DANAMEP 75 MG TABLETS, DISPERSIBLE ASPIRIN TABLETS 75 MG, MANDAPRIN 75 MG DISPERSIBLETABLETS - summary of medicine characteristics

Dispersible Aspirin Tablets 75mg

Danamep 75mg Tablets

Mandaprin 75mg Dispersible Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 75mg Aspirin

3 PHARMACEUTICAL FORM

White, flat, bevelled edged tablet.

Embossed with ‘ASP’ and ‘75’ on one side and plain on the reverse.

4.1 Therapeutic indications

Dispersible aspirin 75mg tablets are indicated for the secondary prevention of thrombotic cerebrovascular or cardiovascular disease and following by-pass surgery.

4.2 Posology and method of administration

For oral administration. The tablets should be dispersed in water before taking.

Adults

The advice of a doctor should be sought before commencing therapy for the first time. The usual dosage, for long term use, is 75 – 150 mg once daily. In some circumstances a higher dose may be appropriate, especially in the short term, and up to 300mg a day may be used on the advice of a doctor.

Elderly

In general, acetylsalicylic acids should be used with caution in elderly patients who are more prone to adverse events. The usual adult dose is recommended in the absence of severe renal or hepatic insufficiency (see sections 4.3 and 4.4). Treatment should be reviewed at regular intervals.

Children under 16 years of age

Do not give to children under 16 years of age, unless specifically indicated (eg for Kawasaki’s di­sease).

4.3 Contraindications

Aspirin is contra-indicated in:

Hypersensitivity to salicylic acid compounds or prostaglandin synthetase inhibitors (e.g. certain asthma patients who may suffer an attack or faint and certain patients who may suffer from bronchospasm, rhinitis and urticaria) and to any of the excipients

Peptic ulceration or history of peptic ulceration and/or gastric/intestinal haemorrhage, or other kinds of bleeding such as cerebrovascular haemorrhages

Severe hepatic impairment

Severe renal impairment

Gout

Children under 16 (except under medical supervision for use for example in juvenile rheumatoid arthritis)

Doses >100 mg/day during the third trimester of pregnancy (see section 4.6)

Breast feeding

Haemorrhagic diathesis; coagulation disorders such as haemophilia and thrombocytopenia and where there is concurrent anti-coagulant therapy

Methotrexate used at doses > 15 mg/week (see section 4.5).

4.4 Special warnings and precautions for use

Dispersible Aspirin 75 mg Tablets are not suitable for use as an anti-inflammatory/a­nalgesic/anti­pyretic.

Before commencing long-term aspirin therapy for the management of cardiovascular or cerebrovascular disease patients should consult their doctor who can advise on the relative benefits versus the risks for the individual patient.

Administer with caution in the presence of allergic disease, renal or hepatic impairment and dehydration. Liver tests should be performed regularly in patients presenting slight or moderate hepatic insufficiency.

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. for Kawasaki’s di­sease).

There is an increased risk of haemorrhage particularly during or after operative procedures (even in cases of minor procedures, e.g. tooth extraction). Use with caution before surgery, including tooth extraction. Temporary discontinuation of treatment may be necessary.

Dispersible Aspirin 75 mg Tablets are not recommended during menorrhagia where it may increase menstrual bleeding.

Dispersible Aspirin 75 mg Tablets are to be used with caution in cases of hypertension and when patients have a past history of gastric or duodenal ulcer or haemorrhagic episodes or are undergoing therapy with anticoagulants.

Patients should report any unusual bleeding symptoms to their physician. If gastrointestinal bleeding or ulceration occurs the treatment should be withdrawn.

Acetylsalicylic acid may promote bronchospasm and asthma attacks or other hypersensitivity reactions. Risk factors are existing asthma, hay fever, nasal polyps or chronic respiratory diseases. The same applies for patients who also show allergic reaction to other substances (e.g. with skin reactions, itching or urticaria).

