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Thursday, October 20, 2016

Bisoprolol Fumarate 7.5 mg Film-coated Tablets

1. Name Of The Medicinal Product

Bisoprolol Fumarate 7.5 mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 7.5 mg bisoprolol fumarate

Excipients:

Each tablet contains lactose (as lactose monohydrate 1.77 mg)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

yellow-white, round tablet with a score and encoded "BIS 7.5" on one side

The tablet can be divided into equal thirds.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides (For additional information see section 5.1).

4.2 Posology And Method Of Administration

Method of administration

Bisoprolol tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.

Treatment of stable chronic heart failure

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocking agent, diuretics, and when appropriate cardiac glycosides. Patients should be stable (without acute failure) when bisoprolol treatment is initiated.

It is recommended that the treating physician should be experienced in the management of chronic heart failure.

Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.

Titration phase

The treatment of stable chronic heart failure with bisoprolol requires a titration phase.

The treatment with bisoprolol is to be started with a gradual up titration according to the following steps:

1.25 mg once daily for 1 week, if well tolerated increase to

2.5 mg once daily for a further week, if well tolerated increase to

3.75 mg once daily for a further week, if well tolerated increase to

5 mg once daily for the 4 following weeks, if well tolerated increase to

7.5 mg once daily for the 4 following weeks, if well tolerated increase to

10 mg once daily for the maintenance therapy.

The maximum recommended dose is 10 mg once daily.

Close monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart failure is recommended during the titration phase. Symptoms may already occur within the first day after initiating the therapy.

Treatment modification

If the maximum recommended dose is not well tolerated, gradual dose reduction may be considered.

In case of transient worsening of heart failure, hypotension, or bradycardia reconsideration of the dosage of the concomitant medication is recommended. It may also be necessary to temporarily lower the dose of bisoprolol or to consider discontinuation.

The reintroduction and/or uptitration of bisoprolol should always be considered when the patient becomes stable again.

Duration of treatment

Treatment of stable chronic heart failure with bisoprolol is generally a long-term treatment.

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

Renal or liver impairment

There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired liver or renal function. Uptitration of the dose in these populations should therefore be made with additional caution.

Elderly

No dosage adjustment is required.

Children and adolescents

There is no experience with bisoprolol in children and adolescents, therefore its use cannot be recommended for children.

4.3 Contraindications

Bisoprolol is contra-indicated in:

• hypersensitivity to bisoprolol or to any of the excipients

• acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy

• cardiogenic shock

• AV block of second or third degree (without a pacemaker)

• sick sinus syndrome

• sinoatrial block

• symptomatic bradycardia

• symptomatic hypotension

• severe bronchial asthma or severe chronic obstructive pulmonary disease

• severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome

• untreated phaeochromocytoma (see section 4.4)

• metabolic acidosis

• combinations with floctafenin and sultopride

4.4 Special Warnings And Precautions For Use

The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase (see section 4.2).

Especially in patients with ischaemic heart disease the cessation of therapy with bisoprolol must not be done abruptly unless clearly indicated, because this may lead to transitional worsening of heart condition (see section 4.2).

The initiation of treatment of stable chronic heart failure with bisoprolol necessitates regular monitoring. For the posology and method of administration please refer to section 4.2.

Bisoprolol must be used with caution in:

• bronchospasm (bronchial asthma, obstructive airways diseases)

• 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.

• AV block of first degree

• Prinzmetal's angina

• peripheral arterial occlusive disease (intensification of complaints might happen especially during the start of therapy)

• General anaesthesia

In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthesist must be aware of beta-blockade because of the potential for interactions with other medicinal products, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the 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.

There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the following diseases and conditions:

• insulin dependent diabetes mellitus (type I)

• severely impaired renal function

• severely impaired liver function

• restrictive cardiomyopathy

• congenital heart disease

• haemodynamically significant organic valvular disease

• myocardial infarction within 3 months

Combination of bisoprolol with calcium antagonists of the verapamil and diltiazem type, with Class I antiarrhytmic medicinal products and with centrally acting antihypertensive medicinal products is generally not recommended, for details please refer to section 4.5.

In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy should be given concomitantly. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of beta₂-stimulants may have to be increased.

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

In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.

Under treatment with bisoprolol the symptoms of a thyrotoxicosis may be masked.

Lactose

This medicinal product contains 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

Combinations contra-indicated:

floctafenine: Beta blocking agents may impede the compensatory cardiovascular reactions associated with hypotension or shock that may be induced by floctafenine.

sultopride: Bisoprolol should not be concomitantly administered with sultopride since there is an increase risk of ventricular arrhythmia.

Combinations not recommended

Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: Negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on β-blocker treatment may lead to severe hypotension and atrioventricular block.

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

Centrally acting antihypertensive medicinal products such as clonidine and others (e.g. methyldopa, moxonodine, rilmenidine): Concomitant use of centrally acting antihypertensive medicinal products may worsen heart failure by a decrease in the central sympathetic tonus (reduction of heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-blocking agent discontinuation, may increase risk of “rebound hypertension”.

Combinations to be used with caution

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 medicinal product (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.

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

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

Insulin and oral antidiabetic medicinal products: Intensification 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.).

Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time.

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

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

Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the α-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

β-blockers.

Concomitant use with antihypertensive agents as well as with other medicinal products 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-blocking agents but also risk for hypertensive crisis.

4.6 Pregnancy And Lactation

Pregnancy:

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-adrenoceptor blocking agents 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 foetus and newborn infant. If treatment with beta-adrenoceptor blocking agents is necessary, beta₁-selective adrenoceptor blocking agents are preferable.

