Source: Health Sciences Authority (SG) Revision Year: 2023 Publisher: <u>France:</u> Les Laboratoires Servier, 50, rue Carnot, 92284 Suresnes cedex, France <u>Singapore:</u> Servier Singapore Pte Ltd, 67 Ubi Avenue 1, #06-09 StarHub Green, Singapore 408942
Carivalan is indicated only for symptomatic treatment of chronic stable angina pectoris because ivabradine has no benefits on cardiovascular outcomes (e.g. myocardial infarction or cardiovascular death) (see section 5.1).
Given that the heart rate may fluctuate considerably over time, serial heart rate measurements, ECG or ambulatory 24-hour monitoring should be considered when determining resting heart rate in patients on treatment with ivabradine when titration is considered. This also applies to patients with a low heart rate, in particular when heart rate decreases below 50 bpm, or after dose reduction (see section 4.2).
Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses its efficacy when a tachyarrhythmia occurs (eg. ventricular or supraventricular tachycardia). Carivalan is therefore not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interfere with sinus node function.
In patients treated with ivabradine, the risk of developing atrial fibrillation is increased (see section 4.8). Atrial fibrillation has been more common in patients using concomitantly amiodarone or potent class I antiarrhythmics. It is recommended to regularly clinically monitor ivabradine treated patients for the occurrence of atrial fibrillation (sustained or paroxysmal), which should also include ECG monitoring if clinically indicated (e.g. in case of exacerbated angina, palpitations, irregular pulse).
Patients should be informed of signs and symptoms of atrial fibrillation and be advised to contact their physician if these occur. If atrial fibrillation develops during treatment, the balance of benefits and risks of continued Carivalan treatment should be carefully reconsidered.
Chronic heart failure patients with intraventricular conduction defects (bundle branch block left, bundle branch block right) and ventricular dyssynchrony should be monitored closely.
Carivalan must not be initiated in patients with a pre-treatment resting heart rate below 50 beats per minute (see section 4.3). If, during treatment with Carivalan, resting heart rate decreases persistently below 50 bpm or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, down titration should be done with the individual components ensuring the patient is maintained at an optimal dose of carvedilol and ivabradine or treatment discontinued (see section 4.2).
Concomitant use of Carivalan with heart rate reducing calcium channel blockers such as verapamil or diltiazem is contraindicated (see sections 4.3 and 4.5). No safety issue has been raised on the combination of ivabradine with nitrates and dihydropyridine calcium channel blockers such as amlodipine. Additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been established (see section 5.1).
Heart failure must be stable before considering Carivalan treatment. Carivalan is not recommended in heart failure patients with NYHA functional classification IV due to limited amount of data with ivabradine in this population.
Carivalan should be used with caution in combination with digitalis glycosides since these products, as well as carvedilol, may slow the AV conduction (see section 4.5).
The use of Carivalan is not recommended immediately after a stroke since no data with ivabradine is available in these situations.
Ivabradine influences retinal function. There is no evidence of a toxic effect of long-term ivabradine treatment on the retina (see section 5.1). Cessation of treatment should be considered if any unexpected deterioration in visual function occurs. Caution should be exercised in patients with retinitis pigmentosa.
Ivabradine intake can be interrupted if necessary, however an abrupt cessation of therapy with a beta-blocker should be avoided, especially in patients with ischaemic heart disease. The cessation of Carivalan therapy should immediately be followed by the intake of carvedilol individual tablet ensuring the patient is maintained at an optimal dose of carvedilol. Posology of individual carvedilol should be decreased gradually; for example by reducing the daily dose by half every three days. If necessary, replacement therapy to prevent the exacerbation of angina pectoris should be initiated simultaneously. If the patient develops any symptoms, the dose should be reduced more slowly.
Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart failure patients with low arterial blood pressure (SBP < 100 mmHg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency.
Limited data are available in patients with mild to moderate hypotension, and ivabradine should therefore be used with caution in these patients. Carivalan is contraindicated in patients with severe hypotension (systolic arterial blood pressure <90 mmHg, diastolic arterial blood pressure <50 mmHg) (see section 4.3).
There is no evidence of risk of (excessive) bradycardia on return to sinus rhythm when pharmacological cardioversion is initiated in patients treated with ivabradine. However, in the absence of extensive data, nonurgent DC-cardioversion should be considered 24 hours after the last dose of Carivalan.
The use of Carivalan in patients with congenital QT syndrome or treated with QT prolonging medicinal products should be avoided (see section 4.5). If the combination appears necessary, close cardiac monitoring is needed. Heart rate reduction, as caused by ivabradine, may exacerbate QT prolongation, which may give rise to severe arrhythmias, in particular Torsade de pointes.
