SUMMARY OF PRODUCT CHARACTERISTICS 1    NAME OF THE MEDICINAL PRODUCT

Maximum Strength Aspro Clear

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Acetylsalicylic acid (As "Coated Acetylsalicylic acid")    500.0 mg

For excipients, see 6.1

3.    PHARMACEUTICAL FORM

Effervescent Tablet to be dissolved in water.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

1.    Symptomatic relief of mild to moderate pain, including headache, migraine pain, neuralgia, toothache, sore throat, period pain, aches and pains.

2.    Symptomatic relief of influenza, feverishness, feverish colds.

3.    Symptomatic relief of sprains, strains, rheumatic pain, sciatica, lumbago, fibrositis, muscular aches and pains, joint swelling and stiffness

4.2 Posology and method of administration

Route of administation:

Oral. The tablets are to be dissolved in water before taking.

Adults:

One or two tablets dissolved in half a glass of water (100ml) every four hours as required. Do not exceed eight tablets in 24 hours.

Elderly

No special dosage regimen required.

Children:

Do not give to children under 16 years, unless specifically indicated (e.g. Kawasaki’s disease).

4.3    Contraindications

Acetylsalicylic acid must not be used in the following cases:

■    Hypersensitivity to acetylsalicylic acid or other salicylates, or to any other components of the product,

■    a history of hypersensitivity reactions (e.g. asthma, rhinitis, urticaria) induced by the administration of salicylates or substances with a similar action, notably non-steroidal anti-inflammatory drugs,

■    active or a history of peptic ulcers,

■    haemorrhagic diathesis,

■    severe renal failure,

■    severe hepatic failure,

■    severe cardiac failure,

■    in combination with methotrexate at doses of 15 mg/week or more (see interactions with other medicinal products and other forms of interaction),

■    third trimester of pregnancy.

4.4    Special warnings and special precautions for use

Acetylsalicylic acid should be used with particular caution in the following cases:

■    hypersensitivity to analgesics / anti-inflammatory agents / anti-rheumatics and in the presence of other allergies,

■    with concomitant treatment with anticoagulants (see interactions with other medicinal products and other forms of interaction),

■    patients with impaired renal function or patients with impaired cardiovascular circulation (e.g. renal vascular disease, congestive heart failure, volume depletion, major surgery, sepsis or major haemorrhagic events), since acetylsalicylic acid may further increase the risk of renal impairment,

■    impaired hepatic function.

Acetylsalicylic acid may precipitate bronchospasm and induce asthma attacks or other hypersensitivity reactions. Risk factors are pre-existing asthma, hay fever, nasal polyps, or chronic respiratory disease. This also applies to patients exhibiting allergic reactions (e.g. cutaneous reactions, itching, urticaria) to other substances.

Due to its inhibitory effect on platelet aggregation which persists for several days after administration, acetylsalicylic acid may lead to an increased bleeding tendency during and after surgical operations (including minor surgeries, e.g. dental extractions).

At low doses, acetylsalicylic acid reduces the excretion of uric acid. This can possibly trigger gout attacks in predisposed patients.

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, unless specifically indicated (e.g. Kawasaki’s disease).

In patients suffering from severe glucose-6-phosphate dehydrogenase (G6PD) deficiency, acetylsalicylic acid may induce haemolysis or haemolytic anaemia. Factors that may increase the risk of haemolysis are high dosage, fever, or acute infections, for example.

4.5 Interactions with other medicaments and other forms of interactions

Contraindicated Interactions:

Methotrexate used at doses of 15 mg/week or more:

Increased haematological toxicity of methotrexate (decreased renal clearance of methotrexate by anti-inflammatory agents in general and displacement of methotrexate from its plasma protein binding by salicylates) (see section 4.3 Contraindications).

Combinations requiring precautions for use:

Methotrexate, used at doses of less than 15 mg/week:

Increased haematological toxicity of methotrexate (decreased renal clearance of methotrexate by anti-inflammatory agents in general and displacement of methotrexate from its plasma protein binding by salicylates).