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

Lactation:

There are no data on the excretion of bisoprolol in human breast milk or the safety of bisoprolol exposure in infants.Therefore, breastfeeding is not recommended during administration of bisoprolol.

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. In a study with coronary heart disease patients bisoprolol did not impair driving performance. However, due to individual variations in reactions to the medicinal product, the ability to drive a vehicle or to operate machinery may be impaired. This should be considered particularly at start of treatment and upon change of medication as well as in conjunction with alcohol.

4.8 Undesirable Effects

The following definitions apply to the frequency terminology used hereafter:

Very common (

Cardiac disorders

Very common: bradycardia in patients with chronic heart failure

Common: worsening of pre-existing heart failure in patients with chronic heart failure

Uncommon: AV-conduction disturbances

Very rare: chest pain

Investigations

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

Nervous system disorders:

Common: dizziness, headache

Rare: syncope

Eye disorders:

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

Very rare: conjunctivitis

Ear and labyrinth disorders

Rare: hearing disorders

Respiratory, thoracic and mediastinal disorders

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

Rare: allergic rhinitis

Gastrointestinal disorders

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

Skin and subcutaneous tissue disorders

Rare: hypersensitivity reactions (itching, flush, rash)

Very rare: beta-blocking agents may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia

Musculoskeletal and connective tissue disorders

Uncommon: muscular weakness and cramps

Vascular disorders

Common: feeling of coldness or numbness in the extremities, hypotension (especially in patients with heart failure)

Uncommon: orthostatic hypotension

General disorders

Common: asthenia, fatigue

Hepatobiliary disorders

Rare: hepatitis.

Reproductive system and breast disorders

Rare: potency disorders

Psychiatric disorders

Uncommon: sleep disorders, depression

Rare: nightmares, hallucinations

4.9 Overdose

With overdose (e.g. daily dose of 15 mg instead of 7.5 mg) third degree AV-block, bradycardia, and dizziness have been reported. In general the most common signs expected with overdose of a beta-blocking agent are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. To date a few cases of overdose (maximum: 2000 mg) with bisoprolol have been reported in patients suffering from hypertension and/or coronary heart disease showing bradycardia and/or hypotension; 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. Therefore it is mandatory to initiate the treatment of these patients with a gradual uptitration according to the scheme given in section 4.2.

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 pharmacologic actions and recommendations for other beta-blocking agents, 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, beta₂-sympathomimetic medicinal products and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Beta blocking agents, selective. ATC Code: C07AB07

Bisoprolol is a highly beta₁-selective-adrenoceptor blocking agent, lacking intrinsic sympathomimetic and relevant membrane stabilising activity. It only shows low affinity to the beta₂-receptor of the smooth muscles of bronchi and vessels as well as to the beta₂-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta₂-mediated metabolic effects. Its beta₁-selectivity extends beyond the therapeutic dose range.

Bisoprolol is used for the treatment of hypertension, angina pectoris and heart failure. As with other Beta-1-blocking agents, the method of acting in hypertension is unclear. However, it is known that Bisoprolol reduces plasma renin activity markedly.

Antianginal mechanism: Bisoprolol by inhibiting the cardiac beta receptors inhibits the response given to sympathetic activation. That results in the decrease of heart rate and contractility this way decreasing the oxygen demand of the cardiac muscle.

The indication heart failure was investigated in the CIBIS II trial. In total 2647 patients were included, 83% (N = 2202) were in NYHA class III and 17% (N = 445) were in NYHA class IV. They had stable symptomatic systolic heart failure (ejection fraction <35%, based on echocardiography). Total mortality was reduced from 17.3% to 11.8% (relative reduction 34%). A decrease in sudden death (3.6% vs 6.3%, relative reduction 44%) and a reduced number of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction 36%) was observed. Finally, a significant improvement of the functional status according to NYHA classification has been shown. During the initiation and titration of bisoprolol hospital admission due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation (4.97%) were observed, but they were not more frequent than in the placebo-group (0%, 0.3% and 6.74%). The numbers of fatal and disabling strokes during the total study period were 20 in the bisoprolol group and 15 in the placebo group.

The CIBIS III trial investigated 1010 patients aged

There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and hospitalization at study end (32.4% in the bisoprolol-first group vs. 33.1 % in the enalapril-first group, per-protocol population). The study shows that bisoprolol can also be used in elderly chronic heart failure patients with mild to moderate disease.

In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases.

5.2 Pharmacokinetic Properties

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 excreted 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.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

calcium hydrogen phosphate, anhydrous

cellulose, microcrystalline

maize starch, pregelatinised

croscarmellose sodium

silica, colloidal anhydrous

magnesium stearate

lactose monohydrate

hypromellose

macrogol 4000

titanium dioxide (E171)

iron oxide, yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Blister:

5 years

HDPE bottles:

1 year

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Blister, which is made of an aluminium bottom and cover foil (OPA-Al-PVC/Al)..

Pack sizes: 7, 10, 20, 28, 30, 50, 56, 60, 90, 98, 100, 10x30 film-coated tablets

HDPE bottles containing 10,20,30,50,60,100,250,500 film-coated tablets.

6.6 Special Precautions For Disposal And Other Handling

The film-coated tablet can be divided by placing it on a solid surface with the score pointing upward. The film-coated tablet is divided by exerting a slight pressure with the thumb.

No special requirements.

