AHFS Class:

• Antileprosy Agents 8:16.08

Generic Name(s):

• Clofazimine

Clofazimine is a phenazine dye with antimycobacterial and anti-inflammatory activity.1,2,4,37,70,76,78,117,118,119,139,141

Restricted Distribution of Clofazimine

As of November 1, 2004, clofazimine is no longer commercially available in the US, but may be obtained for the treatment of leprosy from the National Hansen's Disease Program (NHDP) of the US Department of Health and Human Services, Health Resources and Services Administration (HRSA).214,215,216 In rare circumstances, the drug may also be made available from NHDP for other uses.214,215

For the treatment of leprosy, clofazimine is being distributed under an Investigational New Drug (IND) application held by NHDP.214 The drug is available at no cost after the clinician has registered as an investigator under the IND protocol held by NHDP.214 Clinicians requiring clofazimine for a patient with leprosy should contact the Administrative Officer of the Laboratory Research Branch at NHDP by mail Skip Berman Drive, Baton Rouge, LA 70803, by phone at 225-578-9861 or 800-642-2477, or by fax at 225-578-9856.214,215,216

Use of clofazimine for the treatment of any disease other than leprosy is discouraged by the World Health Organization (WHO) and the manufacturer.214 Safety and efficacy have been established only for the treatment of leprosy and indiscriminate use of clofazimine may promote emergence of resistant strains of Mycobacterium leprae , the causative agent of leprosy.214 If use of clofazimine is considered necessary in situations where there are no other comparable or satisfactory treatments available (e.g., treatment of multidrug-resistant tuberculosis [MDRTB]), the drug can be distributed under a single-patient treatment IND protocol administered by the FDA.214,215 To obtain the drug for any use other than the treatment of leprosy, clinicians must first contact the Division of Special Pathogen and Immunologic Drug Products (HFD-590), Center for Drug Evaluation and Research of the FDA by phone at 301-796-1600 to register as an investigator under the single-patient treatment IND protocol.214,215 After FDA approval of the single-patient treatment IND, FDA will request NHDP to distribute clofazimine directly to the prescriber.214,215

Leprosy

Clofazimine is used in rifampin-based multiple-drug regimens for the treatment of multibacillary and paucibacillary leprosy.1,2,37,86,113,114,115,136,145,146,147,148,149,193,194,195,196,197,198,199,200,201 The drug also has been used in the treatment and prevention of erythema nodosum leprosum (ENL) reactions (lepra type 2 reactions) in leprosy patients.1,2,37,41,69,71,81,82,84,86,93,113,136,147,148,149,154,155,156,157,158,164,193,195,196,198

The WHO and most clinicians recommend that rifampin-based multiple-drug regimens be used for the treatment of all forms of leprosy.193,194,195,196,197,198,199,200,201 Multiple-drug regimens may reduce infectiousness of the patient more rapidly as well as delay or prevent the emergence of resistant organisms.193,200 Rifampin-based multiple-drug regimens are necessary because of the increasing incidence of dapsone-resistant M. leprae , and these regimens are designed to be effective against all strains of M. leprae , regardless of their susceptibility to dapsone.193,196,198,199,200,201 Because rifampin is bactericidal against M. leprae , once-monthly administration of rifampin is the principal component of the recommended multiple-drug regimens; clofazimine and dapsone are included in the regimens to prevent the emergence of rifampin-resistant M. leprae .193,199,200,201

Some adverse effects (e.g., skin discoloration) reported with clofazimine (see Cautions: Dermatologic Effects) may cause a substantial compliance problem in certain patients or populations receiving the drug as part of recommended antileprosy regimens.196,200 Often, appropriate counseling about clofazimine (e.g., advantages of its use, reversibility of skin discoloration) are sufficient to encourage the patient to continue taking the drug.200

Multibacillary Leprosy

For the treatment of multibacillary leprosy (more than 5 lesions or skin smear positive for acid-fast bacteria), WHO recommends a 12-month multiple-drug regimen that includes rifampin, clofazimine, and dapsone.193,198,199,200,201,218 The clofazimine dosage regimen recommended by WHO for use in the treatment of multibacillary leprosy includes both a daily dose and a once-monthly dose of the drug;76,126,193,200 the once-monthly dose is included to ensure that optimal concentrations of clofazimine are maintained in body tissue, even if the patient occasionally misses a daily dose of the drug.76,126,193,200

If a patient with multibacillary leprosy will not accept or cannot tolerate clofazimine, the WHO recommends an alternative regimen that includes ofloxacin and minocycline.200

Paucibacillary Leprosy

For the treatment of paucibacillary leprosy (1-5 lesions), the WHO recommends a 6-month regimen of rifampin and dapsone.193,200,218 If a patient receiving this regimen experiences severe adverse effects related to dapsone, the WHO recommends that dapsone be discontinued and clofazimine substituted.200

Leprosy Reactional States

Erythema Nodosum Leprosum

Clofazimine has been used for the treatment and prevention of erythema nodosum leprosum ( ENL) reactions (lepra type 2 reactions) in leprosy patients.1,2,37,40,41,69,71,81,82,84,86,93,147,148,149,154,155,156,157,158,164,193,195,196,198 The fact that clofazimine has anti-inflammatory and immunosuppressive effects, as well as antimycobacterial effects, apparently contributes to the drug's beneficial effects in the treatment of ENL reactions.2,37,54,58,61,66,80,101,102,154,200 However, clofazimine is not as effective or as rapidly acting as other agents used in the treatment of ENL (e.g., corticosteroids, thalidomide),2,37,93,193,203,210,213 and should not be initiated as the sole agent for the treatment of severe ENL.193,203 Some clinicians suggest that thalidomide may be the drug of choice for the treatment of moderate to severe ENL reactions, especially severe, recurrent reactions; however, the risks versus benefits of thalidomide therapy must be considered, especially in women of childbearing potential.193,194,195,196,202,210,213 (See Uses: Erythema Nodosum Leprosum, in Thalidomide 92:20.)

