PANADOL

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PANADOL OSTEO

PRODUCT INFORMATION


NAME OF THE MEDICINE

Active ingredients Chemical structure CAS Registry Number
Paracetamol

103-90-2


DESCRIPTION

White to off-white film coated capsule shaped tablets with flat edges. Embossed with the
logo 8 on the front face and plain on the back face.

Active Ingredient: Paracetamol 665 mg

Excipients: Hypromellose, Starch pregelatinised maize, Povidone, Croscarmellose sodium,
Magnesium stearate, Stearic acid, Glycerol Triacetate, Carnauba wax

Contains no sugar, lactose or gluten.


PHARMACOLOGY

Paracetamol is a para-aminophenol derivative that exhibits analgesic and anti-pyretic activity.
Its mechanism of action is believed to include inhibition of prostaglandin synthesis, primarily
within the central nervous system. It does not possess anti-inflammatory activity. It provides
relief from mild to moderate pain and fever.

Pharmacodynamics
The combination of immediate release and sustained release paracetamol provides pain
relief, which may last up to 8 hours.
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Pharmacokinetics

Absorption
Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Food
intake delays paracetamol absorption.

PANADOL OSTEO is a unique bi-layer tablet incorporating an immediate release and a
sustained release dose of paracetamol.

The sustained release layer contains HPMC polymer, which rapidly hydrates to form a gel
layer at the matrix periphery. The drug is then released from the matrix by a combination of
diffusion and erosion of the gel layer.

Bioequivalence
PANADOL OSTEO releases drug at a rate which ensures that therapeutically active plasma
paracetamol concentrations are rapidly attained and maintained until up to 8 hours after
administration.

PANADOL OSTEO and standard immediate release paracetamol were bioequivalent in
volunteers with respect to dose-corrected AUC
(0-t)
and AUC
(0-inf)
in both the fed and fasted
states following administration of a single dose. This indicates that the extent of paracetamol
absorption from PANADOL OSTEO was equivalent to that of standard immediate release
paracetamol. Food had little effect on the extent of paracetamol absorption from PANADOL
OSTEO demonstrating that PANADOL OSTEO is suitable to be taken with or without meals.
Paracetamol was rapidly absorbed after administration of PANADOL OSTEO and was
generally measurable in plasma within 15 minutes in fasted subjects. Mean plasma
paracetamol concentrations above the minimum level required for analgesia (>4mcg/mL)
were maintained until up to 6 to 7 hours after administration in fasted subjects and 7 to 8
hours in fed subjects.

At steady state, PANADOL OSTEO was bioequivalent with standard immediate release
paracetamol based on the comparison of AUCs during the final 24 hour dosing period of the
study. Furthermore, comparison of the pharmacokinetic parameters indicated that
PANADOL OSTEO has the characteristics of a formulation containing sustained release
paracetamol.

Fluctuations in the peak and trough values for plasma paracetamol concentrations were
significantly smaller for PANADOL OSTEO than for standard immediate release paracetamol
(mean fluctuation index = 0.957 and 1.388, respectively, p<0.001). Consequently, PANADOL
OSTEO provided more consistent levels of paracetamol. Furthermore, the AUCs at steady
state were equivalent indicating that there was no additional accumulation of paracetamol
from PANADOL OSTEO compared to standard immediate release paracetamol.

Distribution
Paracetamol is distributed into most body tissues. Binding to the plasma proteins is minimal
at therapeutic concentrations but increases with increasing doses.
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Metabolism
Paracetamol is metabolised extensively in the liver and excreted in the urine mainly as
inactive glucuronide and sulfate conjugates. The metabolites of paracetamol include a minor
hydroxylated intermediate which has hepatotoxic activity. This intermediate metabolite is
detoxified by conjugation with glutathione. However, it can accumulate following paracetamol
overdosage (more than 150 mg/kg or 10 g total paracetamol ingested) and if left untreated
can cause irreversible liver damage.

Paracetamol is metabolised differently by premature infants, newborns, infants and young
children compared to adults, the sulphate conjugate being predominant.
1


Excretion
Paracetamol is excreted in the urine mainly as the glucuronide and sulphate conjugates.
Less than 5% is excreted unchanged. Approximately 85% of a dose of paracetamol is
excreted in urine as free and conjugated paracetamol within 24 hours of ingestion.
Administration of paracetamol to patients with moderate to severe renal impairment may
result in accumulation of paracetamol conjugates.
2
The elimination half-life varies from one to
three hours.


