Aminosalicylic Acid

Class: Antituberculosis Agents
VA Class: AM500
CAS Number: 65-49-6
Brands: Paser

Introduction

Antituberculosis agent; structural analog of aminobenzoic acid.a

Uses for Aminosalicylic Acid

Tuberculosis

Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents.102 104 107 Designated an orphan drug by the US FDA for this use.103

Second-line agent used in treatment of drug-resistant TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to aminosalicylic acid.104 107

For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months).104 107 Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months,104 107 ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy.104 A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.104 107

Slideshow: Prescription Drug Addiction - Are You at Risk?

Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.104

Ulcerative Colitis and Crohn's Disease

Has been used in the treatment of mild to moderate ulcerative colitis in patients intolerant of sulfasalazine.a Also has been used in the treatment of Crohn's disease.a Designated an orphan drug by the US FDA for use in these conditions.103

Usually, 5-aminosalicylic acid analogs (e.g., balsalazide, mesalamine, olsalazine) are used in the management of ulcerative colitis or Crohn's disease; aminosalicylic acid is a 4-aminosalicyclic acid analog.105 106 108

Aminosalicylic Acid Dosage and Administration

Administration

Oral Administration

Administer orally.102 Has been administered IV, but a parenteral preparation is not commercially available in the US.104

The delayed-release granules (Paser) have an acid-resistant coating designed to protect against degradation in the stomach so that the drug is released gradually and high peak concentrations are avoided.102

To protect the acid-resistant coating, administer the granules in food or drink with a pH <5.102 The granules can be sprinkled on applesauce or yogurt.102 Alternatively, they can be suspended in a fruit drink (e.g., orange, apple, tomato, grapefruit, grape, or cranberry juices, “fruit punch”); the granules will sink in the juice and must be resuspended by swirling.102 The granules should be swallowed whole without chewing.102

Patients receiving antacids do not need to take the delayed-release granules in an acidic food or drink.102

Dosage

Should not be used alone for treatment of active (clinical) TB; must be given in conjunction with other antituberculosis agents.102 104

Data not available to date to support use of aminosalicylic acid in intermittent (e.g., 1–3 times weekly) multiple-drug TB regimens.104

Pediatric Patients

Tuberculosis
Treatment of Active (Clinical) Tuberculosis
Oral

Children <15 years of age or weighing ≤40 kg: 200–300 mg/kg daily (up to 10 g daily) given in 2–4 divided doses recommended by ATS, CDC, IDSA, and AAP.104 107

Adolescents ≥15 years of age: 8–12 g daily given in 2 or 3 divided doses recommended by ATS, CDC, and IDSA.104

Adults

Tuberculosis
Treatment of Active (Clinical) Tuberculosis
Oral

Manufacturer recommends 4 g 3 times daily.102

8–12 g daily given in 2 or 3 doses recommended by ATS, CDC, and IDSA.104 There is some evidence that 4 g twice daily achieves target serum concentrations.104 109

Prescribing Limits

Pediatric Patients

Treatment of Active (Clinical) Tuberculosis
Oral

Maximum 10 g daily recommended by ATS, CDC, IDSA, and AAP.104 107

Special Populations

Hepatic Impairment

Dosage adjustment not necessary, but increased clinical and laboratory monitoring recommended.104 Clearance is not altered in patients with hepatic impairment, but these patients may not tolerate the drug as well as those with normal hepatic function.102

Renal Impairment

Contraindicated in severe renal disease (end-stage renal disease).102

Some experts recommend 4 g twice daily for treatment of active TB in patients with Clcr <30 mL/minute or undergoing hemodialysis.104 112 Doses should be given after hemodialysis104 since the drug is removed by this procedure;104 112 supplemental doses not necessary.112

Cautions for Aminosalicylic Acid

Contraindications

  • Hypersensitivity to aminosalicylic acid or any ingredient in the formulation.102

  • Severe renal disease (end-stage renal disease).102

Warnings/Precautions

Warnings

Hepatic Effects

Drug-induced hepatitis reported.102 Prompt recognition of symptoms and discontinuance of aminosalicylic acid usually results in recovery; failure to recognize the reaction has resulted in fatalities.102

