Celiprolol Hydrochloride 200mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Celiprolol hydrochloride 200 mg film coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 200 mg celiprolol hydrochloride.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Film-coated tablet.
Yellow coloured, capsule shaped, biconvex film coated tablets, debossed with ‘200’ on one side of the breakline and a deep breakline on the other side.
The tablet can be broken into equal halves.
4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
Celiprolol is indicated for the treatment of hypertension.
4.2. Posology and Method of Administration
Adults: The initial dose is 200 mg orally, taken once daily with a glass of water. Celiprolol should be taken on rising, one hour before meals, or 2 hours after meals. If response is inadequate, the dose may be increased to 400 mg once daily, after 2 to 4 weeks of treatment with 200mg once daily. It may take several weeks of treatment for the anti-hypertensive effect of celiprolol to be fully established. There is no limit for the duration of treatment. This depends on the nature and severity of the disease. Treatment with celiprolol should not be discontinued abruptly, but should be discontinued gradually (i.e. over a period of 7-10 days), as discontinuing treatment abruptly may lead to an acute worsening of the patient’s condition.
Elderly: Dosage as for adults.
Dosage in renal impairment: The dosage of celiprolol should be reduced by half in patients with creatinine clearance values of 15-40 ml/minute. Celiprolol is not recommended for patients with creatinine clearance less than 15 ml/minute.
Dosage in hepatic impairment: Patients with hepatic impairment should also be carefully monitored after commencing therapy and a reduced dosage should be considered.
Children: Not recommended.
4.3. Contra-Indications
Celiprolol is contraindicated in patients who are hypersensitive to celiprolol, to other B-adrenergic blocking agents or to any of the excipients of this product.
Celiprolol is also contraindicated in patients with:
- Second or third degree heart block;
- Severe bradycardia (< 45-50 beats per minute);
- Sick sinus syndrome (including Sinoartrial block);
- Untreated phaeochromocytoma (celiprolol may only be administered once the alpha receptors have been blocked);
- Metabolic acidosis;
- Hypotension;
- Severe peripheral arterial circulatory disturbances
- Uncontrolled heart failure;
- Cardiogenic shock;
- Severe renal impairment with creatinine clearance less than 15ml per minute; and
- Acute episode of asthma, Severe bronchial asthma and severe chronic obstructive pulmonary disease.
Celiprolol should not be prescribed for patients being treatment with theophylline.
4.4. Special Warnings and Special Precautions for Use
Although cardiac 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 bronchiol asthma, unless there are compelling clinical reasons for their use. Where such reasons exist, celiprolol may be used but with the utmost caution under specialist supervision. The label will carry the following warning: If you have a history of asthma or wheezing, please ask your doctor before taking this medicine
The pharmacokinetics are not significantly different in the elderly, however these patients should be regularly monitored and due regard made for decreased renal and liver function in this age group. 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 to 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 15 ml per minute. Patients with hepatic impairment should also be carefully monitored after commencing therapy and a reduced dosage should be considered.
In patients with coronary insufficiency, treatment should not be discontinued abruptly.
Sudden withdrawal of beta-adrenoceptor blocking agents in patients with ischemic heart disease may result in the appearance of anginal attacks of increased frequency or severity or deterioration in cardiac state. Although no adverse effects 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.
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 “Interactions”). In the event of continuation of celiprolol treatment, special care should be exercised when using anaesthetic agents such as ether, cyclopropane or trichloroethylene (sees section 4.5 Interaction with other medicinal products and other forms of interaction). The patient may be protected against vagal reactions by the intravenous administration of atropine.
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.
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.
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 be used with caution in patients with first degree AV block.
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.
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.
Celiprolol should be used with caution in patients with treated phaeochromocytoma and must not be adminstered until after alpha-blockade has been established. Close monitoring is advisable.
Beta-blockers may increase sensitivity to allergens and severity of anaphylactic reactions. Patients who have a history of severe hypersensitivity and patients undergoing desensitisation treatment may suffer severe anaphylactic reactions.
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 (regular monitoring of blood glucose status is necessary) (See Section 4.5 Interaction with other medicinal products and other forms of interaction).
Under treatment with B-blockers (e.g. celiprolol) the symptoms of thyrotoxicosis may be masked.
Celiprolol may give a positive reaction when drug-screening tests are conducted in competitive sport since beta-blockers may be restricted in certain sports. Competitors should check with the appropriate sports authorities.
4.5. Interaction with other Medicinal Products and other forms of Interaction
Combinations not recommended
Celiprolol should not be prescribed for patients being treated with theophylline (see Section 4.3 Contraindications).
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 ECG monitoring. Neither the beta-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.
Patients with pre-existing conduction abnormalities should not be given the two medicinal products together.
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.
Beta blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two medicinal products are co-administered, the beta-adrenoceptor blocking medicinal product should be withdrawn several days before discontinuing clonidine.
There is a theoretical risk that concurrent administration of monoamine oxidase inhibitors and high doses of beta-adrenoceptor blockers, even if they are cardio selective, can produce hypotension and is therefore not recommended.
Precautions for use
Care should be taken in prescribing beta-adrenoceptor blockers with Class I antiarrhythmic agents (e.g. disopyramide, quinidine) and class III antiarrhythmic agents (e.g. amiodarone), because hypotension, bradycardia or other cardiac arrhythmias and/or heart failure may result. Certain antiarrhythmic medicinal products (disopyramide, quinidine, amiodarone, sotalol) may product torsade de pointes. Therefore, ECG monitoring is necessary. In case of torsade de pointes administering of antiarrhythmic agents is not recommended.
