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Adults: 4 g (one sachet) three times per day.
The recommended schedule is 4 g every 8 hours. GRANUPAS can be taken with food. Maximum daily dose is 12 g. Usual duration of treatment is 24 months.
Paediatric population: The optimal dose regimen in children is uncertain. Limited pharmacokinetic data suggest no substantial difference between adults and children.
For infants, children and adolescents the dosage will be adapted to the patient’s weight at 150 mg/kg per day, divided in two intakes. A dosing spoon is provided to measure small doses below 4g for young children.
The safety and efficacy of GRANUPAS in neonates have not been established. No data are available.
Desensitization: Desensitization can be accomplished by starting with 10 mg 4-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 g.
Method of administration: Oral Use. The contents of the sachet should be added to a glass of orange or tomato juice. They will not dissolve, but swirling the juice in the glass will help re-suspend the granules if they sink. It should be drunk at once ensuring that the granules are not left in the glass. Any granules left-over at the bottom of the glass should be swallowed immediately by adding a small quantity of liquid. Smaller doses in children should be measured using the dosing spoon and given by sprinkling on apple sauce or yogurt.
The medicinal product should be swallowed immediately after mixing with orange juice, tomato juice, apple sauce and yogurt whilst the granules are intact.
The granules should not be crushed or chewed.
GRANUPAS is indicated for use as part of an appropriate combination regimen for multi-drug resistant tuberculosis in adults and pediatric patients from 28 days of age and older when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Hypersensitivity to the active substance or to any of the excipients.
Severe renal disease. Patients with severe renal impairment should not receive GRANUPAS. Patients with severe renal disease will accumulate the inactive acetyl metabolite of 4-aminosalicylic acid.
Mild to moderate renal impairment: Given that the metabolites of 4-aminosalicylic acid are largely excreted via glomerular filtration, caution is warranted in patients with mild to moderate renal impairment.
Gastric ulcer: GRANUPAS should be used with caution in patients with peptic ulcer.
Hepatic impairment: GRANUPAS should be used with caution in patients with hepatic impairment.
Hepatic toxicity: 4-aminosalicylic acid may cause hepatitis. The first symptoms usually appear within three months of the start of therapy with a rash as the most common adverse reaction followed by fever and much less frequently by gastrointestinal disturbances of anorexia, nausea or diarrhoea. Treatment should be stopped immediately in this case.
Hypersensitivity: 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.
Hypothyroidism in HIV co-infected patients: 4-aminosalicylic acid may be associated with an increased risk of hypothyroidism in HIV co-infected patients. Thyroid function should be monitored in HIV co-infected patients before commencing treatment and regularly during treatment, in particular when 4-aminosalicylic acid is co-administered with ethionamide/prothionamide.
Patients should be advised that the skeletons of the granules may be seen in the stools.
Most frequent adverse reactions were related to the gastrointestinal system. Cutaneous hypersensitivity reactions were also frequent as well as adverse reactions related to the nervous system.
See prescribing information for full details.
No interaction studies have been performed with GRANUPAS.
Results from literature suggest the following:
Vitamin B12: Vitamin B12 absorption may be reduced by 4-aminosalicylic acid with clinically significant erythrocyte abnormalities developing after depletion; patients on therapy of more than one month should be considered for maintenance of vitamin B12.
Malabsorption syndrome: A malabsorption syndrome can develop in patients on 4-aminosalicylic acid, but is usually not complete.
The complete syndrome includes steatorrhoea, an abnormal small bowel pattern on x-ray, villus atrophy, depressed cholesterol, reduced D-xylose and iron absorption. Triglyceride absorption is always normal.
Digoxin: 4-aminosalicylic acid may decrease the gastrointestinal absorption of digoxin, by inhibiting the absorption function of intestinal cells. Serum digoxin levels should be monitored in patients on concomitant therapy.
Ethionamide: Co-administration of 4-aminosalicylic acid and ethionamide may intensify adverse reactions of 4-aminosalicylic acid, mainly the gastrointestinal effects, including jaundice, hepatitis, nausea, vomiting, diarrhoea, abdominal pain or anorexia. Ethionamide should be withdrawn if these effects are significant.
Diphenylhydramine: This medicinal product decreases the gastrointestinal absorption of 4-aminosalicylic acid, and should not be administered concomitantly.
Antiretrovirals: No drug interaction studies have been conducted in patients with HIV infection taking antiretroviral agents and 4-aminosalicylic acid. Given the metabolic pathway of GRANUPAS no significant drug interaction is anticipated.
Pregnancy and Lactation
Pregnancy: As there are no adequate and well controlled studies of 4-aminosalicylic acid in humans, GRANUPAS should be given to a pregnant woman only if clearly needed.
Lactation: 4-aminosalicylic acid is excreted into breast milk, therefore breastfeeding mothers should not breastfeed during treatment
See prescribing information for full details.
No case of overdose in adults or paediatrics has been reported. Treatment is symptomatic and supportive.