Lamprene

Generic Name: Clofazimine
Class: Antimycobacterials, Miscellaneous
VA Class: AM900
Chemical Name: N,5-Bis(4-chlorophenyl)-3,5-dihydro-3-[(1-methyethyl)imino]-2-phenazinamide
CAS Number: 2030-63-9

Introduction

Phenazine dye with antimycobacterial and anti-inflammatory activity.^{1 2 4 37 70 76 78 117 118 119 139 141}

Uses for Lamprene

Leprosy

Treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy and leprosy complicated by erythema nodosum leprosum (ENL) reactions.^{1 2 37 86 113 114 115 136 145 146 147 148 149 193 194 195 196 197 198 199 200 201 218} Used in conjunction with other anti-infectives active against Mycobacterium leprae.^{1 2 37 86 113 114 115 136 145 146 147 148 149 193 194 195 196 197 198 199 200 201 218}

Treatment of multibacillary leprosy (>5 lesions or skin smear positive for acid-fast bacteria) in rifampin-based multiple-drug regimens.^{1 2 37 86 113 114 115 136 145 146 147 148 149 193 194 195 196 197 198 199 200 201 218} WHO recommends a 12-month multiple-drug regimen that includes rifampin, clofazimine, and dapsone.^{193 198 199 200 201 218}

Treatment of paucibacillary leprosy (1–5 lesions) when dapsone cannot be used.^{1 2 37 86 113 114 115 136 145 146 147 148 149 193 194 195 196 197 198 199 200 201} WHO recommends a 6-month multiple-drug regimen of rifampin and dapsone;^{193 200 218} if dapsone must be discontinued because of severe adverse effects, WHO recommends that clofazimine be substituted.²⁰⁰

Rifampin-based multiple-drug regimens are recommended 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 and delay or prevent emergence of rifampin-resistant M. leprae.^{193 200}

Alternative for 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} 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} do not use alone for treatment of severe ENL.^{193 203}

Has been used for treatment of reversal (type 1) reactions† in patients with borderline or tuberculoid leprosy.^{2 37 71 81 93} Efficacy not fully evaluated;^{37 81 196} may aggravate the reactional state in some patients.⁸¹

Not effective in the treatment of other leprosy-associated inflammatory reactions¹ (e.g., Lucio’s phenomenon, downgrading reactions).^{37 129 130}

Not commercially available in the US, but may be obtained for 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, also may be made available from NHDP for other uses.^{214 215} (See Restricted Distribution under Dosage and Administration.)

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} For information, consult NHDP by phone at 225-578-9861 or 800-642-2477, by fax at 225-578-9856, or on the Internet at .^{215 216 219}

Mycobacterium Avium Complex (MAC) Infections

Has been used in multiple-drug regimens for treatment of pulmonary and localized extrapulmonary Mycobacterium avium complex (MAC) infections†, but safety and efficacy not established.^{28 43 44 45 46 48 49 50 92 95 152 167} ATS and IDSA state the role of clofazimine in the treatment of MAC lung disease is not established.¹⁸³

Should not be used for 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 clofazimine is ineffective in these infections and may even be associated with reduced survival.^{179 183 186}

Use of clofazimine for the treatment of any disease other than leprosy is discouraged by WHO and the manufacturer since indiscriminate use may promote emergence of resistant strains of M. leprae.²¹⁴ (See Restricted Distribution under Dosage and Administration.)

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

Multidrug-resistant Tuberculosis (MDRTB)

Has been used in multiple-drug regimens for the treatment of MDRTB†, but safety and efficacy not established.²¹⁷ Not included in current CDC, ATS, and IDSA recommendations for treatment of tuberculosis.⁴⁷

Use of clofazimine for the treatment of any disease other than leprosy is discouraged by WHO and the manufacturer since indiscriminate use may promote emergence of resistant strains of M. leprae.²¹⁴ (See Restricted Distribution under Dosage and Administration.)

Inflammatory or Pustular Dermatoses

Has been used in a variety of inflammatory or pustular dermatoses†, but safety and efficacy not established.^{53 56 59 62 63 65 100 104 107 110 132 133}

Use of clofazimine for the treatment of any disease other than leprosy is discouraged by WHO and the manufacturer since indiscriminate use may promote emergence of resistant strains of M. leprae.²¹⁴ (See Restricted Distribution under Dosage and Administration.)

