Cycloserine

Cycloserine is part of a group of drugs used in the treatment of drug resistant TB called oral bacteriostatic second-line agents. It is used as part of treatment regimens, generally involving 5 medicines, to treat MDR and XDR TB. It was originally discovered in 1952.

Dosage:

How it works:

Cycloserine is an antibiotic that acts by preventing cell wall synthesis by inhibiting two necessary enzymes.

Side effects:

Cycloserine is associated with neurologic and psychiatric disturbances. Side-effects include chronic headaches, dizziness, nightmares, depression, anxiety, hearing voices or seeing things that do not exist, confusion, sleep disturbances and coma. Cycloserine should be immediately halted if the patient is suicidal or psychotic.

Cycloserine may also cause rashes, peripheral neuropathy (burning/tingling sensation in the hands and feet), jaundice (yellowing of the eyes and skin) and vision disturbances.

Cycloserine should not be given to patients with epilepsy, severe depression or psychosis, severe kidney failure or patients that excessively abuse alcohol.

Clinical evidence and approval:

Cycloserine has been approved by the FDA to treat pulmonary and extra-pulmonary TB.

Cycloserine is one of the cornerstones for treatment of MDR TB.¹ An uncontrolled prospective study demonstrated safety and efficacy of using cycloserine as part of a treatment regimen for drug resistant TB.²

It is recommended that cycloserine is introduced only after thioamides (ethionamide and protionamide) and before paminosalicylic acid. This order is based on their effectiveness, adverse events and cost.³

A retrospective review of four children between 6 and 8, treated for XDR-TB between 2006 and 2007 was carried out. All of the children were HIV positive. All were treated with HAART and XDR treatment regimens. 2 children experienced psychiatric side effects associated with cycloserine. All survived >24 months and were cured.⁴

From 2004 – 2007, 51 patients with drug resistant TB (39 with MDR TB and 12 with XDR TB) were treated with a standardized regimen of ofloxacin, cycloserine, prothionamide and amikacin. The success rates for the 39 MDR-TB the 12 XDR-TB patients was 87.2% (34 patients), and 41.7% (5 patients) respectively.⁵

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 clarify appropriate doses for paediatric treatment. Further research is needed to understand potential interactions with antiretrovirals. [MSF]

• SA public sector prices are 6.4 x higher than internationally available prices.

• SA discontinued purchasing cycloserine as clinicians favoured terizidone (two cycloserine molecules combined). Clinicians found the side effects associated with cycloserine more severe and less manageable that terizidone.

Manufacturers and suppliers:

Eli Lilly filed the initial application to the US FDA in 1964. Since 2003, the company has been actively engaged in technology transfer to three generic manufacturers (Aspen, Purdue GMP and SIA International) and in 2008 ceased production of cycloserine. Two of these manufacturers (Aspen & Purdue GMP) now produce quality-assured cycloserine.

In additional, another manufacturer (Macleods) has cycloserine approved by WHO Prequalification and three other manufacturers (including Lupin and Cipla) have submitted dossiers to WHO Prequalification and have been accepted for evaluation.

Until 2006, the only quality-assured source for the active pharmaceutical ingredient was Eli Lilly. Eli Lilly started the technology transfer for the API to Shasun, India, in 2003 a process that was concluded in 2006. This was a success with the Shasun API being approved by the US FDA in June 2008.

The supply of quality-assured cycloserine is therefore relatively secure.⁷

Source: MSF