ENL is a recurrent immunologically mediated syndrome that occurs principally in patients with multibacillary leprosy.193,202,206,208 While ENL reactions have been reported to occur in 10-50% of lepromatous leprosy patients85,93,112,193,202,208,210,212,213 and 25-30% of borderline lepromatous patients,210,212,213 these reactions are being reported less frequently in patients receiving the currently recommended multidrug antileprosy regimens that include clofazimine than in those who received dapsone monotherapy.193,212,213 ENL usually occurs after initiation of anti-infective therapy for leprosy (generally within the first 2 years of treatment), although occasionally it may occur spontaneously in untreated lepromatous leprosy patients or after treatment is discontinued.202,205,206,208,209,210,212 These reactions are considered to be a manifestation of the disease rather than an adverse reaction to antileprosy regimens.208,210,212 Clinical symptoms include cutaneous papules or nodules that are painful or tender, erythematous, and histologically vasculitic;93,112,130,202,208,213 the papules may pustulate and ulcerate, appear as recurrent crops, and are widely distributed, generally appearing on extensor surfaces of the extremities and on the face.202,208 Cutaneous symptoms of ENL may be accompanied by peripheral neuritis (usually of the ulnar nerve), fever, malaise, wasting, uveitis, lymphadenitis, orchitis, and glomerulonephritis.202,208,210,213 Histologically, ENL is an acute vasculitis or panniculitis that is thought to be secondary to immune (i.e., antigen-antibody) complex deposition.2,79,93,112,202,207,213

Depending on the severity of manifestations, ENL reactions generally are treated using analgesics, corticosteroids, and/or thalidomide.2,37,85,93,112,113,130,158,191,193,195,210,213 While mild ENL reactions in some patients may be adequately managed with a nonsteroidal anti-inflammatory agent (e.g., aspirin, indomethacin) and bed rest,193,194,196,213 moderate to severe ENL reactions generally are treated with corticosteroids and/or thalidomide and hospitalization may be required.2,112,193,196,202 The antileprosy regimen usually is continued while the ENL reaction is treated.2,85,93,112 Corticosteroid therapy (usually prednisolone) generally is effective for the treatment of moderate and severe ENL and usually is necessary when ENL is complicated by neuritis; however, long-term therapy may be required, and there is a risk that ENL patients (especially those with chronic ENL) may become steroid dependent.193,195,196,202,205,210,213 If prolonged corticosteroid therapy becomes necessary, initiation of clofazimine therapy (if the drug is not already included in the regimen) or a temporary increase in clofazimine dosage (in patients already receiving clofazimine as part of a multidrug antileprosy regimen) may allow a reduction in corticosteroid requirements.37,85,93,149,193 Clofazimine dosage effective for the treatment of ENL reactions is slightly higher than that usually recommended for the treatment of leprosy.193,196,213

Early diagnosis and treatment of ENL is important since these reactions are associated with considerable morbidity, especially if chronic, recurrent ENL occurs.193,195,196,202,213 Therapy for leprosy and leprosy reactional states should be undertaken in consultation with an expert in the treatment of leprosy.202

Other Leprosy Reactional States

Clofazimine also has been used for the treatment of reversal (type 1) reactions† in patients with borderline or tuberculoid leprosy.2,37,71,81,93 However, use of clofazimine in type 1 reactions is controversial since efficacy of the drug for these reactions has not been fully evaluated.37,81,196 In some patients with type 1 reactions, use of clofazimine appeared to aggravate the reactional state.81 Reversal reactions presumably occur because the patient is able to mount an enhanced delayed hypersensitivity response to the residual leprosy infection and this leads to swelling of existing skin and nerve lesions.79,93,112,130 Existing lesions become erythematous and edematous and may ulcerate; fever and an increased leukocyte count frequently occur, and acute neuritis and loss of nerve function may develop.112,130 Corticosteroid therapy (usually prednisolone) is the treatment of choice for type 1 reactions;2,37,113,193,196 analgesics and surgical decompression of swollen nerve trunks may also be used.2,37,93,112,113

Clofazimine has not been shown to be effective in the treatment of other leprosy-associated inflammatory reactions1 (e.g., Lucio's phenomenon, downgrading reactions).37,129,130

Treatment of leprosy and management of leprosy reactional states is complicated and should be undertaken in consultation with a specialist familiar with the disease.215,216,219 Information is available from the National Hansen's Disease Program (NHDP) of the US Department of Health and Human Services, Health Resources and Services Administration (HRSA) by phone at 225-578-9861 or 800-642-2477, by fax at 225-578-9856, or on the Internet at [Web].215,216,219

Treatment of Mycobacterium avium Complex (MAC) Infections

Pulmonary and Localized Extrapulmonary MAC Infections

Clofazimine has been used in multiple-drug regimens for the treatment of pulmonary and localized extrapulmonary Mycobacterium avium complex (MAC) infections†.28,43,44,45,46,48,49,50,92,95,152,167 However, the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) state that the role of clofazimine in the treatment of MAC lung disease is not established.183 In addition, use of clofazimine for the treatment of any disease other than leprosy is discouraged by the WHO and the manufacturer since indiscriminate use of clofazimine may promote emergence of resistant strains of M. leprae .214 (See Uses: Restricted Distribution of Clofazimine.)

