Pages 427 - 432 Volume 92, Issue 4
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Benefits of high dose clofazimine

Besides its role in multidrug therapy, clofazimine at higher doses is widely used for relief of Type 2 (ENL) reaction in leprosy. There is a lack of evidence from clinical trials regarding indications, optimum regimen and risk/benefit ratio to support published guidelines on its use as an anti-reaction drug. Clinical experience suggests that in adults it is safe at high doses (up to 300 mg/day) for limited periods of time but caution is needed with patients of low body weight and in those taking other drugs which may interact.

Cite this article
C. Ruth Butlin, Armi Maghanoy;
Benefits of high dose clofazimine; Leprosy Review; 2021; 92; 4; 427-432; DOI: 10.47276/lr.92.4.427
LEPROSY
Leprosy Review
2162-8807
British Leprosy Relief Association
Colchester, UK
Dear Editor,
Benefits of high dose clofazimine
Clofazimine has been used in treatment of leprosy for over 50 years. It has mild bactericidal action against M. leprae as well as having suppressive effect on erythema nodosum leprosum (ENL).18 When the reduction in length of treatment with MDT from 24 months to 12 months for multibacillary cases, as advised by the World Health Organization (WHO), was implemented, it was noted that ENL appeared to be more of a problem.6,9 This was thought to be a result of patients receiving less clofazimine.
Clofazimine may indirectly interfere with the proliferation of T lymphocytes by promoting the release of E-series prostaglandins (PGs), especially PGE2 from neutrophils and monocytes which may have a significant role in controlling Type 2 reactions. However, its effect is only apparent when a certain critical level is reached. Sustained tissue levels of clofazimine may be more important than peak blood levels for its therapeutic effect.7,10,11
Many practising clinicians believe it is useful as an adjunct to steroids for managing ENL reactions, yet there is a dearth of published evidence from trials to show whether it is effective at high doses, either to prevent first episodes or to reduce recurrence of ENL, or for its steroid-sparing effect in chronic ENL, and very little evidence to determine the best regimen for ENL management. Different doses and durations may be found to be appropriate for each scenario.
In a double-blind controlled trial by Karat et al.12 There were 24 lepromatous leprosy patients in reaction who were randomly allocated to receive either clofazimine or prednisolone for 12 weeks and were followed-up for more than 4 months. It showed that clofazimine controlled symptoms of ENL reaction better than prednisolone. It also appeared to be significantly superior in preventing recurrence once the reaction had been controlled. There was no difference in terms of neurological status, bacterial index, morphological index, and renal function among inpatients on clofazimine, as compared with patients on prednisolone; the observed statistically significant rise in serum albumin may not be clinically important. Red/black hyperpigmentation was seen among practically all patients on clofazimine. No other side-effects or deleterious systemic effects were observed.
Recent studies with MDT-treated patients include a retrospective study done by Balagon et al.6 comparing two cohorts, involving 589 patients who were receiving either 12 or 24 months MBMDT and followed for at least 4 years. This study showed that ENL was not significantly more common, but it was longer-lasting and more severe in patients receiving only 12 months of MDT, as compared with those receiving 24 months treatment.
This was followed by a double-blind study, comparing 100 patients randomly allocated to either 100 mg daily clofazimine or placebo for 12 months after completion of 12 months MBMDT. The outcome measures used were a newly developed ENL severity scoring system, total steroid intake, incidence of new ENL episodes and duration of episodes. On some measures, including deaths likely to be related to steroid intake, the placebo group appeared to have more severe ENL, but none of the differences were statistically significant.13
The guidelines suggested by WHO for managing severe, chronic ENL with clofazimine (300 mg/day for 12 weeks, taper to 200 mg/day for 12 weeks then 100 mg/day for 12–24 weeks),6 are widely used and seem beneficial. A gradual improvement of ENL symptoms, steroid-sparing effect and preventing episodes of recurrence are observed among patients. However, none of the various guidelines or recommendations available (see Table  110,1421) are based on results of good quality clinical trials supported by objective criteria and many clinicians use different regimens; consensus on best practice is still lacking. The precise indications for appropriate use of high dose clofazimine (both for ENL patients on MDT and for those who suffer ENL after release from treatment) need to be clarified.