In the SHIFT trial, more patients experienced episodes of increased blood pressure while treated with ivabradine (7.1%) compared to patients treated with placebo (6.1%). These episodes occurred most frequently shortly after blood pressure treatment was modified, were transient, and did not affect the treatment effect of ivabradine. When treatment modifications are made in chronic heart failure patients treated with ivabradine blood pressure should be monitored at an appropriate interval.
Carvedilol may mask symptoms and signs of acute hypoglycaemia. Impaired blood glucose control may occasionally occur in patients with diabetes mellitus and heart failure in connection with the use of carvedilol. Therefore, close monitoring of diabetic patients receiving Carivalan is required by means of regular blood glucose measurements and adjustment of anti-diabetic medication as necessary (see section 4.5).
Carivalan should be used with caution in patients with peripheral vascular diseases, as beta-blockers may precipitate or aggravate symptoms of the disease. The same also applies to those with Raynaud’s syndrome, as there may be exacerbation or aggravation of symptoms. Carivalan is contraindicated in case of severe peripheral vascular disease (see section 4.3).
Beta-blockers reduce the risk of arrhythmias under anaesthesia, but the risk of hypotension may be increased. Caution should therefore be applied when using certain anaesthetics due to the negative synergic, inotropic effects of carvedilol and anaesthetic products (see section 4.5).
Beta-blockers, such as carvedilol, may mask the signs of hyperthyroidism and the symptoms of thyrotoxicosis.
Patients who wear contact lenses and are treated with Carivalan should be advised of the possible reduction of lachrymal secretion due to the carvedilol component.
Carivalan should be used with caution in patients with a history of serious hypersensitivity reactions and in those undergoing desensitisation therapy as beta-blockers, such as carvedilol, may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.
In patients with a personal or family history of psoriasis associated with beta-blocker therapy, Carivalan should only be prescribed after a careful weighing of risks and benefits as beta-blockers may worsen the skin reactions.
In patients with phaeochromocytoma, a treatment with alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Although carvedilol has both alpha- and beta- blocking pharmacological activity, there is no data regarding the use of carvedilol in this condition. Therefore, caution should be considered when in the administration of Carivalan to patients suspected of having phaeochromocytoma.
Due to insufficient clinical data, carvedilol should not be administered to patients with labile or secondary hypertension, orthostatic hypotension, acute myocarditis, a haemodynamically relevant stenosis of the heart valves or ventricular outflow tract, end-stage peripheral arterial disease or who are concomitantly receiving an α1-receptor antagonist or α2-receptor agonist.
Since tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Carivalan contains less than 1 mmol sodium (23mg) per tablet, i.e. essentially ‘sodium-free’.
This medicine contains the active substance carvedilol which may give a positive reaction in doping tests.
No interactions between carvedilol and ivabradine have been observed in an interaction study conducted in healthy volunteers. Information on interactions with other products that are known for the individual active substances is provided below.
Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this cytochrome. Ivabradine was shown not to influence the metabolism and plasma concentrations of other CYP3A4 substrates (mild, moderate and strong inhibitors). CYP3A4 inhibitors and inducers are liable to interact with ivabradine and influence its metabolism and pharmacokinetics to a clinically significant extent. Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine plasma concentrations, while inducers decrease them. Increased plasma concentrations of ivabradine may be associated with the risk of excessive bradycardia (see section 4.4).
Carvedilol is both a substrate and an inhibitor of P-glycoprotein. It is therefore possible that the bioavailability of medicines which are transported by P-glycoprotein will be increased if carvedilol is administered concomitantly. In addition, the bioavailability of carvedilol may be altered by inducers or inhibitors of Pglycoprotein.
Both inhibitors and inducers of the CYP2D6 and CYP2C9 isoenzymes may alter the systemic and presystemic metabolism of carvedilol in a stereoselective manner, which may reduce or elevate the plasma concentration of R- and S-carvedilol (see section 5.2).
Some of these types of interactions which have been observed in patients or healthy subjects are listed below. However, this list is not exhaustive.
