Clofazamine

Clofazimine (Cfz)

Clofazimine was discovered in 1954. At the time, the drug proved to be ineffective at treating TB but showed efficacy in treating leprosy. Clofazimine has shown activity against MDR TB and is now recommended by the WHO to treat drug resistant tuberculosis as a medicine with “unclear efficacy”.

Dosage:

(Clofazimine may decrease absorption rates of rifampicin.)

How it works:

It is thought that clofazimine acts by inhibiting the formation of matrixes within the DNA and thus delaying the growth of the bacterium.

Side effects:

Side effects include dry and flaky skin, nausea, abdominal pain as well as discolouration of the skin, retina, cornea and urine. Clofazimine may also cause irritated eyes, sensitivity to light, headache, fever, increased blood sugar and liver damage.

Potential risks of clofazimine during pregnancy and breastfeeding should be weighed. Clofazimine caused fetal malformations in animal studies, and is secreted in breastmilk.

Clinical evidence and approval:

Clofazimine first received FDA approval in 1986, although its use in the treatment of drug resistant TB has not been approved by any stringent regulatory authorities and it is therefore used “off-label” for this function.

In vitro studies and studies in mice have shown activity of clofazimine against Mycrobacterium TB.²

It is recommended that clofazimine is introduced before linezolid and other medicines with unclear efficacy.³ “Despite restricted clinical experience with clofazimine to treat TB, its role is attracting interest because of its potential intracellular and extracellular activity. Moreover, adequate dose management would help the control of adverse events, especially photosensitivity and gastric intolerance.”⁴

Between 1997 and 2007, an observational study was carried out to evaluate the effectiveness of standardised treatment regimens for patients with MDR-TB. Patients were assigned to one of six standardised regimens. The most effective treatment regimen required a minimum of 9 months of treatment with gatifloxacin, clofazimine, ethambutol, and pyrazinamide throughout the treatment period supplemented by prothionamide, kanamycin, and high-dose isoniazid during an intensive phase for a minimum of 4 months. This regimen had a 87.9% relapse-free cure rate among 206 patients (95% CI, 82.7-91.6). Major adverse drug reactions were infrequent and manageable.⁵

In India, a patient with XDR TB was successfully treated with a regimen containing clofazimine and other medicines (capreomcin, moxifloxacin, PAS, clarithromycin, and ethambutol.)⁶

Pricing (per lowest unit, i.e. single tablet or injection):

* Private sector prices sourced on 26/07/11. Global Drug Facility prices converted to rands on 26/07/11.

* Private and public sector prices may vary between suppliers. The lowest available prices are shown here.

Advocacy issues:

• Further research is needed to establish safety and efficacy for paediatric treatment. There are no appropriate paediatric formulations available. Further research is needed to understand potential interactions with antiretrovirals. [MSF]

• Clofazimine is not available in South Africa.

• Clofazimine is included in the WHO guidelines for the treatment of MDR TB, yet it is used off-label. It is unclear whether liability will fall on doctors if patients experience adverse events. The liability problem would extend to nurses if they began to initiate and manage MDR TB treatment.

Manufacturers and suppliers:

Today there is only one source approved by a stringent regulatory authority. This product is produced by Sandoz for Novartis. Additional manufacturers may exist in China, India, the former Soviet Union and other countries, but whether they comply with WHO quality standards is unknown.

With no market for this product in wealthy countries, there is no reason for a manufacturer to seek authorisation through a stringent regulatory authority. It is therefore imperative that WHO Prequalification includes clofazimine in the next Expression of Interest (EoI), to send a clear message to manufacturers that the product is needed. Even if demand is low, there is a need to have an alternative source to the Novartis product which is not easily available and/or too expensive.⁸

Source: MSF