Treatmentactiongroup.org

An Activist's Guide to
LinezoLid (zyvox)
By erica Lessem and Lauren Volpert
September 2014
Increasingly drug-resistant forms of tuberculosis (TB) are becoming more common worldwide, and Key definitions
few medicines are available to treat them.1 Newly developed TB drugs, such as bedaquiline and and Acronyms
delamanid, offer some hope, but need to be taken along with other drugs. Linezolid, an antibiotic approved for the treatment of other bacterial infections—but not approved by any regulatory authority for the treatment of TB—can be an important drug in a regimen to treat drug-resistant TB when few other options exist. This guide highlights important information about linezolid's safety and efficacy, and offers advocacy recommendations for activists, including community representatives, advocates, clinicians, researchers, policy makers, donors, and private-sector resistant TB; or TB resistant to
at least isoniazid and rifampin,
ii. Mechanism of Linezolid
the two most powerful existing
TB drugs, which are used as part
Linezolid kills TB by preventing the bacteria from turning their genetic information into active of the four-drug first-line
proteins (a process known as translation). Linezolid blocks the initiation step of translation so that the TB bacteria can't make the proteins they need to function.2 XdR-TB: extensively
iii. efficacy of Linezolid
drug-resistant TB; or MDR-
TB that is also resistant to a
Linezolid has not been tested in large clinical trials of people with TB, but information from fluoroquinolone and at least one
observational studies and small trials supports the use of linezolid in highly resistant TB strains and injectable second-line drug
cases that are otherwise complicated to treat (e.g., when someone with MDR-TB cannot tolerate other drugs in his or her regimen). A meta-analysis of 12 nonrandomized studies of linezolid's role in MDR- and XDR-TB treatment found that 82 percent of patients treated with linezolid were cured or completed treatment—higher than in previously reported XDR-TB treatment outcomes.3 In one small trial, 41 people with XDR-TB on individualized regimens were randomized to receive 600 mg daily of linezolid, either immediately or after two months. After four months, or until culture conversion, they received either 600 mg or 300 mg of linezolid daily for at least an additional 18 months. While final results regarding linezolid's effect on cure rates are pending, early data show that immediately starting linezolid increased the percentage of patients whose TB converted after four months (79% vs. 35%; P = .001), and that 87 percent of the 38 patients who received linezolid had a negative sputum culture within six months after starting linezolid.4 Only four patients developed linezolid resistance, despite having few other potent drugs in their regimen to protect against resistance.5 Another small study found linezolid in combination to be an effective option for children with drug-resistant TB, even when other treatments had failed.6 iV. Safety of Linezolid
• bone marrow suppression, resulting in low levels of red blood
cells (anemia) or platelets (thrombocytopenia), which can lead
Side effects and management to many health problems; and8,9 All medicines have side effects, and though linezolid's can be • gastrointestinal disorders (discomfort or problems with the
serious, they are clinically manageable. A systematic review found stomach, intestines, and esophagus).10 that more than half of patients receiving linezolid experienced side effects, and one-third of patients had to discontinue linezolid TB programs and doctors can monitor for and manage these side (see figure 2). Linezolid's most common side effects are: effects as part of routine care. Reducing the dose or changing the dosing schedule of linezolid may help: lowering doses to 600 • optic and peripheral neuropathy (damage to the nerves in the
mg per day or less may reduce side effects without making the eye and body), which can cause pain, numbness, weakness, and drug less effective.11,12 vision problems, and may be irreversible;7 Treatment Outcomes of Patients Given Linezolid Side Effects and Tolerability Linezolid (from a Meta-Analysis of 12 (from a Systematic Review of 11 Nonrandomized Studies)13 Nonrandomized Studies)14 atients (N = 121) 40
atients (N = 148) 40
Neuropathy Bone Marrow Treatment Outcomes* *Numbers do not add up to 100% due to rounding V.=Access to Linezolid
Limited availability and high prices can block access to linezolid A lack of clear guidance from the World Health Organization for patients in urgent need. Linezolid was developed by Pfizer, (WHO) on the importance of linezolid is a barrier to access. which prices the drug exorbitantly (for example, about US$65 in Because there have been no large clinical trials of linezolid for TB, South Africa—or US$46,800 for a 24-month treatment course the WHO currently classifies linezolid as a "group 5" TB drug with at 600 mg per day—and US$154 in the United States per 600 an unclear role in the treatment of MDR-TB.19 Linezolid is also mg pill—or US$110,800 for a 24-month treatment course).15,16 not on the WHO's Essential Medicines List, which helps countries Cheaper, quality-assured generic versions are manufactured, plan which drugs are necessary to treat important diseases however, such as a product by Hetero, which is available through such as TB.20 National TB programs have done little to prioritize the Global Drug Facility (GDF) for just US$6.9 per pill (US$4,968 the diagnosis and treatment of drug-resistant TB, and as such for a 24-month treatment course).17 But access to cheaper options have not demanded linezolid. With recent efforts to diagnose is not always possible in countries where Pfizer holds patents on more drug-resistant TB, and the approval of new treatments, linezolid; the primary patent expires in many countries in 2015, bedaquiline and delamanid, demand for important companion while secondary patents expire several years later.18 drugs such as linezolid should increase.
