Skip to Content

PYRAZINAMIDE 500 MG TABLETS

Active substance(s): PYRAZINAMIDE / PYRAZINAMIDE / PYRAZINAMIDE

View full screen / Print PDF » Download PDF ⇩

PDF Transcript

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Pyrazinamide 500 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 500 mg pyrazinamide.
Excipient(s) with known effect: Lactose
Each 500mg tablet contains 124.5 mg of Lactose monohydrate.
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
White, flat, circular bevelled edge, uncoated tablets with score line on one side and
other side is plain.
The score line is only for aesthetic purposes/to facilitate swallowing of the tablets and
not for subdivision of tablets, i.e. not for the purpose of providing part doses.

4

CLINICAL PARTICULARS

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 antituberculosis 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.

4.3

Contraindications
Pyrazinamide is contraindicated in patients with

-

4.4

severe hepatic impairment, acute liver disease (e.g. hepatitis) and up to 6 months
after occurrence of hepatitis
acute porphyria
acute gouty arthritis
Allergy to pyrazinamide or any of the excipients of Pyrazinamide 500 mg
Tablets (See section 6.1)

Special warnings and precautions for use
Pre-treatment examinations should include renal function, hepatic function and
particularly base-line uric acid determinations
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.
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.

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 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
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 is excreted into the breast milk of lactating mothers.
Pyrazinamide should only be administered to pregnant and lactating women when the
benefit clearly outweighs the risk.

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
Very
Common
common
(≥1/100
(≥1/10)
<1/10)

Uncommo Rare
Very
rare
(<1/10.000
)
n
to
(≥1/10.000 to
(≥1/1.000 <1/1.000)
to <1/100)

Not known
(cannot be
estimated
from the
available
data)

Disorders of the blood and lymphatic system
Haematopoietic splenomegal
system
y
disorders,
sideroblastic
anaemia,
porphyria,
thrombocytopen
ia
with
or
without purpura,
Endocrine disorders
Impairs
adrenocortical
function
(17ketosteroidexcretion
in
urine)
Metabolism and nutrition disorders
Pellagra
Nervous system disorders
Headache,
dizziness,
irritability,
insomnia
Gastrointestinal disorders
Loss of appetite,
nausea,

Aggravatio
n of peptic

Very
common
(≥1/10)

Common
(≥1/100
<1/10)

Uncommo Rare
Very
rare
to n
(≥1/10.000 to (<1/10.000 )
<1/1.000)
(≥1/1.000
to <1/100)

sickness,
vomiting,
heartburn,
abdominal
spasms, weight
loss
Hepatobiliary disorders
Raised
serum
transaminase
levels,
liver
function
disorders

Skin and subcutaneous disorders
Photosensitivity
(see Section 4.4)

Renal and urinary disorders
Hyperuricaemia
(see Section 4.4)

Not known
(cannot be
estimated
from the
available
data)
ulcer

Hepatomeg
aly,
jaundice,
hepatic
failure
(which
may
be
fatal)
Erythema
multiforme

Flushing,
dysuria,
rash,
urticaria,
pruritus

Tubulointerstitial
nephritis

General and administration site disorders
Hypertension

Fever,
malaise

Musculoskeletal, connective tissue and bone disorders
Gout,
athralgia
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

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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Medication for the treatment of tuberculosis,
ATC code: J04AK01
Mechanism of action
Under in vitro conditions, Pyrazinamide is hardly or not at all effective against
most strains of Mycobacterium bovis and atypical mycobacteria. There is a
cross-resistance to morphazinamide, a Pyrazinamide -derivative. No other
cross-resistances to antitubercular agents are known.
The action mechanism of Pyrazinamide against tuberculosis pathogens is not
known. Due to its similarity to nicotinamide, Pyrazinamide is intracellularly
converted by nicotinic acid amidase (also known as pyrazinamidase) into
pyrazinoic acid, which has an antimycobacterial effect.
Resistance mechanism
Acquired resistance of susceptible pathogens from clinical isolates is mainly
caused by a mutation on the pnc A gene. The gene encodes the enzyme
pyrazinamidase, which converts pyrazinamide into its active bactericidal form
pyrazinoic acid. The mutation on the pnc A gene or its promoter region
inhibits this process in bacteria.
Approximately 70 - 97 % of all pyrazinamide-resistant Mycobacterium
tuberculosis isolates carry this mutation, whereas a small proportion of
resistant strains (3-30 %) show no changes in the pnc A gene and/or the

promoter region. Variable resistance rates and pyrazinamidase activity has
been observed. The underlying mechanism of the resistance is not known.
Mycobacterium tuberculosis resistance to pyrazinamide develops rapidly in an
in vitro situation and in patients treated solely with pyrazinamide.
Resistance status
The prevalence of acquired pyrazinamide resistance in tuberculosis caused by
Mycobacterium tuberculosis - the most frequently found and reported
pathogen - varies depending on time and location.