Treatment of MAC infections is complicated and should be directed by clinicians familiar with mycobacterial diseases; consultation with a specialist is particularly important when the patient cannot tolerate first-line drugs or when the infection has not responded to prior therapy or is caused by macrolide-resistant MAC.183

Disseminated MAC Infections

The ATS, IDSA, CDC, and other experts state that clofazimine should not be used for the treatment of disseminated MAC infections, including infections that have failed to respond to or are resistant to other drugs.183,186 There is some evidence that clofazimine is ineffective in these infections and may even be associated with reduced survival.179,183,186

Other Mycobacterial Infections

Clofazimine is active in vitro against M. tuberculosis 30,32,33,76,125,138,139,140 and has been used in multiple-drug regimens for the treatment of multidrug-resistant tuberculosis† (MDRTB).217 However, clofazimine is not included in current CDC, ATS, and IDSA recommendations for the treatment of tuberculosis.47 In addition, use of clofazimine for the treatment of any disease other than leprosy is discouraged by the WHO and the manufacturer since indiscriminate use of clofazimine may promote emergence of resistant strains of M. leprae .214 If use in the treatment of MDRTB is considered necessary, clofazimine may be made available from the NHDP under a single-patient treatment IND protocol administered by FDA.214,215 (See Uses: Restricted Distribution of Clofazimine.)

Although clofazimine is active in vitro against M. ulcerans 138,139,140 and has been used with some success in a limited number of patients as an adjunct to surgery for the treatment of Buruli skin ulcers caused by M. ulcerans †,2,140 the drug generally has been ineffective when used in the treatment of cutaneous lesions caused by M. ulcerans .96,109 The CDC, ATS, and IDSA state that surgical debridement with skin grafting is the treatment of choice for infections caused by M. ulcerans .95,96,183

Other Uses

Clofazimine has been used in a variety of inflammatory or pustular dermatoses†.53,56,59,62,63,65,100,104,107,110,132,133 However, safety and efficacy have not been established and use of clofazimine for the treatment of any disease other than leprosy is discouraged by the WHO and the manufacturer since indiscriminate use of clofazimine may promote emergence of resistant strains of M. leprae .214 (See Uses: Restricted Distribution of Clofazimine.)

Clofazimine has been used with some success in the treatment of pyoderma gangrenosum† either alone or in conjunction with corticosteroid therapy.56,62,65,100,104,107,110,132 Although not all cases of pyoderma gangrenosum have responded to clofazimine therapy, the drug has been effective in some cases that failed to respond to corticosteroids or dapsone therapy.56,100,107 Clofazimine also has been used with some success in a limited number of patients for the treatment of generalized pustular psoriasis†,63 acne vulgaris†,52 Sweet's syndrome† ( acute febrile neutrophilic dermatosis),133 and granuloma faciale†.108

There are conflicting reports on the efficacy of clofazimine in the treatment of lupus erythematosus†.57,104,111 Although the drug appeared to be effective in the treatment of skin lesions in a few patients with annular57 or discoid104,111 lupus erythematosus resistant to conventional antimalarial or corticosteroid therapy, clofazimine was ineffective in other patients with chronic discoid lupus erythematosus or diffuse, photosensitive, systemic lupus erythematosus lesions.51,55

Clofazimine has been used with some success in a limited number of patients for the treatment of Crohn's disease†,53 ulcerative colitis†,53 Miescher's granulomatous cheilitis†,59 and Melkersson-Rosenthal syndrome†.59

Administration

Clofazimine is administered orally.1 Clofazimine should be taken with a meal1 to maximize absorption of the drug.160

Dosage

Clofazimine dosages exceeding 100 mg daily should be given for as short a period as possible and only under close medical supervision.1 (See Cautions.)

Leprosy

The usual adult dosage of clofazimine for the treatment of leprosy is 50-100 mg once daily.1,37,113,118,123,136,146,147 Clofazimine also is given in a dosage regimen that includes 50 mg once daily plus an additional 300-mg dose given once monthly.36,118,193,194,195,196,197,198,199,200,201

Multibacillary Leprosy

For the treatment of multibacillary leprosy (more than 5 lesions or skin smear positive for acid-fast bacteria), the World Health Organization (WHO) and other clinicians recommend that adults receive clofazimine in a dosage of 50 mg once daily (with an additional 300-mg dose given once monthly) in conjunction with rifampin (600 mg once monthly) and dapsone (100 mg once daily) given for 12 months.36,193,194,195,196,197,198,199,200,201,218 Children 10-14 years of age with multibacillary leprosy may receive clofazimine in a dosage of 50 mg once every second day (with an additional 150-mg dose given once monthly) in conjunction with rifampin (450 mg once monthly) and dapsone (50 mg once daily) given for 12 months,198,218 and children younger than 10 years of age† should receive an appropriately adjusted dosage (e.g., rifampin 300 mg once monthly in conjunction with clofazimine 50 mg twice each week plus 100 mg once monthly and dapsone 25 mg daily) given for 12 months.198 The WHO recommends supervised administration of some drug doses included in the regimen (e.g., once-monthly doses).193,195,198,199,200,201,202 While the 12-month regimen is adequate for most patients with multibacillary leprosy, the WHO recommends that multibacillary leprosy patients with a high bacteriologic index who demonstrate no improvement (with evidence of worsening) of leprosy following completion of the initial 12 months of treatment should receive an additional 12 months of therapy.200

If a patient with multibacillary leprosy experiences severe adverse effects related to dapsone, dapsone may be discontinued and therapy continued with rifampin and clofazimine given in the usually recommended dosages.200

If an adult with multibacillary leprosy will not accept or cannot tolerate clofazimine, the WHO states that these adults may receive supervised administration of a once-monthly rifampin-based multiple-drug regimen (ROM) that includes rifampin (600 mg once monthly), ofloxacin (400 mg once monthly), and minocycline (100 mg once monthly) given for 24 months.193

For the treatment of multibacillary leprosy in adults who cannot receive rifampin because of adverse effects, intercurrent disease, or infection with rifampin-resistant Mycobacterium leprae , the WHO recommends supervised administration of a regimen of clofazimine (50 mg once daily), ofloxacin (400 mg once daily), and minocycline (100 mg once daily) given for 6 months, followed by a regimen of clofazimine (50 mg once daily) and either ofloxacin (400 mg once daily) or minocycline (100 mg once daily) given for at least an additional 18 months.193,199,200,201

