5. Clinical particulars
4.1 Therapeutic indications
For the treatment of mild to moderate pain including headache,
migraine, neuralgia, toothache, sore throat, period pains,
symptomatic relief of sprains, strains, rheumatic pain, sciatica,
lumbago, fibrositis, muscular aches and pains, joint swelling and
stiffness, influenza, feverishness and feverish colds.
4.2 Posology and method of administration
Adults, the elderly and young persons aged 16 and over:
2 tablets every 4 hours to a maximum of 8 tablets in 24 hours.
Do not give to children aged under 16 years, unless specifically
indicated (e.g. for Kawasaki's disease).
Hypersensitivity to the active ingredients or any of the other
Peptic ulceration and those with a history of peptic ulceration;
haemophilia concurrent anti-coagulant therapy; children under 16
years and when breast feeding because of possible risk of Reye's
4.4 Special warnings and precautions for use
Caution should be exercised in patients with asthma, allergic
disease, impairment of hepatic or renal function (avoid if severe)
and dehydration. The hazards of overdose are greater in those with
non-cirrhotic alcoholic liver disease.
Do not take if you have a stomach ulcer.
Do not take more medicine than the label tells you to. If you do
not get better, talk to your doctor.
Do not take anything else containing paracetamol while taking this
Talk to your doctor at once if you take too much of this medicine,
even if you feel well. This is because too much paracetamol can
cause delayed, serious liver damage.
There is a possible association between aspirin and Reye's syndrome
when given to children. Reye's syndrome is a very rare disease
which affects the brain and liver, and can be fatal. For this
reason aspirin should not be given to children under 16 years
unless specifically indicated (e.g. Kawasaki's disease).
Patients should be advised that paracetamol may cause severe skin
reactions. If a skin reaction such as skin reddening, blisters, or
rash occurs, they should stop use and seek medical assistance right
This medicine contains aspartame (a source of phenylalanine), which
may be harmful for people with phenylketonuria (PKU).
Patients with rare hereditary problems of galactose intolerance;
the Lapp lactose deficiency or glucose-galactose malabsorption
should be advised not to take this medicine.
4.5 Interaction with other medicinal products and other forms of
Other NSAIDS and corticosteroids: Concurrent use of other NSAIDs or
corticosteroids may increase the likelihood of GI side effects.
Diuretics: Antagonism of the diuretic effect.
Anticoagulants: Increased risk of bleeding due to antiplatelet
Metoclopramide: Metoclopramide increases the rate of absorption of
aspirin. However, concurrent use need not be avoided.
Phenytoin: The effect of phenytoin may be enhanced by aspirin.
However, no special precautions are needed.
Valproate: The effect of valproate may be enhanced by aspirin.
Methotrexate: Delayed excretion and increased toxicity of
Cholestyramine: The speed of absorption of paracetamol is reduced
by cholestyramine. Therefore the cholestyramine should not be taken
within one hour if maximal analgesia is required.
Metoclopramide and Domperidone: The speed of absorption of
paracetamol is increased by metoclopramide and domperidone.
However, concurrent use need not be avoided.
Warfarin: The anticoagulant effect of warfarin and other coumarins
may be enhanced by prolonged regular use of paracetamol with
increased risk of bleeding; occasional doses have no significant
Chloramphenicol: Increased plasma concentration of chloramphenicol.
4.6 Pregnancy and lactation
There is clinical and epidemiological evidence of safety of aspirin
in pregnancy, but it may prolong labour and contribute to maternal
and neonatal bleeding, and so should not be used in late pregnancy.
Aspirin appears in breast milk, and regular high doses may affect
neonatal clotting. Not recommended while breast feeding due to
possible risk of Reye's Syndrome as well as neonatal bleeding due
Epidemiological studies in human pregnancy have shown no ill
effects due to paracetamol used in the recommended dosage, but
patients should follow the advice of their doctor regarding its
Paracetamol is excreted in breast milk but not in a clinically
significant amount. Available published data do not contraindicate
Caffeine appears in breast milk. Irritability and poor sleeping
pattern in the infant have been reported.
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
Side effects are mild and infrequent but there is a high incidence
of gastro intestinal irritation with slight asymptomatic blood
loss. Increased bleeding time. Aspirin may precipitate bronchospasm
and induce asthma attacks or other hypersensitivity reactions in
susceptible individuals. Aspirin may induce gastro intestinal
haemorrhage, occasionally major. It may precipitate gout in
susceptible individuals. Possible risk of Reyes Syndrome in
children under 16 years.
