Linezolid

Linezolid

Linezolid is recommended by the WHO to treat drug resistant tuberculosis as a medicine with “unclear efficacy”. Linezolid was discovered in the 1990s and first approved in 2000. Linezolid was the first oxazolidinone antibacterial agent discovered.

Dosage

How it works:

Linezolid is a synthetic antibiotic that acts by disrupting theproduction of proteins.

Side effects:

Linezolid may cause diarrhoea, constipation, nausea, vomiting, headaches, vision disturbances, flu symptoms, discoloured tongue, and yeast infections. Other side effects include anaemia, peripheral neuropathy, bone marrow suppression and lactic acidosis. Vitamin B6 at 50 mg daily may prevent/ reverse anaemia.

Clinical evidence and approval:

Linezolid was first approved for use in 2000, 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” in this function.

In a review of thirty patients given linezolid as part of their treatment for MDR TB, it was concluded that linezolid was well tolerated, had low rates of discontinuation, and may have efficacy in the treatment of MDR TB.¹

Another retrospective assessment of 85 patients treated with linezolid reported high rates of adverse events. 35 patients (41.2%) experienced major side effects, requiring discontinuation in 27 (77%) cases. The study reported that adverse events were lower for patients prescribed 600 mg daily than patients given 1200 mg daily. The study also found that linezolid is potentially important for patients with XDR TB.

The study concluded that “the data suggest that linezolid may be useful in improving the chances of smear and culture conversion and may provide a better chance at treatment success in only the most complicated cases of MDR/XDR-TB when other treatment alternatives are not available, but that its safety profile does not warrant its use in cases for which other, safer second-line or third-line drugs are available.”²

While there is little evidence on paediatric safety and efficacy of linezolid, an infant in Italy was successfully treated for TB with no adverse reactions.³ A review of 4 patients, ages 4 to 17, concluded “[linezolid] is an option to consider in the treatment of refractory MDR- and XDR-TB, although the optimal dose, timing of introduction and associations are yet to be established, especially in younger patients.”⁴

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:

• Linezolid may be useful for patient with XDR TB but it is not available in the public sector as it remains unaffordable at R593.01 per pill.

• Linezolid 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.

• Linezolid has been approved for use in children and paediatric dosages are available. However more research is needed to establish the safety of extended use. [MSF]

• Further studies are needed to establish potential interactions with antiretrovirals. [MSF]

Patents, manufacturers and suppliers:

The basic patent claiming linezolid was first filed in 1993 by Upjohn Company in the US and is due to expire in May 2015. Similar patents were also granted in China, the Philippines and South Africa.

Today only one manufacturer, Pfizer, is approved by a stringent regulatory authority. A further four manufacturers (Teva, Mylan, Glenmark and Gate Pharma) have tentative approval from the US FDA, waiting to enter the US market when the patent expires.

Additional manufacturers may exist in China, India, the former Soviet Union and other countries, but whether they comply with WHO quality standards is unknown.

Linezolid was not included in the 10th Invitation to Manufacturers to submit an Expression of Interest (EoI) for product evaluation by WHO Prequalification (August 2010 - revised February 2011). Because of this, there are no manufacturers with dossiers currently under evaluation.

The drug was, however, included in the joint GDF/Global Fund Invitation to manufacturers to submit an Expression of Interest for product evaluation issued by the Expert Review Panel in January 2011.

As linezolid has a market in wealthy countries, manufacturers with SRA approval should be approached to make their products available for the DR TB market. It is imperative that WHO Prequalification includes linezolid in the next EoI to send a clear message to manufacturers that this product is needed for the TB market.⁶

Source: MSF

 1^ GF Schecter et al. Linezolid in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis. 2010 Jan 1;50(1):49-55.