Table 1
Published guidelines
DateSourceStatusIndicationsRegimenCumulated dose (in 1st 6 m)
1978Lamprene in Leprosy10  Information from manufacturerIn ENL cases....300 mg daily  for about  3 months. This dose should not normally be maintained for more than 3m25,200 mg in 1st 3 months
1988Expert cttee WHO 6th report14Expert opinionENL in women of child-bearing age300 mg daily for up to  3 months25,200 mg in 3 months
1993Lamprene in Leprosy 4th ed15Basic information from manufacturerENL. Often useful in enabling dose of corticosteroids to be lowered Drug of choice for ENL in females of child-bearing potential1. 300 mg daily for up to 3 months. 2. In severe  cases, must be given in doses of  100 mg tds for at least 6 weeks, then reduced to 200 mg/day  for several more  months. The maintenance dose of 100 mg od will usually be  needed for several years.1. 25,200 mg in 1st 3 months 2.  33,600 mg in 6 m (if given 6  wks at 300 mg,  12 wks at 200 mg, 6 wks at 100 mg)
1997Expert cttee WHO 7th report16Expert opinion. Repeats advice of Expert cttee WHO 5th  report 1977For ENL: Reducing or withdrawing steroids in those who have become dependent on themDaily Dose required is 300 mg, may be given in 3 divided daily doses, total duration should not exceed 12 months50,400 mg in 1st 6 m
2010IAL textbook of leprosy17Expert opinion. Textbook for dermatologist  & leprologistsReduce recurrence of ENL, reduce or withdraw steroids given for ENL300 mg/day for 1month, then 200 mg/day for 2–6 m, then 100 mg /day as long as symptoms persist28,000–36,400 in 1st 6 m
2018ITOL18Reference book. Expert opinion, citing WHO advice  in 8th report  2012For ENL, where steroids contra-indicated or as steroid sparing agent300 mg per day for 12 weeks, then reduced to 200 mg for 12 weeks and maintained thereafter at 100 mg for 12–24 weeks42,000 mg in 1st 6 m
2020Jopling 6th edition19Textbook for graduate doctors. Expert opinion, citing WHOSteroid sparing agent or when  steroids contra-indicatedFor total 12 m course—100 mg tds for 3 months, then tapering over 1–6 months to 100 mg36,400–42,000 mg (if given 200 mg daily for 1–3 m after reduction of dose)
WHO. Management of reactions and prevention of disabilities20Technical guidance: this  is described as “a widely used regimen” Identical to that in ILEP. Learning Guide Two: How to recognize  and manage leprosy reactions. 2002It ... might be effective in mitigating chronic and recurrent ENL. When a second attack occurs, especially if severe, it is advisable to add another drug, either thalidomide if available, or clofazimine, to reduce the need for steroids300 mg, daily, for 1 month; then 200 mg, daily, for 3–6 months; then 100 mg, daily, for as long as ENL
symptoms remain.
30,800–36,400 mg in 1st 6 m
2021WHO Guidelines on management of severe ENL (website)21Guidelines based on expert opinion. Reflects advice of Expert cttee WHO 8th report 20121. In cases with severe ENL who are not responding satisfactorily to treatment with corticosteroids or where the risk of toxicity with corticosteroids is high 2. In cases with severe ENL where use of corticosteroids  is contra-indicated.1. Start clofazimine 100 mg three times a day for maximum of 12 weeks. Complete the standard course of prednisolone. Continue clofazimine. Taper the dose of clofazimine to 100 mg twice a day for 12 weeks and then 100 mg once a day for 12–24 weeks. 2. Start  clofazimine 100 mg three times a day for maximum of 12 weeks. Taper the dose of clofazimine to 100 mg twice a day for 12  weeks and then 100 mg once a day for 12–24 weeks.42,000  mg in 1st 6 m
Range: 28,000–50,400 mg for  first 6 months (24 weeks)
Reversible dose-related skin discoloration, is the most common side effect of clofazimine. Whilst aesthetically undesirable it is not physically harmful and in many people with naturally darker skin tones this is tolerable. The associated xeroderma or ichthyosis, especially on exposed areas, is more problematic. Most studies of adverse effects of clofazimine in leprosy do not enumerate these “expected effects”.2225 Dermatological effects rarely lead to discontinuation of the drug in TB cases.26. Used with other drugs for TB, clofazimine is associated with gastrointestinal side effects in 40–55% cases.27,28 At present, there is still no accurate assessment as to the frequency, nature and incidence of the gastro-intestinal side effects occurring with high dose clofazimine when used for leprosy. Nausea, and diarrhoea have been reported as commonly mild; weight loss has been observed occasionally, while severe abdominal pain is rare.29 However, a retrospective study of the use of clofazimine in TB showed a clear association between skin or gastrointestinal adverse effects and the combination of low body weight with higher drug dosage.30 Other serious adverse effects, such as pulmonary crystal deposition31,32 and cardiac dysrhythmias,33,34 are rare and mainly reported in patients receiving other drugs which interact, those with other medical conditions, and people who have received high dose clofazimine for excessively long periods. An early prospective study of people on high dose clofazimine for 2–8 years found no clinically significant effects on renal function, liver function or haematological parameters.35
Therefore, clofazimine is a relatively safe and a useful drug due to its anti-bacterial and anti-inflammatory effect. It is suitable for patients with steroid dependency, having recurrent ENL. As to its role in preventing the first occurrence of ENL, it has not yet been proven but this might be possible with high dose clofazimine. Future studies should be considered, preferably good quality randomised clinical trials supported by large sample size, with both specific eligibility criteria and objective criteria used for outcome measures. A study targeting patients who already had at least one episode of ENL, which has already obtained ethical approval and has funding approved by the Leprosy Research Initiative, will be conducted soon to validate the effect of high dose clofazimine in these patients. Whether or not extended coverage with clofazimine should also be given to those lepromatous and borderline lepromatous leprosy patients who are at high risk of developing ENL (but have not yet had a first episode), is still uncertain.
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