Spotlight on approaches to access linezolid: South Africa and Moldova
In South Africa, Pfizer's patent ownership and its refusal to lower prices have kept the price of linezolid at ZAR715 (US$65)21 per tablet in the private sector. In the public sector, the Pfizer product is purchased through the national antibiotics tender, but often not prescribed to DR-TB patients based on its high cost. Médecins Sans Frontières (MSF) and advocates' attempts to expand access to linezolid recently accomplished a significant victory on June 26, 2014, when the South African Medicines Control Council (MCC) granted MSF special permission to use a generic linezolid product to expand access to DR-TB patients in its Khayelitsha project. MSF purchases the generic at US$8 per tablet—an 88 percent savings over the Pfizer product. The MCC approval for MSF paves the way for other health care providers—including the National Department of Health—to request similar permission to use generic linezolid within DR-TB treatment regimens. The decision could also set a precedent that facilitates full registration by the MCC of a generic linezolid product. Either action has the potential to expand access to the drug to hundreds more DR-TB patients in need across South Africa; currently, only MSF patients can benefit from this advance. In June 2013, as part of Moldova's efforts to stop XDR-TB, the national TB program and civil society representatives prioritized the procurement of linezolid. Moldova worked with the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) and was able to redirect savings from its GFATM grant toward the purchase of linezolid from the GDF. At the same time, it got permission from the national drug regulatory authority to import Hetero's linezolid, even though it was not yet registered in Moldova, as the generic linezolid had a quality certificate. After months of bureaucratic negotiations, linezolid arrived in Moldova on January 27, 2014. The program now must ensure that patients are started on linezolid and continue to receive appropriate care.
V1. Take Action: Advocacy Messages
doses or with less frequent dosing, and if shorter treatment can reduce side effects. Research into potential new drugs that are in 1. Linezolid is effective in the treatment of the same class as linezolid (such as AZD5847 and sutezolid), but that may be safer, is also needed. To this end: highly drug-resistant strains of TB. While data supporting the efficacy of linezolid are limited, the • Pfizer (which closed its anti-infective unit in 2013) and public drug's importance in regimens for highly resistant strains is clear. funders must support further research into linezolid for TB, In light of this: including a large, well-conducted, randomized controlled trial; • the WHO must publish guidance on the appropriate and   • Pfizer and public funders should conduct additional studies to responsible use of linezolid for treating MDR- and XDR-TB; learn the correct dosage, timing, and duration of treatment to minimize side effects; to see if linezolid is safe for people with • the WHO should reevaluate its classification of linezolid as HIV taking antiretrovirals; and to know how best to safely and a "group 5" drug with an unclear role in MDR-TB treatment; effectively combine linezolid with other new and existing drugs • the WHO should include linezolid on its Essential Medicines List (when it is updated in early 2015) in order to facilitate • AstraZeneca (which also shut its TB research unit but claims that it will continue to invest in AZD5847) and Sequella (which took over the development of sutezolid from Pfizer) must • countries should include linezolid on their Essential Medicines adequately fund and prioritize research into new drug Lists for TB; and candidates that are in the same class of drugs as linezolid and may prove safer than linezolid; and • national health departments must prioritize diagnosing and treating drug-resistant TB, and should include linezolid in their • AstraZeneca and Sequella should also collaborate with public treatment guidelines. and nonprofit TB drug trial sponsors to develop these drugs in effective combinations.
