Capreomycin

Capreomycin is used as part of a treatment regimen, usually involving 5 medicines to treat MDR TB. It is part of a group of medicines called injectables. Capreomycin was discovered in 1960, isolated from Streptomyces capreolus.

Capreomycin is used in addition to South Africa’s standard regimen for treating MDR TB, for patients with XDR TB.

Dosage:

How it works:

Capreomycin is a polypeptide antibiotic. Capreomycin inhibits protein synthesis by binding to the 70S ribosomal unit, making TB unable to grow.

Side effects:

Injectables including Capreomycin can cause damage to the kidneys and hearing loss. It should be avoided in patients with pre-existing kidney damage and hearing loss. However, the risk of permanent deafness is lower than with other injectables. Capreomycin may also cause hypokalaemia (low potassium), rashes and pain at the injection site.

Injectables are warned against during pregnancy as they may cause deafness in the infant.However, if an injectable drug cannot be avoided, capreomycin is recommended by the WHO above the other options.

Clinical evidence and approval:

Capreomycin has been approved by the FDA to treat mycrobacterium tuberculosis once other medications have been tried without success.

A study carried out in China (published in 2003) established the safety and efficacy of treating MDR TB with combination therapy containing capreomycin and lexofloxacin. 82 patients in the intervention arm received a combination therapy containing capreomycin, lexofloxacin and other 2^nd line TB drugs. 79 patients in the control arm received regimens containing streptomycin and ethambutol and other 2^nd line drugs. The sputum negative conversion rate in the study group (83%) was significantly higher than that in the control group (58%) (P < 0.01).¹

A further study carried out in India (published in 2004) established the safety and efficacy of regimens containing azithromycin and capreomycin. 97 patients were divided in two groups. 47 patients in the intervention arm were treated with combination therapy containing capreomycin and azithromycin while 45 cases in the conrol group were treated with streptomycin, ethambutol, pyrazinamide and isoniazid. The sputum negative cases in the intervention group were significantly higher than in the control group (82% vs 56%). The closure rate of the lung cavities inthe study group (65%) was higher than in the control group (44%)(P<0.05). No significant difference was found in side-effectsbetween the two groups.²

A review of available evidence showed that patients with drug resistant TB should be treated with capreomycin before other injectables as there is less risk of cross resistance. Isolates acquiring resistance to capreomycin are usually susceptible to kanamycin and amikacin.

Data also suggests that capreomycin might be associated with less ototoxicity when compared with amikacin.³

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 in infants. Further research is needed to establish safety and efficacy when combined with antiretrovirals that may cause renal failure such as tenofovir. [MSF]

• During 2011, a worldwide shortage of capreomycin was announced. This is because there is too little active pharmaceutical ingredient to ensure supply to manufacturers. There is only one source of the active pharmaceutical ingredient, a company in China. Given the shortage, prices are expected to rise.

• Generic versions have not yet received regulatory approval.

• SA public sector prices are 2.5 x higher than internationally available prices.

Manufacturers and suppliers:

Eli Lilly filed the initial application to the US FDA in 1971. Since 2003, the company has been actively engaged in technology transfer to three generic manufacturers (Aspen, Hisun and SIA International) and today has ceased production of capreomycin in the US.

 None of these manufacturers has yet received regulatory approval by a SRA or WHO PQ. Today, there are no sources of capreomycin approved through WHO PQ. In the US, Eli Lilly's license was sold to Akorn, which today is the only quality-assured source available to GDF.

 An additional manufacturer (Macleods) has submitted a dossier to WHO Prequalification and has been accepted for evaluation, and Aspen is expected to submit during the course of 2011.

 The supply of quality-assured capreomycin therefore remains vulnerable to disruption. Additional manufacturers may exist in China, India, the former Soviet Union, and other countries, but whether they comply with WHO quality standards is unknown.

Source: MSF