Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2021 Publisher: Beximco Pharmaceuticals Australia, 4 Miami Key, Broadbeach Waters, QLD 4218
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.
The combination of immediate release and sustained release paracetamol provides pain relief, which may last up to 8 hours.
In patients with pain associated with osteoarthritis of the knee, sustained release paracetamol (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.
Sustained release paracetamol 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 ofmorning stiffness.
Since sustained release paracetamol (three times daily) was clinically equivalent to standard immediate release paracetamol (four times daily), it was concluded that sustained release paracetamol provides pain relief for up to 8 hours after dosing.
In patients with post-surgical dental pain, a single dose of sustained release paracetamol (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 sustained release paracetamol and standard immediate release paracetamol in either development of analgesia or peak analgesic effect. Trends in favour of sustained release paracetamol were observed at the later time points. Furthermore, sustained release paracetamol 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.
From these results, it was concluded that sustained release paracetamol 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.
Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Food intake delays paracetamol absorption.
Parapane 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.
Parapane 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.
Food had little effect on the extent of paracetamol absorption from Parapane Osteo demonstrating that Parapane Osteo is suitable to be taken with or without meals. Paracetamol was rapidly absorbed after administration of Parapane 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.
Paracetamol is distributed into most body tissues. Binding to the plasma proteins is minimal at therapeutic concentrations but increases with increasing doses.
Paracetamol is metabolised extensively in the liver and excreted in the urine mainly as inactive glucuronide and sulphate conjugates.
The metabolites of paracetamol include a minor hydroxylated intermediate which hashepatotoxic 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 sulfate conjugate being predominant.1
Paracetamol is excreted in the urine mainly as the glucuronide and sulfate 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.
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