None known
None stated
Preclinical safety data on paracetamol in the literature have not revealed any findings which are of relevance to the recommended dosage and use of the product and which have not been mentioned in other sections of the SmPC.
Mutagenicity
There are no studies relating to the mutagenic potential of Panadol (Acetaminophen) Infant Sugar Free Colour Free 120 mg/5 ml Oral Suspension.
In vivo mutagenicity tests of paracetamol in mammals are limited and show conflicting results. Therefore, there is insufficient information to determine whether paracetamol poses a mutagenic risk to man.
Paracetamol has been found to be non-mutagenic in bacterial mutagenicity assays, although a clear clastogenic effect has been observed in mammalian cells in vitro following exposure to paracetamol (3 and 10 mM for 2h).
Carcinogenicity
There are no studies to the carcinogenic potential of Panadol (Acetaminophen) Infant Sugar Free Colour Free 120 mg/5 ml Oral Suspension.
There is inadequate evidence to determine the carcinogenic potential of paracetamol in humans. A positive association between the use of paracetamol and cancer of the ureter (but not of other sites in the urinary tract) was observed in a case-control study in which approximate lifetime consumption of paracetamol (whether acute or chronic) was estimated. However, other similar studies have failed to demonstrate a statistically significant association between paracetamol and cancer of the urinary tract, or paracetamol and renal cell carcinoma.
There is limited evidence for the carcinogenicity of paracetamol in experimental animals. Liver cell tumours can be detected in rats following chronic feeding of 500 mg/kg/day paracetamol.
Teratogenicity
There is no information relating to the teratogenic potential of Panadol (Acetaminophen) Infant Sugar Free Colour Free 120 mg/5 ml Oral Suspension. In humans, paracetamol crosses the placenta and attains concentrations in the foetal circulation similar to those in the maternal circulation. Intermittent maternal ingestion of therapeutic doses of paracetamol are not associated with teratogenic effects in humans.
Paracetamol has been found to be foetotoxic to cultured rat embryo.
Fertility
A significant decrease in testicular weight was observed when male Sprague-Dawley rats were given daily high doses of paracetamol (500 mg/kg/body weight/day) orally for 70 days.
Mechanisms of Action/Effect
Analgesic - the mechanism of analgesic action has not been fully determined. Panadol (Acetaminophen) may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain-impulse generation.
The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.
Antipyretic - Panadol (Acetaminophen) probably produces antipyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.
ATC Code N02B E01
Paracetamol has analgesic and antipyretic actions. The mechanism of action is based on the inhibition of prostaglandin biosynthesis.
Paracetamol is poorly absorbed in the stomach but well absorbed in the small intestine due to the greater surface area and hence adsorptive capacity.
Sodium bicarbonate is an excipient in the formulation which has a role in increasing the rates of gastric emptying and of paracetamol dissolution and hence the speed of absorption of paracetamol to provide faster onset of relief.
The amount of sodium bicarbonate contained in 2 tablets of Panadol (Acetaminophen) ActiFast are required per dose to have such effects. Sodium bicarbonate influences the rate of gastric emptying in a concentration dependant manner with the maximal effect achieved at near isotonic concentrations (150 mmol/litre)(i.e. 150 millimolar) - equivalent to 2 Panadol (Acetaminophen) ActiFast tablets in 100 ml water.
Hypertonic solutions (500-1,000 mmol/litre)(i.e. 500 to 1,000 millimolar - equivalent to the amount of sodium bicarbonate in 6-12 Panadol (Acetaminophen) ActiFast tablets given with 100 ml water) appear to inhibit gastric emptying. The therapeutic application of enhanced gastric emptying has previously been demonstrated with significantly faster rate of absorption of paracetamol and significantly faster onset of pain relief from soluble tablets containing sodium bicarbonate compared to conventional tablets. Panadol (Acetaminophen) ActiFast has been formulated with 630 mg sodium bicarbonate per tablet that results in near isotonicity at a 2-tablet dose in gastric fluid.
The role of the dissolution rate of Panadol (Acetaminophen) ActiFast Tablets in vivo at gastric pH is unknown. Therefore the role of tablet dissolution in the speed of action of Panadol (Acetaminophen) ActiFast Tablets is unclear.
It is likely that no single mode of action is responsible for the pharmacokinetic profile observed with Panadol (Acetaminophen) ActiFast. The relative contributions of the different factors will vary depending on the circumstances under which the product is taken.
Pharmacotherapeutic group: Other Analgesics and Antipyretics (Anilides)
ATC Code: N02 BE01
Paracetamol has analgesic and antipyretic effects similar to those of aspirin and is useful in the treatment of mild to moderate pain. It has only weak anti-inflammatory effects.
Absorption and Fate
Panadol (Acetaminophen) is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged Panadol (Acetaminophen). The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.
A minor hydroxylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following Panadol (Acetaminophen) overdosage and cause liver damage.
Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. It is metabolised in the liver and excreted in the urine as the glucuronide and sulphate conjugates, - less than 5% is excreted unchanged in the urine as unmodified paracetamol. Binding to plasma proteins is minimal.
The mean elimination half-life of paracetamol following administration of Panadol (Acetaminophen) ActiFast is 2 to 3 hours and is similar to that achieved following administration of standard paracetamol tablets in fasted and fed states.
Following administration of Panadol (Acetaminophen) ActiFast, paracetamol has a median time to peak plasma concentrations (tmax) of 25 minutes in fasted subjects and 45 minutes in the fed subjects. Maximum plasma concentrations were reached at least twice as fast for Panadol (Acetaminophen) ActiFast as for standard paracetamol tablets in both the fed and fasted state (p= 0.0002). Following administration of Panadol (Acetaminophen) ActiFast, paracetamol is generally measurable in plasma within 10 minutes in both the fed and fasted state.
Two tablets of Panadol (Acetaminophen) ActiFast are required to be taken with 100 ml of water to obtain this fast rate of absorption of paracetamol. The maximum rate of absorption is obtained on an empty stomach. When one tablet is taken the rate of absorption of paracetamol for Panadol (Acetaminophen) ActiFast is the same as for standard paracetamol tablets. This is thought to be due to insufficient sodium bicarbonate present in the single tablet dose to increase the rate of paracetamol absorption. In addition, tablets taken with insufficient (<100 mls) water are unlikely to have increased speed of action. (See 5.1 Pharmacodynamic properties).
The extent of absorption of paracetamol from Panadol (Acetaminophen) ActiFast tablets is equivalent to that of standard paracetamol tablets as shown by AUC in both fed and fasted states.
Absorption
Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations are reached 30-90 minutes post dose and the plasma half-life is in the range of 1 to 3 hours after therapeutic doses.
Distribution
Drug is widely distributed throughout most body fluids.
Biotransformation
Metabolism occurs almost entirely via hepatic conjugation with glucuronic acid (about 60%), sulphuric acid (about 35%) or cysteine (about 3%). Small amounts of hydroxylated and deacetylated metabolites have also been detected.
Children have less capacity for glucuronidation of the drug than do adults.
In overdosage there is increased N-hydroxylation followed by glutathione conjugation. When the latter is exhausted, reaction with hepatic proteins is increased leading to necrosis.
Elimination
Following therapeutic doses 90-100% of the drug is recovered in the urine within 24 hours.
No special requirements for disposal.
