Levofloxacin

Levofloxacin (Lfx)

Levofloxacin 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 fluoroquinolones. Levofloxacin was discovered in 1987 by Daiichi Pharmaceutical in Japan.

 Dosage:

How it works:

Levofloxacin is a synthetic fluoroquinolone antibacterial agent. It functions by inhibiting enzymes which are necessary to separate bacterial DNA, thereby inhibiting cell replication.

Side effects:

Levofloxacin is generally well tolerated. Occasional side effects include nausea, vomiting, diarrhoea, trouble sleeping, dizziness and sensitivity to light. Rare side effects include peripheral neuropathy and tendon rupture.

It is not known if levofloxacin is harmful during pregnancy and breastfeeding. It is recommended that levofloxacin is discontinued during pregnancy and breastfeeding because of the potential for serious adverse events, particularly cartilage damage. Fluoroquinolones should only be taken during pregnancy if benefits outweigh risks.

Clinical evidence and approval:

The use of levofloxacin in the treatment of drug resistant TB has not been approved by any stringent regulatory authorities and it is therefore used “off-label” in this function.

A study carried out in China, published in 2000, showed that levofloxacin displayed powerful activities against Mycobacterium tuberculosis both in vitro and in vivo. Researchers concluded that levofloxacin is a new safe and effective medicine for MDR TB.¹

Levofloxacin at high doses (1000 mg/day), but not low doses, seems to have better pharmaco-dynamic qualities than do either moxifloxacin or gatifloxacin. ²

A study comparing the combination of pyranzinamide and levofloxain in MDR treatment regimens found that they were poorly tolerated.³ Pyranzinamide is used in standard treatment regimens for MDR TB in South Africa.

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:

• SA private sector prices are 37 x higher than lowest available international prices. Public sector prices are not yet available.

• Levofloxacin 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.

• Levofloxacin has received approval for short term use (14 days) in children. Further research is needed to establish the safety and efficacy of extended use. Paediatric formulations are not widely available in the developing world. [MSF]

• Further research is needed to understand potential interactions with antiretrovirals. [MSF]

Patents, manufacturers and suppliers:

Patents claiming levofloxacin were originally filed in 1981and 1986 by Daiichi Seiyaku, now a subsidiary of Daiichi Sankyo, and licensed to Janssen. Although 20-year patents expired in 2001 and 2006 respectively, patent protection has been extended until June 2011 in several European countries and the US.

As the patent will expire soon, manufacturers are already registering their product in the US and the EU. Those manufacturers should be contacted by GDF to see if they could be interested, once the patent has expired, in also supplying GLC-approved programmes.

Two manufacturers have dossiers submitted and accepted for evaluation by WHO Prequalification. These Cipla (250mg) and Macleods (250mg and 500mg) sources have already been assessed by the Expert Review Panel for the GDF and the Global Fund and are currently listed as purchasable in 2011 with Global Fund money.

An additional manufacturer (Micro Labs) is expected to submit to WHO Prequalification during the course of 2011. The supply of levofloxacin is therefore relatively secure. In addition, there are multiple sources of quality-assured levofloxacin, because other approved indications of use exist for the drug. Indeed, a further 13 manufacturers have obtained US FDA tentative approval for levofloxacin, waiting to enter the US market when the patent expires in the US in June 2011. However, none of these producers have applied for WHO Prequalification, no made their products available to GDF.⁵

 Source: MSF