Paser

Antituberculosis agent; structural analog of aminobenzoic acid.a

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† 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

Contraindications

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

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

Warnings/Precautions

Warnings

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, 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 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

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 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

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

Specific Populations

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

Distributed into milk.102

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.)

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

Storage

Oral

<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

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Mechanism of Action: Aminosalicylic acid is bacteriostatic against Mycobacterium tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. The mechanism of action has been postulated to be inhibition of folic acid synthesis (but without potentiation with antifolic compounds) and/or inhibition of synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis.

Characteristics: The two major considerations in the clinical pharmacology of aminosalicylic acid are the prompt production of a toxic inactive metabolite under acid conditions and the short serum half life of one hour for the free drug. Both are discussed below.

After two hours in simulated gastric fluid, 10% of unprotected aminosalicylic acid is decarboxylated to form meta-aminophenol, a known hepatotoxin. The acid-resistant coating of the Paser granules protects against degradation in the stomach. The small granules are designed to escape the usual restriction on gastric emptying of large particles. Under neutral conditions such as are found in the small intestine or in neutral foods, the acid-resistant coating is dissolved within one minute. Care must be taken in the administration of these granules to protect the acid-resistant coating by maintaining the granules in an acidic food during dosage administration. Patients who have neutralized gastric acid with antacids will not need to protect the acid resistant coating with an acidic food since no acid is present to spoil the drug. Antacids may influence the absorption of other medications and are not necessary for Paser consumed with an acidic food.

Because Paser granules are protected by an enteric coating absorption does not commence until they leave the stomach; the soft skeletons of the granules remain and may be seen in the stool.

Absorption and excretion: In a single 4 gram pharmacokinetic study with food in normal volunteers the initial time to a 2μg/mL serum level of aminosalicylic acid was 2 hours with a range of 45 minutes to 24 hours; the median time to peak was 6 hours with a range of 1.5 to 24 hours; the mean peak level was 20 μg/mL with a range of 9 to 35 μg/mL; a level of 2 μg/mL was maintained for an average of 7.9 hours with a range of 5 to 9; a level of 1 μg/mL was maintained for an average of 8.8 hours with a range of 6 to 11.5 hours. The recommended schedule is 4 grams every 8 hours.

80% of aminosalicylic acid is excreted in the urine, with 50% or more of the dosage excreted in acetylated form. The acetylation process is not genetically determined as is the case for isoniazid. Aminosalicylic acid is excreted by glomerular filtration; although previously reported otherwise, probenecid, a tubular blocking agent, does not enhance plasma concentration. In a 1954 study thyroxine synthesis but not iodide uptake was reported reduced about 40% when the sodium salt (not Paser granules) of aminosalicylic acid was administered one hour before radio-iodine; the sodium salt typically produces a serum level over 120 μg/mL at one hour lasting one hour. Occasional goiter development can be prevented by the administration of thyroxine but not iodide.

Penetration into the cerebrospinal fluid occurs only if the meminges are inflamed.

Approximately 50-60% of aminosalicylic acid is protein bound; binding is reported to be reduced 50% in kwashiorkor.

Microbiology: The aminosalicylic acid MIC for M. tuberculosis in 7H11 agar was less than 1.0 μg/mL for nine strains including three multidrug resistant strains, but 4 and 8 μg/mL for two other multidrug resistant strains. The 90% inhibition in 7H12 broth (Bactec) showed little dose response but was interpreted as being less than or equal to 0.12-0.25 μg/mL for eight strains of which three were multi-resistant, 0.50 μg/mL for one resistant strain, questionable for four non-resistant strains and greater than 1μg/mL for one non-resistant and three resistant strains. Aminosalicylic acid is not active in vitro against M. avium.

(1) General:

All drugs should be stopped at the first sign suggesting a hypersensitivity reaction. They may be restarted one at a time in very small but gradually increasing doses to determine whether the manifestations are drug-induced and, if so, which drug is responsible.