2. High-quality research on linezolid for TB is needed. Linezolid's serious and frequent side effects mean that, currently, it is best suited for people with limited treatment options. More research is needed in both adults and children to determine whether linezolid can still be effective even at lower 3. Registration of linezolid for a TB indication, the • Pfizer (or a generic drug company) must prepare and submit use of generics, appropriate pricing, and widespread a dossier to a stringent regulatory authority (that of Canada, European Union member states, the United States, or Japan) procurement are necessary to ensure access to for linezolid to have an indication for use in the treatment linezolid.
While research is pending, many people with TB urgently need • Pfizer should agree not to assert its patent rights in countries linezolid, and we must work to ensure that they get it. To ensure where its secondary patents on linezolid would prevent access to linezolid: procurement from cheaper, generic sources; and • TB programs must procure linezolid: this includes budgeting for, buying, and distributing linezolid from quality-assured • national drug authorities should permit the importation of sources, preferably through the GDF; quality-assured generic sources of linezolid, even when these are not yet registered in countries, given the urgency of • donors such as the GFATM must be flexible and support treating drug-resistant TB.
countries in planning for and funding this procurement; 1. McKenna L, Zhang A, Lessem E. An activist's guide to tuberculosis drugs. New York: Treatment Action Group; 2014. A 2. Swaney SM, Aoki H, Ganoza MC, Shinabarger DL. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother. 1998 Dec 1;42(12)3251–5. A. (Accessed 2012 May 15) 3. Sotgiu G, Centis R, D'Ambrosio L, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J. 2012;40(6):1430–1442. doi: 10.1183/09031936.00022912.
4. Lee M, Lee J, Carroll M, et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508–1518. doi: 10.1056/nejmoa1201964. Cox H, Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis. 2012 Apr;16(4):447–54. doi: 10.5588/ijtld.11.0451. 5. Lee M, et al. Linezolid for drug-resistant tuberculosis.
6. Rose P, Hallbauer U, Seddon J, Hesseling A, Schaaf H. Linezolid-containing regimens for the treatment of drug-resistant tuberculosis in South African children. Int J Tuberc Lung Dis. 2012;16(12):1588–1593. doi: 10.5588/ijtld.12.0322. 7. Cox H, et al. Linezolid for complicated drug-resistant tuberculosis.
9. Sotgiu G, et al. Efficacy, safety and tolerability of linezolid.
11. Chang KC, Yew WW, Cheung SW, et al. Can intermittent dosing optimize prolonged linezolid treatment of difficult multidrug-resistant tuberculosis? Antimicrob Agents Chemother. 2013 Jul;57(7):3445–3449. doi: 10.1128/AAC.00388–13.
12. Sotgiu G, et al. Efficacy, safety and tolerability of linezolid. 14. Cox H, et al. Linezolid for complicated drug-resistant tuberculosis. 15. Merck Manual. Linezolid: drug information. 2014 May. A (Accessed 2014 July 14) 16. Médecins Sans Frontières. Linezolid fact sheet. 2014 July. A 2014 July 14) 17. Stop TB Partnership. Linezolid product information. 2014. A 2014 July 14) 18. Drugs.com [Internet]. Generic Zyvox availability. [date unknown] [cited 2014 July 14]. Available from: http://www.drugs.com/availability/generic-zyvox.html.
19. McKenna L, et al. An activist's guide to tuberculosis drugs.
20. World Health Organization. WHO model lists of essential medicines. 2013. Available from: 21. We converted data reported in non–U.S. currency into U.S. dollars using the September 12, 2014, currency exchange rate provided by the OANDA Corpor.

Source: http://www.treatmentactiongroup.org/sites/default/files/201409/Linezolid%20Fact%20Sheet%20V7%20LR.pdf