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

7. Marketing Authorisation Holder

Sandoz Limited

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Marketing Authorisation Number(S)

PL 04416/0927

9. Date Of First Authorisation/Renewal Of The Authorisation

20/01/2009

10. Date Of Revision Of The Text

09/2011

Betnovate Cream

1. Name Of The Medicinal Product

Betnovate Cream

2. Qualitative And Quantitative Composition

Betamethasone Valerate BP 0.122% ^W/_W

3. Pharmaceutical Form

Aqueous Cream

4. Clinical Particulars

4.1 Therapeutic Indications

Betamethasone valerate is an active topical corticosteroid which produces a rapid response in those inflammatory dermatoses that are normally responsive to topical corticosteroid therapy, and is often effective in the less responsive conditions such as psoriasis.

Betnovate preparations are indicated for the treatment of eczema in children and adults, including atopic and discoid eczemas, prurigo nodularis, psoriasis (excluding widespread plaque psoriasis); neurodermatoses, including lichen simplex, lichen planus; seborrhoeic dermatitis; contact sensitivity reactions; discoid lupus erythematosus and they may be used as an adjunct to systemic steroid therapy in generalised erythroderma.

4.2 Posology And Method Of Administration

A small quantity of Betnovate should be applied gently to the affected area two or three times daily until improvement occurs. It may then be possible to maintain improvement by applying once a day, or even less often, or by using the appropriate ready-diluted (1 in 4) preparation Betnovate R.D. If no improvement is seen within two to four weeks, reassessment of the diagnosis, or referral, may be necessary.

Betnovate and Betnovate R.D. creams are especially appropriate for dry, lichenified or scaly lesions, but this is not invariably so.

In the more recent resistant lesions, such as the thickened plaques of psoriasis on elbows and knees, the effect of Betnovate can be enhanced, if necessary, by occluding the treatment area with polythene film. Overnight occlusion only is usually adequate to bring about a satisfactory response in such lesions; thereafter improvement can usually be maintained by regular application without occlusion.

Children

Courses should be limited to five days. Occlusion should not be used.

For topical administration.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients in the product.

The following conditions should not be treated with betamethasone valerate:

• Untreated cutaneous infections

• Rosacea

• Acne vulgaris

• Pruritus without inflammation

• Perianal and genital pruritus

• Perioral dermatitis

Betamethasone valerate is contraindicated in dermatoses in infants under one year of age, including dermatitis

4.4 Special Warnings And Precautions For Use

Long-term continuous topical therapy should be avoided where possible, particularly in infants and children, as adrenal suppression, with or without clinical features of Cushing's syndrome, can occur even without occlusion. In this situation, topical steroids should be discontinued gradually under medical supervision because of the risk of adrenal insufficiency (see section 4.8 Undesirable Effects and Section 4.9 Overdose).

The face, more than other areas of the body, may exhibit atrophic changes after prolonged treatment with potent topical corticosteroids. This must be borne in mind when treating such conditions as psoriasis, discoid lupus erythematosus and severe eczema. If applied to the eyelids, care is needed to ensure that the preparation does not enter the eye, as glaucoma might result.

If used in childhood, or on the face, courses should be limited to five days and occlusion should not be used.

Topical corticosteroids may be hazardous in psoriasis for a number of reasons including rebound relapses, development of tolerance, risk of generalised pustular psoriasis and development of local or systemic toxicity due to impaired barrier function of the skin. If used in psoriasis careful patient supervision is important.

Appropriate antimicrobial therapy should be used whenever treating inflammatory lesions which have become infected. Any spread of infection requires withdrawal of topical corticosteroid therapy and systemic administration of antimicrobial agents. Bacterial infection is encouraged by the warm, moist conditions induced by occlusive dressings, and so the skin should be cleansed before a fresh dressing is applied.

Further Information

The least potent corticosteroid which will control the disease should be selected. None of these preparations contain lanolin. Betnovate Cream and Ointment and the corresponding RD preparations do not contain parabens. Betnovate Lotion contains parabens.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

There is inadequate evidence of safety in human pregnancy. Topical administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human foetus.

4.7 Effects On Ability To Drive And Use Machines

There have been no studies to investigate the effect of betamethasone valerate on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the adverse reaction profile of topical betamethasone valerate.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (

Immune system disorders
Very rare:	Hypersensitivity.
If signs of hypersensitivity appear, application should stop immediately.
Endocrine disorders
Very rare:	Features of Cushing's syndrome

As with other topical corticosteroids, prolonged use of large amounts or treatment of extensive areas can result in sufficient systemic absorption to produce suppression of the HPA axis and the clinical features of Cushing's syndrome (see Section 4.4 Special Warnings and Precautions for use). These effects are more likely to occur in infants and children, and if occlusive dressings are used. In infants the napkin may act as an occlusive dressing.

Skin and subcutaneous tissue disorders

Common:

Local skin burning and pruritus.

Very rare:

Local atrophic changes in the skin such as thinning, striae and dilatation of the superficial blood vessels may be caused by prolonged and intensive treatment with highly active corticosteroid preparations, particularly when occlusive dressings are used or when skin folds are involved.

Pigmentation changes, hypertrichosis, allergic contact dermatitis, exacerbation of symptoms, pustular psoriasis (due to treatment of psoriasis with corticosteroids or its withdrawal: see Section 4.4. Special Warnings and Precautions for use)

4.9 Overdose

Acute overdosage is very unlikely to occur. However, in the case of chronic overdosage or misuse the features of Cushing's syndrome may appear and in this situation topical steroids should be discontinued gradually under medical supervision (see Section 4.4 Special Warnings and Precautions for use).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Betamethasone valerate is an active corticosteroid with topical anti-inflammatory activity.

5.2 Pharmacokinetic Properties

Absorption

Topical corticosteroids can be systemically absorbed from intact healthy skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusion, inflammation and/or other disease processes in the skin may also increase percutaneous absorption.

