Sodium Aminosalicylate

(USAN, rINNM)
Synonyms: Aminosalicilato sódico; Aminosalicylan sodný dihydrát; Aminosalicylate Sodium; Aminosalylnatrium; Monosodium 4-Aminosalicylate Dihydrate; Natrii Aminosalicylas; Natrii aminosalicylas dihydricus; Natrii Paraaminosalicylas; Natrii Para-aminosalicylas; Natrio aminosalicilatas dihidratas; Natriumaminosalicylat; Natriumaminosalicylatdihydrat; Natriumaminosalisylaatti; Natriumaminosalisylaattidihydraatti; Pasalicylum Solubile; Sodium (aminosalicylate de) dihydraté; Sodium Para-aminosalicylate; Sodium PAS; Sodu aminosalicylan. Sodium 4-amino-2-hydroxybenzoate dihydrate.
Cyrillic synonym: Аминосалицилат Натрия.

💊 Chemical information

Chemical formula: C7H6NNaO3,2H2O = 211.1.
CAS — 133-10-8 (anhydrous sodium aminosalicylate); 6018-19-5 (sodium aminosalicylate dihydrate).
ATC — J04AA02.
ATC Vet — QJ04AA02.

Pharmacopoeias.

In Chin., Eur., and US.

Ph. Eur. 6.2

(Sodium Aminosalicylate Dihydrate). A slightly hygroscopic, white or almost white, crystalline powder, or white or almost white crystals. Freely soluble in water; sparingly soluble in alcohol, practically insoluble in dichloromethane. A 2% solution in water has a pH of 6.5 to 8.5. Store in airtight containers. Protect from light.

USP 31

(Aminosalicylate Sodium). A white to cream-coloured, practically odourless crystalline powder. Soluble 1 in 2 of water; sparingly soluble in alcohol; very slightly soluble in chloroform and in ether. Its solutions decompose slowly and darken in colour. Prepare solutions within 24 hours of use. Under no circumstances should a solution be used if its colour is darker than that of a freshly prepared solution. pH of a 2% solution in water is between 6.5 and 8.5. Store in airtight containers at a temperature not exceeding 40°. Protect from light.

Stability.

Aqueous solutions of aminosalicylates are unstable and should be freshly prepared. Solutions of sodium aminosalicylate in sorbitol or syrup degraded more quickly to m-aminophenol than those in glycerol or propylene glycol. 1 Colour developed in all solutions but was not found to be an accurate indicator of decomposition of sodium aminosalicylate as it reflected only oxidation of m-aminophenol. 1. Blake MI, et al. Effect of vehicle on the stability of sodium aminosalicylate in liquid dosage forms. Am J Hosp Pharm 1973; 30: 441–3.

💊 Adverse Effects and Treatment

Aminosalicylic acid and its salts may cause the adverse effects of salicylates. Gastrointestinal effects are common and include nausea, vomiting, and diarrhoea; they may be reduced by giving doses with food or with an antacid but occasionally may be severe enough that therapy has to be withdrawn. Alteration of gastrointestinal function may lead to malabsorption of vitamin B12, folate, and lipids. Hypersensitivity reactions have been reported in 5 to 10% of adults, usually during the first few weeks of treatment, and include fever, skin rashes; less commonly, arthralgia, lymphadenopathy, and hepatosplenomegaly may occur and, rarely, a syndrome resembling infectious mononucleosis. Other adverse effects which have been attributed to a hypersensitivity reaction to aminosalicylate include jaundice and encephalitis. Blood disorders reported include haemolytic anaemia in patients with G6PD deficiency, agranulocytosis, eosinophilia, leucopenia, and thrombocytopenia. Psychosis may occasionally occur. Prolonged treatment may induce goitre and hypothyroidism. Crystalluria may occur.

Effects on the liver.

Drug-induced hepatitis occurred in 0.32% of 7492 patients receiving antituberculous drugs; aminosalicylic acid was the most common cause.1
1. Rossouw JE, Saunders SJ. Hepatic complications of antituberculous therapy. Q J Med 1975; 44: 1–16.

