Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents. Designated an orphan drug by the US FDA for this use.
Second-line agent used in treatment of drug-resistant TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to aminosalicylic acid.
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). Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months, 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. A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.
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.
Ulcerative Colitis and Crohn's Disease
Has been used in the treatment of mild to moderate ulcerative colitis† in patients intolerant of sulfasalazine. Also has been used in the treatment of Crohn's disease†. Designated an orphan drug by the US FDA for use in these conditions.
Administer orally. Has been administered IV, but a parenteral preparation is not commercially available in the US.
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.
To protect the acid-resistant coating, administer the granules in food or drink with a pH <5. The granules can be sprinkled on applesauce or yogurt. 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. The granules should be swallowed whole without chewing.
Patients receiving antacids do not need to take the delayed-release granules in an acidic food or drink.
Dosage
Should not be used alone for treatment of active (clinical) TB; must be given in conjunction with other antituberculosis agents.
Data not available to date to support use of aminosalicylic acid in intermittent (e.g., 1–3 times weekly) multiple-drug TB regimens.
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.
Adolescents ≥15 years of age: 8–12 g daily given in 2 or 3 divided doses recommended by ATS, CDC, and IDSA.
Adults
Tuberculosis
Treatment of Active (Clinical) Tuberculosis
Oral
Manufacturer recommends 4 g 3 times daily.
8–12 g daily given in 2 or 3 doses recommended by ATS, CDC, and IDSA. There is some evidence that 4 g twice daily achieves target serum concentrations.
Prescribing Limits
Pediatric Patients
Treatment of Active (Clinical) Tuberculosis
Oral
Maximum 10 g daily recommended by ATS, CDC, IDSA, and AAP.
Special Populations
Hepatic Impairment
Dosage adjustment not necessary, but increased clinical and laboratory monitoring recommended. 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.
Renal Impairment
Contraindicated in severe renal disease (end-stage renal disease).
Some experts recommend 4 g twice daily for treatment of active TB in patients with Clcr <30 mL/minute or undergoing hemodialysis. Doses should be given after hemodialysis since the drug is removed by this procedure; supplemental doses not necessary.
Cautions
Contraindications
Hypersensitivity to aminosalicylic acid or any ingredient in the formulation.
Severe renal disease (end-stage renal disease).
Warnings/Precautions
Warnings
Hepatic Effects
Drug-induced hepatitis reported. Prompt recognition of symptoms and discontinuance of aminosalicylic acid usually results in recovery; failure to recognize the reaction has resulted in fatalities.
Initial symptoms usually appear within 3 months after the drug is initiated. Rash is the most common symptom; fever and GI disturbances (anorexia, nausea, diarrhea) may occur. Premonitory symptoms usually precede jaundice by several days or weeks (mean time to onset is 33 days; range 7–90 days). Hepatomegaly with lymphadenopathy, leukocytosis, and eosinophilia usually is present when hepatitis is diagnosed.
Monitor closely during the first 3 months of treatment. Immediately discontinue the drug at the first sign of a rash, fever, or other premonitory signs of intolerance.
If manifestations of hypersensitivity occur (e.g., rash, fever), immediately discontinue all drugs. 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.
Desensitization
Desensitization has been used when reinitiation of the drug was considered necessary in a patient who had a hypersensitivity reaction.
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).
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. Such reactions are rare after a total daily aminosalicylic acid dosage of 1.5 g is reached.
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.
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. The antituberculosis regimen should be modified as needed. 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).
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.
Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical. Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.
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.
Malabsorption
Malabsorption of vitamin B12, folic acid, iron, and lipids has occurred, possibly as the result of increased peristalsis. 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.
Consider using vitamin B12 maintenance therapy in patients receiving aminosalicylic acid for >1 month.
Laboratory Monitoring
Assess hepatic enzyme concentrations and thyroid function prior to initiation of therapy. Assess thyroid function every 3 months.
Specific Populations
Pregnancy
Category C.
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.
Lactation
Distributed into milk.
Hepatic Impairment
Use with caution. 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. (See Hepatic Effects under Cautions.)
