Alliance Pharmaceuticals Ireland

Nu-Seals 300mg gastro-resistant tablets.

Each tablet contains:

Acetylsalicylic Acid Ph.Eur. (Aspirin) 300mg.

For a full list of excipients see section 6.1.

Gastro-resistant tablet.

Gastro-resistant tablets, white in colour, printed with '300' in red.

Aspirin has analgesic, antipyretic and anti-inflammatory actions. It also has an anti-thrombotic action, mediated through inhibition of platelet activation, which has been shown to be useful in secondary prophylaxis following myocardial infarction, and in patients with unstable angina or ischaemic stroke.

Nu-Seals 300 is indicated wherever high and prolonged dosage of aspirin is required. The special coating resists dissolution in gastric juice, but will dissolve readily in the relatively less acid environment of the duodenum. Owing to the delay that the coating imposes on the release of the active ingredient, Nu-Seals 300 is unsuitable for the short-term relief of pain.

Nu-Seals 300 is for oral administration to adults only.

Analgesic, antipyretic and anti-inflammatory actions: The usual dose of aspirin is 300-900mg repeated three to four times daily according to clinical needs. In acute rheumatic disorders the dose is in the range of 4-8 g daily, taken in divided doses.

Antithrombotic action: For its antithrombotic effect following myocardial infarction, ischaemic stroke and in patients with unstable angina, the recommended dose is 300mg daily.

The Elderly: As for adults. Aspirin should be used with particular caution in elderly patients who are more prone to adverse events.

Undesirable effects may be minimised by using the shortest duration necessary to control symptoms (see section 4.4).

Treatment should be reviewed at regular intervals. Where aspirin is intended for analgesic or anti-inflammatory use, treatment should be discontinued if no benefit is seen.

Children: do not give to children and adolescents aged under 16 years, except on medical advice, where the benefit outweighs the risk (see section 4.4).

Hypersensitivity to aspirin (e.g. bronchospasm, rhinitis, urticaria) or to non-steroidal anti-inflammatory drugs. Hypoprothrombinaemia, haemophilia, cerebral haemorrhage and active peptic ulceration.

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

Severe heart failure.

Undesirable effects associated with non-steroidal anti-inflammatroy drugs (NSAIDs) may be reduced by using the minimum effective dose for the shortest possible duration. Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.

The use of Nu-Seals 300 with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving Nu-Seals 300mg, the treatment should be withdrawn.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see section 4.8 – undesirable effects).

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 and adolescents aged under 16 years unless specifically indicated.

Aspirin should be used with caution in patients with impaired renal, cardiac or hepatic function (avoid if severe), or in patients who are dehydrated, since the use of NSAIDs may result in deterioration of renal function. Assessment of renal function should occur prior to the initiation of therapy and regularly thereafter.

Aspirin should be used with caution in patients with a history of peptic ulceration, inflammatory bowel disease or coagulation abnormalities. They may also induce gastro-intestinal haemorrhage, occasionally major.

Elderly patients are particularly susceptible to the adverse effects of NSAIDs, including aspirin, especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2). Where prolonged therapy is required, patients should be reviewed regularly.

In patients with strokes, aspirin should not be given until the possibility of cerebral haemorrhage has been excluded.

Aspirin may also precipitate bronchospasm or induce attacks of asthma in susceptible subjects.

Patients with hypertension should be carefully monitored.

Aspirin decreases platelet adhesiveness and increases bleeding time. Haematological and haemorrhagic effects can occur, and may be severe. Patients should report any unusual bleeding symptoms to their physician.

Caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Nu-Seals 300mg should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for aspirin.

Care should be taken when stopping therapy in those patients with multiple risk factors as the risk of a cerebrovascular event in the four weeks after aspirin discontinuation is significant. The risk/benefit of stopping aspirin therapy in the case of patients undergoing surgery should be considered.

Aspirin may enhance the effects of anticoagulants, antiplatelet agents and fibrinolytics leading to increased risk of bleeding.

It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.

Care should be taken in patients treated with any of the following drugs as interactions have been reported:

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

Anti-hypertensives: reduced anti-hypertensive effect.

Diuretics: reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels.

Lithium: decreased elimination of lithium.

Methotrexate: decreased elimination of methotrexate.

Cyclosporin: increased risk of nephrotoxity with NSAIDs.

Aminoglycosides: reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Probenecid: reduction in metabolism and elimination of NSAIDs and metabolites.

Oral hypoglycemic agents: inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

Antacids: patients using enteric coated aspirin should be advised against ingesting antacids simultaneously, to avoid premature drug release.

Aspirin may enhance the effects of anticoagulants, antiplatelet agents and fibrinolytics leading to increased risk of bleeding.

Carbonic anhydrase inhibitors: Concurrent administration of carbonic anhydrase inhibitors such as acetazolamide and salicylates may result in severe acidosis and increased central nervous system toxicity.

Corticosteroids: Plasma salicylate concentrations may be reduced by concurrent use of corticosteroids, and salicylate toxicity may occur following withdrawal of the corticosteroids. The risk of gastrointestinal ulceration and bleeding may be increased when aspirin and corticosteroids are co-administered (see Section 4.4).

Other NSAIDs: Avoid concomitant use with other NSAIDs.