Distribution

The use of pharmacodynamic endpoints for assessing the systemic exposure of topical corticosteroids is necessary because circulating levels are well below the level of detection.

Metabolism

Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. They are metabolised, primarily in the liver.

Elimination

Topical corticosteroids are excreted by the kidneys. In addition, some corticosteroids and their metabolites are also excreted in the bile.

5.3 Preclinical Safety Data

Reproductive toxicity

Subcutaneous administration of betamethasone valerate to mice or rats at doses

The effect on fertility of betamethasone valerate has not been evaluated in animals.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Chlorocresol	BP
Cetomacrogol 1000	BP
Cetostearyl Alcohol	BP
White Soft Paraffin	BP
Liquid Paraffin	BP
Sodium Acid Phosphate	BP
Phosphoric Acid	BP
Sodium Hydroxide	BP
Purified Water	BP

6.2 Incompatibilities

None known.

6.3 Shelf Life

Tubes	36 Months
500gm pots	18 months

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

15gm, 30gm and 100gm collapsible aluminium tubes internally coated with an epoxy resin based lacquer and closed with a cap.

500mg opaque high density polythene pots with black urea formaldehyde screw caps having a steran faced wad.

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

Administrative Data

7. Marketing Authorisation Holder

Glaxo Wellcome UK Ltd.,

T/A GlaxoSmithKline UK

Stockley Park West,

Uxbridge,

Middlesex UB11 1BT

8. Marketing Authorisation Number(S)

PL10949/0014

9. Date Of First Authorisation/Renewal Of The Authorisation

24 October 1997

10. Date Of Revision Of The Text

1 February 2012

Boots Allergy Relief 1 Year Plus Antihistamine 2 mg-5ml Syrup

Boots Allergy Relief 1 Year Plus Antihistamine 2 mg/5 ml Syrup

(Chlorphenamine Maleate)

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription to treat minor conditions. However, you still need to give it carefully to get the best results from it.

Keep this leaflet, you may need to read it again

Ask your pharmacist if you need more information or advice

The leaflet is written in terms of giving this medicine to your child, but if you are an adult who is intending to take this medicine yourself the information in this leaflet will apply to you as well

What this medicine is for

This medicine contains Chlorphenamine Maleate, which belongs to a group of medicines called antihistamines, which act to relieve the symptoms of allergic reactions.

It can be used to relieve itching and redness of the skin and swelling associated with allergies, insect bites, hayfever and other allergic conditions including reactions to food and medicines and year round sneezing and runny nose.

Before you give this medicine

This medicine can be given to children from the age of 1 year. However, some children should not be given this medicine or you should seek the advice of their pharmacist or doctor first.

Do not give:

If your child is under 1 year

If your child is having an asthma attack

If your child is allergic to any of the ingredients, or any other antihistamines (your child may have had a rash, difficulty breathing, swollen lips or face after taking them)

If your child is taking monoamine oxidase inhibitors (for depression) or has taken them in the last 14 days

Talk to your pharmacist or doctor:

If your child has epilepsy, heart or circulatory disease, liver problems

If your child has high blood pressure or glaucoma

If your child has asthma, bronchitis or bronchiectasis

If your child has an overactive thyroid

If your child has difficulty passing urine

If your child has an obstruction in their intestine

If your child has a rare blood disease called porphyria

Other important information

Information about some of the ingredients: This medicine contains maltitol liquid, which may have a mild laxative effect. If you have been told by your doctor that your child has an intolerance to some sugars, consult your doctor before giving this medicine. This medicine contains 1 g maltitol per 5 ml spoonful. This provides 2 kcal per spoonful.

This medicine contains small amounts of alcohol (ethanol), less than 100 mg per 5 ml spoonful.

Information for adults intending to take this medicine

Driving and using machines: This medicine may cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.

Talk to your pharmacist or doctor if you are a man with prostate problems.

Pregnancy and breastfeeding: Do not take this medicine.

If your child takes other medicines

Before you give this medicine, make sure that you tell your pharmacist about ANY other medicines you might be giving your child at the same time, particularly the following:

Other antihistamines

Strong painkillers

Sleeping tablets

Tranquillisers, antidepressants or other medicines for mental problems

Phenytoin (for epilepsy)

Atropine

If you are unsure about interactions with any other medicines, talk to your pharmacist. This includes medicines prescribed by your doctor and medicine you have bought for your child, including herbal and homeopathic remedies.

How to give this medicine

Check the seal is not broken before first use. If it is, do not give the medicine.

Use the measuring spoon provided. The small end measures 2.5 ml and the big end measures 5 ml.

Children of 12 to 23 months

2.5 ml - Twice a day. Don’t give more than 5 ml (Two 2.5 ml spoonfuls) in 24 hours.

Children of 2 to 5 years

2.5 ml - Every 4 to 6 hours, if you need to. Don’t give more than 15 ml (Six 2.5 ml spoonfuls) in 24 hours.

Children of 6 to 11 years

5 ml - Every 4 to 6 hours, if you need to. Don’t give more than 30 ml (Six 5 ml spoonfuls) in 24 hours.

Children of 12 years and over, and adults

10 ml - Every 4 to 6 hours, if you need to. Don’t give more than 60 ml (Twelve 5 ml spoonfuls) in 24 hours.

Give this medicine to your child to swallow.

Do not give to children under 1 year.

Do not give more than the amount recommended above.

If symptoms do not go away within 5 days talk to your pharmacist or doctor.

If you give too much:

Talk to your doctor or go to your nearest hospital casualty department straight away. Take the medicine and this leaflet with you.

Possible side effects

Most people will not have problems, but some may get some.

Drowsiness (which may make your child fall asleep)

Dizziness, blurred vision, headaches, fits

Dry mouth, difficulty in passing urine, sweating

Skin rash, sensitivity to sunlight, other allergic reactions

Indigestion, stomach pain, loss of appetite

Tremors, muscle pain or weakness, impaired movement or co-ordination, pins and needles

Change in heart rate, palpitations, low blood pressure, ringing in the ears, hair loss

Blood problems such as anaemia, weariness

Sleep disturbance

Liver problems (which may cause yellowing of the skin or eyes)

Chest pain

Cough, phlegm on the chest – these may be caused by thickened bronchial secretions (mucous) in your lungs

Difficulty concentrating, irritability, depression

Hyperactivity in children

Confusion in the elderly

Very young children and elderly adults may be more likely to get some of these side effects.

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

How to store this medicine

Keep this medicine in a safe place out of the sight and reach of children, preferably in a locked cupboard.

Use by the date on the end flap of the carton.

What is in this medicine

Each 5 ml of oral solution contains Chlorphenamine Maleate 2 mg, which is the active ingredient.

As well as the active ingredient, the solution also contains purified water, glycerol (E422), maltitol liquid (E965), citric acid monohydrate, sodium benzoate (E211), mint flavour (containing ethanol 0.2 vol %).

This pack contains 150 ml. The medicine is a clear, colourless mint flavoured syrup.

Who makes this medicine

Manufactured by the Marketing Authorisation holder

The Boots Company PLC

Nottingham

NG2 3AA

PL00014/0606

Leaflet prepared July 2007

If you would like any further information about this medicine, please contact

The Boots Company PLC

Nottingham

NG2 3AA

Other formats

To request a copy of this leaflet in Braille, large print or audio please call, free of charge: 0800 198 5000 (UK only).

Please be ready to give the following information:

Product Name: Boots Allergy Relief 1 Year Plus Antihistamine 2 mg/5 ml Syrup.

Reference number 00014/0606.

This is a service provided by the Royal National Institute of the Blind.

BTC12108 vG dated 19/09/07

Bisoprolol fumerate 10mg film-coated tablets

1. Name Of The Medicinal Product

Bisoprolol fumerate 10mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 10 mg of bisoprolol fumarate equivalent to 8.48 mg bisoprolol.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet.

Yellow coloured, circular, biconvex, film-coated tablets debossed with 'I and score line' on one side and '13' on the other side. The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Hypertension

Chronic stable angina pectoris

4.2 Posology And Method Of Administration

Adults

For both indications the dosage is 5 mg bisoprolol fumarate once daily. If necessary, the dose may be increased to 10 mg bisoprolol fumarate once daily.

The maximum recommended dose is 20 mg once daily.

In all cases the dosage is adjusted individually, in particular according to the pulse rate and therapeutic success.

Renal or liver impairment

In patients with liver or kidney function disorders of mild to moderate severity, no dosage adjustment is normally required. In patients with severe renal impairment (creatinine clearance < 20 ml/min) and in patients with severe liver function disorders it is recommended that a daily dose of 10 mg bisoprolol fumarate is not exceeded.

Experience with the use of bisoprolol in renal dialysis patients is limited; however, there is no evidence that the dosage regimen needs to be altered.

Elderly

No dosage adjustment is required.

Children

There is no experience with bisoprolol in children, therefore its use cannot be recommended for children.

Duration of therapy for all indications

Treatment with bisoprolol is generally a long-term therapy.

Administration

BISOPROLOL FUMARATE tablets are taken in the morning with or without food. They are swallowed with some liquid and not to be chewed.

4.3 Contraindications

Bisoprolol is contraindicated in patients with:

• acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy

• cardiogenic shock

• second or third degree AV block (without a pacemaker)

• sick sinus syndrome

• sinoatrial block

• symptomatic bradycardia

• symptomatic hypotension

• severe bronchial asthma or severe chronic obstructive pulmonary disease

• severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome

• untreated phaeochromocytoma (see section 4.4)

• metabolic acidosis

BISOPROLOL FUMARATE is contra-indicated in patients with hypersensitivity to bisoprolol or to any of the excipients

4.4 Special Warnings And Precautions For Use

Special warnings:

Precautions:

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

Bisoprolol must be used with caution in:

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

• strict fasting,

• First degree AV block,

• Prinzmetal's angina,

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

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after a careful 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 post-operative period. It is currently recommended that maintenance of 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 reflex tachycardia, and decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.

In bronchial asthma or other chronic obstructive pulmonary diseases, 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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 hypotension and atrio-ventricular block.

Centrally-acting antihypertensive drugs (e.g. clonidine methyldopa, moxonodine, 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 vasodilatation. 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 (e.g. 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-adrenoceptors may mask symptoms of hypoglycaemia.

Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension (see section 4.4).

Digitalis glycosides: Increase of atrio-ventricular conduction time, reduction in heart rate.

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

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

Sympathomimetics that activate both beta- and alpha-adrenoceptors (e.g. norepinephrine, epinephrine): 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 betablockers but also risk of hypertensive crisis.

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

Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.

4.6 Pregnancy And Lactation

Pregnancy:

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, β-adrenoceptor blocking agents reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse reactions (e.g. hypoglycaemia, bradycardia) may occur in the fetus and newborn infant. If treatment with β-adrenoceptor blocking agents is necessary, β₁-adrenoceptor blocking agents 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.