💊 Precautions

Aminosalicylic acid and its salts should be used with great care in patients with hepatic or renal impairment and in patients with gastric ulcer. They should be given with caution to patients with G6PD deficiency. The sodium salt should be used with caution in patients with heart failure. Aminosalicylates interfere with tests for glycosuria using copper reagents and for urobilinogen using Ehrlich’s reagent.

Breast feeding.

Small amounts of aminosalicylic acid are present in breast milk. A maximum concentration of 1.1 microgram/mL has been reported in the breast milk of a lactating woman 3 hours after a 4-g dose of aminosalicylic acid.1
1. Holdiness MR. Antituberculosis drugs and breast feeding. Arch Intern Med 1984; 144: 1888.

Pregnancy.

The use of aminosalicylic acid or its salts is not recommended in pregnant patients due to gastrointestinal intolerance.1 In addition it has been noted that, a study published in 1964 suggested that first-trimester exposure may be associated with congenital defects although other studies had not found similar effects.2
1. Snider D. Pregnancy and tuberculosis. Chest 1984; 86: 10S–13S
2. Briggs GG, et al. Drugs in pregnancy and lactation. 7th ed. Philadelphia: Lippincott Williams and Wilkins, 2005: 59.

💊 Interactions

The adverse effects of aminosalicylates and salicylates may be additive. Probenecid may also increase toxicity by delaying renal excretion and enhancing plasma concentrations of aminosalicylate. The activity of aminosalicylic acid may be antagonised by ester-type local anaesthetics such as procaine.

💊 Antimicrobial Action

Aminosalicylic acid is bacteriostatic and is active against M. tuberculosis. Other mycobacteria are usually resistant. It has a relatively weak action compared with other antituberculous drugs. Resistance develops quickly if aminosalicylic acid is used alone.
1. Rengarajan J, et al. The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Mol Microbiol 2004; 53: 275–82.

💊 Pharmacokinetics

When given orally, aminosalicylic acid and its salts are readily absorbed, and peak plasma concentrations occur after about 1 to 4 hours. Aminosalicylate diffuses widely through body tissues and fluids, although diffusion into the CSF occurs only if the meninges are inflamed. About 15% of the sodium salt, and 50 to 70% of the acid, is bound to plasma proteins. Aminosalicylate is metabolised in the intestine and liver primarily by acetylation. Urinary excretion is rapid, and 80% or more of a dose is excreted within 24 hours; 50% or more of the dose is excreted as the acetylated metabolite. The half-life of aminosalicylic acid is about 1 hour. Aminosalicylate is distributed into breast milk (see under Precautions, above, for more details).

💊 Uses and Administration

Aminosalicylic acid and its salts are second-line antimycobacterials given orally in the treatment of multidrug-resistant tuberculosis. They should always be given with other antituberculous drugs. Aminosalicylic acid may be given as the acid or as the sodium salt. Sodium aminosalicylate 1.38 g is equivalent to about 1 g of aminosalicylic acid. However, a usual daily oral dose is 12 g in 3 divided doses and has been recommended for products containing the acid as well as for those containing the sodium salt. For details of doses in infants, children, and adolescents, see below. Aminosalicylate sodium is also given rectally in the treatment of ulcerative colitis in a usual dose of 2 g once daily. Attempts have been made in formulation to overcome the bulk and exceedingly unpleasant taste of the aminosalicylates. The salts appear to be better tolerated than the free acid and solutions in iced water prepared immediately before use may be less unpleasant to take.

Administration.