Serious skin reactions, including Steven-Johnsons syndrome, have rarely been reported in association with the use of acetylsalicylic acid (see section 4.8). Dispersible Aspirin 75 mg Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

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

Concomitant treatment with Dispersible Aspirin 75 mg Tablets and other drugs that alter haemostasis (i.e. anticoagulants such as warfarin, thrombolytic and antiplatelet agents, anti-inflammatory drugs and selective serotonin reuptake inhibitors) is not recommended, unless strictly indicated, because they may enhance the risk of haemorrhage (see section 4.5). If the combination cannot be avoided, close observation for signs of bleeding is recommended.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration, such as oral corticosteroids, selective serotonin-reuptake inhibitors and deferasirox (see section 4.5).

Acetylsalicylic acid in low doses reduces uric acid excretion. Due to this fact, patients who tend to have reduced uric acid excretion may experience gout attacks (see section 4.5).

The risk of hypoglycaemic effect with sulfonylureas and insulins may be potentiated with Dispersible Aspirin 75 mg Tablets taken at over dosage (see section 4.5).

Dispersible Aspirin 75 mg Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction Contraindicated combinations

Methotrexate (used at doses >15 mg/week):

The combined drugs, methotrexate and acetylsalicylic acid, enhance haematological toxicity of methotrexate due to the decreased renal clearance of methotrexate by acetylsalicylic acid. Therefore, the concomitant use of methotrexate (at doses >15 mg/week) with Dispersible Aspirin 75 mg Tablets is contraindicated (see section 4.3).

Not recommended combinations

Uricosuric agents, e.g. probenecid and sulfinpyrazone

Salicylates reverse the effect of probenecid. The combination should be avoided.

Combinations requiring precautions for use or to be taken into account Anticoagulants e.g. coumarin, heparin, warfarin

Increased risk of bleeding due to inhibited thrombocyte function, injury of the duodenal mucosa and displacement of oral anticoagulants from their plasma protein binding sites. The bleeding time should be monitored (see section 4.4).

Anti-platelet agents (e.g clopidogrel, ticlopidine and dipyridamole) and selective serotonin reuptake inhibitors (SSRIs; such as sertraline or paroxetine)

Increased risk of gastrointestinal bleeding (see section 4.4).

Antidiabetics, e.g. sulphonylureas

Salicylics may increase the hypoglycaemic effect of sulphonylureas.

Digoxin and lithium

Acetylsalicylic acid impairs the renal excretion of digoxin and lithium, resulting in increased plasma concentrations. Monitoring of plasma concentrations of digoxin and lithium is recommended when initiating and terminating treatment with acetylsalicylic acid. Dose adjustment may be necessary

Diuretics and antihypertensives

NSAIDs may decrease the antihypertensive effects of diuretics and other antihypertensive agents. As for other NSAIDs concomitant administration with ACE-inhibitors increases the risk of acute renal insufficiency.

Diuretics: Risk of acute renal failure due to the decreased glomerual filtration via decreased renal prostaglandin synthesis. Hydrating the patient and monitoring renal function at the start of the treatment is recommended.

Aspirin antagonises the diuretic effect of spironolactone.

Carbonic anhydrase inhibitors (acetazolamide)

May result in severe acidosis and increased central nervous system toxicity

Systemic corticosteroids

The risk of gastrointestinal ulceration and bleeding may be increased when acetylsalicylic acid and corticosteroids are co-administered (see section 4.4).

Methotrexate (used at doses <15 mg/week):

The combined drugs, methotrexate and acetylsalicylic acid, may increase haematological toxicity of methotrexate due to decreased renal clearance of methotrexate by acetylsalicylic acid. Weekly blood count checks should be done during the first weeks of the combination. Enhanced monitoring should take place in the presence of even mildly impaired renal function, as well, as in elderly.

Other NSAIDs

Increased risk of ulcerations and gastrointestinal bleeding due to synergistic effects.

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).

Ciclosporin, tacrolimus

Concomitant use of NSAIDs and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin and tacrolimus. The renal function should be monitored in case of concomitant use of these agents and acetylsalicylic a­cid.

Valproate

Acetylsalicylic acid has been reported to decrease the binding of valproate to serum albumin, thereby increasing its free plasma concentrations at steady state.

Phenytoin

Salicylate diminishes the binding of phenytoin to plasma albumin. This may lead to decreased total phenytoin levels in plasma, but increased free phenytoin fraction. The unbound concentration, and thereby the therapeutic effect, does not appear to be significantly altered.

