Overdosage has not been reported.
Hypersensitivity to any component of this medication.
Severe renal disease.
Patients with severe renal disease will accumulate aminosalicylic acid and its acetyl metabolite but will continue to acetylate, thus leading exclusively to the inactive acetylated form; deacetylation, if any, is not significant.
The half life of free aminosalicylic acid in renal disease is 30.8 minutes in comparison to 26.4 minutes in normal volunteers, but the half life of the inactive metabolite is 309 minutes in uremic patients in comparison to 51 minutes in normal volunteers. Although aminosalicylic acid passes dialysis membranes, the frequency of dialysis usually is not comparable to the half-life of 50 minutes for the free acid. Patients with end stage renal disease should not receive aminosalicylic acid.
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, and vasculitis and a reduction in prothrombin.
Crystalluria may be prevented by the maintenance of urine at a neutral or an alkaline pH.
Pas-Fatol N (aminosalicylic acid) is indicated for the treatment of tuberculosis in combination with other active agents. It is most commonly used in patients with Multi-drug Resistant TB (MDR-TB) or in situations when therapy with isoniazid and rifampin is not possible due to a combination of resistance and/or intolerance. When Pas-Fatol N (aminosalicylic acid) is added to the treatment regimen in patients with proven or suspected drug resistance, it should be accompanied by at least one and preferably two other new agents to which the patient's organism is known or expected to be susceptible.
Liver Function
In one retrospective study of 7492 patients on rapidly absorbed aminosalicylic acid preparations, drug-induced hepatitis occurred in 38 patients (0.5%); in these 38 the first symptom usually appeared within three months of the start of therapy with a rash as the most common event followed by fever and much less frequently by GI disturbances of anorexia, nausea or diarrhea. Only one patient was diagnosed on routine biochemistry.
Premonitory symptoms in 90% of these 38 patients preceded jaundice by a few days to several weeks with the mean time of onset 33 days with a range of 7-90 days. Half of the adverse reactions occurred during the third, fourth or fifth weeks. When aminosalicylic acid-induced hepatitis was diagnosed, hepatomegaly was invariably present with lymphadenopathy in 46%, leucocytosis in 79%, and eosinophilia in 55%. Prompt recognition with discontinuation led to the recovery of all 38 patients. If recognized in the premonitory stage, the reaction is reported to "settle" in 24 hours and no jaundice ensues. From other reported studies failure to recognize the reaction can result in a mortality of up to 21%. The patient must be monitored carefully during the first three months of therapy and treatment must be discontinued immediately at the first sign of a rash, fever or other premonitory signs of intolerance.
PRECAUTIONS
(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 Pas-Fatol N (aminosalicylic acid) 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 Pas-Fatol N (aminosalicylic acid) in a refrigerator or freezer. Pas-Fatol N (aminosalicylic acid) 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:
See Drug Interactions Section.
(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 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, Pas-Fatol N (aminosalicylic acid) 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.
Pas-Fatol N (aminosalicylic acid) granules should be administered with other drugs to which the organism is known or expected to be susceptible. It is most commonly administered to patients with Multi-drug Resistant TB (MDR-TB) or in other situations in which therapy with isoniazid or rifampin is not possible due to a combination of resistance and/or tolerance. The adult dosage of four grams (one packet) three times per day or correspondingly smaller doses in children should be given by sprinking on apple sauce or yogurt or by swirling in the glass to suspend the granules in an acidic drink such as tomato or orange juice.
DO NOT USE if the packet is swollen or the granules have lost their tan color, turning dark brown or purple.
