4.1. Therapeutic indications

Pyrazinamide 500mg tablets is indicated in patients with active tuberculosis caused by Mycobacterium tuberculosis. Pyrazinamide should only be given in combination with other antituberculous agents. Pyrazinamide is not active against the atypical mycobacteria.

Consideration should be given to official guidance on the appropriate use of antituberculosis agents.

4.2. Posology and method of administration

Pyrazinamide should be administered under the supervision of a physician trained in the management of tuberculosis.

Posology

Adults and adolescents

Recommended dosage for standard unsupervised 2-month treatment

Under 50 kg bodyweight: maximum 1.5g Pyrazinamide = 3 Pyrazinamide 500 mg Tablets

Over 50kg bodyweight: maximum 2.0 g pyrazinamide = 4 Pyrazinamide 500 mg Tablets

Recommended dosage for intermittent supervised 2-month therapy (only if daily administration is not feasible)

Under 50 kg bodyweight: 2.0 g Pyrazinamide = 4 Pyrazinamide 500 mg Tablets 3 times a week.

Over 50 kg bodyweight: 2.5 g Pyrazinamide = 5 Pyrazinamide 500 mg Tablets 3 times a week.

Children

Recommended dosage for standard unsupervised 2-month treatment: 35 mg / kg body weight per day

Maximum daily dose: 1.5 g

Equivalent in children aged 4-10

0.5-1 g Pyrazinamide = 1-2 Pyrazinamide 500 mg Tablets

And in children aged 11-14

1-1.5 g Pyrazinamide = 2-3 Pyrazinamide 500 mg Tablets

Recommended dosage for intermittent supervised 2 month regimen (only if daily regimen not feasible):

Dosage 50 mg/kg body weight, three times weekly

Method and duration of administration

Method of administration

Pyrazinamide is used in combination with other antitubercular agents.

Duration of administration

In standard tuberculosis treatment, Pyrazinamide is given together with other anti-tuberculosis medication during the initial phase of treatment over a total of 8 weeks. In order to prevent recurrent infection, Pyrazinamide treatment can be continued up to 3 months.

Immunocompromised patients: Multi-resistant M. tuberculosis may be present in immunocompromised patients. The organism should always be cultured to confirm its type and drug sensitivity. Confirmed M. tuberculosis infection sensitive to first-line drugs should be treated with a standard 6 month regimen; after completing treatment, patients should be closely monitored. The regimen may need to be modified if infection is caused by resistant organisms and specialist advice is needed.

In meningeal or pericardial tuberculosis, a corticosteroid should be started at the same time as antituberculosis therapy.

4.3. Contraindications

Pyrazinamide is contraindicated in patients with:

- hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- severe hepatic impairment, acute liver disease (e.g. hepatitis) and up to 6 months after occurrence of hepatitis

- acute porphyria

- hyperuricaemia and/or acute gouty arthritis

Pyrazinamide is also contra-indicated in breast-feeding mothers. (see section 4.6 Pregnancy and lactation).

4.4. Special warnings and precautions for use

Pyrazinamide should only be used when close daily observation of the patient is possible, and when laboratory facilities are available for performing frequent liver-function tests and blood uric acid determinations.

Pre-treatment examinations should include in-vitro sensitivity tests of recent cultures of M. tuberculosis from the patient as measured against the usual antituberculous drugs.

Adverse effects for pyrazinamide primarily involve the liver and range from asymptomatic elevations of liver function tests to serious clinical manifestations of hepatic disease; therefore, liver-function tests, especially aspartate transferase (AST) and alanine transferase (ALT) determinations, should be carried out prior to therapy, and then every two to four weeks during therapy. Therapy with pyrazinamide should be withdrawn and not reinstated if signs of hepatocellular damage occur.

Patients with a regularly high level of alcohol consumption or alcohol abuse and patients taking other potentially hepatotoxic medications or substances are particularly at risk. Patients with pre-existing impairment of the liver and higher susceptibility (e.g. with concomitant alcoholism) must undergo more frequent liver testing.

Patients or their carers should be told how to recognize signs of liver disease, and advised to discontinue treatment and seek immediate medical attention if symptoms such as persistent nausea, vomiting, malaise or jaundice develop.

Patients suffering from gout should be prescribed this medication only if urgent treatment is required.

In patients with renal impairment, the medication should be prescribed in emergencies only. Here, pyrazinamide should be administered intermittently (see section 4.2). Liver and kidney function should be tested before initiating treatment.

Reduction in the size and/or frequency of dose is recommended for patients with renal insufficiency.

Regular liver and kidney function tests should be carried out before and during treatment, at intervals of about 3 - 4 weeks.

High-dose treatment (above standard dosage) may interfere with insulin levels in diabetic patients.

Pyrazinamide inhibits excretion of urates, frequently resulting in hyperuricaemia which is usually asymptomatic. Infrequently, hyperuricaemia (see section 4.8) may cause arthralgia, especially in susceptible patients. Urea levels in the bloodstream should therefore monitored regularly (every 3 - 4 weeks). If hyperuricaemia accompanied by an acute gouty arthritis occurs, therapy should be discontinued and not reinstated. Massively elevated urea levels may require treatment with uricosurics, such as benzbromarone.

