Professional Drug Information > Lamprene

Clofazimine (Systemic)

VA CLASSIFICATION
Primary: AM900

Commonly used brand name(s): Lamprene.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antibacterial (antimycobacterial)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Leprosy (treatment)—Clofazimine is indicated as a secondary agent ^{06} in the treatment of lepromatous leprosy (Hansen's disease), including dapsone-resistant lepromatous leprosy, caused by Mycobacterium leprae (Hansen's bacillus). ^{09} In the initial treatment of multibacillary leprosy, clofazimine is recommended in combination with one or more other antileprosy agents to prevent the development of resistance. ^{{01} {04}}
—Clofazimine is also indicated in the treatment of lepromatous leprosy complicated by erythema nodosum leprosum reactions. ^{09} Corticosteroids may be given concurrently if nerve injury or skin ulceration shows signs of developing. ^{01}

[Mycobacterial infections, atypical (treatment)]—Clofazimine is used in combination with up to 5 other antimycobacterial agents in the treatment of atypical mycobacterial infections caused by Mycobacterium avium-intracellulare (Mycobacterium avium complex; MAC) in patients with acquired immunodeficiency syndrome (AIDS). Despite clofazimine's high degree of in vitro activity, combination therapy has often been clinically ineffective. ^{{02} {03} {04} {05} {06}}

Unaccepted
Clofazimine is not effective in the treatment of other leprosy-associated inflammatory reactions. ^{{01} {09}}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    473.40
    Highly lipophilic; virtually insoluble in water ^{01}

Mechanism of action/Effect:

Exact mechanism unknown; has a slowly bactericidal effect on Mycobacterium leprae ; inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. ^{{01} {09}}


Other actions/effects:

Exerts anti-inflammatory effects in the control of erythema nodosum leprosum reactions. ^{{01} {09}}

Absorption:

Variable (45 to 62%) following oral administration in leprosy patients; however, the bioavailability of the commercially available capsule is approximately 70% ^{16} . Bioavailability and rate of absorption are increased when clofazimine is taken with food. ^{{01} {09} {13}}

Distribution:

Highly lipophilic; deposited primarily in fatty tissue and cells of the reticuloendothelial system; taken up by macrophages throughout the body; also distributed to breast milk, mesenteric lymph nodes, adrenal glands, subcutaneous fat, liver, bile, gallbladder, spleen, small intestine, muscles, bones, and skin. Does not appear to cross the blood-brain barrier. ^{{01} {09} {13}}

Biotransformation:

Three metabolites have been identified; two are conjugated and one is unconjugated. It is not known whether these metabolites have any pharmacologic activity. ^{13}

Half-life:

Approximately 10 days after a single dose. ^{14}

Half-life of 2 to 3 months after long-term, high-dose therapy. ^{13}

Time to peak concentration:

1 to 6 hours, with chronic therapy. ^{13}

Mean serum concentration


After 4 years of therapy:

100 mg daily: 0.7 mcg per mL. ^{13}

300 mg daily: 1.0 mcg per mL. ^{13}

400 mg daily: 1.4 mcg per mL. ^{13}


Elimination:
    Renal—Following daily administration of 300 mg in leprosy patients, approximately 0.6% of the 3 metabolites and 1% of unchanged clofazimine are excreted in the urine. ^{14}
    Fecal/biliary—Up to 50% of clofazimine is recovered unchanged from the feces. ^{13}
    Sputum, sebum, and sweat—Small amounts excreted. ^{{01} {09}}


Precautions to Consider

Carcinogenicity

Long-term carcinogenicity studies have not been done in animals. ^{{01} {09}}

Mutagenicity

Mutagenicity studies (i.e., Ames tests) have not shown that clofazimine is mutagenic. ^{{01} {09}}

Pregnancy/Reproduction
Fertility—
One study in rats given doses of 25 times the usual human dose has shown that clofazimine causes a reduction in the number of offspring and a reduction in the proportion of implantations. ^{{01} {09}}

Pregnancy—
Clofazimine crosses the human placenta. Adequate and well-controlled studies in humans have not been done. Although the skin of infants born to mothers who received clofazimine during pregnancy was deeply pigmented at birth, clofazimine has not been shown to be teratogenic in humans. A gradual fading of pigmentation over a 1-year period has been observed in neonates who were not breast fed. ^{{01} {09} {13}}

Studies in rabbits given 8 times the usual human dose and studies in rats given 25 times the usual human dose have not shown that clofazimine is teratogenic. However, studies in mice given 12 to 25 times the human dose have shown that clofazimine causes retarded fetal skull ossification, increased incidence of abortions and stillbirths, and impaired neonatal survival.

FDA Pregnancy Category C.