Paucibacillary Leprosy

If a patient with paucibacillary leprosy (1-5 lesions) receiving the usually recommended regimen of rifampin and dapsone experiences severe adverse effects related to dapsone, dapsone may be discontinued from the regimen and clofazimine substituted (using the dosage recommended for the treatment of multibacillary leprosy) for 6 months.193,200

Erythema Nodosum Leprosum

The treatment of erythema nodosum leprosum ( ENL) reactions (type 2 reactions) depends on the severity of symptoms.1,2,37,93,94,112,147,154,155,156,157,158,164 (See Leprosy Reactional States in Uses: Leprosy) When prolonged corticosteroid therapy is necessary in patients with ENL, clofazimine in a dosage of 100-300 mg daily given in 2 or 3 divided doses for up to 3 months1,156,157,193,196,198 or longer37,146,154,156,157,164 may eliminate or reduce corticosteroid requirements. In patients with severe, corticosteroid-dependent ENL, adequate control (reduction of severity and frequency of attacks and corticosteroid use) may require prolonged initial clofazimine therapy (for up to about 7 months),147,148,149,157 and extended therapy with the drug (an additional 9-24 months) may be necessary to prevent recurrence.37,147,157 An initial exacerbation may occur in some patients during the first several weeks of clofazimine therapy, but this generally is followed by progressive improvement.147,154 Clofazimine dosages up to 400 mg daily have been used to control ENL in some adults;37,93,136,146,147,148,149,154,155,157,195 however, the manufacturer states that dosages greater than 200 mg daily are not recommended.1 Dosage of clofazimine should be reduced to the lowest effective level (e.g., 100 mg daily) as soon as possible after the reactive episode is controlled.1,37,146,147,154,156,157,196

Mycobacterium avium Complex (MAC) Infections

When used in the treatment of Mycobacterium avium complex (MAC) infections† in adults, clofazimine has been given in a dosage of 100 mg one or 3 times daily in conjunction with other antimycobacterial agents.43,44,48,49,50,167,168 A clofazimine dosage of 1-2 mg/kg daily has been used for the treatment of MAC infections in children†.168 However, higher dosages (up to 50 mg daily in children younger than 4 years of age, or approximately 4 mg/kg daily) also have been used in children.168

Clofazimine generally is well tolerated1,2,9,14,19,36,37,66,71,74 when given in dosages of 100 mg daily or less.1,36 The major adverse effects of the drug involve the skin, eyes, and GI tract.1,2,9,14,19,37,66,68,73,74 Discoloration of various body tissues and fluids occurs in most patients receiving clofazimine,1,9,37,40,66,70,71,73,74 apparently because clofazimine is a bright-red dye and crystals of the drug are distributed to and accumulate in these tissues and fluids.1,2,37,66,70,73,74 Although most adverse effects of clofazimine are mild, dose related, and reversible following discontinuance of the drug,1,2,14,19,37,74 severe GI effects, which may be fatal, have been reported rarely.1,2,9,14,37,68,74,127

Dermatologic Effects

Pink to brownish-black discoloration of the skin occurs in up to 75-100% of patients receiving clofazimine.1,2,9,19,37,40,71,74,82,86,123,141,142,145,147,148,149,154,155,156,157,158 The degree of skin discoloration is dose related37,74,82,146,147 and is most pronounced on exposed parts of the body,19,157 including the thin, hairless skin of the face (particularly periorbital and perinasal areas) and the thick, hairless, hypopigmented skin of the palms and soles,14 and in areas where leprosy lesions are located.9,19,37,40,141,145 Occasionally, patients have described a feeling of tension in succulent, infiltrated lesions of the face accompanying the development of this discoloration.142 Biopsy of discolored skin has revealed the presence of granulomas, the extent of which appears to be related to the amount of drug deposited.126 Discoloration is most apparent in light-skinned individuals and may be particularly disturbing to these individuals.37,74,142,145,149 Skin discoloration usually is evident 1-4 weeks after initiation of clofazimine therapy1,9,19,40,82,142,145,146 and gradually disappears within 6-12 months after discontinuance of the drug;1,2,9,19,40,75,142 however, the skin occasionally may retain traces of color for 4 years or longer.37,74 In addition to discoloration secondary to drug deposits, melanosis similar to that observed with phenothiazines has been reported in patients receiving clofazimine.141,142,145 The blue-grey, blackish brown, to black discoloration associated with clofazimine-induced melanosis resolves more gradually following discontinuance of the drug and may persist as circumscribed hyperpigmented areas in some patients.142 During therapy with the drug, leprosy nodules may be replaced by scar tissue in the form of shiny, jet black, circular macules.142

Ichthyosis1,2,19,40,66,68,71,74,82,90,147 and dry skin,1,2,9,19,37,66,68,71,74,82,147 especially on the legs and forearms,71,82,147 have been reported in 8-38% of patients receiving clofazimine.1,9,147 Clofazimine-induced ichthyosis and dryness generally occur as leprosy resolves147 and may be relieved by applying oil,1,71 petrolatum,71 or an emollient lotion containing 25% urea91 to the affected areas. Desquamation may occur.147

Pruritus1,2,9,15,74,147,149,154 and nonspecific2,66 rash (e.g., follicular and papular)1,2,66,74,147 have been reported in 1-5%1 and seborrheic dermatitis,147 erythroderma,1 erythema multiforme,147 acneiform eruptions,1,2,66,74 monilial cheilosis (perléche),1,147 and phototoxicity1,2,37,74 have been reported in less than 1% of patients receiving clofazimine.1 Severe exfoliative dermatitis, which appeared to be a hypersensitivity reaction, occurred in at least one patient receiving the drug.15,149