Renal Impairment
Use with caution. Contraindicated in patients with severe renal disease (end-stage renal disease).
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.
Common Adverse Effects
GI effects (nausea, vomiting, abdominal pain, diarrhea).
Reduced rate of acetylation of isoniazid (especially in rapid acetylators) reported with some aminosalicylic acid preparations; appears to be dose related
Interaction not studied using commercially available aminosalicylic acid delayed-release granules (Paser®); the lower serum concentrations produced by the delayed-release preparation should result in a reduced effect on acetylation of isoniazid
Decreased serum rifampin concentrations reported with certain aminosalicylic acid preparations; not reported with commercially available aminosalicylic acid delayed-release granules (Paser®)
May be caused by an excipient not included in commercially available aminosalicylic acid delayed-release granules (Paser®)
Vitamin B12
Decreased oral absorption of vitamin B12; clinically important erythrocyte abnormalities reported
Consider use of maintenance vitamin B12 treatment in those receiving aminosalicylic acid for >1 month
Pharmacokinetics
Absorption
Bioavailability
Readily absorbed from GI tract. Median time to peak serum concentrations is 6 hours (range: 1.5–24 hours) following a single 4-g dose in healthy adults.
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. The coating dissolves promptly (within 1 minute) at neutral pH such as that found in the small intestine or in neutral foods.
Distribution
Extent
Distributed into various tissues and fluids including peritoneal fluid, pleural fluid, and synovial fluid in concentrations approximately equal to plasma concentrations. Also distributed into bile in low concentrations.
Distributed into CSF in low concentrations. In patients with inflamed meninges, CSF concentrations are 10–50% of concurrent plasma concentrations.
Not known whether aminosalicylic acid crosses the placenta.
Distributed into milk in low concentrations.
Plasma Protein Binding
50–60%.
Elimination
Metabolism
Inactivated in the intestinal mucosa and liver primarily by acetylation. Major metabolites are N-acetyl-p-aminosalicylic acid and p-aminosalicyluric acid.
The degree of metabolism is concentration-dependent and capacity-limited; the larger the dose absorbed, the lower the percentage of drug metabolized.
Elimination Route
Aminosalicylic acid and its metabolites are excreted in urine by glomerular filtration and tubular secretion. Approximately 77% of a dose is excreted in urine within 24 hours; 56% is excreted as the acetylated metabolite.
Aminosalicylic acid and the acetyl metabolite are removed by hemodialysis.
Half-life
1.5 hours (range 0.55–1.95 hours).
Special Populations
Aminosalicylic acid and its acetyl metabolite accumulate in patients with severe renal impairment. Continued acetylation of the parent drug leads exclusively to accumulation of the inactive acetylated form; deacetylation, if it occurs, is minor.
Stability
Storage
Oral
Delayed-release Granules
<15°C (i.e., in a refrigerator or freezer) prior to dispensing. After dispensing, store in a refrigerator or freezer; may be stored at room temperature for short periods of time. Avoid exposure to excessive heat, moisture, or light.
Do not use if the airtight package containing the granules is swollen. Do not use if the granules have lost their tan color and are turning dark brown or purple.
Actions
Bacteriostatic in action.
Mechanism of action is similar to that of sulfonamides. Aminosalicylic acid prevents synthesis of folic acid in susceptible organisms by competitively blocking conversion of aminobenzoic acid to dihydrofolic acid.
Highly specific antibacterial agent; active only against M. tuberculosis. Inactive against M. avium complex (MAC) and other mycobacteria.
Natural and acquired resistance to aminosalicylic acid demonstrated in vitro and in vivo.
No evidence of cross-resistance between aminosalicylic acid and other antituberculosis agents currently available in the US.
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.
Advise patients to take the drug as prescribed. 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.
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.
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. Advise patients to inform their clinicians or pharmacist about such packets and to return the medication.
Advise patients that skeletons of the delayed-release granules (Paser®) may be seen in the stool.
Importance of immediately discontinuing the drug at the first signs of hypersensitivity (e.g., rash, fever, anorexia, nausea, diarrhea) and contacting their clinicians.
Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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