Initial symptoms usually appear within 3 months after the drug is initiated.102 Rash is the most common symptom; fever and GI disturbances (anorexia, nausea, diarrhea) may occur.102 Premonitory symptoms usually precede jaundice by several days or weeks (mean time to onset is 33 days; range 7–90 days).102 Hepatomegaly with lymphadenopathy, leukocytosis, and eosinophilia usually is present when hepatitis is diagnosed.102

Monitor closely during the first 3 months of treatment.102 Immediately discontinue the drug at the first sign of a rash, fever, or other premonitory signs of intolerance.102

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including fever,102 skin eruptions of various types,102 pruritus,a vasculitis,102 exfoliative dermatitis,102 joint pain,a eosinophilia,a leukopenia,102 agranulocytosis,102 thrombocytopenia,102 hepatitis,102 and jaundice,102 reported.

If manifestations of hypersensitivity occur (e.g., rash, fever), immediately discontinue all drugs.102 After symptoms abate, cautiously reinitiate the drugs one at a time in small and gradually increasing doses to determine whether manifestations were drug-induced and, if so, which drug was responsible.102

Desensitization

Desensitization has been used when reinitiation of the drug was considered necessary in a patient who had a hypersensitivity reaction.102 110

One desensitization procedure used successfully in 15 of 17 patients involved an initial 10-mg dose of the drug, doubling dosage every 2 days until a total daily dosage of 1 g was reached, then continuing dosage escalation while giving the total daily dosage in divided doses according to the usual administration schedule (i.e., 3 times daily).102

If mild temperature elevation or skin reaction develops during the desensitization procedure, manufacturer states desensitization may be continued by decreasing the dosage by one increment (i.e., to the previous level at which no reaction occurred) or maintaining current dosage for another 2-day cycle before continuing dosage progression.102 Such reactions are rare after a total daily aminosalicylic acid dosage of 1.5 g is reached.102

General Precautions

Precautions Related to Treatment of Tuberculosis

Should not be used alone for treatment of active (clinical) TB; must be given in conjunction with other antituberculosis agents.102 104

Clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing should be obtained prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response.104 The antituberculosis regimen should be modified as needed.104 Patients with positive cultures after 4 months of treatment should be considered to have failed treatment (usually as the result of noncompliance or drug-resistant TB).104

If added as a new drug to a regimen in patients experiencing treatment failure who have proven or suspected drug-resistant TB, at least 2 (preferably 3) new drugs known or expected to be active against the resistant strain should be added at the same time.104

Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical.104 Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.104

To ensure compliance, ATS, CDC, IDSA, and AAP recommend that directly observed (supervised) therapy (DOT) be used for treatment of active TB whenever possible, especially when intermittent regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant M. tuberculosis is involved.104 107

Malabsorption

Malabsorption of vitamin B12, folic acid, iron, and lipids has occurred, possibly as the result of increased peristalsis.a As a result of competition, a 5-g dose of aminosalicylic acid may reduce absorption of vitamin B12 by about 55%; clinically important erythrocyte abnormalities may develop.102

Consider using vitamin B12 maintenance therapy in patients receiving aminosalicylic acid for >1 month.102

Laboratory Monitoring

Assess hepatic enzyme concentrations and thyroid function prior to initiation of therapy.104 Assess thyroid function every 3 months.104

Specific Populations

Pregnancy

Category C.102

ATS, CDC, and IDSA state that, although aminosalicylic acid has been used safely during pregnancy, the drug should be used in pregnant women only when there are no alternatives for treatment of MDR TB.104

Lactation

Distributed into milk.102

Hepatic Impairment

Use with caution.102 Metabolism of aminosalicylic acid in patients with hepatic disease is comparable to that in healthy individuals, but such patients may tolerate aminosalicylic acid less well.102 (See Hepatic Effects under Cautions.)