A small study suggested that giving aminosalicylic acid in a dose of 4 g twice daily produced adequate serum concentrations (well in excess of 1 microgram/mL, a typical MIC against Mycobacterium tuberculosis) for up to 12 hours after each dose.1 The drug was taken with an acidic beverage such as fruit juice to prevent early release in the stomach. A single 4-g dose was not sufficient to maintain serum concentrations for the full 24-hour dosage interval. The authors had subsequently changed their practice to use a twice-daily regimen for aminosalicylic acid in patients with multidrug-resistant tuberculosis.
1. Peloquin CA, et al. Once-daily and twice-daily dosing of p-aminosalicylic acid granules. Am J Respir Crit Care Med 1999; 159: 932–4.

Administration in children.

For the treatment of drug-resistant tuberculosis in infants, children, and adolescents the American Academy of Pediatrics (AAP) and WHO suggest an oral dose of para-aminosalicylic acid 200 to 300 mg/kg 2 to 4 times daily, to a maximum dose of 10 g daily.

Administration in renal impairment.

It has been recommended that aminosalicylic acid should be avoided in patients with renal impairment.1 An increase in plasma clearance of aminosalicylic acid (attributed to increased hepatic metabolism) has been noted in patients with renal impairment, hence attempting to give aminosalicylate in reduced doses to such patients may lead to subtherapeutic serum concentrations.2
1. Appel GB, Neu HC. The nephrotoxicity of antimicrobial agents (first of three parts). N Engl J Med 1977; 296: 663–70
2. Holdiness MR. Clinical pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1984; 9: 511–44.

Inflammatory bowel disease.

Together with corticosteroids, derivatives of 5-aminosalicylic acid are one of the mainstays of the treatment of inflammatory bowel disease. However, aminosalicylic acid (4-aminosalicylic acid) has also been investigated, and beneficial results have been reported with both enemas1-4 and oral dose forms5 in ulcerative colitis. Three patients who developed acute pancreatitis while taking mesalazine (5-aminosalicylic acid) for inflammatory bowel disease, later tolerated treatment with 4-aminosalicylic acid enemas.6
1. Campieri M, et al. 4-Aminosalicylic acid (4-ASA) and 5-aminosalicylic acid (5-ASA) in topical treatment of ulcerative colitis patients. Gastroenterology 1984; 86: 1039
2. Ginsberg AL, et al. Treatment of left-sided ulcerative colitis with 4-aminosalicylic acid enemas: a double-blind, placebo-controlled trial. Ann Intern Med 1988; 108: 195–9
3. Sharma MP, Duphare HV. 4-Aminosalicylic acid enemas for ulcerative colitis. Lancet 1989; i: 450
4. O’Donnell LJD, et al. Double blind, controlled trial of 4-aminosalicylic acid and prednisolone enemas in distal ulcerative colitis. Gut 1992; 33: 947–9
5. Beeken W, et al. Controlled trial of 4-ASA in ulcerative colitis. Dig Dis Sci 1997; 42: 354–8
6. Daniel F, et al. Tolerance of 4-aminosalicylic acid enemas in patients with inflammatory bowel disease and 5-aminosalicylic-induced acute pancreatitis. Inflamm Bowel Dis 2004; 10: 258–60.

Manganese toxicity.

Intravenous aminosalicylic acid, given in a course of 6 g daily for 4 days a week, for fifteen courses, produced significant benefit in a patient with parkinsonism induced by chronic occupational manganese exposure.1 The patient remained well on prolonged follow-up. Other cases of benefit had been reported in the Chinese literature.
1. Jiang Y-M, et al. Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study. J Occup Environ Med 2006; 48: 644–9.

💊 Preparations

USP 31: Aminosalicylate Sodium Tablets; Aminosalicylic Acid Tablets.

Proprietary Preparations

Canad.: Nemasol†; Chile: Aflogol; Cz.: Quadrasa†; Fr.: Quadrasa; Ger.: Pas-Fatol N; Ital.: Quadrasa†; Salf-Pas; Port.: Paramino-Corazida; Rus.: Pask-Akri (Паск-Акри); Switz.: Perfusion de PAS†; Thai.: PAS Sodium; Turk.: PAS; USA: Paser. Multi-ingredient: India: Inapas.
Published October 18, 2018.