Anticoagulants, thrombolytics/other inhibitors of platelet aggrega-tion/hemostasis:

Increased risk of bleeding.

Other non-steroidal anti-inflammatory drugs with salicylates at higher doses:

Increased risk of ulcers and gastrointestinal bleeding due to synergistic effect. Selective Serotonin Re-uptake Inhibitors (SSRIs):

Increased risk of upper gastrointestinal bleeding due to possibly synergistic effect Digoxin:

Plasma concentrations of digoxin are increased due to a decrease in renal excretion.

Antidiabetics, e.g. insulin, sulphonylureas:

Increased hypoglycemic effect by high doses of acetylsalicylic acid via hypoglycaemic action of acetylsalicylic acid and displacement of sulphonylurea from its plasma protein binding.

Diuretics in combination with acetylsalicylic acid at higher doses:

Decreased glomerular filtration via decreased renal prostaglandin synthesis.

Systemic glucocorticoids, except hydrocortisone used as replacement therapy in Addison's disease:

Decreased blood salicylate levels during corticosteroid treatment and risk of salicylate overdose after this treatment is stopped via increased elimination of salicylates by corticosteroids.

Angiotensin converting enzyme inhibitors (ACE) in combination with acetylsalicylic acid at higher doses:

Decreased glomerular filtration via inhibition of vasodilatory prostaglandins. Furthermore, decreased antihypertensive effect.

Valproic acid and Phenytoin:

Increased toxicity of valproic acid due to displacement from protein binding sites. Phenytoin is also extensively bound to plasma proteins therefore it can be displaced by acetylsalicylic acid from plasma binding.

Alcohol:

Increased damage to gastro-intestinal mucosa and prolonged bleeding time due to additive effects of acetylsalicylic acid and alcohol.

Uricosurics such as benzbromarone, probenecid:

Decreased uricosuric effect (competition of renal tubular uric acid elimination).

4.6 Pregnancy and lactation Pregnancy

Doses of 500 mg/day and above:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre-and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, acetyl salicylic acid should not be given unless clearly necessary. If acetylsalicylic acid is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

-    cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

-    renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

the mother and the neonate, at the end of pregnancy, to:

-    possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

-    inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, acetylsalicylic acid at doses of 100 mg/day and higher is contraindicated during the third trimester of pregnancy.

Lactation:

Breast feeding is contraindicated at high doses because of the theoretical risk of affecting clotting mechanisms.

4.7 Effects on ability to drive and use machines

None.

4.8 Undesirable effects

The listed adverse drug reactions are based on spontaneous reports, thus an organization according to CIOMS III categories of frequency is not possible.

Blood and lymphatic system disorders

In the context of bleeding: haemorrhagic anaemia, iron deficiency anaemia with the respective laboratory and clinical signs and symptoms. In the context of glucose-6-phosphate dehydrogenase (G6PD) deficiency: haemolysis, haemolytic anaemia

Immune system disorders

Hypersensitivity, drug hypersensitivity, allergic edema and angioedema, anaphylactic reaction, anaphylactic shock with respective laboratory and clinical manifestations

Nervous system disorders

Cerebral and intracranial haemorrhage, dizziness

Ear and labyrinth disorders

Tinnitus

Cardiac disorders

In the context of severe allergic reactions: cardio-respiratory distress Vascular disorders

Haemorrhage, perioperative haemorrhage, haematoma, muscle haemorrhage

Respiratory, thoracic and mediastinal disorders

Epistaxis, analgesic asthma syndrome, rhinitis, nasal congestion

Gastrointestinal disorders

Dyspepsia, gastrointestinal pain, abdominal pain, gingival bleeding, gastrointestinal inflammation, gastrointestinal ulcer, gastrointestinal haemorrhage, gastrointestinal ulcer perforation with the respective laboratory and clinical signs and symptoms

Hepatobiliary disorders

Liver disorder, transaminases increased

Skin and subcutaneous tissue disorders

Rash, urticaria, pruritus

Renal and urinary disorders

Impaired renal function

Injury, poisoning and procedural complications

See overdose section

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.