Renal Impairment

Use with caution.102 Contraindicated in patients with severe renal disease (end-stage renal disease).102

Patients with severe renal disease accumulate aminosalicylic acid and its acetyl metabolite but continue to acetylate the drug, resulting exclusively in the inactive acetylated form.102

Common Adverse Effects

GI effects (nausea, vomiting, abdominal pain, diarrhea).102

Interactions for Aminosalicylic Acid

Specific Drugs

Drug

Interaction

Comments

Ammonium chloride

Increased risk of crystalluriaa

Do not use concomitantlya

Anticoagulants, oral

Enhanced hypoprothrombinemic effecta

Anticoagulant dosage adjustment may be necessarya

Diphenhydramine

Impaired GI absorption of aminosalicylic acida

Avoid concurrent usea

Digoxin

Decreased GI absorption of digoxin100 101 102

Isoniazid

Reduced rate of acetylation of isoniazid (especially in rapid acetylators) reported with some aminosalicylic acid preparations; appears to be dose related102

Interaction not studied using commercially available aminosalicylic acid delayed-release granules (Paser);102 a the lower serum concentrations produced by the delayed-release preparation should result in a reduced effect on acetylation of isoniazid102

Not considered clinically importanta

Probenecid

Conflicting reports, but does not appear to increase plasma concentrations of aminosalicylic acid 102

Rifampin

Decreased serum rifampin concentrations reported with certain aminosalicylic acid preparations;102 a not reported with commercially available aminosalicylic acid delayed-release granules (Paser)102 a

May be caused by an excipient not included in commercially available aminosalicylic acid delayed-release granules (Paser)102

Vitamin B12

Decreased oral absorption of vitamin B12; clinically important erythrocyte abnormalities reported102

Consider use of maintenance vitamin B12 treatment in those receiving aminosalicylic acid for >1 month102

Aminosalicylic Acid Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from GI tract.a Median time to peak serum concentrations is 6 hours (range: 1.5–24 hours) following a single 4-g dose in healthy adults.102 c

The delayed-release granules (Paser) contain an acid-resistant coating to protect against degradation in the stomach; the granules are designed to escape the usual restriction on gastric emptying of large particles.102 The coating dissolves promptly (within 1 minute) at neutral pH such as that found in the small intestine or in neutral foods.102

Distribution

Extent

Distributed into various tissues and fluids including peritoneal fluid, pleural fluid, and synovial fluid in concentrations approximately equal to plasma concentrations.a Also distributed into bile in low concentrations.a

Distributed into CSF in low concentrations.104 In patients with inflamed meninges, CSF concentrations are 10–50% of concurrent plasma concentrations.104

Not known whether aminosalicylic acid crosses the placenta.a

Distributed into milk in low concentrations.102

Plasma Protein Binding

50–60%.102

Elimination

Metabolism

Inactivated in the intestinal mucosa and liver primarily by acetylation.a Major metabolites are N-acetyl-p-aminosalicylic acid and p-aminosalicyluric acid.a

The degree of metabolism is concentration-dependent and capacity-limited; the larger the dose absorbed, the lower the percentage of drug metabolized.a

Elimination Route

Aminosalicylic acid and its metabolites are excreted in urine by glomerular filtration and tubular secretion.a Approximately 77% of a dose is excreted in urine within 24 hours; 56% is excreted as the acetylated metabolite.a

Aminosalicylic acid and the acetyl metabolite are removed by hemodialysis.112

Half-life

1.5 hours (range 0.55–1.95 hours).c

Special Populations

Aminosalicylic acid and its acetyl metabolite accumulate in patients with severe renal impairment.102 Continued acetylation of the parent drug leads exclusively to accumulation of the inactive acetylated form; deacetylation, if it occurs, is minor.102

Stability

Storage

Oral

Delayed-release Granules

<15°C (i.e., in a refrigerator or freezer) prior to dispensing.102 After dispensing, store in a refrigerator or freezer; may be stored at room temperature for short periods of time.102 Avoid exposure to excessive heat, moisture, or light.102 a

Do not use if the airtight package containing the granules is swollen.102 Do not use if the granules have lost their tan color and are turning dark brown or purple.102

Actions and Spectrum

  • Bacteriostatic in action.102

  • Mechanism of action is similar to that of sulfonamides.a Aminosalicylic acid prevents synthesis of folic acid in susceptible organisms by competitively blocking conversion of aminobenzoic acid to dihydrofolic acid.a

