      Document 0180
 DOCN  DRG0180
 UNIQUE IDENTIFIER        DRG-0067
 NAME OF SUBSTANCE        Clofazimine [USAN 1996]
 REGISTRY NUMBER          2030-63-9
 RELATED REGISTRY NUMBER  B 663
 RELATED REGISTRY NUMBER  G 30320
 STANDARD CHEMICAL NAME   N,5-Bis(4-chlorophenyl)-3,5-dihydro-3-
                          ((1-methylethyl)imino)-2-phenazinamine [USAN
                          1996]
 SYNONYMS                 Lamprene [USAN 1996]
 SYNONYMS                 N,10-Bis(4-chlorophenyl)-2,10-dihydro-2-((1-m-
                          ethylethyl)imino)-3-phenazinamine [Merck
                          Index 1983]
 SYNONYMS                 3-(p-Chloroanilino)-10-(p-chlorophenyl)-2,10--
                          dihydro-2-(isopropylimino)phenazine [Merck
                          Index 1989]
 SYNONYMS                 2-(4-Chloroanilino)-3-isopropylimino-5-(4-chl-
                          orophenyl)-3,5-dihydrophenazine [Merck Index
                          1989]
 SYNONYMS                 2-p-Chloroanilino-5-p-chlorophenyl-3,5-dihydr-
                          o-3-isopropyl-iminophenazine [Merck Index
                          1983]
 PROTOCOL ID NUMBERS      NIAID ACTG 135
 PROTOCOL ID NUMBERS      FDA 027A
 PROTOCOL ID NUMBERS      NIAID 92 I-165
 PROTOCOL ID NUMBERS      NIAID ACTG 223
 PROTOCOL ID NUMBERS      NIAID ACTG 238
 PROTOCOL ID NUMBERS      FDA 214a
 PROTOCOL ID NUMBERS      NIAID CPCRA 027
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: This drug exerts a slow
                          bactericidal effect on Mycobacterium leprae
                          (Hansen's bacillus) by inhibiting
                          mycobacterial growth via binding
                          preferentially to mycobacterial DNA. It also
                          exerts anti-inflammatory properties in
                          controlling erythema nodosum leprosum
                          reactions. Its precise mechanisms of action
                          are unknown. Its absorption in leprosy
                          patients ranges from 45-62 percent after oral
                          administration. Average serum concentrations
                          in leprosy patients treated with 100 mg and
                          300 mg daily were 0.7 and 1.0 micrograms/ml,
                          respectively. Clofazimine exhibits a
                          prolonged body retention, with a half-life
                          following repeated oral doses estimated to be
                          at least 70 days. Following ingestion of a
                          single 300 mg dose, elimination of unchanged
                          clofazimine and its metabolites in a 24-hour
                          urine collection was negligible. Part of the
                          ingested drug recovered from the feces may
                          represent excretion via the bile; a small
                          amount also is eliminated in the sputum,
                          sebum, and sweat. The drug is highly
                          lipophilic and tends to be deposited
                          predominantly in fatty tissue and in
                          reticuloendothelial system cells; it is taken
                          up by macrophages throughout the body.
                          Autopsies performed on leprosy patients
                          revealed clofazimine crystals predominantly
                          in the mesenteric lymph nodes, adrenals,
                          subcutaneous fat, liver, bile, gall bladder,
                          spleen, small intestine, muscles, bones, and
                          skin. Clofazimine has a half-life of about 10
                          days after a single dose and 2-3 months after
                          long term, high dose therapy. During chronic
                          therapy peak blood levels are attained
                          between 1 to 6 hours. [USP DI 1995] [PDR
                          1995]
 DISEASES STUDIED/TREATED Clofazimine has been used in combination with
                          other antimycobacterial drugs in
                          immunocompromised patients with Mycobacterium
                          avium complex infections [AHFS Drug
                          Information 1995]
 DISEASES STUDIED/TREATED Results have been ineffective, bacteriologic
                          cures are unusual and prognosis is poor [AHFS
                          Drug Information 1995]
 CLASSIFICATION CODE      Antimicrobial [Merck Index 1989]
 CLASSIFICATION CODE      Antileprotic [PDR 1995]
 OTHER MAJOR USES         Treatment of bacterial infections
                          (tuberculostatic, leprostatic). Used in
                          treatment of lepromatous leprosy, including
                          dapsone-resistant lepromatous leprosy and
                          lepromatous leprosy complicated by erythema
                          nodosum leprosum, and for treatment of other
                          leprosy-associated inflammatory reactions
                          [PDR 1995]
 SUBSTANCE INTERACTIONS   Clofazimine does not show cross-resistance
                          with dapsone or rifampin; preliminary data
                          which suggest that dapsone may inhibit the
                          anti-inflammatory activity of clofazimine
                          have not been confirmed. [PDR 1995]
 ADVERSE EFFECTS          Generally, clofazimine is well tolerated when
                          doses not exceeding 100 mg/day are used.
                          Clofazimine may cause skin pigmentation (pink
                          to brownish-black) in 75-100 percent of the
                          patients within a few weeks of treatment.
