Celiprolol Hydrochloride Tablets 200mg

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Celiprolol Hydrochloride Tablets, 200 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 200 mg tablet contains celiprolol hydrochloride 200 mg.

Excipient with known effect: Each 200 mg tablet contains 2 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Yellow film-coated, round biconvex tablets, 9.5 mm diameter, imprinted ‘CL breakline 200’ on one side and ‘G’ on the other.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Celiprolol hydrochloride is indicated for the management of mild to moderate hypertension and for prophylaxis of angina pectoris.

4.2 Posology and method of administration Posology

Adults

Hypertension

In hypertensive patients additional treatment with other anti-hypertensive agents is possible, in particular with diuretics. When a combination is initiated an increased monitoring of the blood pressure is recommended.

Treatment with celiprolol should not be discontinued abruptly, but should be discontinued gradually (i.e. over a period of 15 days), as discontinuing treatment abruptly may lead to an acute worsening of the patient’s condition.

Angina Pectoris

The initial dose is 200mg orally, taken once daily with a glass of water. Celiprolol should be taken on rising, 30 minutes before meals, or 2 hours after meals. If the response is inadequate, the dose may be increased to two 200mg in one single administration of 400mg, or one 400mg tablet once daily, after 2 to 4 weeks of treatment with 200mg once daily. Treatment with celiprolol should be discontinued gradually (i.e. over a period of 15 days), as discontinuing treatment abruptly may lead to an acute worsening of the patient’s condition, especially in the case of pre-existing ischaemic cardiac disease.

Elderly _ patients

Dosage as for adults. However close monitoring of elderly patients should be exercised, as renal and hepatic functions may be decreased in this population.

Patients with renal impairment

The dosage of celiprolol should be reduced by half in patients with creatinine clearance values of 15-40ml/minute. Celiprolol is not recommended for patients with creatinine clearance less than 15ml/minute (see section 4.4).

Paediatric population

Celiprolol is not indicated for use in children.

Method of administration

Tablets for oral administration.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Hypersensitivity to other beta-adrenergic blocking agents.

• Second or third degree heart block.

• Severe bradycardia (pulse rate at rest lower than 45-50 beats per minute before beginning of treatment).

• Sick sinus syndrome (including sino-atrial block).

• Untreated phaeochromocytoma (celiprolol may only be administered once the alpha receptors have been blocked).

• Metabolic acidosis.

• Hypotension.

• Uncontrolled heart failure.

• Cardiogenic shock.

• Severe renal impairment with creatinine clearance less than 15ml per minute.

• Severe bronchial asthma, or acute asthmatic attack and severe chronic obstructive pulmonary disease.

• Severe peripheral arterial circulatory disturbances.

Celiprolol should not be prescribed for patients being treated with theophylline. Verapamil and beta-blockers both slow A-V conduction and depress myocardial contractility through different mechanisms. When changing from verapamil to celiprolol and vice-versa, a period between stopping one and starting the other is recommended. Neither the beta-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other (see Section 4.5 Interaction with other medicinal products and other forms of interaction).

4.4 Special warnings and precautions for use

Celiprolol may be used in patients with mild to moderate degrees of reduced renal function as celiprolol is cleared by both renal and non-renal excretory pathways. A reduction in dosage by half may be appropriate in patients with creatinine clearances in the range of 15-40ml per minute. However, careful surveillance of such patients is recommended until steady state blood levels are achieved which typically would be within one week. Celiprolol is not recommended for patients with creatinine clearance less than 15ml per minute. Patients with hepatic impairment should also be carefully monitored after commencing therapy and a reduced dosage should be considered.

Celiprolol should only be used with caution in patients with well-controlled congestive cardiac failure (patients treated with digitalis and/or diuretics).under strict medical surveillance. Evidence of decompensation should be regarded as a signal to discontinue therapy.

Although cardio selective beta-blockers may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers, these should be avoided in patients with chronic obstructive airways disease, and in patients with a history of bronchospasm or bronchial asthma, unless there are compelling clinical reasons for use (see section 4.3). Where such reasons exist, celiprolol may be used but with the utmost caution under specialist supervision.