CLINICAL TRIALS

Chronic Pain
In patients with pain associated with osteoarthritis of the knee, PANADOL OSTEO (2 tablets
taken three times daily) and standard immediate release paracetamol (2 tablets taken 4 times
daily) were clinically equivalent at a total daily dose of 4 g based on patient global
assessment after treatment for 7 days.

PANADOL OSTEO and standard immediate release paracetamol were not significantly
different for a range of secondary efficacy parameters including pain during the day, pain on
walking, pain relief, number of times woken during the night due to pain and duration or
morning stiffness.

Since PANADOL OSTEO (three times daily) was clinically equivalent to standard immediate
release paracetamol (four times daily), it was concluded that PANADOL OSTEO provides
pain relief for up to 8 hours after dosing.

Acute Pain
In patients with post-surgical dental pain, a single dose of PANADOL OSTEO (2 tablets) was
therapeutically equivalent to standard immediate release paracetamol (2 tablets) based on
patient global assessment 4 hours after treatment. Onset of action was apparent 30 minutes
after administration.

There was no significant difference between PANADOL OSTEO and standard immediate
release paracetamol in either development of analgesia or peak analgesic effect. Trends in
favour of PANADOL OSTEO were observed at the later time points. Furthermore, PANADOL

1
Core Paracetamol PI
2
American Hospital Formulary Service Drug Information 2012
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OSTEO was significantly more effective than standard immediate release paracetamol for the
summed pain intensity difference at 6 hours (p = 0.0344) and 8 hours (p = 0.0500), as
measured on a visual analogue scale.

Summary
From these results, it was concluded that PANADOL OSTEO has a similar time to onset of
action compared to standard immediate release paracetamol and provides more prolonged
analgesia than standard immediate release paracetamol. For the patient, this translates to
longer lasting pain relief and the improved convenience of fewer doses. This is as expected
for a formulation containing sustained release paracetamol and consistent with results from
the pharmacokinetic studies.


INDICATIONS

PANADOL OSTEO provides effective relief from persistent pain for up to 8 hours. Effective
for the relief of persistent pain associated with osteoarthritis and muscular aches and pains
such as backache. Provides effective temporary relief of pain and discomfort associated with:
headache, tension headache, cold and flu, period pain, toothache and pain after dental
procedures. Reduces fever.


CONTRAINDICATIONS

PANADOL OSTEO is contraindicated in patients with a previous history of hypersensitivity to
paracetamol or any of the exipients.


PRECAUTIONS

Underlying liver disease increases the risk of paracetamol-related liver damage. Patients
who have been diagnosed with liver or kidney impairment must seek medical advice before
taking this medication.

If symptoms persist, medical advice must be sought.

Keep out of sight and reach of children.

Use in pregnancy
Category A
Paracetamol has been taken by a large number of pregnant women and women of
childbearing age without any proven increase in the frequency of malformations or other
direct or indirect harmful effects on the foetus having been observed.

Maternal ingestion of paracetamol in usual analgesic does not appear to present a risk to
breastfed infants.
3



3
Core Paracetamol PI
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Use in Lactation
Paracetamol is excreted in breast milk. Human studies with paracetamol have not identified
any risk to lactation or the breast-fed offspring. These results are based on immediate
release preparations of paracetamol. There is no data available on the excretion of
sustained-release paracetamol preparations in breast milk. However, it is not expected that
PANADOL OSTEO would provide any increase in the excretion of paracetamol in breast milk
as this product is designed to maintain rather than increase plasma paracetamol
concentrations compared to immediate release preparations. Maternal ingestion of
paracetamol in usual analgesic doses does not appear to present a risk to the breastfed
infant.

Use in Children
Not recommended for children under 12 years of age.


INTERACTIONS WITH OTHER MEDICINES

The following interactions with paracetamol have been noted:

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged
regular daily use of paracetamol with increased risk of bleeding. Anticoagulant dosage may
require reduction if paracetamol and anticoagulants are taken for a prolonged period of time.

Paracetamol absorption is increased by substances that increase gastric emptying, eg
metoclopramide.

Paracetamol absorption is decreased by substances that decrease gastric emptying, eg
propantheline, antidepressants with anticholinergic properties and narcotic analgesics.