  • Highly specific antibacterial agent; active only against M. tuberculosis.a Inactive against M. avium complex (MAC) and other mycobacteria.a

  • Natural and acquired resistance to aminosalicylic acid demonstrated in vitro and in vivo.111 a

  • No evidence of cross-resistance between aminosalicylic acid and other antituberculosis agents currently available in the US.a

Advice to Patients

  • Advise patients that poor compliance with antituberculosis regimens can result in treatment failure and development of drug-resistant TB, which can be life-threatening and lead to other serious health risks.102 104

  • Advise patients to take the drug as prescribed.102 Importance of sprinkling it on acidic food (e.g., applesauce, yogurt) or suspending it in a fruit drink (e.g., tomato, orange, grapefruit, grape, cranberry, or apple juice, “fruit punch”) to protect the coating of the drug.102

  • Importance of storing the packets containing the delayed-release granules in a refrigerator or freezer; the drug should be stored at room temperature only for short periods of time.102

  • Importance of not using the packet of delayed-release granules if the packet is swollen or if the granules have lost their tan color and are dark brown or purple.102 Advise patients to inform their clinicians or pharmacist about such packets and to return the medication.102

  • Advise patients that skeletons of the delayed-release granules (Paser) may be seen in the stool.102

  • Importance of immediately discontinuing the drug at the first signs of hypersensitivity (e.g., rash, fever, anorexia, nausea, diarrhea) and contacting their clinicians.102

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.102

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.102

  • Importance of informing patients of other important precautionary information.102 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Aminosalicylic Acid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Granules, delayed-release (enteric-coated)

4 g/packet

Paser

Jacobus

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Hooymans PM, Merkus FWHM. Current status of cardiac glycoside drug interactions. Clin Pharm. 1985; 4:404-13. [IDIS 203177] [PubMed 2412751]

101. Brown DD, Juhl RP, Warner SL. Decreased bioavailability of digoxin due to hypocholesterolemic interventions. Circulation. 1978; 58:164-72. [IDIS 114616] [PubMed 647881]

102. Jacobus Pharmaceutical Co. Paser granules (aminosalicylic acid granules) prescribing information. Princeton, NJ; 1996 Jul.

103. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

104. Centers for Disease Control and Prevention. Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Recomm Rep. 2003; 52(RR-11):1-77.

105. Hanauer SB. Inflammatory bowel disease. N Engl J Med. 1996; 334:841-8. [IDIS 361805] [PubMed 8596552]

106. Podolsky DK. Inflammatory Bowel Disease. N Engl J Med. 2002; 347:417-29. [IDIS 484721] [PubMed 12167685]

107. American Academy of Pediatrics. 2006 Red Book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

108. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007; 369:1641-57. [PubMed 17499606]

109. Peloquin CA, Berning SE, Huitt GA et al. Once-daily and twice-daily dosing of p-aminosalicylic acid granules. Am J Respir Crit Care Med. 1999; 159:932-4. [PubMed 10051275]

110. Wilson JW, Kelkar P, Frigas E. Para-aminosalicylic acid (PAS) desensitization review in a case of multidrug-resistant pulmonary tuberculosis. Int J Tuberc Lung Dis. 2003; 7:493-7. [PubMed 12757053]

111. Rengarajan J, Sassetti CM, Naroditskaya V 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. [PubMed 15225321]

112. Malone RS, Fish DN, Spiegel DM et al. The effect of hemodialysis on cycloserine, ethionamide, para-aminosalicylate, and clofazimine. Chest. 1999; 116:984-90. [IDIS 437367] [PubMed 10531163]

a. AHFS Drug Information 2007. McEvoy GK, ed. Aminosalicylic Acid. American Society of Health-System Pharmacists; 2007:544-6.

b. AHFS Drug Information 2007. McEvoy GK, ed. Antituberculosis Agents General Statement. American Society of Health-System Pharmacists; 2007:534-44.

c. Peloquin CA, Henshaw TL, Huitt GA et al. Pharmacokinetic evaluation of para-aminosalicylic acid granules. Pharmacotherapy. 1994; 14:40-6. [PubMed 8159600]

Hide
(web4)