Lamprene Dosage and Administration

Administration

Restricted Distribution

Not commercially available in the US, but may be obtained for 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, may also may be made available from NHDP for other uses.^{214 215}

For treatment of leprosy, clofazimine is distributed under an Investigational New Drug (IND) application held by NHDP and is available at no cost after the clinician has registered as an investigator under the IND protocol.²¹⁴ Clinicians requiring clofazimine for a patient with leprosy should contact the Administrative Officer of the Laboratory Research Branch at NHDP by mail at 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}

If use of clofazimine is considered necessary in situations where there are no other comparable or satisfactory treatments available (e.g., treatment of MDRTB), the drug can be distributed by NHDP under a single-patient treatment IND protocol administered by FDA.^{214 215} To obtain the drug for any use other than 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}

Oral Administration

Administer orally.¹ To maximize absorption,¹⁶⁰ give with a meal.¹

Dosage

Pediatric Patients

Leprosy

Multibacillary Leprosy

Oral

Children ≤10 years of age†: Appropriately adjust dosage (e.g., clofazimine 50 mg twice weekly plus 100 mg once monthly given in conjunction with rifampin [300 mg once monthly] and dapsone [25 mg daily]).¹⁹⁸ Continue multiple-drug regimen for 12 months.¹⁹⁸

Children 10–14 years of age: 50 mg once every second day plus 150 mg once monthly given in conjunction with rifampin (450 mg once monthly) and dapsone (50 mg once daily).^{198 218} Continue multiple-drug regimen for 12 months.^{198 218}

Adolescents ≥15 years of age: 50 mg once daily plus 300 mg once monthly given in conjunction with rifampin (600 mg once monthly) and dapsone (100 mg once daily).^{36 193 194 195 196 197 198 199 200 201 218} Continue multiple-drug regimen for 12 months.^{36 193 194 195 196 197 198 199 200 201 218}

An additional 12 months of therapy may be indicated for patients with a high bacteriologic index who demonstrate no improvement (with evidence of worsening) following completion of the initial 12 months of treatment.²⁰⁰

Adults

Leprosy

Multibacillary Leprosy

Oral

50 mg once daily plus 300 mg once monthly given in conjunction with rifampin (600 mg once monthly) and dapsone (100 mg once daily).^{36 193 194 195 196 197 198 199 200 201 218} Continue multiple-drug regimen for 12 months.^{36 193 194 195 196 197 198 199 200 201 218}

An additional 12 months of therapy may be indicated for patients with a high bacteriologic index who demonstrate no improvement (with evidence of worsening) following completion of the initial 12 months of treatment.²⁰⁰

Paucibacillary Leprosy in Patients Unable to Take Dapsone

Oral

50 mg once daily plus 300 mg once monthly given in conjunction with rifampin (600 mg once monthly).^{193 200 218} Continue multiple-drug regimen for 6 months.^{193 200 218}

Erythema Nodosum Leprosum (ENL) Reactions

Oral

Dosage and duration of clofazimine treatment depend on severity of symptoms.^{1 2 37 93 94 112 147 154 155 156 157 158 164}

100–300 mg daily given in 2 or 3 divided doses for up to 3 months^{1 156 157 193 196 198} or longer^{37 146 154 156 157 164} may reduce or eliminate corticosteroid requirements.^{37 85 93 149 193} Severe, corticosteroid-dependent ENL may require more prolonged treatment (up to 7 months)^{147 148 149 157} and extended treatment (an additional 9–24 months) may be necessary to prevent recurrence.^{37 147 157}

Although 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} manufacturer states dosage >200 mg daily not recommended.¹

Reduce clofazimine dosage to lowest effective level (e.g., 100 mg daily) as soon as possible after reactive episode is controlled.^{1 37 146 147 154 156 157 196}

Prescribing Limits

Pediatric Patients

Leprosy

Oral

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

Dosage >200 mg daily not recommended.¹

Adults

Leprosy

Oral

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

Dosage >200 mg daily not recommended.¹

Special Populations

No special population dosage recommendation at this time.¹

Cautions for Lamprene

Contraindications

Manufacturer states no known contraindications.¹

Warnings/Precautions

Warnings

GI Effects

Severe GI effects (e.g., splenic infarction, bowel obstruction, GI bleeding) reported rarely.^{1 2 11 14 19 22 37 68 127} Exploratory laparotomies were necessary in some patients; several fatalities reported.^{1 2 11 14 19 22 37 68 127} Although exact cause unknown, autopsies revealed massive deposits of clofazimine crystals in various tissues (e.g., intestinal mucosa, liver, spleen, mesenteric lymph nodes).^{1 2 14 19 22 37 68 74 127 155}