Paracetamol may increase chloramphenicol concentrations.

The risk of paracetamol toxicity may be increased in patients receiving other potentially
hepatotoxic drugs or drugs that induce liver microsomal enzymes such as alcohol and
anticonvulsant drugs.

Paracetamol excretion may be affected and plasma concentrations altered when given with
probenecid.

Colestyramine reduces the absorption of paracetamol if given within one hour of
paracetamol.
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ADVERSE REACTIONS

Adverse events from historical clinical trial data are both infrequent and from small patient
exposure. Accordingly, events reported from extensive post-marketing experience at
therapeutic/labelled dose and considered attributable are tabulated below by System Organ
Class and frequency.

The following convention has been utilised for the classification of undesirable effects: very
common (1/10), common (1/100, <1/10), uncommon (1/1,000, <1/100), rare (1/10,000,
<1/1,000), very rare (<1/10,000), not known (cannot be estimated from available data.

Adverse event frequencies have been estimated from spontaneous reports received though
post-marketing data.

Body System Undesirable Effect Frequency
Blood and lymphatic system
disorders
Thrombocytopenia Very rare
Immune system disorders Anaphylaxis
Cutaneous hypersensitivity
reactions including skin
rashes, angioedema and
Stevens Johnson syndrome
Very rare
Respiratory, thoracic and
mediastinal disorders
Bronchospasm Very rare
Hepatobiliary disorders Hepatic dysfunction Very rare


DOSAGE AND ADMINISTRATION

Adults and children aged 12 years and over: 2 caplets swallowed whole three times a day
every 6 to 8 hours. Maximum of 6 caplets in 24 hours

Do not use for more than a few days at a time in adults except on medical advice.

Children under 12 years: Not recommended for children under the age of 12 years.

Should not be used for more than 48 hours for children aged 12 17 years except on
medical advice.

Take with water or other fluid.

Can be taken with or without food.

Doses should be equally spaced throughout the day.

The caplets must not be crushed.

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Do not exceed the stated dose.

Should not be used with other paracetamol-containing products.

Minimum dosing interval: 6 hours

Renal and Hepatic impairment
Patients who have been diagnosed with liver or kidney impairment must seek medical advice
before taking this medication. The restrictions related to the use of paracetamol products in
patients with hepatic impairment are primarily a consequence of the paracetamol content of
the drug. (See PREACUTIONS.)


OVERDOSAGE

Poisons Information Centre
If an overdose is taken or suspected, contact the Poisons Information Centre immediately for
advice (131 126), or the patient should go to the nearest hospital straight away. This should
be done even if they feel well because of the risk of delayed, serious liver damage. (See
ADVERSE EFFECTS.)

Because PANADOL OSTEO is a sustained-release formulation of paracetamol, absorption
will be prolonged in overdose. It is recommended that for the management of overdose,
where PANADOL OSTEO is suspected, that an additional plasma paracetamol level be
obtained 4-6 hours after the initial measurement. If either level is above or close to the
treatment line on the paracetamol overdose nomogram, administration of antidote would be
indicated.


Treatment
Paracetamol overdose may cause liver failure.

Immediate medical management is required in the event of an overdose, even if the
symptoms of overdose are not present.

Administration of acetylcysteine may be required.

In cases of overdosage, methods of reducing absorption of ingested drug are important.
Activated charcoal may reduce absorption of the medicine if given within one hour after
ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration
should be given to administering activated charcoal via a nasogastric tube, once the airway is
protected.


PRESENTATION AND STORAGE CONDITIONS

Active ingredient: Paracetamol 665 mg

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White to off-white film coated capsule shaped tablets with flat edges. Embossed with the
logo 8 on the front face and plain on the back face.
Packs of 6 and 96 caplets.

Not all pack sizes may be marketed.

Store below 30C.


NAME AND ADDRESS OF THE SPONSOR

GlaxoSmithKline Consumer Healthcare
82 Hughes Avenue
Ermington
NSW 2115


POISON SCHEDULE OF THE MEDICINE

S2 Pharmacy Medicine


DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC
GOODS (THE ARTG)

17.2.2005


DATE OF THE MOST RECENT AMENDMENT

06.11.2012


PANADOL

is a registered trade mark of the GlaxoSmithKline group of companies.