Ocular Effects

Reversible, dose-related, red-brown discoloration of the conjunctiva,1,9,17,19,37,71,74,142,145,147 cornea,1,17,19,37,74 and lacrimal fluid1,17,71,74 may occur during clofazimine therapy. Conjunctival discoloration has been reported in 38-57% of patients receiving the drug.9 Bilateral, linear or branched, brownish lines or streaks in the cornea have been reported in some patients receiving clofazimine dosages of 100-400 mg daily for 2 months or longer;2,21,75,128 these lines slowly disappeared after clofazimine therapy was completed.2,75,128 Discoloration in the macular areas of the eye21,37,74,128 and bluish discoloration of the lens71 have also been reported rarely. Although discoloration of the conjunctiva and other parts of the eye during clofazimine therapy does not appear to affect visual acuity,2,17,19,71,75 diminished vision has been reported rarely in patients receiving the drug.1,9,21

Dryness,1,9 burning,1,9 itching,1,9 irritation,1,9 and watering9 of the eye have been reported in 2-32% of patients receiving clofazimine.9

GI Effects

GI effects are the major dose-limiting adverse effects of clofazimine.73 Abdominal and epigastric pain,1,2,9,11,14,19,22,66,68,69,71,88,127,147,155 diarrhea,1,2,9,14,19,40,68,73,88,126,147,157 nausea,1,2,9,66,68,145,154 vomiting,1,2,9,11,40,66,68,69,155,157 and GI intolerance1 have been reported in up to 60% of patients receiving the drug.1,9,69 Anorexia,1,2,9,40,66,68,155 weight loss,1,2,9,11,66,68,147,155 malabsorption,127 constipation,1,66,147 bowel congestion22 or obstruction,1 GI bleeding,1,155 splenic infarction,1,22 and eosinophilic enteritis1,94,146 have been reported in less than 1% of patients receiving the drug.1

Adverse GI effects appear to be dose related and occur most frequently in patients receiving more than 100 mg of clofazimine daily.2,40,74,136,155 In patients who receive usual dosages of the drug, adverse GI effects may occur within a few days or weeks after initiation of clofazimine therapy and apparently are caused by a direct irritant effect of the drug on the intestinal mucosa;2,14,19,74 GI symptoms in these patients generally subside following a decrease in clofazimine dosage.37,69,74,147 In patients who receive 300 mg or more of the drug daily, a severe syndrome of crampy or colicky abdominal pain, persistent diarrhea, and weight loss may occur 3 months or longer after initiation of clofazimine therapy; discontinuance of the drug usually is, and hospitalization may be, necessary.2,11,14,19,68,71,74,147,155 If clofazimine therapy is not discontinued, partial or complete bowel obstruction may occur.19,37 Severe abdominal symptoms have necessitated exploratory laparotomies in some patients and several fatalities have been reported.1,2,11,14,19,22,37,68,127 Although the exact cause of this syndrome is unknown, massive deposits of clofazimine crystals in various tissues including the intestinal mucosa, liver, spleen, and mesenteric lymph nodes have been observed.1,2,14,19,22,37,68,74,127,155

Nervous System Effects

Dizziness,1 drowsiness,1 fatigue,1 headache,1 giddiness,1,66,145,149 neuralgia,1 and taste disorder1 have been reported in less than 1% of patients receiving clofazimine.1 Depression, secondary to skin discoloration, may occur in some patients receiving clofazimine; this may have contributed to at least 2 suicides in patients receiving the drug.1,86

Other Effects

Reversible, dose-related, red-brown discoloration of sweat,1,2,19,71,74 sputum,1,2,74 urine,1,2,19,71,74,142 feces,1,2,19,74 nasal secretions,71 semen,71 and breast milk71,142 may occur during clofazimine therapy.

Although a causal relationship has not been established,66 increased blood glucose concentrations have been reported in more than 1% of patients receiving the drug.1,66 Eosinophilia,1,154 anemia,1 hypokalemia,1 elevated erythrocyte sedimentation rate (ESR),1 and elevated concentrations of serum albumin,1 bilirubin,1,66 and AST (SGOT)1 have been reported in less than 1% of patients receiving clofazimine.1 Thromboembolism, cystitis, bone pain, edema, fever, lymphadenopathy, vascular pain, hepatitis, jaundice, and enlarged liver also have been reported in less than 1% of patients receiving the drug.1

Precautions and Contraindications

Clofazimine dosages exceeding 100 mg daily should be used for as short a period as possible and only under close medical supervision.1

Severe GI effects, including splenic infarction, bowel obstruction, and GI bleeding, have been reported rarely during clofazimine therapy and have been fatal in a few patients.1,2,11,14,19,22,37,68,127 (See Cautions: GI Effects.) Clofazimine should be used with caution in patients with GI symptoms such as abdominal pain and diarrhea.1 If a patient complains of colicky or burning abdominal pain, nausea, vomiting, or diarrhea during clofazimine therapy, dosage of the drug should be reduced and, if necessary, the interval between doses increased, or the drug should be discontinued.1

Patients receiving clofazimine should be warned that the drug may cause a pink to brownish-black discoloration of the skin as well as discoloration of the conjunctiva, lacrimal fluid, sweat, sputum, urine, feces, nasal secretions, semen, and breast milk.1,71 Patients should be advised that skin discoloration, although reversible, may take several months or years to disappear after completion of clofazimine therapy.1 The fact that skin discoloration may result in mental depression in some patients should be considered; depression secondary to skin discoloration may have contributed to at least 2 suicides in patients receiving clofazimine.1,86

The manufacturer states that there are no known contraindications to use of clofazimine.1

Pediatric Precautions

Safety and efficacy of clofazimine in children 12 years of age or younger have not been established.1,160 The drug has been used in a limited number of children.1,86,160

