4.1. Therapeutic indications

GRANUPAS is indicated for use as part of an appropriate combination regimen for multi-drug resistant tuberculosis in adults and paediatric 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.

4.2. Posology and method of administration

Posology

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.

Desensitization

Desensitization can be accomplished by starting with 10 mg para-aminosalicylic acid (PAS) 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.

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 4 g for young children.

The safety and efficacy of para-aminosalicylic acid in neonates have not been established. No data are available.

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, as this impairs the gastro-resistant coating.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe renal disease. Patients with severe renal impairment should not receive para-aminosalicylic acid. Patients with severe renal disease will accumulate the inactive acetyl metabolite of para-aminosalicylic acid.

4.4. Special warnings and precautions for use

Mild to moderate renal impairment

Given that the metabolites of para-aminosalicylic acid are largely excreted via glomerular filtration, caution is warranted in patients with mild to moderate renal impairment (see also section 4.3).

Gastric ulcer

Para-aminosalicylic acid should be used with caution in patients with peptic ulcer.

Hepatic impairment

Para-aminosalicylic acid should be used with caution in patients with hepatic impairment.

Hepatic toxicity

Para-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. See section 4.2 for posology adjustments for desensitization.

Hypothyroidism in HIV co-infected patients

Para-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 para-aminosalicylic acid is co-administered with ethionamide/prothionamide.

Patients should be advised that the skeletons of the granules may be seen in the stools.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Results from literature suggest the following:

Vitamin B12

Vitamin B12 absorption may be reduced by para-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.

Digoxin

Para-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 para- aminosalicylic acid and ethionamide may intensify adverse reactions of para-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 para-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 para-aminosalicylic acid. Given the metabolic pathway of para-aminosalicylic acid no significant drug interaction is anticipated.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of para-aminosalicylic acid in pregnant women. Studies in animals have shown some reproductive toxicity (see section 5.3).

GRANUPAS is not recommended during pregnancy and in women of childbearing potential not using contraception.

Literature reports on para- aminosalicylic acid in pregnant women always report co-administration of other medicinal products. As there are no adequate and well controlled studies of para- aminosalicylic acid in humans, para-aminosalicylic acid should be given to a pregnant woman only if clearly needed.

Breast-feeding

Para-aminosalicylic acid is excreted in human milk. There is insufficient information on the effects of para-aminosalicylic acid in newborns/infants..

GRANUPAS should not be used during breast-feeding.

Fertility

There is no evidence available on the effect of para-aminosalicylic acid on fertility.

4.7. Effects on ability to drive and use machines

Para-aminosalicylic acid has negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

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.

Tabulated list of adverse reactions

In the table below all adverse reactions are listed by system organ class and by frequency. Frequency is defined as very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Class

Frequency

Adverse reaction

Blood and lymphatic system disorders

Very rare

Thrombocytopenia, purpura, leukopenia, anemia, methemoglobinemia, agranulocytosis.

Metabolism and nutrition disorders

Rare

Hypothyroidism*.

Very rare

Hypoglycemia.

Nervous system disorders

Very rare

Tendon pain, headache, visual abnormalities, peripheral neuropathy, dizziness.

Common

Giddiness, vestibular syndrome.

Gastrointestinal disorders

Common

abdominal pain, vomiting, nausea, bloating, diarrhea, soft stools.

Uncommon

Anorexia.

Rare

Malabsorption syndrome*, peptic ulcer, gastrointestinal bleeding, jaundice, metallic taste.

Hepatobiliary disorders

Unknown

Hepatitis

Skin and subcutaneous tissue disorders

Common

Cutaneous hypersensitivity, skin rash.

Rare

Urticaria.

Renal and urinary disorders

Very rare

Crystalluria.

Investigations

Very rare

Decreased prothrombine level, hepatocytolysis.

Increased blood alkaline phosphatase, transaminases, weight loss.

*see Description of selected adverse reactions below

Description of selected adverse reactions

Hypothyroidism

Hypothyroidism in HIV co-infected patients is a very common event and occurs in ≥ 1/10 subjects, particularly when para-aminosalicylic acid is administered with ethionamide/prothionamide.

Malabsorption syndrome

A malabsorption syndrome can develop in patients on para-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.

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no experience with overdose in humans. In the event of overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse reactions and that appropriate symptomatic treatment is instituted immediately.