Source: European Medicines Agency (EU)
Rapibloc must be reconstituted before administration and used immediately after opening (see section 6).
Landiolol should be used with caution in diabetics or in case of hypoglycaemia. Hypoglycaemia is more severe with less cardio-selective beta-blockers. Beta-blockers can mask the prodromal symptoms of hypoglycaemia such as tachycardia. Dizziness and sweating, however, may not be affected.
The most frequently observed side effect is hypotension which is rapidly reversible with dosage reduction or discontinuation.
It is advised to continuously monitor the blood pressure and the ECG in all patients treated with landiolol.
Beta-blockers should be avoided in patients with pre-excitation syndrome in combination with atrial fibrillation. In these patients beta-blockade of the atrioventricular node may increase the conduction through the accessory pathway and may precipitate ventricular fibrillation.
Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block (see also section 4.3).
Concomitant administration of landiolol with verapamil or diltiazem is not recommended in patients with atrioventricular conduction abnormalities (see section 4.5).
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. Non-selective betablockers should not be used for these patients and beta-1 selective blockers only with the utmost care.
The use of landiolol for the control of ventricular response in patients with supraventricular arrhythmias should be undertaken with caution in patients with (pre-existing) heart failure or when the patient is compromised hemodynamically or is taking other drugs that decrease any or all of the following: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse propagation in the myocardium. The benefits of potential rate control should be balanced against the risk of further depressing myocardial contractility. At the first sign or symptom of further worsening, dose should not be increased and, if considered necessary, landiolol should be discontinued and patients should receive appropriate medical management.
The use of landiolol for the control of ventricular response in patients with supraventricular arrhythmias should be undertaken with caution when the patient is compromised hemodynamically or is taking other drugs that decrease any or all of the following: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse propagation in the myocardium. The main metabolite of landiolol (M1) is excreted through the kidneys and is likely to accumulate in patients with renal impairment. Although this metabolite has no beta-blocking activity even at doses 200 times higher than the parent drug, landiolol should be used with caution in patients with insufficient renal function.
Landiolol should be used with caution and only after pre-treatment with alpha-receptor blockers in patients with phaeochromocytoma (see also section 4.3).
Patients with bronchospastic disease should, in general, not receive beta-blockers. Because of the high relative beta-1 selectivity and titratability, landiolol can be used with caution in such patients. Landiolol should be carefully titrated to obtain the lowest possible effective dose. In the event of bronchospasm, the infusion should be terminated immediately and a beta-2 agonist should be administered, if necessary. If the patient already uses a beta-2 receptor-stimulating agent, it might be necessary to re-evaluate the dose of this agent.
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.
Beta-blockers may increase both the sensitivity toward allergens and the seriousness of anaphylactic reactions. Patients using beta-blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions (see also section 4.5).
Calcium antagonists such as dihydropyridine derivatives (e.g. nifedipine) may increase the risk of hypotension. In patients with cardiac insufficiency, concomitant treatment with beta-blocking agents may lead to cardiac failure. Careful titration of landiolol and appropriate hemodynamic monitoring is recommended.
Administration of landiololshould be titrated with caution when concomitantly used with verapamil, diltiazem, class I antiarrhythmic agents, amiodarone or digitalis preparations since co-administration can result in excessive suppression of cardiac function and/or atrioventricular conduction abnormalities.
Landiolol should not be used concomitantly with verapamil or diltiazem in patients with atrioventricular conduction abnormalities (see section 4.4).
Concomitant use of landiolol and insulin or oral antidiabetic medicinal products may affect the blood sugar lowering effect. Attention should be given to the blood sugar levels when these medicinal products are administered concomitantly, as beta-adrenergic blockade may mask signs of hypoglycaemia such as tachycardia.
Continuation of the beta-blocker use during induction of narcosis, intubation and termination of narcosis reduces the risk of arrhythmia.
In case the patient’s intravascular volume status is uncertain or antihypertensive medicinal products are concomitantly administered with landiolol, reflex tachycardia may be attenuated and the risk of hypotension can increase.
The anaesthesiologist should be informed when the patient is receiving a beta-blocking agent in addition to landiolol. The hypotensive effects of inhalation anaesthetic agents may be increased in the presence of landiolol. The dosage of either agent may be adjusted as needed to maintain the desired hemodynamics.
Administration of landiolol should be titrated with caution when concomitantly used with anaesthetics with bradycardic effect, esterase substrates (e.g. suxamethonium chloride) or cholinesterase inhibitors (e.g. neostigmine) since co-administration may intensify the bradycardic effect or prolong the duration of action of landiolol.
An in vitro study using human plasma found that co-administration of suxamethonium could increase the maximum blood concentration of landiolol hydrochloride by about 20%. The antagonistic inhibition may also cause a prolongation of the duration of suxamethonium chloride induced neuromuscular blockage.
The combination of landiolol with ganglion blocking agents can enhance the hypotensive effect.
NSAIDs may decrease the hypotensive effects of beta-blockers. Special caution must be taken when using floctafenine or amisulpride concomitantly with beta-blockers.
Concomitant administration of landiolol with tricyclic antidepressants, barbiturates, phenothiazines or antihypertensive agents may increase the blood pressure lowering effect. Administration of landiolol should be adjusted carefully to avoid unexpected hypotension.
The effects of landiolol may be counteracted if concomitantly administered with sympathomimetic medicinal products having beta-adrenergic agonist activity. The dose of either agent may need to be adjusted based on patient response, or use of alternate therapeutic agents considered.
Catecholamine-depleting agents or antisympathotonic agents (e.g. reserpine, clonidine, dexmedetomidine) may have an additive effect when concomitantly administered with landiolol. Patients treated concurrently with these agents should be closely monitored for evidence of hypotension or marked bradycardia.
Concomitant use of clonidine and beta-blockers increase the risk of “rebound” hypertension. Although a rebound hypertensive effect was not observed after landiolol administration for 24 hours, such an effect cannot be excluded if landiolol is used in combination with clonidine.
Anaphylactic reactions caused by other medicinal products may be more serious in patients taking betablockers. These patients can be resistant to treatment with epinephrine at the normal dose, but intravenous injection of glucagon is effective (see also section 4.4).
When heparin was administered intravenously during landiolol infusion in patients undergoing cardiovascular surgery, there was a 50% decrease in landiolol plasma levels in conjunction with a heparin induced decrease in blood pressure and an increase in landiolol circulation time. Heart rate values did not change in this situation.
The interaction potential of the landiolol metabolites M1 and M2 with concomitant used medicinal products is not known. The pharmacodynamic effects of the metabolites are considered not clinically relevant (see section 5.2).
Interaction studies have only been performed in adults.
It is not known if the extent of the pharmacokinetic or pharmacodynamic drug interactions is similar in the paediatric population compared to that in adults.
There are no data from the use of Rapibloc in pregnant women available. Animal studies do not indicate clinically relevant effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of landiolol during pregnancy.
Based on the pharmacological action of beta-blocking agents, in the later period of pregnancy, side effects on the foetus and neonate (especially hypoglycaemia, hypotension and bradycardia) should be taken into account. If the treatment with landiolol is considered necessary, the uteroplacental blood flow and foetal growth should be monitored. The newborn must be closely monitored.
It is unknown whether landiolol or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of landiolol in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from landiolol therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Landiolol was not shown to alter fertility in animal studies (see section 5.3).
Not relevant.
The most frequently observed adverse drug reaction (ADR) reported for clinical trials (1,569 patients) and for postmarketing treatment outcome studies/use surveys (1,257 patients) for landiolol was hypotension and bradycardia (≥1 to <10%).