Although celiprolol is relatively cardio-selective and exerts mild P2 receptor agonism it should not be used in patients suffering from asthma or nocturnal wheeze. In case of crisis salbutamol could be used. Beta selective adrenoreceptor antagonist is contraindicated in the case of acute asthma attack.

In patients with coronary insufficiency, treatment should not be discontinued abruptly.

Beta-blockers may increase the number and the duration of anginal attacks in patients with Prinzmetal’s angina, due to unopposed alpha-receptor mediated coronary artery vasoconstriction. The use of beta-1 selective adrenoceptor blocking drugs such as celiprolol may be considered in these patients, but the utmost care should be exercised.

Celiprolol may induce bradycardia. If the pulse rate decreases to less than 5055 beats per minute at rest and the patient experiences symptoms related to bradycardia, the dosage should be reduced. Treatment with celiprolol should be stopped if the heart rate decreases to less than 45 beats per min.

Due to its negative effect on conduction time, celiprolol should only be given with caution to patients with first degree heart block.

Sudden withdrawal of beta-adrenoceptor blocking agents in patients with ischaemic heart disease may result in the appearance of anginal attacks of increased frequency or severity or deterioration in cardiac state. Although no adverse events due to abrupt cessation of celiprolol have been studied in clinical trials, therapy should be gradually reduced over 1-2 weeks, at the same time, if necessary, initiating replacement therapy to prevent exacerbation of angina pectoris.

In patients with peripheral circulatory disorders (Raynaud’s disease or syndrome, intermittent claudication), beta-blockers should be used with great caution as aggravation of these disorders may occur. Close monitoring is advisable.

Beta blockers should be used with caution in patients with apparent or latent Diabetes Mellitus because severe hypoglycaemic conditions are possible or symptoms of hypoglycaemia can be masked in particular, tachycardia (regular monitoring of blood glucose status is necessary).

Under treatment with beta-blockers (e.g. celiprolol) the symptoms of a thyrotoxicosis may be masked.

Beta-blockers may in individual cases cause psoriasis, aggravate the symptoms of the pre-existing disease, or lead to psoriasis-like exanthema. Patients with a history of psoriasis should take celiprolol only after careful consideration.

In patients with a history of anaphylactic reactions, beta-blockers may increase sensitivity to allergens and severity of anaphylactic reactions. Patients undergoing desensitisation treatment may suffer severe anaphylactic reactions.

Celiprolol therapy must be reported to the anaesthetist prior to general anaesthesia. If it is decided to withdraw the medicinal product before surgery, 48 hours should be allowed to elapse between the last dose and anaesthesia. Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation, although reflex tachycardia may be attenuated and the risk of hypotension may be increased (see section 4.5). In the event of continuation of celiprolol treatment, special care should be exercised when using anaesthetic agents such as ether, cyclopropane or trichloroethylene. The patient may be protected against vagal reactions by the intravenous administration of atropine.

Celiprolol should be used with caution in patients with treated phaeochromocytoma and must not be administered until after alpha-blockade has been established. Close monitoring is advisable.

These tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction Combinations not recommended

It has been shown that the bioavailability of celiprolol is impaired when it is given with food. Co-administration of chlorthalidone and hydrochlorothiazide also reduces the bioavailability of celiprolol.

Calcium channel antagonists such as verapamil (and to a lesser extent diltiazem) and beta-blockers both slow A-V conduction and depress myocardial contractility through different mechanisms. When changing from verapamil to celiprolol and vice-versa, a period between stopping one and starting the other is recommended. Concomitant administration of both medicinal products is not recommended and should only be initiated with both clinical signs and ECG monitored carefully. Patients with pre-existing conduction abnormalities should not be given the two medicinal products together.

Calcium antagonists of the verapamil- or diltiazem-type and anti arrhythmic agents (e.g. disopyramide, quinidine, amiodarone) should not be given intravenously during therapy with celiprolol because the co-administration may lead to profound hypotension and atrioventricular block (see section 4.3).

In case of shock or hypotension due to floctafenine, beta-blockers may reduce the effectiveness of drugs used to compensate these symptoms.

Digitalis glycosides, in association with beta-adrenoceptor blocking drugs, may increase A-V conduction time.

Celiprolol should not be prescribed for patients being treated with theophylline (see section 4.3).

Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine and other central antihypertensive drugs (alpha-methyldopa, guanfacine, moxonidine, rilmenidine). If the two medicinal products are co-administered, the beta-adrenoreceptor blocking medicinal product should be withdrawn several days before discontinuing clonidine and other central antihypertensive drugs.

There is a theoretical risk that the simultaneous administration of monoamine oxidase inhibitors and high doses of beta-adrenoceptor blockers but also the risk of hypertensive crisis even if they are cardioselective, can produce hypotension and is therefore not recommended.

Combinations to be used with caution

Care should be taken in prescribing beta-adrenoceptor blocking agents with Class I anti arrhythmic agents (e.g., disopyramide, quinidine) and Class III antiarrhythmic agents (e.g. amiodarone), because these agents may potentiate the negative effects on A-V conduction and myocardial contractility. Hypotension, bradycardia or other cardiac arrhythmias and/or heart failure may result. Clinical and ECG monitoring must be performed.

Beta-blockers may intensify the blood sugar lowering effects of insulin and oral antidiabetic drugs, and the dosage of antidiabetics may therefore require adjustment. In addition, beta-adrenoceptor blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia (in particular, tachycardia) (see section 4.4). Therefore, it is recommended that the blood glucose values be regularly monitored.

Therapy with beta-adrenoceptor blockers must be reported to the anaesthetist prior to general anaesthesia as they may attenuate the reflex tachycardia and increase the risk of hypotension. An anaesthetic drug with a minimal negative inotropic effect should preferably be used (see section 4.4).

Combination with propafenone may induce cardiac contractility, automatism and conduction disorders (due to removal of compensating sympathetic mechanisms). ECG and clinical monitoring is recommended.

Certain antiarrhythmic medicinal products may produce torsade de pointes.

Medications inducing torsades de pointes (except sultopfride):

- Class Ia antiarrhythmic agents (hydroquinidine, disopyramide),

- Class III antiarrhythmic agents (dofetilide, ibutilide, sotalol),

- Neuroleptic agents; phenotiazinic drugs (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamide drugs (amisulpride, sulpride, tiapride), butyrophonone drugs (droperidol, haloperidol) and other neuroleptic drugs (pimozide),

- Other drugs: bepridil, cisapride, diphemanil, IV spiramycin, IV erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, IV vincamycin, astemizole, terfenadine.

ECG and clinical monitoring recommended.

Combinations take into account

Concomitant therapy with dihydropyridine calcium channel antagonists, such as nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent or uncontrolled cardiac insufficiency. Blood pressure should be closely monitored in case of co-administration of celiprolol and dihydropyridine derivatives especially when therapy is initiated.

Drugs inhibiting prostaglandin synthetase, such as ibuprofen or indomethacin, may decrease the hypotensive effects of beta-adrenoceptor blocking drugs.

The simultaneous administration of celiprolol and reserpine, alpha-methyldopa, guanfacine, clonidine or digitalis glycosides can cause an excessive reduction in the heart rate or an increase in the atrioventricular conduction time.

Celiprolol can enhance the effect of antihypertensive medications that are given simultaneously.

Simultaneous administration of celiprolol and adrenaline, noradrenaline or other sympathomimetic agents (e.g. those contained in cough medicine or nose and eye drops) may cause an increase of blood pressure.

Concomitant use of vasodilators, other antihypertensive agents, or of tricyclic antidepressants, barbiturates or phenothiazines and other antidepressants as well as alcohol, may potentiate the orthostatic hypotensive effects of beta-blockers.

Care should be taken when administering NSAIDs including selective COXII inhibitors and acetylsalicylic acid (aspirin) >3g daily.

Simultaneous administration of urologic alpha blocking agents (alfuzosin, doxazosin, prazosin, tamsulosin, terazosin), may increase the risk of hypotensive effect and consequently of orthostatic hypotension.

Concomitant therapy with mefloquine may cause bradycardia.

4.6 Fertility, pregnancy and lactation Pregnancy

The safety of celiprolol for use in human pregnancy has not been established. Celiprolol passes the placenta in humans. An evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to reproduction, development of the embryo or foetus, the course of gestation and peri- and post-natal development.

However, beta-adrenoceptor blocking agents in general have been associated with reduced placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. For this reason celiprolol should not be used during pregnancy unless there is no safer alternative.