Lactation:

There are no data on the excretion of bisoprolol in human breast milk or the safety of bisoprolol exposure in infants. Therefore, breastfeeding is not recommended during administration of {Tradename}.

4.7 Effects On Ability To Drive And Use Machines

In a study with coronary heart disease patients, bisoprolol did not impair driving performance. However, depending on the individual patients response to treatment an effect on the ability to drive a vehicle or to use machines cannot be excluded. This needs to be considered particularly at start of treatment, upon change of medication, or in conjunction with alcohol.

4.8 Undesirable Effects

The following undesirable effects have been observed during treatment with bisoprolol with the following frequencies:

Very common (

common (

uncommon (

rare (

very rare (<0.01%)

Investigations

Rare:

increased triglycerides, increased liver enzymes (ALT, AST)

Cardiac disorders

Uncommon:

AV-conduction disturbances; worsening of pre-existing heart failure; bradycardia

Nervous system disorders

Common:	dizziness, headache
Rare:	syncope

Eye disorders

Rare:	reduced tear flow (to be considered if the patient uses contact lenses)
Very rare:	conjunctivitis

Ear and labyrinth disorders

Rare:

hearing disorders

Respiratory, thoracic and mediastinal disorders

Uncommon:	bronchospasm in patients with bronchial asthma or a history of obstructive airway disease
Rare:	allergic rhinitis

Gastrointestinal disorders

Common:

gastrointestinal complaints such as nausea, vomiting, diarrhoea, Constipation

Skin and subcutaneous tissue disorders

Rare:	hypersensitivity reactions such as itching, flush, rash
Very rare:	alopecia. Beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash.

Musculoskeletal and connective tissue disorders

Uncommon:

muscle weakness, muscle cramps

Vascular disorders

Common:

feeling of coldness or numbness in the extremities, hypotension especially in patients with heart failure

General disorders

Common:	fatigue*
Uncommon:	asthenia

Hepatobiliary disorders

Rare:

hepatitis.

Reproductive system and breast disorders

Rare:

potency disorders

Psychiatric disorders

Uncommon:	depression, sleep disorders
Rare:	nightmares, hallucinations

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

4.9 Overdose

The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited experience with overdose of bisoprolol, only a few cases of overdose with bisoprolol have been reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide inter-individual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive.

In general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and symptomatic treatment is recommended.

Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures may be considered when clinically warranted.

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 temporary pacing.

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

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

Limited data suggest that bisoprolol is hardly dialysable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Beta blocking agents, selective

ATC code: C07AB07

Bisoprolol is a highly beta1-selective-adrenoceptor blocking agent, lacking intrinsic sympathomimetic and relevant membrane stabilising activity. It only shows low affinity to the beta2-receptor of the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta2-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.

Bisoprolol is used for the treatment of hypertension and angina pectoris. As with other Beta-1-blocking agents, the method of acting in hypertension is unclear. However, it is known that Bisoprolol reduces plasma renin activity markedly.

5.2 Pharmacokinetic Properties

Bisoprolol is absorbed almost completely from the gastrointestinal tract. Together with the very small first pass effect in the liver, this results in a high bioavailability of approximately 90%. The plasma protein binding of bisoprolol is about 30 %. The distribution volume is 3.5 l/kg. The total clearance is approximately 15 l/h

The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage.

Bisoprolol is excreted 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 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 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

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Cellulose, microcrystalline

Calcium Hydrogen Phosphate, Anhydrous

Silica Colloidal Anhydrous

Crospovidone (Type A)

Magnesium stearate

Tablet coat:

Hypromellose 6cP (E464)

Titanium Dioxide (E171)

Macrogol 400

Iron Oxide Yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

BISOPROLOL FUMARATE film-coated tablets are available in –Polyamide/Aluminium/PVC/Paper/Polyester/Aluminium blisters and HDPE container with PP closure containing silica gel sachet.

Pack sizes:

Blister pack: 20, 28, 30, 50, 90, 100 film-coated tablets

HDPE container pack: 30, 500 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

Aurobindo Pharma (Malta) Limited

Vault 14, Level 2, Valletta Waterfront

Floriana FRN 1913

Malta

8. Marketing Authorisation Number(S)

PL 32256/0090

9. Date Of First Authorisation/Renewal Of The Authorisation

23/05/2011

10. Date Of Revision Of The Text

23/05/2011

Boots Acid Reflux 10 mg Gastro-Resistant Tablets

1. Name Of The Medicinal Product

Boots Acid Reflux 10 mg Gastro-Resistant Tablets

Care Heartburn Relief 10 mg Tablets

Co-op Heartburn Relief 10 mg Tablets

Dexcel Heartburn Relief 10 mg Tablets

Galpharm Heartburn Relief 10 mg Tablets

Numark Heartburn Relief 10 mg Tablets

Sainsbury's Heartburn Relief 10 mg Tablets

Superdrug Heartburn Relief 10 mg Tablets

Tesco Heartburn Relief 10 mg Tablets

Unichem Heartburn Relief 10 mg Tablets

Vantage Pharmacy Heartburn Relief 10 mg Tablets

Lloydspharmacy Heartburn Relief 10mg Tablets

2. Qualitative And Quantitative Composition

Omeprazole 10 mg

For excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant tablets.

Brownish-pink, capsule-shaped film-coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Relief of reflux-like symptoms (e.g. heartburn) in patients aged 18 and over.

4.2 Posology And Method Of Administration

The tablets should be swallowed whole with plenty of liquid (e.g., water or fruit juice) prior to a meal. It is important that the tablets should not be crushed or chewed.

Initially the dosage is 20mg once daily.

