Source: Web Search Revision Year: 2012 Publisher: Acino Pharma AG, Liesberg
ATC code: N02BE01
Paraconica, with the active substance paracetamol, is an analgesic and antipyretic which contains no salicylic acid or opioids. Regarding the analgesic action of paracetamol, prostaglandin synthesis inhibition is more predominant on a central level than on a peripheral level. The antipyretic action is based on inhibition of the effect of endogenous pyrogens on the hypothalamic temperature regulation centre. Paracetamol has no pronounced antiinflammatory effect and has no influence on haemostasis or the gastric mucosa.
With an I.V. infusion of paracetamol over 15 minutes, the maximum analgesic effect is achieved in 1 hour; the analgesic action generally lasts 4-6 hours. With an I.V. infusion of paracetamol over 15 minutes, defervescence begins within 30 minutes after the start of administration and the antipyretic action lasts for at least 6 hours.
The pharmacokinetics of paracetamol in adults is linear up to a dose of 2 g, administered as a single dose and after repeated administration over 24 hours. The peak plasma concentration (Cmax) is approximately 15 µg/mL at the end of a 15-minute intravenous infusion of 500 mg paracetamol and about 30 µg/mL after infusion of 1 g paracetamol.
The volume of distribution of paracetamol in adults is about 1 litre/kg. Plasma protein binding is less than 20%, but up to 50% in cases of overdose.
In adults, paracetamol is metabolised in the liver via the following two main metabolic pathways: glucuronide conjugation (60-80%) and sulphate conjugation (20-40%). The latter pathway can become very rapidly saturated at dosages above the therapeutic range. A small fraction (less than 4%) is converted by cytochrome P450 into the two toxic metabolites paminophenol and N-acetyl-p-benzoquinone imine, which are rapidly inactivated by conjugation with glutathione and cysteine. In a massive overdose, the amount of these toxic metabolites is increased.
Excretion mainly takes place via the kidneys. 90% of the administered dose is excreted within 24 hours in the urine as glucuronide conjugates (60-80%), as sulphate conjugates (20-30%) and less than 5% in unchanged form.
The mean plasma half-life is 2.7 hours and total body clearance is approximately 18 litres/h. Paracetamol does not pass into bile. It crosses the placenta and is excreted in human milk. The distribution of paracetamol in cerebrospinal fluid was investigated after a short infusion (1 g paracetamol) in 43 patients hospitalised for compression pain of the lumbosacral nerve root. Significant paracetamol concentrations (approximately 1.5 µg/mL) were detected in cerebrospinal fluid 20 minutes after the infusion. Peak paracetamol concentrations in cerebrospinal fluid were measured between 2 and 4 hours and were higher than the plasma concentrations between 4 and 12 hours.
In the case of severe renal insufficiency (creatinine clearance 10–30 mL/min), paracetamol elimination is decelerated slightly; the elimination half-life is between 2 and 5.3 hours. The elimination rate of the glucuronide and sulphate conjugates is 3 times slower in patients with severe renal insufficiency than in healthy persons. However, no dose adjustment is necessary in this population, as these glucuronide and sulphate conjugates are not toxic. However, it is recommended that the minimum interval between the individual administrations be extended to 6 hours when paracetamol is used in patients with severe renal insufficiency (creatinine clearance ≤30 mL/min) (see “Posology/Administration”). If creatinine clearance is less than 10 mL/min, paracetamol should not be administered I.V., as no relevant data exist.
The plasma half-life is largely unaltered in patients with mild hepatic insufficiency. However, it is significantly prolonged in patients with severe hepatic insufficiency.
The pharmacokinetics and metabolism of paracetamol are not modified in elderly patients. Therefore, no dose adjustment is needed in this population. Neonates, infants and children: The pharmacokinetic factors of paracetamol observed in infants and children are similar to those in adults, except for the plasma half-life, which is slightly shorter (1.5 to 2 hours). In neonates, the plasma half-life is longer than in infants, i.e. about 3.5 hours. Neonates, infants and children up to 10 years eliminate significantly fewer glucuronide conjugates and more sulphate conjugates than adults. Total excretion of paracetamol and its metabolites is not dependent on age.
Preclinical data indicate no special hazards for humans beyond the information in other sections of this prescribing information. Local tolerability studies of paracetamol I.V. in rats and rabbits showed good tolerability. Studies in guinea pigs showed no delayed contact hypersensitivity.
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