as Anti-Inflammatory Agents.)

Absorption varies from 45 to 62% following oral administration in leprosy patients. Co-administration of a 200mg dose of clofazimine with food resulted in a C_max of 0.41 mg/L with a T_max of 8 h; administered in a fasting state, the corresponding C_max was 30% lower while the time to Cmax was 12 h.|Part of an ingested dose of clofazimine is found in the feces, which may represent excretion in the bile, and a small amount is also eliminated in the sputum, sebum, and sweat. Excretion of unchanged drug and metabolites in a 24-hour urine collection was negligible.|Clofazimine is highly lipophilic and therefore deposits primarily in fatty tissues and cells of the reticuloendothelial system, where it is taken up by macrophages and further distributed throughout the body. Crystalized deposits have been found in the mesenteric lymph nodes, adrenals, subcutaneous fat, liver, bile, gall bladder, spleen, small intestine, muscles, bones, and skin.

Three metabolites have been identified in the urine following repeated oral doses of clofazimine. It is unclear whether these metabolites are pharmacologically active. Metabolite I may be the result of the hydrolytic dehalogenation of clofazimine and metabolite II presumably is formed by a hydrolytic deamination reaction followed by glucuronidation.

The mean elimination half-life is approximately 25 days.

Although the precise mechanism(s) of action of clofazimine have not been elucidated, its antimicrobial activity appears to be membrane-directed. It was previously thought that, due to its lipophilicity, clofazimine participated in the generation of intracellular reactive oxygen species (ROS) via redox cycling, specifically H₂O₂ and superoxide, which then exerted an antimicrobial effect. A more recent and compelling theory involves clofazimine interacting with bacterial membrane phospholipids to generate antimicrobial lysophospholipids - bactericidal efficacy may, then, arise from the combined membrane-destabilizing effects of both clofazimine and lysophospholipids, which interfere with K+ uptake and, ultimately, ATP production. The anti-inflammatory activity of clofazimine is the result of its inhibition of T-lymphocyte activation and proliferation. Several mechanisms have been proposed, including direct antagonism of T-cell Kv 1.3 potassium channels and indirect action by promoting the release of E-series prostaglandins and reactive oxygen species from bystander neutrophils and monocytes.

B 663

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