                          Other adverse reactions may include
                          ichthyosis and dryness, rash and pruritus,
                          abdominal and epigastric pain, diarrhea,
                          nausea, vomiting, gastrointestinal
                          intolerance, conjunctival and corneal
                          pigmentation (due to clofazimine crystal
                          deposits), ocular dryness, burning, itching
                          and irritation, discoloration of urine,
                          feces, sputum, and sweat, elevated blood
                          sugar, and elevated erythrocyte sedimentation
                          rate (ESR). Rare adverse reactions (occurring
                          in less than 1 percent of patients) may
                          include: effects on the skin (phototoxicity,
                          erythroderma, acneiform eruptions, monilial
                          cheilosis); gastrointestinal system (bowel
                          obstruction, gastrointestinal bleeding,
                          anorexia, constipation, weight loss,
                          hepatitis, jaundice, eosinophilic enteritis,
                          enlarged liver); eyes (diminished vision);
                          nervous system (dizziness, drowsiness,
                          fatigue, headache, giddiness, neuralgia,
                          taste disorder); psychiatric (depression
                          secondary to skin discoloration); and
                          clinical values (elevated albumin, serum
                          bilirubin, and AST (SGOT); eosinophilia;
                          hypokalemia); other effects (splenic
                          infarction, thromboembolism, anemia,
                          cystitis, bone pain, edema, fever,
                          lymphadenopathy, vascular pain). [PDR 1995]
 CONTRAINDICATIONS        No known contraindications, however,
                          clofazimine should be used with caution in
                          patients who have gastrointestinal problems
                          such as abdominal pain and diarrhea. [PDR
                          1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Iminophenazine derivative
                          [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C27H22C12N4 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 473.41 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 210-212 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Readily soluble in benzene,
                          soluble in chloroform, poorly soluble in
                          acetone and in ethyl acetate, sparingly
                          soluble in methanol, and virtually insoluble
                          in water [PDR 1995]
 CHEMICAL/PHYSICAL DATA   STABILITY: The commercially available
                          capsules have an expiration date of 5 years
                          following the date of manufacture [AHFS Drug
                          Information 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Dark red crystalline
                          powder [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL COMMENT: The commercially available
                          capsules contain micronized clofazimine in an
                          oil-wax base [PDR 1995]
 CHEMICAL/PHYSICAL DATA   PERCENT ELEMENTAL COMPOSITION: C68.50%,
                          H4.68%, Cl14.98%, N11.83% [Merck Index 1989]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Capsules. [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store below 86 F in a tight
                          container (USP), protected from moisture.
                          [PDR 1995]
 MANUFACTURERS            Ciba-Geigy
 REFERENCES               Kemper CA, Havlir D, Haghighat D, Dube M,
                          Bartok AE, Sison JP, Yao Y, Yangco B, Leedom
                          JM, Tilles JG, et al. The individual
                          microbiologic effect of three
                          antimycobacterial agents, clofazimine,
                          ethambutol, and rifampin, on Mycobacterium
                          avium complex bacteremia in patients with
                          AIDS. J Infect Dis. 1994 Jul;170(1):157-84.
 REFERENCES               Singer J, Fanning M, Thorne A, Turgeon F,
                          Duperval R, Schlech W, Shafran S. The
                          Canadian randomized open-level trial of
                          combination therapy for MAC bacteremia:
                          quality of life outcomes. Int Conf AIDS. 1994
                          Aug 7-12;10(2):70 (abstract no. 556B).
 REFERENCES               Phillips P, Chomyc S, Talbot J, Gill J,
                          Raboud J, Singer J, Shafran S. The Canadian
                          randomized open-label trial of combination
                          therapy for MAC bacteremia: blood culture
                          results. Int Conf AIDs. 1994 Aug
                          7-12;10(2):70 (abstract no. 555B).
 REFERENCES               Abrams DI, Mitchell TF, Child CC, Shiboski
                          SC, Brosgart CL, Mass MM. Clofazimine as
                          prophylaxis for disseminated Mycobacterium
                          avium complex infection in AIDS. J Infect
                          Dis. 1993 Jun;167(6):1459-63.
 REFERENCES               Ravi S, Holubka J, Veneri R, Youn K, Khatib
                          R. Clofazimine-induced eosinophilic
                          gastroenteritis in AIDS [letter]. Am J
                          Gastroenterol. 1993 Apr;88(4):612-3.
 REFERENCES               Saint-Marc T, Marneff E, Touraine JL.
                          [Mycobacterium avium intracellulare
                          infections. Treatment with a
                          clarithromycin-clofazimine combination. 18
                          cases]. Presse Med. 1993 Dec 4;22(38):1903-7.
 REFERENCES               Kemper CA, Meng TC, Nussbaum J, Chiu J,
                          Feigal DF, Bartok AE, Leedom JM, Tilles JG,
                          Deresinski SC, McCutchan JA. Treatment of
                          Mycobacterium avium complex bacteremia in
                          AIDS with a four-drug oral regimen. Rifampin,
                          ethambutol, clofazimine, and ciprofloxacin.
                          Ann Intern Med. 1992 Mar 15;116(6):466-72.
 REFERENCES               Dautzenberg B, Truffot C, Mignon A, Rozenbaum
                          W, Katlama C, Perronne C, Parrot R, Grosset
                          J. Rifabutin in combination with clofazimine,
                          isoniazid and ethambutol in the treatment of
                          AIDS patients with infections due to
                          opportunist mycobacteria. Tubercle 1991
                          Sep;72(3):168-75.
 REFERENCES               Garrelts JC. Clofazimine: a review of its use
                          in leprosy and Mycobacterium avium complex
                          infection. DICP. 1991 May;25(5):525-31.
 REFERENCES               Cunningham CA, Friedberg DN, Carr RE.
                          Clofazamine-induced generalized retinal
                          degeneration. Retina. 1990;10(2):131-4
 ENTRY MONTH              8911
 LAST REVISION DATE       951031
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