Breast-feeding

Clofazimine is excreted in breast milk. Use is not recommended in nursing mothers. The skin and fatty tissues of animal offspring become discolored approximately 3 days after birth. This has been attributed to the presence of clofazimine in the maternal milk. A gradual fading of pigmentation followed discontinuation of breast-feeding. ^{{01} {09} {13}}

Pediatrics

Appropriate studies on the relationship of age to the effects of clofazimine have not been performed in the pediatric population. However, there have been a few reports in the literature of children who have been treated with clofazimine. ^{09}


Geriatrics


No information is available on the relationship of age to the effects of clofazimine in geriatric patients.


Dental

Clofazimine may cause discoloration of the sputum and changes in taste. ^{{01} {09}}


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Erythrocyte sedimentation rate (ESR)    (may be increased ^{{01} {09}})

With physiology/laboratory test values
Albumin, serum and
Aspartate aminotransferase (AST [SGOT]), serum and
Bilirubin, serum and
Blood glucose, serum    (concentrations may be increased ^{{01} {09}})


Potassium, serum    (concentrations may be decreased ^{{01} {09}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Gastrointestinal problems, history of^{01}{09}    (clofazimine may cause splenic infarction, bowel obstruction, gastrointestinal bleeding, colicky or burning pain in the abdomen, enteritis, and death following severe gastrointestinal symptoms)


Hepatic function impairment^{06}{09}    (clofazimine may on rare occasion cause hepatitis and jaundice)


Sensitivity to clofazimine


Side/Adverse Effects

Note: Clofazimine has rarely caused splenic infarction, bowel obstruction, gastrointestinal bleeding, eosinophilic enteritis, and death following severe abdominal symptoms. Crystalline deposits of clofazimine have been recovered on autopsy in various tissues, including the intestinal mucosa, liver, spleen, and mesenteric lymph nodes. ^{{01} {04} {09}}
Reversible pink or red to brownish-black discoloration of the skin may occur in 75 to 100% of patients within a few weeks of treatment. It may require several months or years to completely disappear after discontinuation of clofazimine. Also, 2 suicides have been reported as a result of mental depression secondary to skin discoloration. ^{{01} {04} {09}}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
^{09}{13}    
Gastrointestinal bleeding (bloody or black, tarry stools)
    
gastrointestinal toxicity (colicky or burning abdominal or stomach pain)
    
hepatitis or jaundice (yellow eyes or skin)—may be obscured due to pink to brownish-black discoloration of skin, cornea, and conjunctiva
    
mental depression, secondary to skin discoloration



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
^{09}{13}    
Gastrointestinal disturbances (anorexia; diarrhea; nausea or vomiting)
    
ichthyosis (dry, rough, or scaly skin)
    
pink or red to brownish-black discoloration of skin
    
skin rash and itching

Incidence less frequent or rare
^{09}{13}    
Changes in taste
    
dryness, burning, itching, or irritation of the eyes
    
photosensitivity (increased sensitivity of skin to sunlight)



Those not indicating need for medical attention
Incidence more frequent
    
Discoloration of feces, lining of the eyelids, sputum, sweat, tears, and urine

Note: Clofazimine may also cause bloody or black, tarry stools, a symptom of gastrointestinal bleeding, which does require medical attention. ^{{01} {04} {07}}






Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Recommended treatment consists of the following: ^{01}

To decrease absorption—Emptying the stomach by induction of vomiting or gastric lavage.

Supportive care—Giving supportive, symptomatic treatment as necessary. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Clofazimine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Clofazimine crosses the placenta; it can cause deeply pigmented skin in the infant; clofazimine has not been shown to be teratogenic in humans





Breast-feeding—Clofazimine is excreted in breast milk; it has caused skin discoloration in animals probably due to the presence of clofazimine in maternal milk





Dental—May cause discoloration of sputum and changes in taste
Other medical problems, especially a history of gastrointestinal problems

Proper use of this medication
Taking with meals or milk

» Compliance with full course of therapy, which may take years

» Importance of not missing doses and taking at same time every day

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within 1 to 3 months; may take up to 6 months before full therapeutic benefit is seen

» May cause mental depression, possibly leading to suicide, secondary to reversible skin discoloration; several months or years may be required for skin discoloration to disappear; checking with physician immediately if mental depression or suicidal thoughts occur

» Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing and sun block product; avoiding use of sunlamp, tanning bed, or tanning booth

Using skin cream, lotion, or oil to treat dry, rough, or scaly skin


Side/adverse effects
Signs of potential side effects, especially gastrointestinal bleeding, gastrointestinal toxicity, hepatitis or jaundice, and mental depression secondary to skin discoloration

Discoloration of feces, lining of the eyelids, sputum, sweat, tears, and urine may be alarming to patient, although medically insignificant; however, bloody or black, tarry stools may be due to gastrointestinal bleeding and requires medical attention


General Dosing Information
Clofazimine should be taken with meals or milk. ^{{01} {04}}