Many patients (40–50%) experience 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 intolerance.¹

GI effects are dose related and occur most frequently with dosage >100 mg daily.^{2 40 74 136 155} Dosage >100 mg daily should be used for as short a period as possible and only under close medical supervision.¹

Use with caution in patients with GI problems such as abdominal pain and diarrhea.¹

If patient complains of colicky or burning abdominal pain, nausea, vomiting, or diarrhea, reduce clofazimine dosage and, if necessary, increase interval between doses or discontinue the drug.¹

General Precautions

Dermatologic Effects

Pink to brownish-black discoloration of skin occurs in most patients (75–100%) and is evident within 1-4 weeks after initiation of clofazimine.^{1 2 9 19 37 40 71 74 82 86 123 141 142 145 147 148 149 154 155 156 157 158} Degree of discoloration is dose related^{37 74 82 146 147} and is most pronounced on exposed body parts^{19 157} (e.g., hairless facial skin in periorbital and perinasal areas, hairless hypopigmented skin on palms and soles)¹⁴ and in areas with leprosy lesions.^{9 19 37 40 141 145} Gradually disappears within 6-12 months after drug discontinued,^{1 2 9 19 40 75 142} but traces of color may remain for ≥4 years in some individuals.^{37 74}

Clofazimine is a bright-red dye and skin discoloration apparently occurs because drug crystals distribute to and accumulate in tissues and fluids.^{1 2 37 66 70 73 74} May be particularly disturbing to light-skinned individuals; may cause substantial compliance problems in certain patients or populations.^{37 74 142 145 149 196 200} Depression secondary to skin discoloration reported; may have contributed to at least 2 suicides.^{1 86} Warn patients that skin discoloration, as well as discoloration of the conjunctiva and body fluids, may occur.^{1 71} (See Ocular Effects under Cautions.) Appropriate counseling (e.g., advantages of clofazimine, reversibility of discoloration) may be sufficient to encourage patients to continue treatment.²⁰⁰

Melanosis, similar to that reported with phenothiazines, also has caused skin discoloration in patients receiving clofazimine.^{141 142 145} Discoloration is blue-grey or blackish brown to black; resolves gradually following discontinuance of the drug but may persist as circumscribed hyperpigmented areas in some patients.¹⁴² During treatment, leprosy nodules may be replaced by scar tissue in the form of shiny, jet black, circular macules.¹⁴²

Ichthyosis^{1 2 19 40 66 68 71 74 82 90 147} and dry skin (especially on legs and forearms)^{1 2 19 37 66 68 71 74 82 147} generally occurs as leprosy resolves.¹⁴⁷ May be relieved by applying oil,^{1 71} petrolatum,⁷¹ or an emollient lotion containing 25% urea⁹¹ to affected areas. Desquamation may occur.¹⁴⁷

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 fluid^{1 17 71 74} may occur. Bilateral, linear or branched, brownish lines or streaks in the cornea reported in some patients receiving clofazimine dosages of 100–400 mg daily for ≥2 months;^{2 21 75 128} these lines slowly disappeared after clofazimine treatment was completed.^{2 75 128} Discoloration in the macular areas of the eye^{21 37 74 128} and bluish discoloration of the lens⁷¹ also reported rarely.

Discoloration of the conjunctiva and other parts of the eye does not appear to affect visual acuity,^{2 17 19 71 75} but diminished vision reported rarely.^{1 9 21}

Dryness, burning, itching, irritation, and watering of the eyes also reported.^{1 9}

Discoloration of Body Fluids

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 milk^{71 142} may occur.