Close monitoring is advised to detect any increasing difficulty in the management of patients with a history of gout or diabetes mellitus. If hyperuricaemia accompanied by an acute gouty arthritis occurs, treatment with pyrazinamide should be discontinued.

Pyrazinamide treatment may elicit photosensitivity (see section 4.8). Patients treated with pyrazinamide should therefore not be exposed to strong sunlight.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Compared to fast acetylators, individuals known as slow acetylators have a higher risk of liver intoxication during combination treatment of Pyrazinamide, rifampicin and isoniazid.

Treatment with Pyrazinamide may affect the following lab parameters:

Bilirubin, urea levels, prothrombin time, serum-aminotransferase levels, thyroxin levels.

Pyrazinamide was found to interfere with the determination of serum iron with Ferrochem II.

Pyrazinamide should be used with caution in pregnant women.

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

Undesirable interaction may occur in combination with the following drugs:

Acetyl salicylic acid, ascorbic acid, radiocontrast agents containing iodine, gout medication that affects the excretion of urea, such as probenecid (Pyrazinamide antagonizes the effects of uricosuric agents such as probenecid and sulfinpyrazone), blood glucose-lowering medication (accelerates lowering of blood sugar levels). Patients taking blood glucose-lowering medication and those taking gout medications must therefore be monitored more closely.

Pyrazinamide may reduce rifampicin blood levels (reduced bioavailability and enhanced rifampicin clearance). No further information available.

Pyrazinamide may reduce the contraceptive effects of oestrogens and should be avoided 3 days before and after oral typhoid vaccination since it may inactivate the vaccine.

Alcohol should not be taken during pyrazinamide treatment, as this could increase the risk of damage to the liver and significantly impair reactivity.

4.6. Fertility, pregnancy and lactation

Pregnancy:

No sufficient clinical data on pregnant women exposed to Pyrazinamide exist. Animal studies do not suggest any detrimental effect on pregnancy, embryonic/foetal development, birth or postnatal development (see section 5.3).

Pyrazinamide should only be administered to pregnant when the potential benefit clearly outweighs the risk to the foetus.

Breast-feeding:

Pyrazinamide is excreted into the breast milk of lactating mothers.

Pyrazinamide is contra-indicated in breast-feeding mothers. If its use is deemed essential, the patient should stop breast-feeding.

4.7. Effects on ability to drive and use machines

Even when used appropriately, Pyrazinamide may impair a patient's reactions to such an extent that it affects the ability to drive, use machines or work without secure support.

4.8. Undesirable effects

A hepatic reaction is the most common side effect of Pyrazinamide and may occur at any time during therapy. This varies from a symptomless abnormality of hepatic cell function, detectable only by laboratory tests, through a mild syndrome of fever, anorexia, malaise, liver tenderness, hepatomegaly and spleenomegaly, to more serious reactions such as clinical jaundice, and rare cases of hepatic failure and death.

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)

Disorders of the blood and lymphatic system

Haematopoietic system disorders, sideroblastic anaemia, porphyria, thrombocytopenia with or without purpura,

splenomegaly

Endocrine disorders

Impairs adrenocortical function (17-ketosteroid-excretion in urine)

Metabolism and nutrition disorders

Pellagra

Nervous system disorders

Headache, dizziness, irritability, insomnia

Gastrointestinal disorders

Loss of appetite, nausea, sickness, vomiting, heartburn, abdominal spasms, weight loss

Aggravation of peptic ulcer

Hepatobiliary disorders

Raised serum transaminase levels, liver function disorders

Hepatomegaly, jaundice, hepatic failure (which may be fatal)

Skin and subcutaneous disorders

Photosensitivity (see Section 4.4)

Erythema multiforme

Flushing, dysuria, rash, hypersensitivity reactions such as urticaria, pruritus

Renal and urinary disorders

Hyperuricaemia (see Section 4.4)

Tubulo-interstitial nephritis

General and administration site disorders

Hypertension

Fever, malaise

Musculoskeletal, connective tissue and bone disorders

Gout, athralgias

Immune system disorders

Angiooedema

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

Overdose symptoms

Specific pyrazinamide intoxication symptoms are not known. However, known undesired effects (see section 4.8) may be enhanced. Liver toxicity and hyperuricaemia may occur with overdosage.

In one study, flushing with pruritus on the entire skin surface was observed immediately after taking 4g of pyrazinamide, but disappeared after a few hours without any lasting effect.

Overdose treatment

In an emergency, intensive medical care is required, including gastric lavage. There is no specific antidote. Pyrazinamide and its metabolites are haemodialysable (see section 5.2).

General supportive measures should be employed. Liver function should be monitored closely, and a high- carbohydrate, low - fat diet employed. Care should be taken to avoid exposure of the patient to other potential hepatotoxic agents, including alcohol. Probenecid may be given for hyperuricaemia.

Benzodiazepines may be given if there is evidence of central nervous system stimulation.