Adverse effects of paracetamol are rare. Very rare cases of serious
skin reactions have been reported. There have been reports of blood
dyscrasis including thrombocytopenia and agranulocytosis, but these
were not necessarily causality related to paracetamol.
High doses of caffeine can cause tremor and palpitation.
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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
This product contains both paracetamol and aspirin, and as such,
any overdose events should be assessed using information available
on both active substances.
Liver damage is possible in adults who have taken 10g or more of
paracetamol. Adults who have consumed more than 5g of paracetamol,
may experience liver damage if they have one of the following risk
• long term treatment with either anti-infectives, anti-epileptics
or St John's Wort, or any other drugs that induce liver enzymes
• regular consumption of ethanol in excess of recommended amounts
• likely to be glutathione deplete e.g. eating disorder, cystic
fibrosis, HIV infection, starvation, cachexia.
Salicylate poisoning is usually associated with plasma
concentrations >350 mg/L (2.5 mmol/L). Most adult deaths occur
in patients whose concentrations exceed 700 mg/L (5.1 mmol/L).
Single doses less than 100 mg/kg are unlikely to cause serious
Symptoms: Common features exist for both active substances when
taken in overdose, but these can be tabulated as follows:
Within the first 24 hours:
After 12-48 hours:
Abnormalities of glucose metabolism and metabolic acidosis
Hepatic failure may progress to Encephalopathy, Haemorrhage,
Hypoglycaemia, cerebral oedema and death.
With or without severe liver damage:
Acute renal failure with acute tubular necrosis strongly suggested
by loin pain haematuria and proteinuria.
Vomiting, Dehydration, Tinnitus, Vertigo, Deafness
Warm extremities with bounding pulses
Increased respiratory rate
Acid base disturbance
Mixed respiratory alkalosis and metabolic acidosis with normal or
high arterial pH (normal or reduced hydrogen ion concentration) in
adults and children aged over 4 years.
In children aged 4 years or less, a dominant metabolic acidosis
with low arterial pH (raised hydrogen ion concentration) is common.
Acidosis can increase salicylate transfer across the blood brain
Thrombocytopenia, Increased INR/PTR
Intravascular coagulation, Renal failure
Non-cardiac pulmonary oedema
Confusion, disorientation, coma and convulsions are more common in
children than adults.
Other symptoms of overdosage, associated with the caffeine
CNS stimulation; anxiety, nervousness, restlessness, insomnia,
excitement, muscle twitching, confusion, convulsions
Cardiac: tachycardia, cardiac arrhythmia
Gastric: Abdominal or stomach pains
Other: diuresis, facial flushing.
Immediate treatment is essential in the management of overdose due
to the paracetamol content of the product.
There may be few or no initial symptoms, and these can be limited
to nausea or vomiting and may not reflect the severity of overdose
or the risk of organ damage. Management should be in accordance
with established treatment guidelines, see BNF overdose section.
Treatment with activated charcoal should be considered if the
overdose has been taken within 1 hour.
Plasma paracetamol concentrations should be measured at 4 hours or
later after ingestion (earlier concentrations are unreliable).
Treatment with N-acetylcysteine may be used up to 24 hours after
ingestion of paracetamol; however, the maximum protective effect is
obtained up to 8 hours post-ingestion. The effectiveness of the
antidote declines sharply after this time. If required the patient
should be given intravenous N-acetylcysteine, in line with the
established dosage schedule. If vomiting is not a problem, oral
methionine may be a suitable alternative for remote areas, outside
Management of patients who present with serious hepatic
dysfunction, or are under 10 years or over 70, beyond 24h from
ingestion should be discussed with the National Poisons Information
Service (NPIS) or a liver unit.
Treatment with activated charcoal should be considered if
salicylate plasma concentration is greater than 250mg/kg.
Plasma salicylate concentrations should be measured although the
severity of poisoning cannot be determined from this alone and the
clinical and biochemical features must be taken into account.
Elimination of aspirin is increased by urinary alkalinisation,
which is achieved by the administration of 1.26% sodium
bicarbonate. The urine pH should be monitored. Metabolic acidosis
should be corrected with intravenous 8.4% sodium bicarbonate (first
check serum potassium). Forced diuresis should not be used since it
does not enhance salicylate excretion and may cause pulmonary
Haemodialysis is the treatment of choice for severe poisoning and
should be considered in patients with plasma salicylate
concentrations >700 mg/L (5.1 mmol/L), or lower concentrations
associated with severe clinical or metabolic features.
Patients under 10 years or over 70 years of age may be at an
increased risk of salicylate toxicity and may require dialysis at
an earlier stage.
