PAS was discovered in 1944. Initially, PAS was used to treat TB, but with the discovery of other more potent drugs including rifampicin, its use in first line regimens was discontinued. PAS is still useful as part of a treatment regimen for XDR TB although its benefit is limited and it is extremely toxic.
PAS is used as part of regimens to treat XDR TB in South Africa.
Dosage:
|
Adults: |
Adults with liver damage - creatine clearance < 30 ml/min: |
Children: |
|
150 mg/kg daily (max dose 12 g) |
No change to dosage. PAS-sodium should be avoided. |
150 mg/kg daily (max dose 8 g) |
|
Take PAS twice daily, generally 4g per dose |
|
|
|
PASER granules should be taken with an acidic liquid such as fruit juice |
|
|
How it works:
PAS is a chemotherapeutic agent. The precise mechanisms of action are unknown.
Side effects:
The most common side effects of PAS are persistent nausea, vomiting and diarrhoea. If the patient experiences fatigue, it may be due to hypothyroidism (when the thyroid gland produces insufficient thyroid hormone) caused by PAS.
PAS may cause hepatitis (inflammation of the liver), usually preceded by a rash or a fever. Other occasional side effects include increased prothrombin time (time for blood to clot) and malabsorption syndrome (disorders in the intestines' ability to absorb nutrients).
While there is no dose adjustment for patients with liver disease, PAS should be avoided in patients with severe liver disease as it may cause crystalluria (crystals in the urine). PAS should not be taken by patients that are allergic to aspirin.
There is insufficient evidence on its safety in humans. Studies on PAS in animals have documented malformation in foetuses. PAS should only be given during pregnancy as a last resort. It is secreted in breast milk and the effect to the infant is unknown.
Clinical evidence and approval:
PAS is indicated for the treatment of TB. Activity against tuberculosis was demonstrated in vitro and in vivo was demonstrated in 1947.1 With the development of more effective drugs, its use in treating drug susceptible TB was discontinued. However, it has demonstrated use in treating drug resistant TB. An uncontrolled prospective study demonstrated safety and efficacy of using PAS as part of a treatment regimen for drug resistant TB.2
PAS has very low effectiveness, is poorly tolerated, and is expensive, which mean it is the last-choice drug among the second-line group.3
In a review of 108 MDR patients treated in Uzbekistan, no resistance to PAS was observed at baseline. Of 86 patients given PAS as part of their regimens, 24% of them stopped due to adverse events associated with the drug.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.
Advocacy issues:
PAS is extremely expensive and only one source (Jacobus) is registered for sale in South Africa. PAS accounts for 33% of the cost of treating an XDR patient during the injectable phase and 50% of the cost of treatment during the continuation phase.
PAS is used for treating XDR TB in South Africa, which is associated with extremely high mortality rates, but the efficacy of PAS is limited and the medicine is poorly tolerated. Newer medicines demonstrating better efficacy remain unavailable.
Further research is needed to establish the safety and efficacy of paediatric use. There are no paediatric formulations. [MSF]
Further research is needed to understand potential interactions with antiretrovirals. [MSF]
Manufacturers and suppliers:
Today there is only one quality assured source of PAS (Jacobus), and two quality-assured sources of PAS sodium (Macleods and Olainfarm), with no products in the pipeline. This means the supply of quality-assured product is vulnerable.
The PAS-Sodium formulation from Macleods was approved by WHO PQ in 2009, but the unexpectedly large demand for this product led to capacity problems, resulting in long lead times for orders. This should be rectified in 2011.
Additional manufacturers may exist in China, India, the former Soviet Union and other countries, but whether they comply with WHO quality standards is unknown.7
Source: MSF
1 P Guy et al. The Tuberculostatic Action of Para-Aminosalicylic Acid. May 31, 1947. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC526571/pdf/jbacter00662-0012.pdf
2 R. Prasad et al. Efficacy and Safety of Kanamycin, Ethionamide, PAS and Cycloserine in Multidrug-resistant Pulmonary Tuberculosis Patients. Indian J Chest Dis Allied Sci 2006; 48: 183-186
3 JA Caminero et al. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis. 2010 Sep;10(9):621-9.
4 S Helen. Multidrug-Resistant Tuberculosis Treatment Outcomes in Karakalpakstan, Uzbekistan: Treatment Complexity and XDR-TB among Treatment Failures. PLoS ONE. 2007; 2(11): e1126.
5 Dr N Ndjeka, The new DR-TB National Policy and State of Implementation, 10 August 2011. TAC, MSF, SECTION27, SA HIV SOC Consultation on TB.
6 The procurement arm of the Green Light Committee, a mechanism started by the World Health Organisation and partners to expand access to quality assured TB medicines.