5.2

Pharmacokinetic properties
Absorption
Pyrazinamide is administered orally and absorbed rapidly by the
gastrointestinal tract. Maximum serum levels (approx. 33 µg/mL after
administration of 1.5 g of Pyrazinamide and approx. 65 µg/mL after
administration of 3 g of Pyrazinamide) are reached after 1 - 3 hours.
Distribution
There are no consistent data on the distribution and penetration of
Pyrazinamide.
Biotransformation
In humans, Pyrazinamide is mainly metabolised in the liver-microsomal P-450
cytochrome system converting pyrazinamide into pyrazinoic acid, which, in
turn, is converted by xanthinoxidase into 5-hydroxy- pyrazinoic acid, the end
product of the Pyrazinamide metabolism that is completely excreted through
the kidneys. Other Pyrazinamide metabolites are probably less important.
The conversion of Pyrazinamide into pyrazinoic acid in humans is a slow
process and, in connection with the relatively slow renal excretion, explains
the fairly long half-life of Pyrazinamide (see below).
Elimination
Pyrazinamide is eliminated though renal excretion only. Over 24 hours,
approximately 70 % of the oral Pyrazinamide dose is eliminated,
predominantly through glomerular filtration. About 4 - 14 % are excreted
unmodified, while the rest forms metabolites.
Elimination half life is between 4 and 17 hours with statistically significant
individual differences.
Linearity
Within the range of 0.5 to 3 g, Pyrazinamide serum concentrations are directly
proportionate to the dose.
Pharmacokinetics in special populations:

Impaired renal function
Studies in patients with renal failure have shown that Pyrazinamide, pyrazinoic acid,
5-hydroxy- Pyrazinamide and 5-hydroxy- pyrazinoic acid can be eliminated
effectively through haemodialysis.
Hepatic impairment
In patients with hepatic failure, increased clearance and longer Pyrazinamide halflives were observed, as well as an exposure (AUC) increased by a factor of 3 and a
double pyrazinoic acid half-life.
See section 4.4 regarding monitoring requirements.
Children
Compared to adults, the proportion of children with incomplete or delayed
Pyrazinamide absorption may be higher. No further information is available.

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, toxicity to reproduction and development.
In animal studies, Pyrazinamide proved to be a medication that was well
absorbed and tolerated and of very low toxicity. Its toxicity is well below the
toxicity of other antitubercular agents.
A dose of 3.0 g/kg body weight was lethal to approximately 30 % of mice and
rats. Significant reactions with signs of serious liver toxicity (increased amino
transferase parameters and icterus) were observed in dogs with Pyrazinamide
levels of 1.0 g/kg body weight. The reactions occurred just before the death of
the animals, with extensive liver necrosis.
An oral dose of 1.5 g/kg body weight over several weeks was well tolerated by
mice and rats. Many animal studies showed that a dose of 500 mg/kg body
weight did not cause any (histologically) manifest liver damage.
The many studies show beyond doubt that Pyrazinamide only has toxic effects
at very high doses of 1.5-3.0 g/kg body weight (depending on the animal
species).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate, maize starch, pregelatinised starch, talc, colloidal anhydrous
silica, hydrogenated castor oil.

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
PVC-PVDC/Aluminium Blister pack - 36 month
HDPE container pack - 48 months
After opening the HDPE container pack, the tablets can be used for six months
(180 days).

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Pyrazinamide 500 mg tablets are available as PVC-PVDC/aluminium blister
packs & HDPE container with PP Cap pack in the following pack sizes:
Blister pack containing 10, 14, 28, 30, 50, 56, 60, 90, 100, 120, 500 tablets
HDPE container with PP cap containing 90, 1000 tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Morningside Healthcare Ltd
115 Narborough Road
Leicester
LE3 0PA
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20117/0014

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/12/2013

10

DATE OF REVISION OF THE TEXT
20/12/2013

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide