iMedi.co.uk

Bisoprolol And Aspirin 5mg/75mg Capsules

Document: spc-doc_PL 32226-0001 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bisoprolol and Aspirin 5mg/75mg Capsules, hard

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 5 mg Bisoprolol fumarate and 75 mg Acetylsalicylic acid. Excipient(s) with known effect: Lecithin (Soya)

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Capsule, hard

White capsule printed 5/75, size 1

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of hypertension in patients previously stabilised on the individual components.

Treatment of angina pectoris in patients previously stabilised on the individual components.

4.2    Posology and method of administration

Posology

Capsules for oral administration. One capsule to be taken daily

Special populations

Older people: No dosage adjustment is normally required, but 5 mg of bisoprolol per day may be adequate in some patients.

Renal or hepatic impairment:.

Due to the acetylsalicylic acid component, Bisoprolol and Aspirin 5mg /75mg capsules is contraindicated in patients with severe hepatic or renal insufficiency (see section 4.3). Caution should be exercised in patients with mild or moderate hepatic or renal insufficiency (see section 4.4 and 5.2).

Paediatric population: The safety and efficacy of Bisoprolol in children and adolescents has not been established. Therefore, Bisoprolol and Acetylsalicylic acid capsules should not be used in children or adolescents.

Duration of therapy:

Treatment with bisoprolol is generally a long-term therapy.

The treatment with bisoprolol must not be stopped abruptly since this might lead to a transitory worsening of condition. Especially in patients with ischemic heart disease, treatment must not be discontinued suddenly. Gradual reduction of daily dose is recommended.

4.3 Contraindications

This medicine is contraindicated in patients with:

•    hypersensitivity to bisoprolol

•    hypersensitivity to salicylic acid compounds or prostaglandin synthetase inhibitors (e.g. certain asthma patients who may suffer an attack or faint)

•    hypersensitivity to any of the excipients

•    acute heart failure or during    episodes of heart failure decompensation

requiring i.v. inotropic therapy

•    cardiogenic shock,

•    sinoatrial block,

sick sinus syndrome

second or third degree AV block, (without pacemaker) symptomatic bradycardia symptomatic hypotension

severe bronchial asthma, or severe chronic obstructive pulmonary disease severe forms of peripheral arterial occlusive disease and Raynaud's syndrome untreated phaeochromocytoma (see section 4.4) metabolic acidosis

gastric symptoms or patients who have suffered from stomach ache when previously using this medicine.

acute peptic ulcer and/or gastric/intestinal bleeding (see section 4.4) history of haemorrhagic cerebrovascular accident. severe hepatic or renal insufficiency.

haemorrhagic diathesis or coagulation disorders such as haemophilia and hypoprothrombinaemia.

glucose-6-phosphatedehydrogenase deficiency (G6Pd deficiency) methotrexate used at doses > 15mg/week peanut or soya allergies.

4.4 Special warnings and precautions for use Bisoprolol

Bisoprolol must be used with caution in:

•    diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia (e.g. tachycardia, palpitations or sweating) can be masked

•    strict fasting

•    ongoing desensitisation therapy. As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Epinephrine treatment may not always yield the expected therapeutic effect first degree AV block

• Prinzmetal's angina

• peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when starting therapy.

Bisoprolol must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after carefully balancing of benefits against risks.

The symptoms of thyrotoxicosis may be masked under treatment with bisoprolol In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.

In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the postoperative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthetist must be aware of beta-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocking agent therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.

In bronchial asthma or other chronic obstructive pulmonary disease, which may cause symptoms, concomitant bronchodilating therapy is recommended. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of beta2-stimulants may have to be increased.

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type or with centrally acting antihypertensive drugs is generally not recommended, for details please refer to section 4.5.

Athletes: Athletes should note that this product contains an active substance which may cause a positive reaction in doping tests.

Acetylsalicylic acid

Concomitant treatment with anticoagulants (coumarin derivatives, heparin) is not recommended and should generally be avoided. If concurrent use cannot be avoided, frequent monitoring of the International Normalisation Ratio (INR) is indicated and patients should be cautioned to watch for signs of bleeding, especially in the gastrointestinal tract.

Close medical monitoring is also necessary for patients with bronchial asthma, allergic rhinitis (Acetylsalicylic acid may cause severe urticaria, angioedema, or bronchospasm).

Patients with a history of peptic ulcer disease and/or gastrointestinal haemorrages should avoid using Acetylsalicylic acid (which can cause gastric mucosal irritation and bleeding). If bleeding signs and symptoms continue due to the Acetylsalicylic acid component, the physician may discontinue this product.

Caution should be exercised in patients with hepatic insufficiency (as Acetylsalicylic acid is metabolised mainly via the liver, see section 5.2) and in patients with renal failure.

The concomitant administration of this active substance with uricosuric agents like benzbromarone, probenecid, sulphinpyrazone is not recommended (see section 4.5).

Acetylsalicylic acid must be used with care in cases of very severe menstrual bleeding.

It is preferable to stop use of Acetylsalicylic acid before a surgical procedure (including tooth extraction) because of the risk of a prolonged bleeding time or an aggravation of the bleeding. The length of the interruption of the treatment should be determined on a case-by-case basis, but will usually be one week.

This medicine contains soya lecithin and is contraindicated in patients who have peanut or soya allergies.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Bisoprolol

Combinations not recommended

Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: negative effect on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypoension and atrio-ventricular block.

Centrally-acting antihypertensive drugs (e.g. clonidine methyldopa, moxonidine, rilmenidine): concomitant use of centrally-acting antihypertensive drugs may further decrease the central sympathetic tonus and may thus lead to reduction of heart rate and cardiac output and to vasodilation. Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase the risk of "rebound hypertension".

Combinations to be used with caution

Class-I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone): effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine: Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded.

Class-III antiarrhythmic drugs (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.

Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.

Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.

Insulin and oral antidiabetic drugs: Increase of blood sugar lowering effect. Blockade of beta-adrenoreceptors may mask symptoms of hypoglycaemia.

Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension(for further information on general anaesthesia see also section 4.4).

Cardiac glycosides (e.g.digoxin): Reduction of heart rate, increase of atrioventricular conduction time.

Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.

Beta-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.

Sympathomimetics that activate both beta- and alpha-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the alpha-adrenoceptor-mediated vasoconstrictor effects of these agents leading to blood pressure increase and exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective beta-blockers.

Concomitant use with antihypertensive agents as well as with other drugs with blood pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of hypotension.

Combinations to be considered

Mefloquine: increased risk of bradycardia

Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blockers but also risk for hypertensive crisis.

Rifampicin: Slight reduction of the half-life of bisoprolol possible due to the induction of hepatic drug metabolising enzymes. Normally no dosage adjustment is necessary.

Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances. Acetvlsalicvlic acid

The use of several platelet aggregation inhibitors, i.e. Acetylsalicylic acid, NSAIDs, ticlopidine, clopidogrel, tirofiban, eptifibatide, increases the risk of bleeding, likewise their combination with heparin and its derivatives (hirudine, fondaparinux), oral anticoagulants and thrombolytics. Clinical and biological parameters of haemostasis should be regularly monitored.

Contraindicated combinations

Methotrexate (used at doses > 15 mg/week): the combined drugs, methotrexate and Acetylsalicylic acid, increase haematological toxicity of methotrexate due to the decreased renal clearance of methotrexate by Acetylsalicylic acid. Therefore, the concomitant use of methotrexate with this medicine is contraindicated (see section 4.3).

Not recommended associations

Uricosurics agents (benzbromarone, probenecid, and sulphinpyrazone): reduced effect of uric acid excretion by competition of renal tubular uric acid elimination. Therefore, the concomitant use of this medicine with uricosurics agents is not recommended (see section 4.4).

Combinations requiring precautions for use

Diuretics: risk of acute renal failure due to the decreased glomerular filtration via decreased renal prostaglandin synthesis. Hydrating the patient and monitoring renal function at the start of the treatment.

Corticosteroids: the concomitant administration of steroids may enhance the risk of GI bleeding or ulceration.

Methotrexate used at doses lower than 15 mg/week: the combined drugs, methotrexate and Acetylsalicylic acid, increased haematological toxicity of methotrexate due to the decreased renal clearance of methotrexate by Acetylsalicylic acid. Weekly blood count checks should be done during the first weeks of the combination. Enhanced monitoring in the presence of even mildly impaired renal function, as well as in elderly.

Heparin used at curative dosage or in elderly patients: when Acetylsalicylic acid is coadministered with heparin at curative dosage or in elderly patients, there is an increased risk of bleeding. Close monitoring of the INR, aPTT and/or bleeding time should be performed in the case of concomitant administration of both drugs.

Cardiac glycosides (e.g. digoxin): NSAIDs (including acetylsalicylic acid) may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels.

Lithium : decreased elimination of lithium.

Combinations to be taken into account

Other anticoagulants (coumarin derivatives, heparin at preventive dosage), other platelet antiaggregants and other thrombolytics: increased risk of bleeding.

NSAIDs: increased risk of bleeding and of damage on gastrointestinal mucosa and enhancement of prolonging bleeding time.

Antacids: antacids can increase the renal excretion of Acetylsalicylic acid by alkalinising the urine.

Alcohol: addition of their own damage on gastrointestinal mucosa and enhancement of prolonging bleeding time.

4.6 Fertility, pregnancy and lactation

Bisoprolol and Aspirin 5mg /75mg capsules are not recommended during pregnancy unless clearly necessary

Pregnancy

There are no data from the use of Bisoprolol and Aspirin 5mg /75mg capsules in pregnant women.

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn (see section 5.3). In general, P-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If treatment with P-adrenoceptor blockers is necessary, p1-selective adrenoceptor blockers are preferable.

Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

The effects of Acetylsalicylic acid can include inhibition of labour; premature (intrauterine) closure of ductus arteriosis; pulmonary hypertension of the neonate and insufficiency of the tricuspid valve; renal injury with possible renal insufficiency and oligohydramnios; and blood clotting.

Breastfeeding

It is not known whether bisoprolol is excreted in human milk. Salicylates and their metabolites are excreted in small amounts in human milk. Therefore, breastfeeding is not recommended during administration of this product.

Fertility

There is no data on the possible effects of this medicine on male or female fertility.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive or use machines have been performed. In a study of coronary heart disease patients, bisoprolol did not impair driving performance. However, due to individual variations in reactions to the drug, the ability to drive a vehicle or to operate machinery may be impaired. This should be considered particularly at the start of treatment and upon change of medication as well as in conjunction with alcohol.

4.8 Undesirable effects

Tabulated summary of adverse reactions

Adverse reactions are classified according to frequency and System Organ Class. The following definitions apply to the frequency terminology used hereafter:

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)

Not known (cannot be estimated from the available data)

Bisoprolol

The following data results from bisoprolol:

Investigations:

Rare: increased triglycerides, increased liver enzymes (ALAT,ASAT)

Cardiac disorders:

Uncommon: bradycardia, worsening of pre-existing heart failure AV-stimulus disturbances,.

Ear and labyrinth disorders:

Rare: hearing disorders.

Eye disorders:

Rare: reduced tear flow (to be considered if the patient uses lenses).

Very rare: conjunctivitis.

Gastrointestinal disorders:

Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.

General disorders:

Common:, fatigue1

Uncommon: asthenia.

Hepatobiliary disorders:

Rare: hepatitis.

Nervous system disorders:

Common: dizziness1, headache1.

Rare: syncope

Reproductive system and breast disorders:

Rare: Potency disorders.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Bronchospasm in patients with bronchial asthma or a history of obstructive airways disease.

Rare: allergic rhinitis.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (such as itching, flush, rash).

Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.

Musculoskeletal and connective tissue disorders:

Uncommon: muscle weakness, muscle cramps.

Vascular disorders:

Common: Feeling of coldness or numbness in the extremities.

Uncommon: hypotension.

Psychiatric disorders

Uncommon: Sleep disturbances, depression.

Rare: Nightmares, hallucinations,

Acetvlsalicvlic acid

The undesirable effects are often dose-dependent and are due to the pharmacological effect of Acetylsalicylic acid (see section 5.1). Most undesirable effects are usually associated with the gastrointestinal tract. Patients with known allergies or asthma are at increased risk of hypersensitivity reactions. Crosshypersensitivity to other NSAIDs may develop.

Blood and the lymphatic disorders:

Common: prolongation of the bleeding time. This effect can persist for several days after stopping the treatment and can give rise to haemorrhagic risks in the event of surgery or can lead to heavier menstruation

Uncommon: intracranial bleeding, blood in urine

Rare: haemorrhagic syndrome (nosebleeds, bleeding gums, bloody vomiting and blood loss via the faeces, etc.).

Endocrine disorders:

Very rare: hypoglycemia

Metabolism and nutrition disorders:

Very rare: Low-dose Acetylsalicylic acid can reduce the excretion of uric acid (which can lead to acute gout in predisposed patients).

Nervous system disorders:

Rare: dizziness, headache, tinnitus. These are usually the first indications of overdose (see section 4.9).

Gastrointestinal disorders:

Very common: gastric complaints such as hyperacidity and nausea

Common: vomiting, gastritis, mild to moderate blood loss in the gastrointestinal tract, diarrhoea. With long-term or repeated use this blood loss can lead to anaemia.

Uncommon: gastric bleeding, gastric ulcers

Very rare: gastrointestinal perforation

Hepato-biliarv disorders:

Very rare: liver impairment.

Skin and subcutaneous tissue disorders:

Very rare: severe skin reactions (e.g. erythema exsudativum multiforme)

Renal and urinary disorders:

Very rare: acute renal insufficiency, especially in patients with existing renal insufficiency, heart decompensation, nephrotic syndrome or concomitant treatment with diuretics

Hypersensitivity reactions:

Uncommon: urticaria, skin rash, angio-oedema, rhinitis, bronchial spasms

Very rare: anaphylactic shock, aggravation of the allergic symptoms of food allergy

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/vellowcard.

4.9 Overdose

Bisoprolol

The most common signs expected with overdosage of a B-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. To date a few cases of overdose (maximum: 2000 mg) with bisoprolol have been reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide interindividual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive. .

In general, if overdose occurs, bisoprolol treatment should be stopped and supportive and symptomatic treatment should be provided. Limited data suggest that bisoprolol is hardly dialysable. Based on the expected pharmacological actions and recommendations for other B-blockers, the following general measures should be considered when clinically warranted.

Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenaline or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.

Hypotension: Intravenous fluids and vasopressors should be administered. Intravenous glucagon may be useful.

AV block (second or third degree): Patients should be carefully monitored and treated with isoprenaline infusion or transvenous cardiac pacemaker insertion.

Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, B2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

Acetylsalicylic acid

Overdosage is unlikely due to the low level of Acetylsalicylic acid in this product. However intoxication (accidental overdose) in very young children or therapeutic overdose in older people may present as follows: The following are associated with moderate intoxication: dizziness, headache, tinnitus, confusion and gastrointestinal symptoms (nausea, vomiting and gastric pain).

With severe intoxication, serious disturbances of the acid-base equilibrium occur. Initial hyperventilation leads to respiratory alkalosis. Subsequently a respiratory acidosis occurs as a result of a suppressive effect on the respiratory centre. A metabolic acidosis also arises due to the presence of salicylate. Given that children, infants and toddlers are often only seen at a late stage of intoxication, they will usually have already reached the acidosis stage. The following can also arise: hyperthermia and perspiration, leading to dehydration, restlessness, convulsions, hallucinations and hypoglycaemia. Depression of the nervous system can lead to coma, cardiovascular collapse and respiratory arrest. The lethal dose of Acetylsalicylic acid is 25-30 gram. Plasma salicylate concentrations above 300 mg/l (1,67 mmol/l) suggest intoxication.

If a toxic dose has been ingested then admission to hospital is necessary. With moderate intoxication an attempt can be made to induce vomiting; if this fails, gastric lavage is indicated. Activated charcoal (adsorbent) and sodium sulphate (laxative) are then administered. Alkalising of the urine (250 mmol NaHCO3 for 3 hours) while monitoring the urine pH is indicated. Haemodialysis is the preferred treatment for severe intoxication. Treat other signs of intoxication symptomatically.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: beta blocking agents; bisoprolol combinations, ATC code: C07AB57

Bisoprolol is a potent, highly Pi-selective adrenoreceptor blocking agent. The mode of action in hypertension is not clear but it is known that bisoprolol markedly depresses plasma renin activity. In patients with angina, the blockade of p1 -receptors reduces heart action and thus reduces oxygen demand. Hence bisoprolol is effective in eliminating or reducing the symptoms.

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

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.

Acetylsalicylic acid extends bleeding time on average by approximately 50 to 100%, but individual variations can be observed.