In the newborn of treated mother, beta-blocking activity persists for several days after birth and this may result in an increased risk of cardiac and pulmonary complications in the neonate in the post-natal period. In addition, adverse effects (especially hypoglycaemia, bradycardia and respiratory distress) may occur in the foetus and neonate. Therefore close monitoring of the neonate is recommended for the first 3 to 5 days of life.

Where possible the therapy with celiprolol should be discontinued 48-72 hours before the calculated delivery date.

Breast-feeding

Most beta-blockers will pass into breast milk, although to variable extents. The use of celiprolol is therefore not recommended in breast-feeding mothers.

4.7 Effects on ability to drive and use machines

It has been shown that driving ability is unlikely to be impaired in patients taking celiprolol. However, it should be taken into account that occasional dizziness or fatigue may occur as well as the potential for tremor, headaches or impaired vision. If affected, patients should be advised not to drive or operate machines.

4.8 Undesirable effects

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

Occasional adverse reactions, which are usually mild and transient, have occurred. These include headache, hot flushes, asthenia, dizziness, fatigue, somnolence and insomnia (sleep disturbances). Additional side effects associated with beta-2 agonist activity, tremor and palpitations, have been reported. These effects usually do not require withdrawal of therapy.

Bronchospasm, skin rashes and/or visual disturbances have been reported in association with the use of beta blockers. Celiprolol should be discontinued if these effects occur.

The following undesirable effects have been observed during treatment with celiprolol and other beta-blockers with the following frequencies: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000) and not known (frequency cannot be estimated from the available data).

Immune system disorders
Rare:	Hypersensitivity pneumonitis.
Not known:	Exceptional and reversible lupus syndrome.
Endocrine disorders
Not known:	Hot flushes.
Metabolism and nutrition disorders

Not known:

Hypoglycaemia, hyperglycaemia.

Latent diabetes mellitus may come to light and apparent diabetes mellitus may worsen.

Psychiatric disorders

Common:

Rare:

Very rare: Not known:

Nightmares, insomnia (sleep disturbances). Depression.

Hallucinations, psychoses.

Nervousness.

Nervous system disorders

Common:

Headache, fatigue, dizziness, somnolence, tremor and sensation of coldness in the extremities have been reported.

Rare:

Very rare:

Paraesthesia.

Confusion.

Eye disorders

Very rare:

Impaired vision, dry eyes with reduced lacrimation (to be considered if the patient uses contact lenses).

Ear and labyrinth disorders

Rare:

Tinnitus.

Cardiac disorders

Common:	Palpitations, bradycardia, significant decrease in blood pressure including when standing up from a lying position (orthostatic dysregulation), have been reported.
Rare:	AV-conduction disorders, increased cardiac insufficiency with peripheral oedema and/or exertional dyspnoea (heart failure), Raynaud’s disease or syndrome, increase of symptoms in patients with peripheral circulatory disturbances (with existing intermittent claudication, in patients suffering from Raynaud’s syndrome).
Not known:	Precipitation of existing A-V block in susceptible patients, arrhythmias.

Respiratory, thoracic and mediastinal disorders

Rare:

Dyspnoea, interstitial pneumonitis. Bronchospasm may occur in patients with bronchial asthma or with a history of bronchial complaints.

Gastrointestinal disorders

Common:	Vomiting, nausea, abdominal pain and abdominal discomfort (gastralgia).
Rare:	Diarrhoea, constipation.

Hepatobiliary disorders

Not known:

Increase in transaminases.

Skin and subcutaneous tissue disorders
Rare:	Allergic skin reactions (e.g. itching, flush, rash, pruritus, urticaria, purpura).
Very rare:	Beta-blockers can cause psoriasis in isolated cases, worsen the symptoms of this disease or lead to the formation of psoriasiform exanthemes.
Musculoskeletal disorders
Common:	Muscle cramps.
Rare:	Muscle weakness.
Reproductive system and breast disorders
Rare:	Impotence.
Not known:	Libido decrease.
General disorders and administration site conditions
Not known:	Asthenia.
Investigations
Rare:	An increase in antinuclear antibodies (ANA) has been reported, although its clinical relevance is not clear.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

No data are available regarding celiprolol overdose in humans.