Specific Populations

Pregnancy

Category C.¹

Crosses the placenta.¹ Deeply pigmented skin reported in infants born to women who received clofazimine during pregnancy;^{1 20 69 71 142 149 157} discoloration gradually faded over the first year.⁷¹ No evidence of teratogenicity in these infants.^{1 20 69 71 146 147 149 157}

Use during pregnancy only if potential benefits justify risk to fetus.¹

Lactation

Distributed into human milk.¹ Red-brown discoloration of breast milk may occur.^{71 142} Do not use in nursing women unless clearly indicated.¹

Pediatric Use

Safety and efficacy not established in children¹ ≤12 years.¹⁶⁰

Has been used in pediatric patients;¹ included in WHO guidelines for treatment of multibacillary leprosy in children.^{198 218}

Geriatric Use

Insufficient experience in patients ≥65 years of age and older to determine whether geriatric patients respond differently than younger adults.¹ Clinical experience has not identified differences in response relative to younger adults.¹

Select dosage with caution, usually initiating therapy at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Common Adverse Effects

Discoloration of skin, eyes, urine, feces, sputum, sweat, tears; GI effects (abdominal and epigastric pain, diarrhea, nausea, vomiting, GI intolerance); eye irritation, itching, dryness, burning.¹

Interactions for Lamprene

Specific Drugs

Drug	Interaction	Comments
Dapsone	Concomitant use of dapsone and clofazimine does not have a clinically important effect on dapsone pharmacokinetics7 18 83 Some evidence suggests dapsone may decrease or nullify some anti-inflammatory effects of clofazimine and theoretically might adversely affect clofazimine’s efficacy in patients with 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 alone102	Manufacturer states that an interaction between dapsone and clofazimine that adversely affects clofazimine’s anti-inflammatory effects has not been confirmed and advises that treatment with both drugs be continued in patients who develop leprosy-associated inflammatory reactions, including ENL, during concomitant therapy1
Isoniazid	Possible increased clofazimine plasma and urine concentrations and decreased clofazimine skin concentrations18
Rifampin	Although one study indicated that concomitant use of clofazimine in leprosy patients receiving rifampin alone or in conjunction with dapsone may decrease plasma concentrations and AUC of rifampin,8 concomitant use of clofazimine in another study in lepromatous leprosy patients receiving dapsone (100 mg daily) and rifampin (600 mg daily) did not affect rifampin pharmacokinetics7

Lamprene Pharmacokinetics

Absorption

Bioavailability

Incompletely absorbed from GI tract following oral administration.^{1 2 3 6 72 76 77} Extent of absorption exhibits considerable interindividual variation^{1 2 3 87} and depends on several factors (e.g., particle size, dosage form, dosage, presence of food in GI tract).^{2 3 6 139 146}

When clofazimine capsules are used, 45-70% of dose is absorbed.^{1 2 139 146 160}

Peak serum concentrations usually attained within 4-12 hours when dose is given with food.⁶

Food

Food increases rate and extent of absorption.⁶ If administered with food containing fat and protein, AUC increased by 60% and peak serum concentrations increased by 30%.⁶

Plasma Concentrations

Steady-state serum concentrations average 0.7 and 1 mcg/mL after dosages of 100 mg and 300 mg once daily, respectively.^{1 2 77 160}

Multiple-dose studies indicate steady-state serum concentrations may not be attained until ≥30 days after initiation after clofazimine therapy.^{6 160}

Distribution

Extent

Highly lipophilic.^{1 2 37 70 78 126 138 139 146} Distributed principally to fatty tissue and cells of the reticuloendothelial system;^{1 2 37 70 78 126 138 139 146} taken up by macrophages throughout the body.^{1 2 70 126 127 138}

Accumulates in highest concentrations in 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 spleen.^{1 2 22 70 73 78 126} Lower concentrations in 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}

Does not distribute into brain or CSF.^{2 70 78 126}

Crosses human placenta.¹

Distributed into human milk.¹

Elimination

Metabolism

Metabolic fate not fully elucidated.^{2 4 5 37} Appears to be partially metabolized; at least 3 metabolites appear to be eliminated in urine.^{4 5}

Elimination Route

Principally excreted in feces,^{1 2 3 76 77 78} both as unabsorbed drug and via biliary elimination.^{1 2 77 78} Following a single oral dose, 35–74% of dose may be excreted unchanged in feces^{2 3 76 77} over the first 72 hours.^{3 76}

Elimination of unchanged clofazimine and its metabolites in urine is negligible during the first 24 hours.^{1 76 77} Following multiple oral doses, <1% of daily dose is excreted in urine over a 24-hour period.^{4 76 77}

Small amounts excreted in sputum, sebum, and sweat.¹