Clofazimine

Registered South African indications: 

• Multidrug-resistant tuberculosis
• Leprosy

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Acquired or congenital QT interval prolongation, including Torsades de Pointes
• Coadministration with medicines known to prolong QTc interval up to the time intervals known to induce serious dysrhythmias

Cautions

• Pregnancy
• Breastfeeding
• Females of reproductive potential
• Renal impairment
• Hepatic impairment
• Elderly
• Children
• Co-infection with HIV and on HIV treatment
• Co-infection with hepatitis B and/or C
• Monotherapy
• Irregularity of administration and poor adherence
• Interruption of therapy during lepra reactions
• High dose therapy for prolonged periods
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Multidrug-resistant pulmonary tuberculosis (additional agents required)

• Oral (cap): ≥30 kg: 100mg, dly
• Oral (cap): <30 kg: 50mg, dly

Multibacillary leprosy (additional agents required)

• Oral (cap): Day 1: 300mg, dly, under supervision; Day 2-28: 50mg, dly

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Administered as part of a triple combination, with dapsone and rifampicin, for 12 months (12 consecutive 28-day treatment cycles)

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An additional 12 month treatment cycle may be necessary for patients showing evidence of relapse

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Erythema nodosum leprosum (additional agents required)

• Oral (cap): 200-300mg, dly, under supervision; Max duration: 3 months; THEN 100mg, 12hrly, for 12 weeks; THEN 100mg, dly, for 12-24 weeks

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Combination treatment with dapsone and rifampicin should be continued

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Capsules should be taken with a meal or with a glass of milk

Paed. forms avail. in SA and covered in this monograph: tab

Multidrug-resistant pulmonary tuberculosis (additional agents required)

Younger than 10 years

• Not established for use

Older than 10 years

• Oral (cap): ≥30 kg: 2-5mg/kg, dly; Max: 100mg/24hrs
• Oral (cap): <30 kg: 2-5mg/kg, dly; Max: 50mg/24hrs 

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If <50 mg/day is required, the 50mg dose can be given 48hrly (every other day)

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Multibacillary leprosy (additional agents required)

 Below 10 years

• Oral (cap): 1-2mg/kg, dly (dose adjusted according to body weight)

Between 10-14 years

• Oral (cap): Day 1: 150mg, dly, under supervision; Day 2-28: 50mg, 48hrly (starting on day 3)

Older than 15 years

• See adult dosage

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Below 10 years: Example supplied by manufacturer, clofazimine 100 mg capsule once a month under supervision + 50 mg twice a week as self-
medication

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Administered as part of a triple combination, with dapsone and rifampicin, for 12 months (12 consecutive 28-day treatment cycles)

---

An additional 12 month treatment cycle may be necessary for patients showing evidence of relapse

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Erythema nodosum leprosum (additional agents required)

• See adult dosage

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Capsules should be taken with a meal or with a glass of milk

Pregnancy

• Caution
• The safety of clofazimine in pregnancy has not been established as experience is limited
• Clofazimine crosses the placenta. Harm to the foetus cannot be excluded. In newborn babies exposed to clofazimine in utero, skin discolouration has been observed. Use of clofazimine in pregnancy may be considered in patients with limited treatment options
• No evidence of teratogenicity has been found in animal studies, although adverse effects in the foetus were observed at high doses. In the mouse, signs of foetotoxicity (retardation of foetal skull ossification) were observed at high doses
• Pregnant women and their partners should receive appropriate counselling

Breastfeeding

• Caution; not recommended
• The safety of clofazimine in breastfeeding has not been established. As clofazimine passes into breast milk and skin discolouration may occur in the infant, women using clofazimine should not breastfeed their infants

Fertility

• The effect of clofazimine on fertility in humans is unknown. There was evidence of impaired fertility in one study in female rats receiving clofazimine 50 mg/kg/day

Renal impairment

• Caution; no information available

Hepatic impairment

• Caution; no information available 
  No dosing recommendations can be made as efficacy and safety have not been established

Elderly

• No dose adjustment recommended

Porphyria

• Not classified (NC) 

Drugs in sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Headache
• Dizziness
• Fatigue

Cardiovascular Disorders

• QT prolongation
• Cardiac dysrhythmias, including Torsade de Pointes

Respiratory Disorders

• Discoloured sputum

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Diarrhoea
• Discoloured faeces
• Eosinophilic gastroenteritis
• Decreased appetite
• Intestinal obstruction
• Gastrointestinal haemorrhage
• Abdominal discomfort
• Upper abdominal pain  
• Constipation

Hepatobiliary Disorders

• Hepatitis
• Increased blood bilirubin
• Jaundice
• Increased aspartate aminotransferase

Genitourinary Disorders

• Chromaturia

Endocrine and Metabolic Disorders

• Decreased weight
• Increased blood glucose

Skin and Subcutaneous Tissue Disorders

• Sweat discolouration
• Skin discolouration
• Hair colour changes
• Ichthyosis
• Dry skin
• Rash
• Pruritus
• Photosensitivity reaction
• Dermatitis acneiform
• Dermatitis exfoliative

