Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Ranbaxy (UK) Limited, 5th floor, Hyde Park, Hayes 3, 11 Millington Road, Hayes, UB3 4AZ, United Kingdom
Hypersensitivity to celiprolol hydrochloride or to any of the excipients listed in section 6.1.
Celiprolol is also contraindicated in patients with:
Celiprolol should not be prescribed for patients being treatment with theophylline.
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.
The initial treatment of severe malignant hypertension should be so designed as to avoid reduction in diastolic blood pressure with impairment of autoregulatory mechanisms.
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) or with a history of asthma 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 50-55 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 administered 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 (such as tachycardia) 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 ß-blockers (e.g. celiprolol) the symptoms of thyrotoxicosis (trachycardia and tremor) may be masked.
Patients with hepatic or renal insufficiency should be carefully monitored after treatment has commenced.
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.
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.
Fingolimod: Concomitant use of fingolimod and beta blockers may potentiate bradycardia effects and is not recommended. Where such co-administration is considered necessary, appropriate monitoring at treatment initiation, i.e. at least overnight monitoring, is recommended.
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.
Celiprolol is a substrate of the intestinal update transporters OPTPs, specifically OATP1A2 and OATP2B1. OATPs inhibitors may result in a decrease in celiprolol absorption. Citrus juices have been shown to decrease the absorption of celiprolol from the gastrointestinal tract through inhibition of OATP2B1 update transporter activity, resulting in approximately 90% decrease in AUC and Cmax. Patients should be advised to avoid such beverages.
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).
Concomitant use with drugs that inhibit P-gp (e.g. verapamil, erythromycin, clarithromycin, ciclosporin, quinidine, ketoconazole and itraconazole) are likely to result in increased plasma concentrations of celiprolol. Co-administration of celiprolol 100mg and the P-gp-inhibitor itraconazole 200mg resulted in an 80& increase in celiprolol AUC. A dose-reduction of celiprolol could be considered when concomitantly used with drugs that inhibit P-gp.
Concomitant use with drugs that induce P-gp (e.g. rifampicin and St. John’s wort) could result in decreased plasma concentrations of celiprolol. Co-administration of celiprolol 200mg and rifampicin 600mg o.d. for 5 consecutive days resulted in a 40% decrease of celiprolol AUC. A more pronounced effect after longer treatment with rifampicin cannot be ruled out. A dosage adjustment of celiprolol might be necessary when treatment with a P-gp inducing drug is initiated or discontinued.
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.
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 (See section 4.9 Overdose).
In general beta blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. Plasma volume should not be increased as risk of acute pulmonary oedema may exist. 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.
When given within 48 hours of delivery of an obstetric patient, hypotension and bradycardia may be seen in the infant.
Most beta blockers will pass into breast milk, although to variable extents. There is insufficient information on the excretion of celiprolol in human milk.
The risk of hypoglycaemia and bradycardia occurring in the nursing infant have not been evaluated. A risk to the newborns/infants cannot be excluded.
The use of Celiprolol is therefore not recommended in breast-feeding mothers.
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.
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).
Not known: 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).
Common: depression has been reported.
Uncommon: insomnia
Very rare: psychoses
Not known: hallucinations, nightmare, libido decrease
Common: headache and dizziness, somnolence, nightmares and insomnia (sleep disturbances), tremor and sensation of coldness in the extremities have been reported, paraesthesia, asthenia.
Very rare: confusion
Not known: syncope
Not known: impaired vision, visual disturbances have been reported including xerophthalamias; dry eyes (to be considered if the patient uses contact lenses).
Rare: tinnitus
Common: significant decrease in blood pressure including when standing up from a lying position (orthostatic hypotension), have been reported.
Uncommon: palpitations
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.
Not known: bradycardia, cardiac failure
Common: Hot flush, In susceptible patients: exacerbation of intermittent claudication Raynaud’s disease or syndrome have been reported.
Uncommon: Cold extremities, hypotension
Uncommon: Dyspnoea
Rare: hypersensitivity pneumonitis, asthmatic dyspnoea especially in patients with bronchial asthma or a history of asthmatic complaints.
Not known: Interstitial pneumonitis, bronchospasm
Common: nausea, vomiting, abdominal pain and abdominal discomfort can occur, dry mouth
Rare: constipation.
Not known: diarrhoea.
Not known: Increase in transaminases
Common: rash, pruritus, hyperhidrosis, erythema
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.
Common: muscle cramps
Uncommon: arthralgia
Rare: muscle weakness
Not known: systemic lupus erythmatosus
Common: erectile dysfunction
Rare: male impotence, libido decrease
Common: fatigue.
Common: 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
Not known: hepatic transaminases increased
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.
Not applicable.
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