4.9 Overdose

Salicylates / aspirin

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 poisoning.

Symptoms

Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases.

A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of four years. In children aged four years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier.

Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.

Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.

Management

Give activated charcoal if an adult presents within one hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration 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 is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis 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 oedema.

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 ten years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Analgesia: Aspirin effects analgesia by virtue of both a peripheral and a central nervous system effect. Inhibition of prostaglandin synthesis at the site of origin of pain prevents sensitisation of the pain receptors to mediators of the pain response, such as bradykinin.

Antipyresis: Aspirin rapidly and effectively lowers the body temperature in febrile patients, by adjusting the "set point" at which body temperature is maintained in the hypothalamic nuclei. Heat production is not inhibited, but heat dissipation is augmented by increased peripheral blood flow and sweating.

Anti-inflammatory action: The basic action of aspirin in rheumatic disease appears to be concerned with effects on inflammatory and immunological processes in mesenchymal and connective tissue. The anti-inflammatory effect of aspirin is due to blockade of an early step in the synthesis of prostaglandins from precursor fatty acids, by inhibition of prostaglandin synthetase.

5.2 Pharmacokinetic particulars

Absorption of non-ionised aspirin occurs in the stomach and upper intestine. Hydrolysis to salicylic acid occurs rapidly in the intestine and in the circulation. Appreciable plasma concentrations are found in less then 30 minutes. After a single dose, a peak value is reached in about 2 hours and then gradually declines. Salicylates are extensively bound to plasma proteins (50-90%); aspirin to a lesser degree. Aspirin and salicylates are rapidly distributed to all body tissues. They appear in milk and cross the placenta.

The effervescent formulation of Maximum Strength Aspro Clear permits more rapid absorption of aspirin, as compared to regular hard tablets, and causes less gastrointestinal irritancy.

Aspirin is excreted mainly by the kidneys as salicylic acid and as glucuronide conjugates; also as salicyluric and gentisic acids. The biological half life of aspirin after a small single dose is in the region of 4 hours.

5.3    Preclinical safety data

The preclinical safety profile of acetylsalicylic acid is well documented.

In animal studies, salicylates caused kidney damage at high dosages but no other organic lesions. Acetylsalicylic acid has been extensively studied in vitro and in vivo for mutagenicity; no relevant evidence of a mutagenic potential was found. The same applies to carcinogenicity studies.

Salicylates have exhibited teratogenic effects in animal studies and a number of different species. Implantation disorders, embryotoxic and foetotoxic effects and impairment of learning ability in the offspring after prenatal exposure have been described.

6.    PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Malic Acid *

Dioctyl sodium sulphosuccinate* Mannitol*

Povidone*

(* Combined as coated acetylsalicylic acid)

Anhydrous Citric Acid

Sodium Hydrogen Carbonate

Sodium Carbonate

Saccharin Sodium

Lemon Flavour

6.2 Incompatibilities

None.

6.3 Shelf life

3 years.

6.4 Precautions for storage

Store below 25^oC. Protect from moisture.

No Data Held

6.5 Nature and contents of container

Tablets are packed in polyethylene-coated, soft tempered, aluminium foil, with four tablets per strip. These strips are then packed into cardboard cartons to contain 8, 12, 16, 20, 24 or 60 tablets.

6.6 Instructions for use, handling and disposal

Not applicable.

7.    MARKETING AUTHORISATION HOLDER

Bayer Plc T/A Bayer PLC Consumer Care Division

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA

UK

8.    MARKETING AUTHORISATION NUMBER

PL 00010/0332

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

25/11/2005

10 DATE OF REVISION OF THE TEXT

20/07/2016