Indications TB.

Dosage Adult : PO As part of a mulitdrug regimen: <50 kg: 1.5 g daily or 2 g 3 times wkly; ≥50 kg:
2 g daily or 2.5 g 3 times wkly.

Dosage Details Oral

Tuberculosis
Adult: As part of a mulitdrug regimen: For standard unsupervised 2-mth treatment: <50 kg:
1.5 g daily; ≥50 kg: 2 g daily. For intermittent supervised 2-mth treatment: <50 kg: 2 g 3
times wkly; ≥50 kg: 2.5 g 3 times wkly.
Child: As part of a mulitdrug regimen: For standard unsupervised 2-mth treatment: 35
mg/kg daily. For intermittent supervised 2-mth treatment: 50 mg/kg 3 times wkly.

Renal Impairment May need dose reduction.

Hepatic Impairment Severe: Contraindicated.

Administration Should be taken with food.

Contraindications Hypersensitivity. Hyperuricaemia and/or gouty arthritis, acute porphyria. Severe hepatic
impairment.

Special Precautions Patient w/ DM, history of gout. Mild to moderate hepatic and renal impairment. Pregnancy
and lactation.

Adverse Drug Reactions Hyperuricaemia, leading to acute gout; anorexia, nausea, vomiting, aggravation of peptic
ulcer, arthralgia, malaise, fever, sideroblastic anaemia, thrombocytopenia, dysuria. Rarely,
photosensitivity, pellagra, rash.
Potentially Fatal: Hepatotoxicity.

Pregnancy Category
(US FDA) ROUTE(S) : PO

Category C: Either studies in animals have revealed adverse effects on the foetus
(teratogenic or embryocidal or other) and there are no controlled studies in women or
studies in women and animals are not available. Drugs should be given only if the potential
benefit justifies the potential risk to the foetus.

Monitoring Parameters Monitor liver function, serum uric acid, sputum culture; chest x-ray 2-3 mth into treatment
and at completion.

Overdosage Symptoms: Liver toxicity and hyperuricaemia. Management: Empty the stomach by gastric
lavage if necessary. Employ general supportive measures. May give benzodiazepine if
there is evidence of CNS stimulation and probenecid for hyperuricaemia.

Drug Interactions Antagonises the effect of uricosuric agents (e.g. probenecid, sulfinpyrazone). May reduce
the contraceptive effect of oestrogens. May inactivate oral typhoid vaccine. May increase
the serum concentration of ciclosporin. May enhance the hepatotoxic effect of rifampicin.

Lab Interference May interfere w/ Acetest® and Ketostix® urine tests to produce pinkish-brown color.

Mechanism of Action Description: Pyrazinamide may be bacteriostatic or bactericidal in action, depending on

 the concentration of the drug attained at the site of the infection and the susceptibility of
the infecting organism. Its activity appears to partly depend on conversion of the drug to
pyrazinoic acid (POA), which lowers the pH of the environment below that which is
necessary for growth of Mycobacterium tuberculosis. Susceptible strains of M. tuberculosis
produce pyrazinamidase, an enzyme that deaminates pyrazinamide to POA, and the in
vitro susceptibility of a given strain of the organism appears to correspond to its
pyrazinamidase activity.
Pharmacokinetics:
Absorption: Readily absorbed from the GI tract. Time to peak plasma concentration:
Approx 2 hr.
Distribution: Widely distributed in body fluids and tissues, diffuses in the CSF and enters
breast milk. Plasma protein binding: 50%.
Metabolism: Undergoes hepatic metabolism via hydrolysis to pyrazinoic acid (major active
metabolite) and subsequently hydroxylated to 5-hydroxypyrazinoic acid (major excretory
product).
Excretion: Via urine by glomerular filtration (approx 70% mainly as metabolites, approx
4% as unchanged drug). Half-life: Approx 9-10 hr.

Storage Store between 15-30°C.

1. NAME OF THE MEDICINAL PRODUCT

Pyrazinamide 400 mg Tablets*

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains: Pyrazinamide 400 mg

3. PHARMACEUTICAL FORM

Tablets White, circular, convex, bevelled-edge tablets, plain on both sides. The tablets should
not be divided.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications: Pyrazinamide 400 mg Tablets is indicated in combination with other
antituberculosis agents for the treatment of all forms of tuberculosis caused by Mycobacterium
tuberculosis.

4.2 Posology and method of administration Oral use

Pyrazinamide 400 mg Tablets must always been given in combination with other
antituberculosis agents.
Daily regimen 25 mg/kg (20-30 mg/kg) body weight as a single daily dose.

35 mg/kg (30-40 mg/kg) body weight for children weighing less than 30 kg, as a single daily
dose.

Number of Pyrazinamide 400 mg Tablets for treatment according to weight bands Daily
regimen (adults and children)

Weight in kg 11-20 21-39 40-54 55-70 >70 Number of tablets per day 1 2 3 4 5

Intermittent regimen 35 mg/kg (30-40 mg/kg) body weight 3 times a week as a single dose or 50
mg/kg (40-60 mg/kg) body weight 2 times a week as a single dose (The latter 50 mg twice
weekly regimen, however, is not recommended by WHO).