ADRs are tabulated below by system organ class and frequency; very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
uncommon: Pneumonia
rare: Mediastinitis
rare: Thrombocytopenia, platelet disorder
uncommon: Hyponatraemia
rare: Hyperglycaemia
uncommon: Cerebral ischemia, headache
rare: Cerebral infarction, cerebrovascular accident, seizure
common: Bradycardia
uncommon: Cardiac arrest, sinus arrest, tachycardia
rare: Myocardial infarction, ventricular tachycardia, atrial fibrillation, low cardiac output syndrome, atrioventricular block, bundle branch block right, supraventricular extrasystole, ventricular extrasystole
uncommon: Hypertension
rare: Shock, hot flush
uncommon: Pulmonary oedema
rare: Asthma, respiratory distress, respiratory disorder, bronchospasm, dyspnoea, hypoxia
uncommon: Vomiting, nausea
rare: Abdominal discomfort, oral discharge, breath odour
uncommon: Liver disorder
rare: Hyperbilirubinemia
rare: Erythema, cold sweat
rare: Muscle spasms
rare: Renal failure, acute kidney injury, oliguria
rare: Pyrexia ,chills, chest discomfort, administration site pain
not known: Application site pain, injection site reaction, sensation of pressure
common: Blood pressure decreased
uncommon: Electrocardiogram ST segment depression, cardiac index abnormal, alanine aminotransferase (ALT/GPT) abnormal, aspartate aminotransferase (AST/GOT) abnormal, blood bilirubin abnormal, white blood cell count abnormal, red blood cell count abnormal, haemoglobin abnormal, haematocrit abnormal, platelet count abnormal, blood lactate dehydrogenase abnormal, blood urea abnormal, blood creatinine increased, blood creatine phosphokinase abnormal, protein total abnormal, blood albumin abnormal, blood sodium abnormal, blood potassium abnormal, blood cholesterol abnormal, blood triglycerides abnormal, protein urine present
rare: Blood pressure increased, electrocardiogram T wave inversion, electrocardiogram: prolonged QRS complex, heart rate decreased, pulmonary arterial pressure increased, PO2 decreased, neutrophil count abnormal, blood alkaline phosphatase abnormal, leukocyte alkaline phosphatase, free fatty acids abnormal, blood chloride abnormal, glucose urine
Hypotension and bradycardia (see also section 4.2) were the most common adverse events observed in landiolol treated patients. Hypotension was observed in 8.5% of 948 patients treated with landiolol in controlled clinical studies (vs. 2.1% treated with placebo, 8.5% with comparator treatment and 5.7% with no treatment) and in 8.6% of 581 patients in uncontrolled studies. Bradycardia was observed in 2.1% of 948 patients treated with landiolol in controlled clinical studies (vs. 0% treated with placebo, 2.5% with comparator treatment and 2.4% with no treatment) and in 0.5% of 581 patients in uncontrolled studies. In postmarketing treatment outcome studies/use surveys with landiolol, the adverse event frequency for hypotension and bradycardia was 0.8% and 0.7%, respectively (of 1,257 patients). All cases of hypotension and bradycardia related to landiolol treatment in the described studies resolved or improved, without any action being taken or within minutes after discontinuation of landiolol and/or additional treatment.
Serious adverse events based on clinical studies/postmarketing use surveys: Shock due to excessive hypotension was reported in one perioperative clinical trial patient with heavy bleeding (the event resolved 10 minutes after landiolol, prostaglandine and isoflurane discontinuation). Cardiac arrest, complete AV block, sinus arrest, and severe bradycardia reported from clinical trials and post-marketing surveillance for landiolol treatment were mainly associated with elderly patients or with patients having hypertension or cardiac diseases as complications.
Measures to be taken if these specific adverse reactions occur are described in section 4.2.
Laboratory parameters: Abnormal changes in laboratory values were reported in the context of adverse events but were also reported separately. In controlled studies abnormal changes in ALT, AST or bilirubin were reported in 5% of landiolol treated patients (n=241) and in 7% of the control group (n=243). The overall frequency of changes in laboratory parameters in these studies was 8.7% in landiolol treated patients and 13.6% in the control group. The changes in laboratory values were resolved or remitted and were not considered clinically relevant.
There are limited safety data for the use of landiolol in the elderly. Uncertainties regarding the safety profile of landiolol need to be considered, as adverse advents could also result from the use of co-medications or from the anaesthesia.
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 national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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