Ibuprofen: Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Phenytoin and valproate: The effect of phenytoin and valproate may be enhanced by aspirin. However, no special precautions are needed.

Pregnancy: Although clinical and epidemiological evidence suggests the safety of aspirin for use in pregnancy, caution should be exercised when considering use in pregnant patients. Aspirin has the ability to alter platelet function and there may be a risk of haemorrhage in infants whose mothers have consumed aspirin during pregnancy. Prolonged pregnancy and labour, with increased bleeding before and after delivery, decreased birth weight and increased rate of stillbirth have been reported with high blood salicylate levels. With high doses there may be premature closure of the ductus arteriosus and possible persistent pulmonary hypertension in the newborn. Analgesic doses of aspirin should be avoided during the last trimester of pregnancy.

Lactation: As aspirin is secreted into breast milk, Nu-Seals should not be taken by patients who are breast-feeding, as there is a risk of Reye's syndrome in the infant. High maternal doses may impair platelet function in the infant.

None known.

Gastrointestinal: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4 - Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed. The special coating of Nu-Seals 300 helps to reduce the incidence of side effects resulting from gastric irritation.

Blood & lymphatic system: Aspirin prolongs bleeding time, and bleeding disorders, have occasionally been reported. Haemorrhages and haematoma in various organ systems may result, and fatalities have occurred. Anaemia may occur following chronic gastrointestinal blood loss or acute haemorrhage. Very rarely, a reduction in platelet count (thrombocytopenia) may occur.

Immune system: Hypersensitivity reactions include skin rashes, urticaria, angioedema, bronchospasm and rarely, anaphylaxis.

Nervous system: Cerebral haemorrhage

Ear & labyrinth: Tinnitus

Respiratory: Asthma (see section 4.4 Special warnings and precautions), epistaxis, haemoptysis

Skin & subcutaneous tissue: Purpura, ecchymoses (see also Immune System)

Renal & urinary: Haematuria, urate kidney stones.

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare).

Clinical trial and epidemiologcal data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

If overdosage is suspected, the patient should be kept under observation for at least 24 hours, as symptoms and salicylate blood levels may not become apparent for several hours. With the enteric coated formulation, peak plasma levels may not occur for up to 12 hours.

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.

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

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

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.

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 4 years. In children aged 4 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.

Management

Give oral activated charcoal if an adult presents within one hour of ingestion of more than 125 mg/kg. The plasma salicylate concentration should be measured for patients who have ingested >125mg/kg. However, the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account.

Urea and electrolytes, INR/PTR and blood glucose should be monitored. Elimination is increased by urinary alkalisation, which is achieved by the administration of intravenous sodium bicarbonate. The urine pH should be monitored and further intravenous sodium bicarbonate may be required to maintain urinary pH 7.5-8.5 (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 10 years and over 70 have increased risk of salicylate toxicity, and may require dialysis at an earlier stage.

Pharmacotherapeutic group: Salicylic Acid & Derivatives

ATC code: N02B A

Aspirin has analgesic, antipyretic and anti-inflammatory actions.

It also has antithrombotic action which is mediated through inhibition of platelet activation.

Nu-Seals 300 tablets have an enteric coat sandwiched between a sealing coat and a top coat. The enteric coat is intended to resist gastric fluid whilst allowing disintegration in the intestinal fluid.

Owing to the delay that the coating imposes on the release of the active ingredient, Nu-Seals 300 is unsuitable for the short-term relief of pain.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg vas taken within 8 h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

In a bioequivalence study comparing the pharmacokinetics of the 300mg product with 4 x 75mg presentation in human volunteers, measures such as terminal phase half-life, area-under-the curve and peak plasma concentrations were recorded on days 1 and 4. On day 1 salicylate reached a peak plasma concentration of between 10.34 and 31.57 mcg/ml and between 11.76 and 27.47mcg/ml for the 300mg and 75mg tablets respectively. Time to peak concentration ranged from 4 to 8 hours and from 3 to 6 hours respectively. AUC ranged from 54.0 to 131.2 and from 64.3 to 137.6 h.mcg/ml respectively. The terminal phase half-life ranged from 1.33 to 2.63 hours and from 1.47 to 2.59 hours respectively. On day 4 C_max varied from 15.01 to 48.97 mcg/ml for the 300mg tablet and from 11.26 to 60.21 mcg/ml for 4 x 75mg tablets. T_max ranged from 4 to 8 hours and from 3 to 8 hours, whilst AUC ranged from 89.8 to 297.4 h.mcg/ml and from 61.5 to 293.4 h.mcg/ml respectively.

There are no pre-clinical data of relevance to the prescriber in addition to that summarised in other sections of the Summary of Product Characteristics.

Maize Starch

Hypromellose

Talc

Methacrylic acid – ethyl acrylate (1:1) copolymer dispersion 30 per cent

Emulsion silicone

Polyethylene glycol 3350

Propylene glycol

Benzyl alcohol

Printing ink containing shellac, iron oxide (E172), isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide (E527) and simeticone

Not applicable.

3 years.

Do not store above 25°C. Keep containers tightly closed.

Glass and/or HDPE bottles with screw caps containing 14, 100 or 500 tablets.

No special requirements.

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

PA 943/6/2

25^th November 2011