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).
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 (see section 4.4 “Special warnings and special precautions for use”). Therefore, before administering anaesthetic agents, the anaesthesiologist should be informed. An anaesthetic drug with a minimal negative inotropic effect should preferably be used (see Section 4.4 Special warnings and special precautions for use).
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.
The simultaneous administration of celiprolol and resperine, 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 counteract the effects of beta blockers
Simultaneous administration of vasodilators, tricyclic antidepressants, barbiturates, phenothiazines and other antidepressants as well as alcohol may increase the orthostatic hypotensive effect of celiprolol.
Drugs inhibiting prostaglandin synthetase, such as ibuprofen or indomethacin, may decrease the hypotensive effects of beta-adrenoceptor blocking drugs. Concomitant therapy with mefloquine may cause bradycardia.
4.6. Pregnancy and Lactation
Pregnancy
The safety of celiprolol product for use in human pregnancy has not been established. 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 drugs in general have been associated with reduced placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. Celiprolol should therefore not be used during pregnancy unless there is no safer alternative.
In the newborn of treated mothers, 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 foetus and neonate. Therefore close monitoring of the neonate is recommended for the first 3 to 5 days of life.
Lactation
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).
Occasional side effects, 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.
The frequencies of adverse events are ranked according to the following: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000), Not known (cannot be estimated from available data).
Metabolism and nutrition disorders Hypoglycaemia, Hyperglycaemia
Latent diabetes mellitus may come to light, and apparent diabetes mellitus may worsen.
Beta-blockers may mask the symptoms of hypoglycaemia or thyrotoxicosis (in particular tachycardia and tremor).
Psychiatric disorders
Rare: depression has been reported.
Very rare: hallucinations, psychoses
Nervous system disorders
Common: headache and dizziness, somnolence, nightmares and insomnia (sleep disturbances), tremor and sensation of coldness in the extremities have been reported.
Rare: paraesthesia
Very rare: confusion
Eye disorders
Very rare: impaired vision,
Visual disturbances have been reported including xerophthalamias;dry eyes (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 hypotension), have been reported.
Rare: slowed AV-conduction, increased cardiac insufficiency with peripheral oedema and/or exertional dyspnoea. Heart failure, cold and cyanotic extremities. In susceptible patients: precipitation of existing A-V block.
Vascular disorders
In susceptible patients: exacerbation of intermittent claudication Raynaud’s disease or syndrome have been reported.
Respiratory, thoracic and mediastinal system disorders
Rare: hypersensitivity pneumonitis, bronchospasm, asthmatic dyspnoea especially in patients with bronchial asthma or a history of asthmatic complaints. Dyspnoea and interstitial pneumonitis have also been rarely reported.
Gastrointestinal disorders
Common: nausea, vomiting, abdominal pain and abdominal discomfort can occur.
Rare: diarrhoea, constipation.
Hepatobiliary disorders Increase in transaminases
Skin and subcutaneous tissue disorders
Rare: allergic skin reactions (e.g. itching, flush, rash, pruritus, urticaria, purpura).
Very rare: Betablockers can cause psoriasis in isolated cases, worsen the symptoms of this disease or lead to the formation of psoriasiform exanthemes.
Musculoskeletal and connective tissue disorders Common: muscle cramps
Rare: muscle weakness.
Reproductive system and breast disorders Rare: male impotence, libido decrease
General disorders and administration site conditions Common: fatigue.
Investigations
Rare: An increase in antinuclear antibodies (ANA) has been seen, its clinical relevance is not clear.
Antinuclear antibodies have been observed, exceptional and reversible lupus syndrome
4.9. Overdose
No data are available regarding overdose in humans.
The most common symptoms to be expected following overdosage with a beta-adrenoceptor blocking drug are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.
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 occassions. 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 occassionally 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.
5.1. Pharmacodynamic Properties
Pharmacotherapeutic group: Betablocking agents, selective.
ATC Code: C07A B08
Mode 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. Bioavailability of orally administered celiprolol ranges from 30 to 70% depending upon the dose administered. Plasma half-life is approximately 5-6 hours and pharmacodynamic effects are present for at least 24 hours. At plasma concentrations of 0.11 to 0.86 pmol/L, celiprolol is about 25% bound to human plasma proteins. 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 bioavailability 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. Pre-clinical Safety Data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity.
6.1. List of Excipients
Microcrystalline cellulose Mannitol
Croscarmellose sodium Colloidal anhydrous silica Magnesium stearate Film coating material:
Hypromellose Titanium dioxide (E171) Macrogol 400 Quinoline yellow (E104)
6.2. Incompatibilities
Not applicable.
6.3. Shelf-Life
3 Years
6.4. Special Precautions for Storage
Store in original container
6.5. Nature and Content of Container
Blister strips comprising of white opaque PVC film with a backing of aluminium foil coated with heat seal lacquer.
Pack of 10, 20, 28, 30, 50, 56 and 100 tablets.
6.6. Instructions for Use, Handling and Disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited 5th floor, Hyde Park, Hayes 3 11 Millington Road Hayes, UB3 4AZ United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
PL 14894/0045
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
27/06/2007
10 DATE OF REVISION OF THE TEXT
15/08/2016