Concomitant use contraindicated (see section 4.3):
| Known interaction with the product | Component | Interaction with other medicinal product |
|---|---|---|
| Potent CYP3A4 inhibitors (azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone) | Ivabradine Concomitant use contraindicated | Pharmacokinetic interaction: The concomitant use of ivabradine with potent CYP3A4 inhibitors is contraindicated. The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increased ivabradine mean plasma exposure by 7 to 8 fold. (see section 4.3) |
| Carvedilol Concomitant use with precaution | Patients receiving medications that inhibit cytochrome P450 enzymes (e.g. cimetidine, fluoxetine, verapamil, ketoconazole, haloperidol, erythromycin) should be closely monitored during concomitant treatment with carvedilol. | |
| Moderate CYP3A4 inhibitors (diltiazem, verapamil) | Ivabradine Concomitant use contraindicated | Pharmacokinetic and pharmacodynamic interaction: Specific interaction studies in healthy volunteers and patients have shown that the combination of ivabradine with the heart rate reducing agents diltiazem or verapamil resulted in an increase in ivabradine exposure (2- to 3-fold increase in AUC) and an additional heart rate reduction of 5 bpm (see section 4.3). |
| Carvedilol Concomitant use with precaution | Isolated cases of conduction disturbances (rarely with haemodynamic effect) have been observed when carvedilol has been administered with diltiazem, verapamil. Similar to other beta-blockers, if carvedilol is to be concomitantly orally administered with calcium channel blockers of the verapamil- or diltiazem-type, it is recommended to monitor ECG and blood pressure as concomitant administration of carvedilol with these substances may increase the risk of AV conduction disturbances. |
Concomitant use not recommended (see section 4.4):
| Known interaction with the product | Component | Interaction with other medicinal product |
|---|---|---|
| QT prolonging medicinal products Cardiovascular QT prolonging medicinal products (e.g. quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone). Non-cardiovascular QT prolonging medicinal products (e.g. pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin). | Ivabradine Concomitant use not recommended | The concomitant use of cardiovascular and non-cardiovascular QT prolonging medicinal products with ivabradine should be avoided since QT prolongation may be exacerbated by heart rate reduction. If the combination appears necessary, close cardiac monitoring is needed (see section 4.4). |
| Carvedilol Concomitant use with precautions with amiodarone | In patients presenting with heart failure, amiodarone reduced the clearance of S-carvedilol, most probably by inhibiting CYP2C9. The average plasma concentration of R-carvedilol remained unchanged. As a result, there is the potential risk of increased beta-blockade caused by an increase in the plasma concentration of S-carvedilol. Isolated cases of conduction disturbances (rarely with haemodynamic effect) have been observed when carvedilol has been administered with amiodarone. Concomitant administration with carvedilol and amiodarone (oral) must be carefully monitored as bradycardia, cardiac arrest and ventricular fibrillation have been reported shortly after the initiation of treatment following the concomitant use of beta-blockers (such as carvedilol) with amiodarone. | |
| Intravenous antiarrhythmic agent (other than verapamil, diltiazem) | Carvedilol Concomitant use not recommended | There is a risk of heart failure in the event of concomitant intravenous administration of class Ia or Ic antiarrhythmic agents with carvedilol. The concomitant use of beta-blockers with this type of agents should be carefully monitored. |
| Grapefruit juice | Ivabradine Concomitant use not recommended | Ivabradine exposure was increased by 2-fold following the co-administration with grapefruit juice. Therefore the intake of grapefruit juice with ivabradine should be avoided. |
Concomitant use with precaution:
| Known interaction with the product | Component | Interaction with other medicinal product |
|---|---|---|
| Moderate CYP3A4 inhibitors (other than diltiazem, verapamil) e.g. fluconazole | Ivabradine Concomitant use with precaution | The concomitant use of ivabradine with other moderate CYP3A4 inhibitors (e.g. fluconazole) may be considered at the starting dose of 2.5 mg twice daily and if resting heart rate is above 70 bpm, with monitoring of heart rate. |
| Cytochrome P450 enzymes inducers | Ivabradine Concomitant use with precaution | CYP3A4 inducers: CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, Hypericum perforatum [St John’s Wort]) may decrease ivabradine exposure and activity. The concomitant use of CYP3A4 inducing medicinal products may require an adjustment of the dose of ivabradine. The combination of ivabradine 10 mg twice daily with St John’s Wort was shown to reduce ivabradine AUC by half. The intake of St John’s Wort should be restricted during the treatment with ivabradine. |
| Carvedilol Concomitant use with precaution with rifampicin | In a study of 12 healthy subjects, administering rifampicin with carvedilol reduced plasma concentrations of carvedilol by around 70%, most probably by inducing P-glycoprotein. This caused a decrease in intestinal absorption of carvedilol and antihypertensive effect. | |
| Cimetidine | Carvedilol Concomitant use with precaution | Cimetidine increased carvedilol AUC by about 30% but causes no change in Cmax. Care may be required for patients receiving inhibitors of mixed function oxidase, e.g. cimetidine, as serum levels of carvedilol may be increased. However, based on the relatively small effect of cimetidine on carvedilol drug levels, the likelihood of any clinically important interaction is minimal. |