Treatment of caffeine overdose is primarily symptomatic and
supportive. Diuresis should be treated by maintaining fluid and
electrolyte balance and CNS symptoms can be controlled by
intravenous administration of diazepam.
6. Pharmacological properties
5.1 Pharmacodynamic properties
Mechanisms of action/effect
Salicylates inhibit the activity of the enzyme cyclo-oxygenase to
decrease the formation of precursors of prostaglandins and
thromboxanes from arachidonic acid. Although many of the
therapeutic effects may result from inhibition of prostaglandin
synthesis (and consequent reduction of prostaglandin activity) in
various tissues, other actions may also contribute significantly to
the therapeutic effects.
Produces analgesia through a peripheral action by blocking pain
impulse generation and via a central action, possibly in the
Exact mechanisms have not been determined. Salicylates may act
peripherally in inflamed tissue probably by inhibiting the
synthesis of prostaglandins and possibly by inhibiting the
synthesis and/or actions of other mediators of the inflammatory
May produce antipyresis by acting centrally on the hypothalamic
heat regulating centre to produce peripheral vasodilation resulting
in increased cutaneous blood flow, sweating and heat loss.
Mechanism of action/effect
Analgesic - the mechanism of analgesic action has not been fully
determined. Paracetamol may act predominantly by inhibiting
prostaglandin synthesis in the central nervous system (CNS) and, to
a lesser extent, through a peripheral action by blocking
The peripheral action may also be due to inhibition of
prostaglandin synthesis or to inhibition of the synthesis or
actions of other substances that sensitize pain receptors to
mechanical or chemical stimulation.
Antipyretic - paracetamol 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.
Mechanisms of action/effect
Central nervous system stimulant - caffeine stimulates all levels
of the CNS, although its cortical effects are milder and of shorter
duration than those of amphetamines.
Caffeine constricts cerebral vasculature with an accompanying
decrease in the cerebral blood flow and in the oxygen tension of
the brain. It is believed that caffeine helps to relieve headache
by providing more rapid onset on action and/or enhanced pain relief
with lower doses of analgesic. Recent studies with ergotamine
indicate that the enhancement of effect by the addition of caffeine
may also be due to improved gastrointestinal absorption of
ergotamine when administered with caffeine.
5.2 Pharmacokinetic properties
Absorption and fate
Absorption is generally rapid and complete following oral
administration. It is largely hydrolysed in the gastrointestinal
tract, liver and blood to salicylate which is further metabolised
primarily in the liver.
Absorption and Fate
Paracetamol 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 paracetamol. The elimination
half-life varies from about 1 to 4 hours. Plasma-protein binding is
negligible at usual therapeutic concentrations but increases with
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 paracetamol overdosage and cause liver damage.
Absorption and fate
Caffeine is completely and rapidly absorbed after oral
administration with peak concentrations occurring between 5 and 90
minutes after dose in fasted subjects. There is no evidence of
pre-systemic metabolism. Elimination is almost entirely by hepatic
metabolism in adults.
In adults, marked individual variability in the rate of elimination
occurs. The mean plasma elimination half life is 4.9 hours with a
range of 1.9 - 12.2 hours. Caffeine distributes into all body
fluids. The mean plasma protein binding of caffeine is 35%.
Caffeine is metabolised almost completely via oxidation,
demethylation and acetylation and is excreted in the urine. The
major metabolites are 1-methylxanthine, 7-methylxanthine,
1,7-dimethylxanthine (paraxanthine). Minor metabolites include
1-methyluric acid and 5-acetylamino-6-formylamino-3-methluracil
5.3 Preclinical safety data
The active ingredients in Anadin Extra Soluble Tablets have a well
established safety record. The combination of ingredients has been
marketed for a number of years.
6. Pharmaceutical particulars
6.1 List of excipients
Citric Acid Anhydrous
Hydrogenated Vegetable Oil
Lemon Flavour 6334
Dioctyl Sodium Sulfosuccinate
Colloidal Silicon Dioxide
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
Blisters of cold-formable bottom foil: PA 25 µm / Aluminium foil 47
µm /PVC 60 µm, with a soft aluminium 25 µm foil lid.
Blisters of cold-formable bottom foil: PA 25 µm / Aluminium foil 47
µm /PVC 60 µm, with an aluminium 9 µm / glassine paper 35g/sqm.
The blisters are packed into cardboard cartons with a patient
information leaflet in pack sizes of 8, 12, 16, 20, 24 and 32.
Not all pack sizes may be marketed.