Symptoms

The most common symptoms to be expected following overdosage with a beta-adrenoceptor blocking drug are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.

Management

General treatment should be symptomatic and supportive and be conducted under close supervision, with the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastro-intestinal tract. Haemodialysis or haemoperfusion may be considered.

Bradycardia or extensive vagal reactions should be treated with intravenous atropine, 1-2mg. Cardiac pacing should be considered in refractory bradycardia and heart block. Hypotension should be treated with plasma or plasma substitutes and, if necessary, intravenous catecholamines including dopamine and dobutamine.

Glucagon is the treatment of choice for severe hypotension, heart failure or cardiogenic shock. A bolus of 2-10mg IV in adults (50-150 micrograms/kg in a child) should be followed by an infusion of 1-5mg/hour (50 micrograms/kg/hour), titrated to clinical response. Note vials normally contain 1mg = 1 unit and other treatments may be more convenient to use. Some patients do not respond to glucagon and if vomiting occurs without any improvement in blood pressure, further glucagon is unlikely to be of benefit. Adverse effects of glucagon administration include vomiting, hyperglycaemia, hypokalaemia and hypocalcaemia.

If glucagon is not available or if there is severe bradycardia and hypotension, which is not improved by glucagon, use isoprenaline starting at an infusion rate of 5-10 micrograms/minute (0.02 micrograms/kg/min in children increasing to a maximum of 0.5 micrograms/kg/min) and increased as necessary depending on clinical response. Large doses (up to 800 micrograms/min) have been reported to be necessary on some occasions. Isoprenaline may be ineffective at improving blood pressure despite increasing heart rate.

In severe hypotension additional inotropic support may be necessary with a beta agonist such as dobutamine 2.5-40 micrograms/kg/min (adults and children). Other inotropes such as dopamine, adrenaline (epinephrine) or noradrenaline (norepinephrine) may occasionally be of benefit or consider the use of an intra-aortic balloon pump to sustain an adequate cardiac output. Management of cases of severe hypotension and cardiogenic shock should be discussed with your local poisons service in the UK NPIS 0844 892 0111.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta-blocking agents, selective.

ATC Code: C07A B08 Mechanism of action

Celiprolol is a vasoactive, beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity indicated in mild to moderate hypertension. The beta-2 agonist activity is thought to account for its mild vasodilating properties. It lowers blood pressure in hypertensive patients at rest and on exercise. The effects on heart rate and cardiac output are dependent on the pre-existing background level of sympathetic tone.

Under conditions of stress such as exercise, celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. However, at rest, minimal impairment of cardiac function is seen.

Celiprolol therapy has not been shown to adversely affect plasma lipid profiles.

5.2 Pharmacokinetic properties

Celiprolol is a hydrophilic compound that is incompletely absorbed from the gastrointestinal tract. Celiprolol hydrochloride crosses the blood-brain barrier only to a negligible extent.

Plasma half-life is approximately 5-6 hours and pharmacodynamic effects are present for at least 24 hours. After once daily administration celiprolol is only slightly metabolised before excretion in the bile and urine in almost equal quantities.

It has been shown that the bioavailablity of celiprolol is impaired when it is given with food. Co-administration of chlorthalidone, hydrochlorothiazide and theophylline also reduces the 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

Tablet Core

Cellulose, microcrystalline Mannitol (E421)

Croscarmellose sodium Magnesium stearate

Film Coat Clear film coat:

Hypromellose (E464)

Macrogol 400

Yellow film coat:

Lactose monohydrate Titanium dioxide (E171)

Hypromellose

Iron oxide yellow (E172)

Quinoline Yellow Lake (E104)

Glycerol triacetate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

No special precautions for storage.

6.5 Nature and contents of container

Celiprolol hydrochloride tablets 200mg are available either:

• in cartoned PVC/PVdC/Aluminium foil blister packs of 5, 7, 10, 14, 15, 20, 21, 28, 30, 50, 56, 60, 84, 90 and 100 tablets

• in polypropylene (PP) bottles fitted with low density polyethylene (LDPE) caps (30 and 100 tablets)

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Generics (UK) Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04569/0427

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/04/2001 / 22/04/2006

10 DATE OF REVISION OF THE TEXT

06/03/2014