Desensitization has been accomplished successfully in 15 of 17 patients starting with 10 mg aminosalicylic acid given as a single dose. The dosage is doubled every 2 days until reaching a total of 1 gram after which the dosage is divided to follow the regular schedule of administration. If a mild temperature rise or skin reaction develops, the increment is to be dropped back one level or the progression held for one cycle. Reactions are rare after a total dosage of 1.5 grams.

Patients with hepatic disease may not tolerate aminosalicylic acid as well as normal patients, even though the metabolism in patients with hepatic disease has been reported to be comparable to that in normal volunteers.

(2) Information for Patients:

The patient should be advised that the first signs of hypersensitivity include a rash, often followed by fever, and much less frequently, GI disturbances of anorexia, nausea or diarrhea. If such symptoms develop, the patient should immediately cease taking the medication and arrange for a prompt clinical visit.

Patients should be advised that poor compliance in taking anti-TB medication often leads to treatment failure, and, not infrequently, to the development of resistance of the organisms in the individual patient.

Patients should be advised that the skeleton of the granules may be seen in the stool.

The coating to protect the Paser granules dissolves promptly under neutral conditions; the granules therefore should be administered by sprinkling on acidic foods such as apple sauce or yogurt or by suspension in a fruit drink which will protect the coating, but the granules sink and will have to be swirled. The coating will last at least 2 hours in either system. All juices tested to date have been satisfactory; tested are: tomato, orange, grapefruit, grape, cranberry, apple, “fruit punch”.

Patients should be advised to store Paser in a refrigerator or freezer. Paser packets may be stored at room temperature for short periods of time.

Patients should be advised NOT to use if the packets are swollen or the granules have lost their tan color and are dark brown or purple. The patient should inform the pharmacist or physician immediately and return the medication.

(3) Laboratory Tests:

Aminosalicylic acid has been reported to interfere technically with the serum determinations of albumin by dye-binding, SGOT by the azoene dye method and with qualitative urine tests for ketones, bilirubin, urobilinogen or porphobilinogen.

(4) Drug Interactions:

Aminosalicylic acid at a dosage of 12 grams in a rapidly available form has been reported to produce a 20 percent reduction in the acetylation of isoniazid, especially in patients who are rapid acetylators; INH serum levels, half lives and excretions in fast acetylators still remain half of the levels seen in slow acetylators with or without p-aminosalicylic acid. The effect is dose related and, while it has not been studied with the current delayed release preparation, the lower serum levels with this preparation will result in a reduced effect on the acetylation of INH.

Aminosalicylic acid has previously been reported to block the absorption of rifampin. A subsequent report has shown that this blockade was due to an excipient not included in Paser granules. Oral administration of a solution containing both aminosalicylic acid and rifampin showed full absorption of each product.

As a result of competition, Vitamin B12 absorption has been reduced 55% by 5 grams of aminosalicylic acid with clinically significant erythrocyte abnormalities developing after depletion; patients on therapy of more than one month should be considered for maintenance B12.

A malabsorption syndrome can develop in patients on aminosalicylic acid but is usually not complete. The complete syndrome includes steatorrhea, an abnormal small bowel pattern on x-ray, villus atrophy, depressed cholesterol, reduced D-xylose and iron absorption. Triglyceride absorption always is normal.

In one literature report 8 hours after the last dosage of aminosalicylic acid at 2 gm qid serum digoxin levels were reduced 40% in two of ten patients but not changed in the remaining eight.

(5) Carcinogenesis, mutagenesis, impairment of fertility:

Sodium aminosalicylate produced an occipital bone defect, probably with a dose response, when administered to ten pregnant Wistar rats at five doses from 3.85 to 385 mg/kg from days 6 to 14. There were no significant changes from controls in any group in corpora lutea, early resorptions, total resorptions, fetal death, litter size, or hematomas. For all except the 77 mg/kg group, fetal weights were significantly greater than controls. Chinchilla rabbits on 5 mg/kg from days 7 to 14 did not show any significant differences as compared to controls for the same parameters studied.

