SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Celiprolol 200mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 200mg of Celiprolol hydrochloride.

For excipients, see 6.1

3    PHARMACEUTICAL FORM

White, oval tablets embossed on one side with the initials “JF” and a breakline, and on the other side embossed with the initial “C”.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The management of mild to moderate hypertension.

4.2    Posology and method of administration

Route of Administration: Oral Adults:

Initially, one 200mg tablet should be taken once daily, on rising, with a glass of water, half an hour before food. If adequate response is not achieved, the dose may be increased to 400mg once daily.

Elderly:

As for adults.

Children:

Not recommended.

4.3    Contraindications

Celiprolol is contraindicated in the following cases, as with other beta-adrenoceptor antagonists:

•    Cardiogenic shock

•    Uncontrolled heart failure

•    Sick-sinus syndrome

•    Second or third degree heart block

•    Severe bradycardia

•    Severe renal impairment (creatinine clearance less than 15ml/minute)

•    Acute episodes of asthma

•    Untreated phaeochromocytoma

•    Metabolic acidosis

•    Hypotension

•    Hypersensitivity to the active ingredient or any of the excipients

•    Severe peripheral arterial circulatory disturbances

Cardioselective beta-blockers, such as celiprolol, may have less effect on lung function than non-selective beta-blockers. Nevertheless, all beta-blockers should be avoided in patients with chronic obstructive pulmonary disease, history of bronchospasm or bronchial asthma, unless there are overwhelmingly convincing clinical reasons for their use. In such cases where these reasons exist, celiprolol may be used very cautiously.

The medicine label will carry the following warning: If you have a history of asthma or wheezing, please ask your doctor before taking this medicine.

Celiprolol tablets should not be prescribed for patients who are also being prescribed theophylline.

4.4 Special warnings and precautions for use

The pharmacokinetics for celiprolol are not significantly different in the elderly to the general adult population. However, elderly patients should be monitored regularly, taking into account any reduction in renal or hepatic function.

As celiprolol is cleared by both renal and non-renal pathways, the drug may be used in patients with mild to moderate renal impairment. It may be appropriate in patients with a creatinine clearance in the range 15 to 40ml/minute to reduce the celiprolol dose by half. Steady state blood levels after a reduction in dose are usually reached within a week and it is recommended that such patients be observed carefully during this period. Celiprolol is not recommended in patients where creatinine clearance is less than 15ml/minute. Hepatically impaired patients may require reduced doses. This group of patients should also be carefully monitored, especially after commencement of treatment and after any dose alteration.

Patients with ischaemic heart disease may experience an increase in frequency and/or severity of angina attacks or worsening of cardiac state, should beta-blockers be discontinued abruptly. As a precaution therefore, should it be necessary to withdraw celiprolol therapy, this should be done gradually over a one to two week period, concurrently introducing any replacement angina pectoris prophylaxis treatment if necessary.

Prior to general anaesthesia, the anaesthetist must be told of any patient taking celiprolol. If celiprolol is to be withdrawn prior to the operation, 48 hours minimum must have elapsed between the last dose and the start of anaesthesia.

Continuation of beta blockade reduces risk of arrhythmia during induction and intubation, but reflex tachycardia may be attenuated and risk of hypotension increased (see section 4.5 Interactions). If celiprolol is to be continued, special care must be taken when using ether, trichloroethylene or cyclopropane for anaesthesia. Intravenous atropine may be used to protect the patient against vagal reactions.

Use of celiprolol is cautioned in patients with controlled congestive cardiac failure. Therapy should be discontinued if evidence of decompensation becomes apparent.

Aggravation of certain peripheral vascular disorders such as Raynaud’s disease/syndrome and intermittent claudication may occur with beta-blockers. Celiprolol should be used with great caution in such cases.

Celiprolol may induce bradycardia. Should a patient experience bradycardic symptoms and have a pulse rate of 50-55 beats per minute or less, at rest, a lower dose of celiprolol should be used.

Celiprolol reduces conduction time and should only be given with caution to patients with first degree heart block.

