Leprosy Mailing List – March 24, 2021
Ref.: (LML) Clofazimine risk?
From: Ruth Butlin, London, UK
Dear Pieter,
Since no-one else was able to offer information, I am trying to answer my own question (LML 29.1.21). This is not authoritative as I am no cardiologist, simply a leprosy specialist with an interest in ENL management. I am grateful to Infolep* for their kind assistance in sourcing publications.
How big a risk is QT prolongation during clofazimine therapy for leprosy?
The USPI (2019) for clofazimine available from Novartis states that: "QT prolongation and Torsade de Pointes may occur with LAMPRENE. Concomitant use with other QT prolonging drugs or bedaquiline (bedaquiline is used to treat multi-drug-resistant tuberculosis along with other medications for tuberculosis) may cause additive QT prolongation. Monitor ECGs and discontinue LAMPRENE if significant ventricular arrhythmia or QTcF interval greater than or equal to 500 ms develop."
Torsade de Pointes is a dangerous cardiac arrhythmia. Some people with a family history of sudden cardiac death might be at increased risk of this. It is a ventricular tachycardia with varying axis, which sometimes occurs post-myocardial infarction or in presence of congenital, biochemical or drug-induced prolongation of QT interval. Most leprosy patients treated in the field will not be screened by ECG before receiving clofazimine as facilities are not available.
There appears to be only one published case report of a possible cardiotoxic effect of clofazimine when used in leprosy, and that was in a case treated with very high dose for a long time. This was a patient from 1987, reported in 1995, by Choudhri (1). The 66 year old Indian male patient had received 300mg /day clofazimine for 11 months (well above usual dosage regiments nowadays), in combination with several other drugs. Although the authors said none of his other current medications (including azathioprine, prednisolone, thalidomide, warfarin, insulin, diuretic, buscopan) were known to cause QT prolongation, there was the possibility of interactions, and he did have evidence of chloroquine retinopathy from previously receiving this drug for ENL. While suffering from an abdominal syndrome typical of clofazimine overload, and hypo-magnesaemia, the patient had ventricular tachycardia, which settled after prolonged lidocaine administration and correction of his electrolyte disturbance. The authors recommend that a patient on clofazimine with any signs of electrolyte imbalance or signs of clofazimine toxicity, should be screened by ECG .
If decades of experience of using clofazimine in leprosy, both in MDT and at higher doses in managing ENL reaction, in many diverse populations, have not produced other reports of cardio-toxicity of clofazimine in the leprosy literature, this suggests that if it does occur it is very rare. Official guidelines, such as from WHO, do not advise ECG as initial screening or for monitoring of patients given clofazimine.
A detailed case history (2,3) of a patient with multidrug resistant Tuberculosis described a man having significant and sustained prolongation of QT interval (asymptomatic) which began within a few days after commencing clofazimine therapy at 200mg daily dose, and persisted for another 12 weeks after his clofazimine was discontinued at 5 weeks. This man was also taking bedaquiline and delamanid, which are known to cause QT prolongation, and he initially had hypokalaemia. The authors said that while there are ongoing safety concerns when bedaquiline is used in combination with clofazimine, as yet there has been no life-threatening arrhythmia reported. Their advice was ECG and electrolytes should be checked before starting the two drugs together.
A review of patients treated with clofazimine for MDR Tb in Brazil national Tuberculosis control programme (4) found no difference between the clofazimine treated group (taking 50- 100mg/day, depending on body weight) and the comparator group (on pyrazinamide containing regimens) in adverse effects. Amongst 1446 patients, 50.2% had hyperpigmentation, 10.5% had adverse events related to Gastro-Intestinal system, and 9-13% had neurological adverse events. This was not a randomised trial - there were some differences between the 2 cohorts. The slightly higher death rate in the clofazimine group was attributed to other confounding factors (eg more drug-resistance cases) not to cardiac toxicity. This study also confirmed that up to 100mg/day is an adequate dose for MDR Tb.
A systematic review (5) of 8 cohort studies using clofazimine in regimens for MDR Tb found about 11.4% patients had adverse events but only <1% needed to discontinue the medication. No QT prolongation nor other cardio-toxicity was mentioned.
A meta-analysis (6) of 5 observational studies (1993-2012) of multidrug resistant patients treated with clofazimine, involved 861 patients most of whom received 50-100mg/day (but in one study 300mg/day). It found median frequency of adverse effects of 5.1% and only 0.1% (0-0.6%) had to discontinue the drug. There was no mention of cardio-toxicity.
A prospective multicentre study (2012-2017) of clofazimine in regimens for nontuberculous mycobacterial infection (7) included monitoring ECG recordings before and during therapy. They found that there was no significant prolongation of QT interval amongst their 18 patients.
Further trials on clofazimine in MDR Tb regimens might clarify the picture but at present it appears that the main problem from clofazimine might be interaction with other drugs which themselves prolong QT interval (8), and the increased risk of QT prolongation in presence of electrolyte disturbance should be heeded. It might be wise to screen by ECG anyone with recent myocardial infarction or a relevant family history. The likelihood of clofazimine as used in leprosy causing QT prolongation, and more importantly, acute cardiac death, is questionable.
References.
1. Choudhri Shurjeel H, Harris Louise, Jagadish W Butany, Keystone Jay S. Lepr Rev (1995) 66, 63-68
Clofazimine induced cardiotoxicity-a case report
2. Tadolini M, Lingtsang RD, Tiberi S, et al. First case of extensively drug-resistant tuberculosis treated with both delamanid and bedaquiline. Eur Respir J 2016; 48: 935–938.
3. Marina Tadolini, Rangjung Dolma Lingtsang, Simon Tiberi, Martin Enwerem, Lia D'Ambrosio, Tsetan Dorji Sadutshang, Rosella Centis, Giovanni Battista Migliori. Cardiac safety of extensively drug-resistant tuberculosis regimens including bedaquiline, delamanid and clofazimine
4. Margareth Dalcolmo, Regina Gayoso, Giovanni Sotgiu et al. Effectiveness and safety of clofazimine in multidrug-resistant tuberculosis: a nationwide report from Brazil. European Respiratory Journal 2017: https://erj.ersjournals.com/content/49/3/1602445.long
5. M. Gopal, N. Padayatchi, J. Z. Metcalfe, and M. R. O'Donnell, Systematic review of clofazimine for the treatment of drug resistant Tuberculosis. Int J Tuberc Lung Dis. 2013 August ; 17(8): 1001–1007. doi:10.5588/ijtld.12.0144
6. Hwang TJ, Dotsenko S, Jafarov A, et al. Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis: analysis of published guidance and meta-analysis of cohort studies. BMJ Open 2014;4:e004143. doi:10.1136/bmjopen-2013- 004143
7. S. Zweijpfenning, H. van Groningen et al. Clofazimine does not lead to significant QT interval prolongation: a multicentre study. European Respiratory Journal 2018 52: https://erj.ersjournals.com/content/52/5/1801386.long
8. for a list of drugs presenting risk of QT prolongation see: https://crediblemeds.org/blog/four-drugs-added-crediblemeds-qtdrugs-lists1/
* Infolep is the international knowledge center for access to (digital) information resources on leprosy and related subjects. Go to www.leprosy-information.org
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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