The European Medicines Agency has waived the obligation to submit the results of studies with Bisoprolol and Aspirin 5mg /75mg capsules in all subsets of the paediatric population in essential (primary) hypertension, secondary hypertension, angina pectoris. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Bisoprolol

Bisoprolol is absorbed and has a biological availability of about 90% after oral administration. The plasma protein binding of bisoprolol is about 30%. The distribution volume is 3.5 l/kg. Total clearance is approximately 15 l/h. The half-life in plasma of 10-12 hours gives a 24 hour effect after dosing once daily.

Bisoprolol is eliminated from the body by two routes. 50% is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in an unmetabolised form. Since the elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for patients with impaired liver function or renal insufficiency. The pharmacokinetics in patients with stable chronic heart failure and with impaired liver or renal function has not been studied.

The kinetics of bisoprolol are linear and independent of age.

In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the half-life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64±21 ng/ml at a daily dose of 10 mg and the half-life is 17±5 hours.

Acetylsalicylic acid

Absorption

Maximum plasma concentration (Cmax) is reached after about 50 minutes (tmax). The principal site of absorption is the proximal small intestine. A significant portion of the dosage, however, is already hydrolysed to salicylic acid in the intestinal wall during the absorption process.

The degree of hydrolysis is contingent on the rate of absorption.

Simultaneous ingestion of food delays the absorption of acetyl salicylic acid (lower plasma concentrations) but does not reduce it.

Distribution

The volume of distribution of acetyl salicylic acid is ca. 0.16 l/kg of body weight. The salicylic acid, which is the first conversion product made from acetyl salicylic acid, is bound to plasma protein, largely albumin, by more than 90%. Salicylic acid slowly diffuses into the synovial fluid. It passes the placenta and passes into breast milk.

Biotransformation

Acetyl salicylate is primarily converted into salicylic acid through hydrolysis.

The half-life of acetyl salicylic acid is short: ca. 15 - 20 minutes.

Salicylic acid is subsequently converted into glycine and glucuronic acid conjugates, and traces of gentisic acid. At higher therapeutic dosage rates the conversion capacity of salicylic acid is exceeded with the pharmacokinetics becoming non-linear.

This results in protraction of the apparent elimination half-life of salicylic acid from a few hours to around a twenty-four hour period.

Elimination

Elimination largely occurs through the kidneys. The tubular reabsorption of acetyl salicylic acid is pH-contingent. Through the alkalisation of the urine, the portion of unaltered acetyl salicylic acid in the urine may increase from ca. 10% up to ca. 80%.

5.3 Preclinical safety data

Bisoprolol

Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. Like other beta-blockers, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resoprtions, reduced birth weight of the offspring, retarded physical development) at high doses, but was not teratogenic.

Acetvlsalicvlic acid

In rat studies, fetotoxicity and teratogenic effects were observed with Acetylsalicylic acid at maternotoxic doses. Clinical relevance is unknown as the doses used in nonclinical studies are much higher (7 times at least) than the maximal recommended doses in targeted cardiovascular indications.

No carcinogenic effects were observed in mice and rat studies.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Aspirin tablet:

Maize Starch,

Cellulose, microcrystalline Stearic acid

Film Coating:

Polyvinyl alcohol hydrolysed Titanium dioxide (E171)

Talc

Lecithin (Soya) (E322)

Xanthan gum

Bisoprolol powder:

Cellulose, microcrystalline Magnesium stearate,

Capsule:

Gelatin

Titanium dioxide (E171)

Ink containing:

Shellac, Iron oxide black (E172), propylene glycol, ammonium hydroxide.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

4 years

6.4 Special precautions for storage

Do not store above 25oC.

6.5 Nature and contents of container

Polychlorotrifluoroethylene /PVC blister with aluminium /PVC foil. Pack sizes: 14, 28, 30 & 90 capsules Not all pack sizes may be marketed

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

ASA Pharma PLC

6 Northbrook Road, Dublin 6, Ireland.

8    MARKETING AUTHORISATION NUMBER(S)

PL 32226/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 04/11/2015

10


DATE OF REVISION OF THE TEXT

04/11/2015

1

These symptoms especially occur at the beginning of the therapy. They are generally mild and usually disappear within 1-2 weeks.