Geriatric Precautions

Clinical studies of clofazimine did not include sufficient numbers of geriatric patients 65 years of age or older to determine whether they respond differently than younger patients.1 Other reported clinical experience has not identified differences in responses between geriatric and younger patients.1

When used in geriatric patients, clofazimine dosage should be selected with caution, usually initiating therapy at the low end of the dosage range and taking into consideration the greater frequency of decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy in the elderly.1

Mutagenicity and Carcinogenicity

Clofazimine was not mutagenic in the Ames microbial mutagen test1,13,121 with or without metabolic activation.13 Studies have not been performed to date to evaluate the carcinogenic potential of clofazimine.1

Pregnancy, Fertility, and Lactation

Pregnancy

Clofazimine did not appear to be teratogenic in rabbits or rats when given at dosages 8 or 25 times the usual human dosage, respectively.1 However, in reproduction studies in mice using clofazimine dosages 12-25 times the usual human dosage, the drug caused retardation of fetal skull ossification, an increased incidence of abortions and stillbirths, and impaired neonatal survival.1 There are no adequate and controlled studies to date using clofazimine in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1 Clofazimine has been used during (including throughout) pregnancy in a limited number of women without evidence of teratogenicity.1,20,69,71,146,147,149,157 However, clofazimine does cross the placenta, and the skin of some neonates born to women who received the drug during pregnancy was discolored at birth;1,20,69,71,142,149,157 the discoloration gradually faded over the first year.71 Several neonates born to women receiving the drug during pregnancy have died, but a causal relationship to clofazimine has not been established.20,69 Although further study is needed, there is some evidence that estrogen excretion may be decreased in pregnant women receiving clofazimine.89

Fertility

In reproduction studies in rats receiving a clofazimine dosage 25 times the usual human dosage, there was some evidence of impaired fertility since the number of offspring was reduced and there was a lower proportion of implantations.1

Lactation

Because clofazimine is distributed into milk, the drug should not be used in nursing women unless clearly indicated1 since skin discoloration can occur in nursing infants of such women.20,69,71,142,145,149

Dapsone

Results of several studies indicate that concomitant clofazimine does not affect the pharmacokinetics of dapsone,18,83 although a transient increase in urinary excretion of dapsone reportedly occurred in a few patients receiving concomitant therapy with the drugs.67 In a study in lepromatous leprosy patients receiving dapsone (100 mg daily) and rifampin (600 mg daily), concomitant administration of clofazimine (100 mg daily) did not affect plasma dapsone concentrations or the plasma half-life or urinary elimination of dapsone.7

There is some evidence that dapsone may decrease or nullify some of the anti-inflammatory effects of clofazimine.54,58,61,102 In vitro, clofazimine and dapsone have opposing effects on neutrophil motility and lymphocyte transformation.54,58,102,103 Some clinicians suggest that this theoretically could adversely affect the efficacy of clofazimine in patients with erythema nodosum leprosum (ENL) reactions.54,58,61,102 Several borderline leprosy and lepromatous leprosy patients with severe, recurrent ENL reactions reportedly required higher clofazimine dosage to control these reactions when dapsone therapy was given concomitantly than when clofazimine was given alone.102 The manufacturer of clofazimine, however, suggests that this effect has not been confirmed and states that it is advisable to continue treatment with both clofazimine and dapsone in patients who develop leprosy-associated inflammatory reactions, including ENL, during concomitant therapy with the drugs.1 There is no evidence to date that clofazimine and dapsone interfere with the antimycobacterial activity of each other.102

Rifampin

Concomitant administration of clofazimine in leprosy patients receiving rifampin alone or in conjunction with dapsone reportedly may decrease the rate of absorption of rifampin, delay the time to reach peak serum rifampin concentrations, and result in a slight decrease in the area under the plasma concentration-time curve (AUC) of the drug.8 However, in a study in lepromatous leprosy patients receiving dapsone (100 mg daily) and rifampin (600 mg daily), concomitant administration of clofazimine (100 mg daily) did not affect plasma rifampin concentrations or the AUC, plasma half-life, or urinary elimination of rifampin.7

Isoniazid

In a study in lepromatous leprosy patients receiving clofazimine (300 mg daily), concomitant administration of isoniazid (300 mg daily) apparently resulted in increased plasma and urinary concentrations of clofazimine and decreased concentrations of the drug in skin.18

Acute Toxicity

There currently is no information available on overdosage of clofazimine in humans.1 The oral LD₅₀ of the drug is 3.3 g/kg in rabbits and greater than 5 g/kg in mice, rats, and guinea pigs.2,159

If acute overdosage of clofazimine occurs, the stomach should be emptied by inducing emesis or by gastric lavage, and supportive and symptomatic treatment should be initiated.1

Mechanism of Action

Antimycobacterial Effects

The mechanism of action of clofazimine against mycobacteria has not been fully elucidated.1,2,37,118,120 The drug appears to bind preferentially to mycobacterial DNA and inhibit mycobacterial replication and growth.1,2,119,120,121,122,124 Binding of the drug to DNA appears to occur principally at base sequences containing guanine,120,121,124 with preferential binding to mycobacterial DNA resulting from the relatively high proportion of guanine and cytosine in this DNA compared with that in human DNA.120,122 Clofazimine does not appear to undergo intercalative binding between base pairs of DNA.120,121

Clofazimine reportedly is slowly bactericidal against Mycobacterium leprae in vivo;1,36,37,76,118,119,123 however, evaluation of the effects of the drug on the organism is difficult since M. leprae cannot be cultured in vitro.37 Clofazimine is bactericidal against M. tuberculosis 163 and M. marinum 98 in vitro, but appears to be only bacteriostatic in vitro against other mycobacteria,2 including M. avium complex (MAC).35