Pyrazinamide 400 mg Tablets should preferably be taken without food (1). Tablets should be
swallowed whole with drinking water. Tablets should neither be crushed nor chewed. In
patients requiring less than 400 mg pyrazinamide per dose, another formulation containing less
pyrazinamide should be used. * Trade names are not prequalified by
WHO. This is under local DRA responsibility. Throughout this WHOPAR the proprietary name is
given as an example only.

Renal impairment:

Dose adjustment is necessary in patients with CrCL <30 ml/min. It is recommended to

administer 20-30 mg/kg per dose three times per week (not daily). Patients on haemodialysis:
On dialysis days, Pyrazinamide 400 mg Tablets should be administered after the dialysis session.
Hepatic impairment: Pyrazinamide must not be used in severe liver disease (see section 4.3).
Children and adolescents: Appropriate studies on the relationship of age to the effects of
pyrazinamide have not been performed in the paediatric population. However, no paediatrics-
specific problems have been documented to date. Duration of therapy: In standard, first-line
treatment of Mycobacterium tuberculosis, pyrazinamide is used during the first 2 months of
therapy, in combination with two or three further drugs. However, the duration of
antituberculous therapy depends on the regimen chosen, the patient’s clinical and
radiographical responses, smear and culture results, and susceptibility studies of
Mycobacterium tuberculosis isolates from the patient or the suspected source case. If therapy
is interrupted, the treatment schedule should be extended to a later completion date
depending, e.g. on the length of the interruption, the time during therapy (early or late) or the
patient’s status.

4.3 Contraindications Pyrazinamide 400 mg Tablets is contraindicated in patients with -

hypersensitivity to the active substance or to any of the excipients, - severe liver impairment or -
acute gout.
4.4 Special warnings and special precautions for use Patients started on Pyrazinamide 400 mg
Tablets should have baseline serum uric acid and liver function determinations. In patients with
severe renal impairment (CrCl < 30 ml/min) the dose should be adjusted (see section 4.2).
Patients with impaired renal function, with a history of gout or with diabetes should be carefully
monitored. Whenever possible, the use of pyrazinamide should be avoided in patients with
preexisting hepatic impairment (ALT> 3 x ULN) due to the risk of liver toxicity (2). Patients at
increased risk for hepatic impairment, such as drug-related hepatitis (e.g. patients with a high
level of alcohol consumption) should be followed closely (2). In all patients, serum transaminase
levels should be monitored during treatment with Pyrazinamide 400 mg Tablets. If transaminase
levels exceed five times the ULN, with or without symptoms, or three times the ULN with
jaundice and/or hepatitis symptoms, Pyrazinamide 400 mg Tablets should be discontinued and
is not to be resumed (2). Cross-sensitivity: Patients hypersensitive to ethionamide, isoniazid,
niacin (nicotinic acid), or other chemically related medications may also be hypersensitive to
Pyrazinamide 400 mg Tablets.

4.5 Interaction with other medicinal products and other forms of interaction Probenecid: There
is a complex pharmacokinetic and pharmacodynamic two-way interaction between
pyrazinamide and probenecid. The appropriate dose of probenecid in co-treatment has not
been established. Therefore, concomitant use should be avoided (3). Allopurinol: Co-
administration increased the AUC of the active metabolite of pyrazinamide, pyrazinoic acid, by
approximately 70% (4). Since pyrazinoic acid inhibits urate elimination, allopurinol is not
effective in treating pyrazinamide-associated hyperuricaemia (5). Ofloxacin and levofloxacin:
Co-treatment with pyrazinamide and either of these fluoroquinolones has been associated with
a high levels of adverse events (e.g. hepatic, gastrointestinal, musculoskeletal). leading to
discontinuation of therapy (6,7). Co-treatment is not recommended. However, when deemed
necessary, careful safety monitoring should be applied. Co-treatment with hepatotoxic drugs
(e.g. rifampicin, isoniazid, ethionamide): Co-treatment may potentiate hepatotoxicity (2).

Pyrazinamide may interfere with urinary ketone determination tests that utilise the sodium
nitroprusside method (8).

4.6 Pregnancy and lactation No adverse effects of pyrazinamide on the fetus have been
reported. However, it is to be used only when the benefits outweigh the potential risks (9).
Pyrazinamide is excreted into the breast milk of lactating mothers. No adverse effects in the
baby have been reported (9).

4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive
and use machines have been performed. Nevertheless, the clinical status of the patient and the
 adverse reaction profile of Pyrazinamide 400 mg Tablets should be borne in mind when
considering the patient’s ability to drive or operate machinery.