Unopposed alpha-receptor medicated vasoconstriction of the coronary artery resulting in increased frequency and duration of angina attacks can occur when beta-blockers are given to patients with Prinzmetal’s angina. Beta-1 selective adrenoreceptor blocking drugs, such as celiprolol, may be considered, with utmost caution, in such patients.

Patients with psoriasis should consider carefully reports that beta-blockers can aggravate psoriasis, before commencing celiprolol.

Beta-blockers may increase the sensitivity to allergens and seriousness of reactions in patients with a history of anaphylactic reactions.

Symptoms of thyrotoxicosis or hypoglycaemia (particularly tachycardia) may be masked by beta-blockers.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations contraindicated

•    Celiprolol should not be taken by patients receiving theophylline in order to

avoid bronchospasm.

Combinations not recommended

•    Celiprolol bioavailability is reduced when taken with food.

•    Concurrent chlorthalidone or hydrochlorothiazide also reduce celiprolol bioavailability.

•    Calcium channel blockers (e.g. verapamil, diltiazem) and beta-blockers both slow A-V conduction and depress myocardial contractility though by different mechanisms. When changing from verapamil to celiprolol or vice versa, there should be a break period between stopping one and starting the other. Concurrent administration of both is not recommended. If initiated, ECG monitoring is recommended. Patients who already have conduction abnormalities should not receive the two drugs together.

•    A-V conduction time may increase through concomitant use of beta-blockers and digitalis glycosides.

•    Beta-blockers may exacerbate rebound hypertension following clonidine withdrawal, such that if a patient is receiving both drugs, it is advised that the beta-blocker be withdrawn first, several days before the clonidine withdrawal.

•    Theoretically, there is a risk of hypertension from co-administration of monoamine oxidase inhibitors and high doses of beta-blockers (including cardio-selective ones).

Combinations to be used with caution

•    Care should be taken in co-administration of beta-blockers with other agents that may potentiate the negative effects of A-V conduction and myocardial contractility, such as Class I antiarrhythmics (e.g. disopyramide, quinidine) or amiodarone.

•    As beta-blockers may potentially increase the hypoglycaemic effects of insulin and oral antidiabetic drugs, the dose of the latter may require adjustment in co-administration situations.

•    Beta-blockers may mask the symptoms of hypoglycaemia or thyrotoxicosis (in particular, tachycardia).

•    Prior to general anaesthesia, the anesthetist must be informed of any beta-blocker therapy (see “Special warning and precautions for use”). Continuation of beta-blockade reduces arrhythmia risk during induction and intubation, but may attenuate reflex tachycardia and increase risk of hypotension. Avoid myocardially depressive anaesthetics such as ether, cyclopropane and trichloroethylene.

Combinations to be considered

• Dihydropyridine calcium channel blockers (e.g. nifedipine) taken concomitantly with beta-blockers may increase risk of hypotension. Cardiac failure may occur in cases of latent cardiac insufficiency.

•    Drugs that inhibit prostaglandin synthetase, such as non-steroidal antiinflammatory drugs (e.g. ibuprofen, indometacin) may diminish the beta-blocker hypotensive effect.

•    Adrenaline (epinephrine) or other sympathomimetics may counteract beta-blocker effects.

• Other antihypertensives,    tricyclic    antidepressants, barbiturates or

phenothiazines may potentiate beta-blocker hypotensive effects.

4.6 Pregnancy and lactation

Pregnancy

The safety profile of celiprolol in human pregnancy has not been established. Animal studies have not revealed any harmful effects on reproduction, embryonic/foetal development, gestation or peri- and post-natal development. Beta-blockers, have though, been associated with reduced perfusion of the placenta that can result in intrauterine foetal death, immature and premature deliveries. The foetus or neonate may experience adverse effects especially hypoglycaemia and bradycardia. Neonates may also have increased risk of cardiac and pulmonary complications.

Lactation

Most beta-blockers are excreted in breast milk to some extent. Celiprolol is not recommended in breast-feeding mothers.