Clofazimine should preferably be used in combination with one or more other antileprosy agents to prevent the development of resistance in the initial treatment of multibacillary leprosy. ^{{01} {04}}

Clofazimine may also be used in combination with corticosteroids in the treatment of lepromatous leprosy complicated by erythema nodosum leprosum reactions if nerve injury or skin ulceration appears likely to occur. ^{01}

Depending on the drug regimen used, therapy may have to be continued for 2 years to life in multibacillary (borderline, borderline-lepromatous, and lepromatous) leprosy. ^{06}

Doses of more than 100 mg daily should be given for as short a period of time as possible and only under close medical supervision. ^{01}


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CLOFAZIMINE CAPSULES USP

Usual adult and adolescent dose
Dapsone-resistant multibacillary leprosy
In combination with one or more other antileprosy agents: Oral, 50 to 100 mg of clofazimine once a day. ^{{01} {06}}

Multibacillary leprosy complicated by erythema nodosum leprosum reactions
Without threatened nerve injury or skin ulceration: See Dapsone-resistant multibacillary leprosy .

With threatened nerve injury or skin ulceration: In combination with corticosteroids—Oral, 100 to 300 mg of clofazimine daily. This dosage of clofazimine may be useful in reducing or eliminating corticosteroid requirements (e.g., up to 40 to 80 mg of prednisone daily) ^{{06} {11}}. Clofazimine dosage should be tapered to 100 mg daily as soon as possible after control of the reaction is achieved. ^{01} Since it may take approximately two months to reach adequate clofazimine tissue concentrations, corticosteroids should be tapered only after two months of clofazimine therapy. Both drugs may be tapered simultaneously. ^{06}

[Mycobacterium avium-intracellulare infections]
In combination with up to five or six antitubercular agents: Oral, 100 mg of clofazimine every eight hours. ^{04}


Note: In the treatment of dapsone-sensitive, multibacillary leprosy, combination therapy with two other antileprosy agents is recommended. This triple-drug regimen should be followed for at least two years and continued, if possible, until skin smears are negative. Following this, monotherapy with the appropriate antileprosy agent may be continued. ^{01}


Usual adult prescribing limits
Leprosy
Doses above 300 mg daily are not recommended. ^{{01} {06} {11}}

[Mycobacterial infections, atypical]
Up to 300 mg daily. ^{04}


Usual pediatric dose
Dosage has not been established. ^{{01} {09}}

Strength(s) usually available
U.S.—


50 mg (Rx) [Lamprene (parabens)]


100 mg (Rx) [Lamprene (parabens)]

Canada—
Not commercially available.

Packaging and storage:
Store below 30 °C (86 °F), in a tight container, unless otherwise specified by manufacturer. ^{09}

Auxiliary labeling:
   • Take with meals or milk.
   • Avoid too much sun or use of sunlamp.
   • May discolor skin and body fluids.
   • Continue medicine for full time of treatment.

Additional information:
Lamprene brand of clofazimine capsules contains micronized clofazimine suspended in an oil-wax base.

Revised: 02/23/93

References

1. Package insert, Lamprene (Geigy), Rev 12/86, Rec 2/87.
   

2. Hawkins CC, et al. Mycobacterium avium complex infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med 8/86; 105: 184-8.
   

3. Morbid and Mortal Weekly Rept. 7/18/86; 35: 448-52.
   

4. Furio MM, Wordell CJ. Treatment of infectious complications of acquired immunodeficiency syndrome. Clin Pharm Sep-Oct 1985; 4: 539-54.
   

5. Indications Index Review, 1985.
   

6. Panel comments, Clofazimine (Systemic), 7/20/87.
   

7. USP DI Review comments, Clofazimine (Systemic), 9/10/87.
   

8. USP DI 1989, VA Medication Classification System, p 2472.
   

9. Package insert, Lamprene (Geigy), Rev 9/87, Rec 1/89.
   

10. USAN 1989, p 138.
    

11. Panel comment, 7/20/87.
    

12. Personal communication, Ciba (Canada), 5/30/89.
    

13. Holdiness MR. Clinical pharmacokinetics of clofazimine. Clin Pharmacokinetics 1989; 16: 74-85.
    

14. Venkatesan K. Clinical pharmacokinetic considerations in the treatment of patients with leprosy. Clin Pharmacokinetics 1989; 16: 365-86.
    

15. Hudson V, et al. Pulmonary clofazimine crystals in a child with acquired immunodeficiency syndrome and disseminated Mycobacterium avium-intracellulare infection. Ped Infect Dis J 12/88; 7(12): 880-2.
    

16. Garrelts JC. Clofazimine: a review of its use in leprosy and Mycobacterium avium complex infection. DICP Ann Pharmacother 5/91; 25: 525-31.
    

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