Subsequently, symptomatic relief from heartburn can be achieved in some subjects by taking 10mg once daily, increasing to 20mg if symptoms return.

The lowest effective dose should always be used.

If no relief is obtained within two weeks then the patient should be referred to their doctor.

If continuous treatment for more than 4 weeks is required to relieve symptoms then the patient should be referred to their doctor.

4.3 Contraindications

Known hypersensitivity to omeprazole or to any of the other ingredients.

4.4 Special Warnings And Precautions For Use

Decreased gastric acidity, due to any means - including proton- pump inhibitors - increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs leads to a slightly increased risk of gastrointestinal infections such as salmonella or campylobacter.

Special warnings and precautions for patients taking non-prescription indigestion or heartburn remedies:

Patients should be referred to their doctor if:

• They have had to take an indigestion or heartburn remedy continuously for 4 or more weeks in order to control their symptoms

• They are aged over 45 years with new or recently changed symptoms

• They have unintentional weight loss, anaemia, gastrointestinal bleeding, dysphagia, pain on swallowing, persistent vomiting or vomiting with blood, epigastric mass, previous gastric ulcer or surgery, jaundice or any other significant medical condition (including hepatic and renal impairment).

Patients with long-term recurrent symptoms of indigestion or heartburn should see their doctor at regular intervals. Patients aged over 45 years taking any “over the counter” (OTC, non-prescription) indigestion or heartburn remedy on a daily basis should inform their pharmacist or doctor.

Patients should not take another “acid suppressor” e.g. H₂ antagonist concomitantly.

Patients should consult their doctor before taking this product if they are due to have an endoscopy.

The Patient Information Leaflet will contain advice that the tablets will not provide immediate relief of symptoms.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

As with many indigestion and heartburn remedies, omeprazole may interact with other medications. Therefore, patients who are also taking other medications should first consult with either their pharmacist or doctor before taking omeprazole.

As omeprazole is metabolized in the liver through cytochrome P450 it can delay the elimination of diazepam, phenytoin and warfarin. Monitoring of patients receiving warfarin or phenytoin is recommended and a reduction of the warfarin or phenytoin dose may be necessary. However concomitant treatment with omeprazole 20 mg daily did not change the blood concentration of phenytoin in patients on continuous treatment with phenytoin. Similarly, concomitant treatment with omeprazole 20 mg daily did not change coagulation time in patients on continuous treatment with warfarin. Interactions with other medicinal products which are also metabolized via the cytochrome P-450 isoenzyme of group 2C cannot be excluded.

Due to the decreased intragastric acidity, the absorption of ketoconazole or itraconazole may be reduced during omeprazole treatment, as it is during treatment with other acid secretion inhibitors.

Concomitant use of omeprazole and cilostazol results in an increase in the plasma concentration of cilostazol, therefore concomitant use should be avoided. It is possible that omeprazole also increases the plasma-tacrolimus concentration, whereas voriconazole increases the plasma concentration of omeprazole.

Simultaneous treatment with omeprazole and digoxin in healthy subjects led to a 10% increase in the bioavailability of digoxin as a consequence of the increased intragastric pH.

Omeprazole as so far tested has no influence on the metabolism of the following substances: amoxycillin, antacids, quinidine, caffeine, ciclosporin, diclofenac, estradiol, lidocaine, metoprolol, naproxen, phenacetin, piroxicam, propranolol, theophylline.

Treatment with omeprazole may cause false negative results in ¹³C-Urea breath tests.

Alcohol and food do not affect the absorption of omeprazole.

4.6 Pregnancy And Lactation

This product should not be used during pregnancy or whilst breast feeding.

Pregnancy

There is no evidence on the safety of omeprazole in human pregnancy. Animal studies have revealed no teratogenic effect, but reproduction studies have revealed reduced litter weights. Avoid in pregnancy, unless there is no safer alternative.

Lactation

There is no information available on the passage of omeprazole into breast milk or its effects on the neonate. Breast-feeding should therefore be discontinued if the use of omeprazole is considered essential.

4.7 Effects On Ability To Drive And Use Machines

In rare cases, drowsiness has been reported. If affected, patients should not drive or operate machinery.

4.8 Undesirable Effects

Omeprazole is well tolerated and adverse reactions have generally been mild and reversible. The following have been reported as adverse events in clinical trials or reported from routine use but in many cases a relationship to treatment with omeprazole has not been established.

Skin and subcutaneous tissue disorders

Skin rash, urticaria and pruritus have been reported, usually resolving after discontinuation of treatment. In addition photosensitivity, bullous eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, alopecia and increased sweating have been reported in isolated cases.

Musculoskeletal disorders

Arthritic and myalgic symptoms have been reported and have usually resolved when therapy is stopped.

Respiratory disorders

In isolated cases bronchospasm has been reported.

Gastrointestinal disorders

Diarrhoea has been reported and may be severe enough to require discontinuation of therapy. Constipation, abdominal pain, nausea/vomiting and flatulence have been reported. In isolated cases dry mouth, stomatitis and candidiasis have been reported.

Hepato-biliary disorders

Increases in liver enzyme have been observed. In isolated cases, encephalopathy in patients with pre-existing severe liver disease, hepatitis with or without jaundice and rarely hepatic failure.

Renal & urinary disorders

Interstitial nephritis which has resulted in acute renal failure has been reported in isolated cases.

Reproductive disorders

In isolated cases gynaecomastia and impotence have been reported.

Nervous system disorders

Headache has been reported which may be severe enough to require discontinuation of therapy. Rarely paraesthesia has also been reported. Taste disturbances have been reported in isolated cases.