Anti-inflammatory and Immunosuppressive Effects

Clofazimine exerts anti-inflammatory and immunosuppressive effects in vitro and in vivo,1,2,37,54,58,60,61,66,80,101,102,139,146 although the precise mechanisms of these effects have not been fully elucidated.1,37,60,61,80 In vitro, clofazimine causes a progressive, dose-dependent inhibition of neutrophil motility54,61,80,101,102 and also inhibits mitogen-induced lymphocyte transformation.54,60,61,80,101 These effects also generally occurred in vivo in healthy adults and those with leprosy who received an oral clofazimine dosage of 200 mg daily for 5 days.54 In vitro, clofazimine increases both spontaneous and induced synthesis of prostaglandin E₂ by polymorphonuclear leukocytes obtained from healthy individuals or patients with leprosy.58,61 Although results of some studies are conflicting,2,54 most studies indicate that clofazimine enhances the phagocytic activity of polymorphonuclear cells and macrophages in vitro and in vivo2,99,103 and also enhances membrane-associated oxidative metabolism in these cells.58,61

The anti-inflammatory and immunosuppressive effects of clofazimine, in addition to its antimycobacterial effects, apparently contribute to the efficacy of the drug in the treatment and prevention of erythema nodosum leprosum (ENL) reactions.2,37,54,58,61,66,80,101,102,139 Limited data, however, indicate that dapsone may decrease or nullify some of the anti-inflammatory effects of clofazimine and theoretically could adversely affect clofazimine's efficacy in the treatment of ENL reactions.54,58,61,102 (See Drug Interactions: Dapsone.)

The mechanism of action of clofazimine in the treatment of inflammatory or pustular dermatosis (e.g., pyoderma gangrenosum) is unknown,56,100,104,107,108,110 but may be related to the drug's enhancement of neutrophil and macrophage phagocytosis.63,65,100,107

Spectrum

Clofazimine is active against various Mycobacterium , including M. leprae ,1,2,27,76,138,139,143,162,163 M. tuberculosis ,30,32,33,76,125,138,139,140,162,163 M. avium complex (MAC),1,23,29,30,31,32,33,35,44,49,125,138,163 M. bovis ,1,138,139,162,163 M. chelonei ,30,34,125 M. fortuitum ,30,34,125,163 M. kansasii ,30,32,33,138,162,163 M. marinum ,39,98,163 M. scrofulaceum ,125 M. simiae ,33 and M. ulcerans .138,139,140,163 Although clofazimine has exhibited in vitro activity against some other bacteria, the drug is substantially less active against most of these bacteria than against mycobacteria139,162,163 and generally is not effective against these bacteria in vivo.139,163 The drug generally is inactive against other organisms, including fungi and protozoa.1,136,162

M. leprae cannot be cultured in vitro, but in vivo mouse footpad studies indicate that M. leprae generally is inhibited by clofazimine concentrations of 0.0001-0.001% in the diet.1,2,27,76,143 Although mycobacterial killing may begin shortly after initiation of clofazimine therapy, it cannot be measured in biopsy tissues taken from patients for mouse footpad studies until approximately 50 days after the start of therapy.1,2,118,119,123

Because clofazimine is highly hydrophobic,4,5,9 the drug must be dissolved in organic solvents (e.g., dimethyl sulfoxide, dioxane, methoxyethanol, or dimethylformamide) for use in in vitro susceptibility tests.23,34,160 Agar or broth dilution susceptibility tests are generally preferred for determining the in vitro susceptibility of mycobacteria to clofazimine160,161 since poor diffusion of the drug into agar media may occur in in vitro disk-diffusion susceptibility tests.31,160,161

MAC isolates, including those obtained from patients with acquired immunodeficiency syndrome (AIDS), generally are inhibited in vitro by clofazimine concentrations of 0.1-10 mcg/mL.1,23,29,30,32,33,35,44,49,125,138,163 MICs of clofazimine for susceptible MAC strains generally are higher when determined using Lowenstein-Jensen media than when determined using Middlebrook 7H9, 7H10, or 7H11 media.32 In an in vitro study using Middlebrook 7H9 broth and MAC isolates from patients with AIDS, the MIC of clofazimine was 0.5-2 mcg/mL, but the MBC was greater than 32 mcg/mL.35

In vitro, M. tuberculosis ,30,32,33,125,138,139,140,163 M. bovis ,1,138,139,163 and M. ulcerans 138,139,140,163 generally are inhibited by clofazimine concentrations of 0.01-3.3 mcg/mL,30,32,33,125,138,139,140,163 and M. kansasii 30,32,33,138,163 and M. marinum 30,98,163 are inhibited by clofazimine concentrations of 0.15-6.4 mcg/mL. In an in vitro study using cation-supplemented Mueller-Hinton agar, M. chelonei and M. fortuitum were inhibited by clofazimine concentrations of 0.25-8 mcg/mL;34 however, in another study using Middlebrook 7H9 broth, the MIC of the drug for these organisms was 32 mcg/mL or higher.30 Several strains of an unidentified Mycobacterium sp. isolated from patients with Crohn's disease were inhibited by clofazimine concentrations of 1-2 mcg/mL.131

Resistance

Mycobacterium leprae resistant to clofazimine have been reported only rarely.24,26,27,87,163,193 In at least one patient, resistance to clofazimine was reported after 7 years of therapy with the drug;87 mouse footpad studies indicated that this isolate was resistant to clofazimine concentrations of 0.0001%, but was susceptible to concentrations of 0.001%.24,27

Cross-resistance between clofazimine and dapsone or rifampin has not been reported to date.1,2,135,139,163 However, M. leprae resistant to both clofazimine and dapsone, but susceptible to rifampin, has been reported rarely.26

Pharmacokinetics

Absorption

Clofazimine is incompletely absorbed from the GI tract following oral administration.1,2,3,6,72,76,77 The extent of oral absorption of the drug exhibits considerable interindividual variation1,2,3,87 and depends on several factors including particle size, dosage form administered, dosage, and presence of food in the GI tract.2,3,6,139,146