Alcohol

Concomitant administration of alcohol and acetylsalicylic acid increases the risk of gastrointestinal bleeding.

Antacids will reduce the effect of aspirin. Principle incompatibilities are iron salts, carbonates and alkali hydroxides.

Metoclopramide potentiates the effect of aspirin.

Metamizole

Metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation, when taken concomitantly. Therefore, this combination should be used with caution in patients taking low dose aspirin for cardioprotection.

4.6 Fertility, pregnancy and lactation

Pregnancy

Low doses (up to 100 mg/day):

Clinical studies indicate that doses up to 100 mg/day for restricted obstetrical use, which require specialised monitoring, appear safe.

Doses of 100 – 500 mg/day:

There is insufficient clinical experience regarding the use of doses above 100 mg/day up to 500 mg/day. Therefore, the recommendations below for doses of 500 mg/day and above apply also for this dose range.

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, acetylsalicylic 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

Low quantities of salicylates and of their metabolites are excreted into the breast milk. Since adverse effects for the infant have not been reported up to now, short-term use of the recommended dose does not require suspending lactation. In cases of long-term use and/or administration of higher doses, breastfeeding should be discontinued.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed with Aspirin 75mg Gastro-resistant Tablets.

Based on the pharmacodynamic properties and the side effects of acetylsalicylic acid, no influence on the reactivity and the ability to drive or use machines is expected.

4.8 Undesirable effects

Side effects are grouped on the basis of System Organ Class. Within each system organ class the frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to

<1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

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

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents: platelet aggregation inhibitors excl. heparin, ATC code: B01AC06.

Acetylsalicylic acid inhibits the platelet activation: blocking the platelet cyclooxygenase by acetylation, it inhibits thromboxane A2 synthesis, a physiological activating substance released by the platelets and which would play a role in the complications of the atheromatosic lesions.

Inhibition of TXA2-synthesis is irreversible, because thrombocytes, which have no nucleus, are not capable (due to lack of protein synthesis capability) to synthesise new cyclooxygenase, which had been acetylated by acetylsalicylic a­cid.

The repeated doses from 20 to 325 mg involve an inhibition of the enzymatic activity from 30 to 95%.

Due to the irreversible nature of the binding, the effect persists for the lifespan of a thrombocyte (7–10 days). The inhibiting effect does not exhaust during prolonged treatments and the enzymatic activity gradually begins again upon renewal of the platelets 24 to 48 hours after treatment interruption.

Excretion

Salicylic acid and its metabolites are predominantly excreted via the kidneys.

5.3 Preclinical safety data

In experimental animal studies, salicylates have shown no other organ injury than renal damage.

In rat studies, fetotoxicity and teratogenic effects were observed with acetylsalicylic acid at maternotoxic doses. Clinical relevance is unknown as the doses used in non-clinical studies are much higher (7 times at least) than the maximal recommended doses in targeted cardiovascular indications. Acetylsalicylic acid was extensively investigated with regard to mutagenic and carcinogenic effects. The results as a whole show no relevant signs for any mutagenic or carcinogenic effects in mice and rat studies.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The tablets contain Starch, Lactose, Sodium Saccharin, Citric Acid Anhydrous, Calcium Carbonate, Talc and Sodium Lauryl Sulphate

6.2 Incompatibilities

None known

6.3 Shelf life

36 months

6.4 Special precautions for storage

For bottles, store in original container, keep container tightly closed. For blister packaging, store in original package, inside outer carton.

6.5 Nature and contents of container

HDPE or Snapsafe polypropylene containers with LDPE lids. Packs of 25, 50, 100 and 1000 tablets.

Child resistant Blister strips of 0.25mm PVC/ 35gsm Glassine (Pergamin) paper/ 0.009mm aluminium enclosed in a cardboard carton:

10, 14, 16, 20, 24, 28, 30, 32, 40, 42, 50, 56, 60, 70, 80, 84, 90, 98 and 100 tablets.

6.6 Special precautions for disposal

Not applicable

7 MARKETING AUTHORISATION HOLDER

M & A Pharmachem Ltd

Wigan Road

Westhoughton

Bolton BL5 2AL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04077/0182

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/06/2008