Psychiatric disorders

In isolated cases reversible mental confusion, agitation, depression and hallucinations occurring predominantly in severely ill patients. Agression has also been reported in isolated cases.

Disorders of the eye

In isolated cases blurred vision has been reported.

Haematological

In isolated cases leucopenia, thrombocytopenia, agranulocytosis, hyponatraemia and pancytopenia have been reported.

Disorders of the ear

Vertigo has been reported.

Disorders of the immune system

Anaphylactic shock and angioedema have been reported in isolated cases.

General disorders

Dizziness, light-headedness and feeling faint have been associated with treatment, but all usually resolve on cessation of therapy. Somnolence and insomnia have also been reported. In isolated cases peripheral oedema, malaise and fever have been reported.

4.9 Overdose

There is no information available on the effects of overdosage in man. Beside ventilatory and circulatory control according to general guidelines on the treatment of intoxication no further direct therapeutic measures are indicated. Single oral doses of omeprazole of up to 400 mg have not resulted in any severe symptoms; elimination remained first order and no specific treatment was needed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Omeprazole, a substituted benzimidazole, is a selective proton pump inhibitor which inhibits directly and in dose-dependent fashion the H+/K+-ATPase of the parietal cells of the stomach responsible for gastric acid secretion. By this selective intracellular attack, independently from membrane located receptors like histamine H2-, muscarine M1- or gastrineric receptors, omeprazole belongs to an independent class of inhibitors which block the terminal secretion process. By its mode of action, omeprazole reduces not only basal but also stimulus-induced acid secretion, independently of the kind of stimulus. Omeprazole thus increases the pH-value and reduces the secretory volume.

Oral dosing with 20 mg omeprazole once daily produces inhibition of gastric acid secretion within 1-2 hours of the first dose. The maximum effect is achieved within 4 days of starting treatment after which the degree of inhibition remains constant. The mean decrease in pentagastrin-stimulated peak acid output twenty-four hours after dosing is about 70%.

During long-term treatment an increased frequency of gastric glandular cysts have been reported. These changes are a physiological consequence of pronounced inhibition of acid secretion. The cysts are benign and appear to be reversible. No other treatment related mucosal changes have been observed in patients treated continuously with omeprazole for periods of up to 5 years.

Site and Mechanism of Action: Omeprazole is a weak base and is concentrated and converted to the active form by protonation in the acid environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme, H+,K+-ATPase - the proton pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for effective inhibition of both basal acid secretion and stimulated acid secretion irrespective of the stimulus. All pharmacodynamic effects observed are explained by the effect of omeprazole on acid secretion.

5.2 Pharmacokinetic Properties

Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. The systemic bioavailability of omeprazole from a single oral dose is approximately 35%. After repeated once-daily administration, the bioavailability increases to about 60%. Concomitant intake of food has no influence on bioavailability. The plasma protein binding of omeprazole is about 95%.

The average half-life of the terminal phase of the plasma concentration-time curve is approximately 40 minutes. There is no change in half-life during treatment. The inhibition of acid secretion is related to the area under the plasma concentration time-curve (AUC) but not to actual plasma concentration at a time.

Omeprazole is entirely metabolized, mainly in the liver. Identified metabolites in plasma are the sulphone, the sulphide and hydroxy-omeprazole; these metabolites have no significant effect on acid secretion. About 80% of the metabolites are excreted in the urine and the rest in the faeces. The two main urinary metabolites are hydroxy-omeprazole and the corresponding carboxylic acid.

The systemic bioavailability of omeprazole is not significantly altered in patients with reduced renal function. The area under the plasma concentration time-curve is increased in patients with impaired liver function, but no tendency to accumulation of omeprazole has been found.

Available data from children (1 year and older) suggest that the pharmacokinetics within the recommended doses is similar to those reported in adults. At steady state, lower plasma levels of omeprazole were seen in some children.

5.3 Preclinical Safety Data

Omeprazole is a well-established drug for which there are adequate published safety data. Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or toxicity to reproduction.

Carcinogenic Potential: 2 years' carcinogenicity studies in rats (i.e., life-long treatment) showed development of ECL-cell-carcinoids; but rats which have been treated with high doses of omeprazole over a year have not shown any carcinoids in the later 1-year period. The mechanism for the build-up of the stomach carcinoids has been investigated very carefully and various studies lead to the conclusion that this is a secondary reaction due to the extreme increased serum gastrin levels of the rats during the treatment period. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition and not from a direct effect of any individual drug. Similar development of ECL-cell-carcinoids was observed in rats subjected to partial fundectomy. ECL-cell-carcinoids were not seen in mice or dog studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core

lactose monohydrate

sodium starch glycollate

sodium stearate

sodium stearyl fumarate

Enteric Coating

hydroxypropyl methylcellulose (HPMC) acetate succinate

talc

triethyl citrate

monoethanolamine

sodium lauryl sulphate

Sepisperse AP-3527 (containing:

propylene glycol

titanium dioxide (E-171)

red iron oxide (E-172)

yellow iron oxide (E-172)

hydroxypropyl methylcellulose)

Polish

carnauba wax

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store in the original package. Do not store above 30°C.

6.5 Nature And Contents Of Container

Aluminium/aluminium blisters strips containing 7, 14 or 28 tablets, in a cardboard box.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Dexcel-Pharma Limited

7 Sopwith Way, Drayton Fields, Daventry, Northamptonshire NN11 8PB

United Kingdom

8. Marketing Authorisation Number(S)

PL 14017/0069

9. Date Of First Authorisation/Renewal Of The Authorisation

19 January 2004

10. Date Of Revision Of The Text

June 2011