About 20% of a dose is absorbed from the GI tract when clofazimine is administered as coarse crystals, but 45-70% 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.1,2,139,146,160 The fraction of the dose absorbed appears to decrease as oral dosage of clofazimine is increased.2,3 In a study in fasting lepromatous leprosy patients who received a single 100-, 300-, 400-, or 600-mg dose of clofazimine, approximately 62.5, 48.7, 44.3, or 42.6% of the dose, respectively, was absorbed.3

Presence of food in the GI tract may increase the rate and extent of absorption of clofazimine.6 Results of a study in healthy adults indicate that the area under the serum concentration-time curve (AUC) of clofazimine is increased by about 60% and peak plasma concentrations are increased by about 30% when the drug is administered with food containing fat and protein, compared with the fasting state.6

In healthy adults who received a single 200-mg oral dose of clofazimine with food, peak plasma concentrations of the drug were attained 4-12 hours after the dose.6 Results of multiple-dose studies indicate that steady-state plasma concentrations of clofazimine may not be attained until after at least 30 days of clofazimine therapy.6,160 In leprosy patients receiving clofazimine in a dosage of 100 or 300 mg once daily, steady-state serum concentrations of the drug generally average 0.7 or 1 mcg/mL, respectively.1,2,77,160 In a study in leprosy patients receiving 100 mg of the drug 3 times weekly, steady-state serum clofazimine concentrations averaged 0.5 mcg/mL.2,160 In other leprosy patients receiving 100 mg of clofazimine 3 times weekly, steady-state serum concentrations of the drug have ranged from 0.05-0.4 mcg/mL.87,160

The relationship between plasma clofazimine concentrations and the therapeutic effects of the drug has not been determined.87

Distribution

Clofazimine is highly lipophilic and is distributed principally to fatty tissue and cells of the reticuloendothelial system;1,2,37,70,78,126,138,139,146 the drug is taken up by macrophages throughout the body.1,2,70,126,127,138 In leprosy patients, clofazimine appears to distribute to and accumulate as crystals in highest concentrations in the mesenteric lymph nodes,1,2,70,78,126 adipose tissue,1,2,78 adrenals,1,2,78 liver,1,2,70,73,78,126 lungs,78 gallbladder,1,2,78 bile,1,2,78 and spleen1,2,22,70,73,78,126 and in lower concentrations in the skin,1,2,78,126 small intestine,1,2,70,73,126,127 lungs,70,73,78,126 heart,78 kidneys,66,70,78,126 pancreas,78 muscle,1,2,78 omentum,126 and bone.1,2 Clofazimine crystals have also been found in bone marrow,66 sputum,1,66 sebum,1,2 and sweat,1,2 and in the iris, conjunctiva, macula, sclera, and cornea.71,128 The drug does not appear to distribute into the brain or CSF.2,70,78,126

Clofazimine crosses the placenta and is distributed into milk.1,20,139,146

Elimination

Following oral administration of a single dose of clofazimine in healthy adults, there is an initial distribution phase followed by a slow elimination phase with a terminal elimination half-life of approximately 8 days.160 The tissue160 half-life of clofazimine following multiple oral doses of the drug is estimated to be at least 70 days.1,2,76,118,160 The drug remains in body tissues for prolonged periods and is eliminated very slowly;1,2,3,4,6,76,126 clofazimine has been found in skin126 and in mesenteric lymph nodes68 2 and 4 years, respectively, after therapy with the drug was discontinued. In mice infected with Mycobacterium leprae , once-daily and twice-weekly administration of the drug had comparable antileprotic activity.144

The metabolic fate of clofazimine has not been fully elucidated,2,4,5,37 but the drug appears to accumulate in the body and to be excreted principally unchanged.139 Clofazimine appears to be partially metabolized and a least 3 metabolites have been found in urine of patients receiving the drug.4,5 Metabolite I is formed by hydrolytic dehalogenation of clofazimine,4 metabolite II presumably is formed by a hydrolytic deamination reaction followed by glucuronidation,4 and metabolite III appears to be a hydrated clofazimine glucuronide.5

Clofazimine is excreted principally in feces,1,2,3,76,77,78 both as unabsorbed drug and via biliary elimination.1,2,77,78 Fecal elimination of clofazimine exhibits considerable interindividual variation,2,3 and 35-74% of a single oral dose may be excreted unchanged in feces2,3,76,77 over the first 72 hours after the dose.3,76 Following oral administration of a single 200- or 300-mg dose, elimination of unchanged clofazimine and its metabolites in urine is negligible during the first 24 hours.1,76,77 Following multiple doses of the drug, less than 1% of the daily dose is excreted in urine over a 24-hour period.4,76,77 Small amounts of the drug also are excreted via sebaceous and sweat glands.1,2,139

Chemistry and Stability

Chemistry

Clofazimine is a phenazine dye with antimycobacterial and anti-inflammatory activity.1,2,4,37,70,76,78,117,118,119,139,141 The dye is a substituted iminophenazine derivative and generally is described as bright red;1,2,4,146 however, the color varies depending on the degree of protonation, ranging from colorless (triprotonated) to orange (un-ionized or monoprotonated) or red (biprotonated).141 The drug is commercially available as capsules containing micronized clofazimine suspended in an oil-wax base.1 Clofazimine occurs as a fine, reddish brown powder.1,116 The drug is highly hydrophobic4,5,9,120 and is practically insoluble in water.1,160 The solubility of clofazimine in alcohol is 1 mg/mL at room temperature.160

Stability

Clofazimine capsules should be stored in tight containers at 30°C or less and should be protected from moisture.1,2 However, USP states that the capsules can be stored in well-closed containers.165 Commercially available clofazimine capsules have an expiration date of 5 years following the date of manufacture.2

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