4.7 Effects on ability to drive and use machines

Whilst it has been shown that celiprolol is unlikely to impair driving ability, occasional dizziness or fatigue may occur in some patients and this should be taken into account.

4.8 Undesirable effects

Beta-blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia (particularly tachycardia).

Common (>1%)

Usually mild and transient include:

CNS: dizziness, fatigue, headache, and insomnia.

Neurological: tremor.

Uncommon

CNS: Nausea, somnolence, confusion, hallucinations, psychoses, and nightmares.

Respiratory: bronchospasm (in patients with bronchial asthma or history of bronchial problems).

Neurological: paraesthesia.

Gastro-intestinal: vomiting, diarrhoea.

Others: skin disorders (rash), dry eyes, disturbances in libido and potency, increase in ANA (antinuclear antibodies).

Rare

CNS: Depression.

Respiratory: hypersensitivity pneumonitis.

Cardiovascular: bradycardia, slowed A-V conduction, hypotension, heart failure, cold & cyanotic extremities. In susceptible patients: precipitation of existing A-V block, exacerbation of intermittent claudication, Raynaud's disease/syndrome.

4.9 Overdose

No data relating to human overdose are available. The most common symptoms that could be anticipated in overdose with beta-blockers are bradycardia, bronchospasm, hypotension and acute cardiac insufficiency.

Overdose patients should be closely supervised, provided gastric lavage, activated charcoal and laxative to prevent further absorption of any residual drug in the gastro-intestinal tract. Haemodialysis or haemoperfusion might be considered.

1-2mg intravenous atropine should be used to treat any bradycardia or extensive vagal reactions. In refractory bradycardia and heart block, cardiac pacing may be considered. Hypotension should be treated using plasma (or its substitutes) and intravenous catecholamines (e.g. dopamine, dobutamine) where necessary.

Slow intravenous infusion of a beta-adrenoceptor stimulant can be used to counteract excessive beta blockade effects. Such stimulants might include isoprenaline (starting at 5 micrograms/minute with close cardiac monitoring) or dobutamine (starting at 2.5 micrograms/minute), utilised until the required effect is obtained. Severe overdosage may be treated with intravenous glucagon: initially a 10mg bolus dose, which may be followed up one hour later by a repeat bolus dose of 10mg or an intravenous infusion at a rate of 110 milligrams/hour dependant on response.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Celiprolol is a vasoactive beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity. ATC code C07A B08.

Celiprolol’s mild vasodilating properties are probably attributable to the beta-2 agonist activity. It reduces blood pressure in hypertensive patients whether they are resting or exercising. Existing levels of sympathetic tome influence the level of effect celiprolol has on cardiac rate and output.

Under stressful circumstances (e.g. exercise), celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. At rest, minimal impairment of cardiac function is observed.

5.2 Pharmacokinetic properties

Celiprolol is hydrophilic and is incompletely absorbed from the gastrointestinal tract. It has a plasma half-life approximating 5 to 6 hours and exhibits pharmacodynamic effects for at least 24 hours. Following once daily oral administration, celiprolol is excreted, only partially metabolised, in similar proportions in bile and urine.

Food or co-administration of chlorthalidone, hydrochlorothiazide or theophylline can reduce bioavailability of celiprolol.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium Carboxymethylcellulose 2000

Microcrystalline Cellulose 102

Crospovidone

Colloidal Silicon Dioxide

Sodium Lauryl Sulphate

Magnesium Stearate

Film coating:

Hydroxypropylmethylcellulose (E5)

Polyethylene Glycol 6000 Titanium Dioxide

6.2    Incompatibilities

None stated

6.3    Shelf life

36 months

6.4    Special precautions for storage

No special precautions for storage.

6.5    Nature and contents of container

Container    Pack size

Blister packs -250pm PVC foil with 25pm aluminium foil. 10, 20, 28, 30, 50,

60 and 90 tablets

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley Barnstaple North Devon

EX32 8NS

8    MARKETING AUTHORISATION NUMBER

PL 00142/0553

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/03/2003    / 26/03/2009

10    DATE OF REVISION OF THE TEXT

26/03/2009