Aminosalicylic Acid (Monograph)

Brand name: Paser
Drug class: Antituberculosis Agents
VA class: AM500
CAS number: 65-49-6

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}

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^{† [off-label]} in patients intolerant of sulfasalazine.^a Also has been used in the treatment of Crohn's disease^{† [off-label]}.^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 Cl_cr <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

Drug Interactions

Specific Drugs

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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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