Sodium aminosalicylic acid was not mutagenic in Ames tester strain TA 100. In human lymphocyte cultures in-vitro clastogenic effects of achromatic, chromatid, isochromatic breaks or chromatid translocations were not seen at 153 or 600 μg/mL. At 1500 and 3000 μg/mL there was a dose related increase in chromatid aberrations.

Patients on isoniazid and aminosalicylic acid have been reported to have an increased number of chromosomal aberrations as compared to controls.

(6) Pregnancy: Pregnancy Category C:

Aminosalicylic acid has been reported to produce occipital malformations in rats when given at doses within the human dose range. Although there probably is a dose response, the frequency of abnormalities was comparable to controls at the highest level tested (two times the human dosage). When administered to rabbits at 5 mg/kg, throughout all three trimesters, no teratologic or embryocidal effects were seen. Literature reports on aminosalicylic acid in pregnant women always report coadministration of other medications. Because there are no adequate and well controlled studies of aminosalicylic acid in humans, Paser granules should be given to a pregnant woman only if clearly needed.

(8) Nursing mothers:

After administration of a different preparation of aminosalicylic acid to one patient, the maximum concentration in the milk was 1 μg/mL at 3 hours with a half-life of 2.5 hours; the maximum maternal plasma concentration was 70 μg/mL at two hours.

The most common side effect is gastrointestinal intolerance manifested by nausea, vomiting, diarrhea, and abdominal pain.

Hypersensitivity reactions: Fever, skin eruptions of various types, including exfoliative dermatitis, infectious mononucleosis-like, or lymphoma-like syndrome, leucopenia, agranulocytosis, thrombocytopenia, Coombs' positive hemolytic anemia, jaundice, hepatitis, pericarditis, hypoglycemia, optic neuritis, encephalopathy, Leoffler's syndrome, vasculitis and a reduction in prothrombin.

Crystalluria may be prevented by the maintenance of urine at a neutral or an alkaline pH.

More frequent side effects include: eosinophilia and leukocytosis. See below for a comprehensive list of adverse effects.

Applies to aminosalicylic acid: compounding powder, oral granule enteric coated

Gastrointestinal

Gastrointestinal side effects have been reported the most frequently. These have included nausea, vomiting, and abdominal pain.[Ref]

The incidence of gastrointestinal side effects is reduced with lower doses (8 g daily) and with the granular formulation of the drug.[Ref]

Hypersensitivity

Hypersensitivity side effects have been reported rarely. The first signs have included rash, often followed by fever, and much less frequently, anorexia, nausea or diarrhea. The drug has been restarted in small but gradually increasing doses under a closely followed desensitization protocol.[Ref]

Hepatic

Patients should be closely monitored during the first three months of therapy and treatment must be discontinued immediately at the first signs of rash, fever, jaundice, or other sign of intolerance.[Ref]

Hepatic side effects have included jaundice and hepatitis. In patients diagnosed with hepatitis, hepatomegaly was invariably present with lymphadenopathy (45%), leukocytosis (79%), and eosinophilia (55%). Prompt recognition of symptoms with discontinuation of therapy led to recovery. Failure to recognize symptoms of liver injury can result in a mortality of up to 21%.[Ref]

Endocrine

A reduction in thyroxine synthesis has been associated with the administration of the sodium salt of aminosalicylic acid (the active ingredient contained in Paser) The development of goiter can be prevented by the administration of thyroxine but not iodide.[Ref]

Endocrine side effects have included hypothyroidism, especially with prolonged administration. It may be accompanied by goiter development.[Ref]

Hematologic

Hematologic side effects have included leukopenia, agranulocytosis, thrombocytopenia, Coombs' positive hemolytic anemia, and reduction in prothrombin.[Ref]

Some side effects of Paser may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.