4.8 Undesirable effects The most important adverse effect of pyrazinamide is liver damage,
ranging from asymptomatic increases of serum transaminases to symptomatic liver dysfunction,
and in rare cases also fatal liver failure (2). Adverse events considered at least possibly related to
pyrazinamide treatment are listed below by body system, organ class and frequency. Frequency
estimates are in many cases not based on adequately sized randomised trials, but on published
data generated during post-approval use. Often, no frequency data can be given. Frequencies
are defined as very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100),
rare (≥ 1/10000, <1/1000), very rare (<1/10000), ‘not known’.

Nervous system disorders: Not known: headache, dizziness, nervousness, insomnia.

Gastrointestinal disorders: Common: nausea, vomiting Not known: abdominal cramps, anorexia.

Hepatobiliary disorders: Very common: Increased liver enzymes Uncommon: jaundice Rare: liver
failure.

Metabolism and nutrition disorders Very common: hyperuricaemia Very rare: pellagra, aggravated
porphyria.

Renal and urinary disorders Not known: Interstitial nephritis.

Skin and subcutaneous tissue disorders: Rare: rash, photosensitivity reaction, urticaria.

General disorders Very common: flushing Not known: malaise, fever, weight loss, allergic reactions.

Blood and lymphatic systems disorders: Not known: anaemia, thrombocytopenia, neutropenia.

Musculoskeletal disorders: Very common: arthralgia Unknown: gouty arthritis.

Vascular disorders: Not known: hypertension.

4.9 Overdose Symptoms: Data on pyrazinamide overdosing are scarce. However, liver toxicity and
hyperuricaemia might occur. Treatment: Emesis and gastric lavage may be of value if undertaken within
few hours. Further treatment is essentially symptomatic; there is no specific antidote. Pyrazinamide is
dialyzable (10).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antimycobacterial ATC Code for

Pyrazinamide - J04AK01 Properties Pyrazinamide is bactericidal against intracellular mycobacterium
tuberculosis (11). Mechanism of action Pyrazinamide is a prodrug that is converted into its active form,
pyrazinoic acid, by a mycobacterial enzyme, pyrazinamidase, as well as through hepatic metabolism.
Pyrazinoic acid is bactericidal to Mycobacterium tuberculosis at acid pH values but not at neutral pH
(11). The precise mechanism of action is unknown. Pyrazinamide is inactive against atypical
mycobacteria (11). Resistance develops rapidly if pyrazinamide is used as sole antitubercular agent (8).

5.2 Pharmacokinetic properties Absorption: Pyrazinamide is almost completely absorbed from the
gastrointestinal tract (8). Following single dose administration of one tablet Pyrazinamide 500 mg in
healthy volunteers, the mean (SD) pyrazinamide Cmax value was 9.4 μg/ml (±2.62) and the
corresponding values for AUC0-t was 98.9 μg*hr/ml (±32.2) and AUC0-inf was 114 μg*hr/ml (±31.1).
The mean pyrazinamide tmax value was 1.6 (± 0.94) hours.

Distribution: Pyrazinamide is widely distributed to most fluid compartments and tissues. The volume of
distribution has been reported as 0.57-0.84 l/kg (8). The plasma protein binding of pyrazinamide is low,
approximately 10-20% (12). Metabolism: Pyrazinamide is hydrolysed by a microsomal deaminase to the
active metabolite, pyrazinoic acid, which is then hydroxylated by xanthine oxidase to 5-
hydroxypyrazoinoic acid (8). Elimination: Pyrazinamide is eliminated renally, mostly in the form of
various metabolites. Approximately 3% of a pyrazinamide dose is eliminated unchanged (12). The half-
life of pyrazinamide is approximately 10 hours. The half-life for the active metabolite pyrazinoic acid
after a single dose is approximately 10-20 hours (13,14).

Pharmacokinetics in special populations Impaired renal function: Pyrazinamide is excreted through renal
elimination, mainly in the form of the active metabolite pyrazinoic acid. Hence, pyrazinamide doses
should probably be reduced in patients with renal failure. A single-dose study in haemodialysis patients
compared with healthy controls showed an approximately twofold increase in pyrazinamide AUC and a
5-fold increase in the AUC of pyrazinoic acid. The half-lives of pyrazinamide and pyrazinoic acid were
estimated to 26 and 22 hours respectively (13). Hepatic impairment: In a single dose, parallel group
study comparing the pharmacokinetics of pyrazinamide in patients with severe liver disease
(hypoalbuminaemia, increased INR, ascites, in most cases hyperbilirubinaemia) and healthy volunteers
demonstrated a 40% reduction in pyrazinamide clearance and a threefold increase in the exposure to
pyrazinoic acid. The half-lives of pyrazinamide and pyrazinoic acid were increased by approximately 60%
and 100%, respectively (14).

5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, or
reproduction toxicity.

6. PHARMACEUTICAL PARTICULARS

6.1 List of Excipients Maize starch, Povidone, Sodium starch glycolate, Purified talc, Colloidal anhydrous
silica, Magnesium stearate.

6.2 Incompatibilities Not applicable

6.3 Shelf life 48 months

6.4 Special precautions for storage Do not store above 30ºC, protect from moisture.