Immune, Blood and Lymphatic System Disorders

• Lymphadenopathy
• Splenic infarction
• Anaemia
• Fever

Sensory Disorders

• Conjunctival discolouration
• Corneal pigmentation
• Tear discolouration
• Reduced visual acuity
• Dry eye
• Eye irritation
• Maculopathy
• Corneal deposits

• Isoniazid
• Agents that prolong QT interval
• Bedaquiline
• Fluoroquinolones
• Delamanid
• Azithromycin
• Rilpivirine
• Lopinavir
• Atazanavir
• Nelfinavir
• Saquinavir
• CYP3A substrates
• Antimycobacterial agents
• Clarithromycin
• Antiretroviral agents (unboosted)
• Amprenavir
• Delavirdine
• Efavirenz
• Etravirine
• Indinavir
• Raltegravir
• Simeprevir
• Maraviroc
• Antihyperlipidaemic agents
• Antihypertensive agents
• Simvastatin
• Lovastatin
• Losartan
• Verapamil
• Diltiazem
• Nitrendipine
• Amlodipine
• Nisoldipine
• Nifedipine
• Eplerenone
• Felodipine
• Lercanidipine
• Antidiabetic agents
• Pioglitazone
• Repaglinide
• Saxagliptin

None routine. Specific cases may require

• ECG
• Hepatic function
• Kidney function
• Pregnancy test

Multidrug therapy

• Clofazimine should not be used as monotherapy for the treatment of leprosy ( to prevent the emergence of resistant strains of Mycobacterium leprae) or multidrug-resistant pulmonary tuberculosis. Clofazimine should be used in combination with other appropriate agents according to indication

Patient adherence

• Patients should be counselled on the importance of adherence with the prescribed treatment regimen in order to prevent antimicrobial resistance. Irregularity in administration and poor adherence to therapy can lead to delayed and/or failed treatment. This could render the patient a source of contamination
• Patients should be trained to recognise reactions and relapses after treatment completion and should be made aware of the importance of immediate reporting of the earliest manifestations thereof to the healthcare professional

Accumulation of clofazimine in tissues and organs

• Adverse reactions to clofazimine are mainly associated with uptake by tissue and organs as after prolonged administration in high doses, accumulation in various organs, body fluids and tissues (as crystals) may occur. Because of this, the use of high doses for long periods should be avoided. Symptoms may slowly regress on withdrawal of clofazimine
• Patients should be warned that the use of clofazimine may cause discolouration of the conjunctiva, lacrimal fluid, sweat, sputum, urine, faeces, nasal secretions, semen and breast milk
• Clofazimine may cause reddish to brownish-black skin discolouration. Health professionals should be aware that skin discolouration may result in depression and cases of depression with suicide have been reported

Lepra reactions

• Multidrug treatment should not be interrupted during lepra reactions, including erythema nodosum leprosum. Some data indicate a trend towards reduction in the frequency and severity of erythema nodosum leprosum in leprosy patients treated with multidrug therapy. This trend may be attributed to the anti-inflammatory properties of clofazimine
• However, temporary and unexplained increases in reversal reactions have also been observed in leprosy patients, usually during the first year of treatment with multi-drug therapy. Lepra reactions usually respond satisfactorily to standard anti-inflammatory therapy

Clofazimine exerts its antimycobacterial effect through multiple mechanisms. The primary mechanism of antimicrobial action is membrane-directed activity, involving the bacterial respiratory chain and ion transporters. Intracellular redox cycling, including the oxidation of reduced clofazimine, leads to the generation of antimycobacterial reactive oxygen species (ROS), superoxide-hydrogen peroxide (H2O2). Secondly, clofazimine interacts with membrane phospholipids resulting in the generation of antimycobacterial lysophospholipids that promotes membrane dysfunction. This results in interference with K⁺ uptake. These mechanisms result in the disruption of ATP production and cellular energy metabolism. Thirdly, an additional proposed mechanism involves preferential binding, with particular affinity to guanine bases, to mycobacterial deoxyribonucleic acid (DNA) resulting in the inhibition of mycobacterial replication and growth. Clofazimine may also exert antimycobacterial activity by its effect on tissue macrophages as clofazimine has shown apoptosis-inducing properties in activated macrophages. Clofazimine may inhibit MtSerB2, a phosphatase produced by Mycobacterium tuberculosis, that is believed to help the pathogen evade host immune response.

Clofazimine displays anti-inflammatory activity primarily through inhibition of T lymphocyte activation and proliferation. Clofazimine may indirectly interfere with the proliferation of T cells by promoting the release of ROS and E-series prostaglandins (PGs), especially PGE2 from neutrophils and monocytes. Clozafimine's anti-inflammatory activity is thought to contribute to its effect in controlling erythema nodosum leprosum reactions.

Capsule 50mg

• Lamprene (Novartis) originator

Capsule 100mg

• Lamprene (Novartis) originator