| Fluoxetine | Carvedilol Concomitant use with precaution | In a randomized, cross-over study in 10 patients with heart failure, co-administration of carvedilol with fluoxetine, a strong inhibitor of CYP2D6, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in mean R(+) enantiomer AUC. However, no difference in adverse events, arterial blood pressure or heart rate were noted between treatment groups. |
| Cardiac glycosides (digoxin, digitoxin) | Carvedilol Concomitant use with precaution | Digoxin and digitoxin concentrations are increased when digoxin and carvedilol are administered concomitantly. Digoxin, digitoxin and carvedilol all prolong the AV conduction time and therefore increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing Carivalan treatment. |
| Cyclosporin | Carvedilol Concomitant use with precaution | Two studies in renal and cardiac transplant patients receiving oral cyclosporine have shown an increase in cyclosporine plasma concentration following the initiation of carvedilol. Carvedilol appears to increase absorption of orally administered cyclosporine by inhibiting activity of P-glycoprotein in the intestine. In order to maintain therapeutic levels, in approximately 30% of patients a reduction of cyclosporine dose was necessary, while other patients required no dose adjustment. On average, the dose in these patients was reduced by approximately 20%. Due to wide individual variability of the dose among the patients, it is recommended that cyclosporine concentrations are monitored closely after initiation of Carivalan and that the dose of cyclosporine be appropriately adjusted. No interaction with carvedilol is expected with intravenous administration of cyclosporine. |
| Insulin or oral hypoglycaemics | Carvedilol Concomitant use with precaution | Medicines with beta-blocking effects may enhance the blood glucose-lowering effects of insulin and oral anti-diabetic medicines. Hypoglycaemic symptoms (especially tachycardia and palpitations) may be masked or attenuated. Therefore, blood glucose levels must be closely monitored in patients receiving insulin or oral antidiabetic medicines. |
| Catecholamine-depleting agents | Carvedilol Concomitant use with precaution | Patients taking both a beta-blocker (such as carvedilol) and a medicinal product that can deplete catecholamines (e.g. reserpine, guanethidine, methyldopa, guanfacine and monoamine oxidase inhibitors (except for MAO-B inhibitors)) should be carefully observed for signs of hypotension and/or severe bradycardia. |
| Clonidine | Carvedilol Concomitant use with precaution | Concomitant administration of clonidine with beta-blockers (such as carvedilol) may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with beta-blockers and clonidine is to be terminated, the beta-blocker should be discontinued first. Clonidine therapy may be discontinued several days later by gradually decreasing the dosage. |
| Dihydropyridine | Carvedilol Concomitant use with precaution | Concomitant administration of dihydropyridines and carvedilol should be closely monitored as there have been reports of heart failure and severe hypotension in this situation. |
| Anaesthetics | Carvedilol Concomitant use with precaution | Careful monitoring of vital signs is recommended during anaesthesia due to the synergistic, negative, inotropic and hypotensive effects of carvedilol and anaesthetic drugs. |
| Beta-agonist bronchodilators | Carvedilol Concomitant use with precaution | Non-cardioselective beta-blockers antagonise the bronchodilatory effects of beta-receptor agonists. These patients must be monitored closely. |
| Potassium-depleting diuretics (thiazide diuretics and loop diuretics) | Ivabradine Concomitant use with precaution | Hypokalaemia can increase the risk of arrhythmia. As ivabradine may cause bradycardia, the resulting combination of hypokalaemia and bradycardia is a predisposing factor to the onset of severe arrhythmias, especially in patients with long QT syndrome, whether congenital or substance-induced. |
Concomitant use to be taken into consideration (due to carvedilol):
| Known interaction with the product | Interaction with other medicinal product |
|---|---|
| Antihypertensive medicines | As with other agents with beta-blocking activity, carvedilol may potentiate the effect of other concomitantly administered drugs that have an antihypertensive effect (e.g. alpha1-receptor antagonists) or have hypotension as part of their adverse effect profile. |
| Non-steroidal anti-inflammatory drugs (NSAID) | Concomitant administration of NSAIDs and beta- blockers may lead to an increase in blood pressure and reduced ability to control blood pressure. The antihypertensive effect of carvedilol is decreased due to water and sodium retention. |
| Oestrogens and corticosteroids | Carvedilol’s antihypertensive activity may be reduced due to water and sodium retention in patients with a stabilised blood pressure who are receiving additional treatment such as oestrogens or corticosteroids. |
| Nitrates | Nitrates increase hypotensive effect. |
| Sympathomimetics with alpha-mimetic and beta-mimetic effects | Sympathomimetics with alpha-mimetic and beta-mimetic effects increase the risk of hypotension and excessive bradycardia. |
| Ergotamine | Vasoconstriction increased. |
| Neuromuscular blocking agents | Increased neuromuscular block. |
| Beta-blockers in the form of eye drops | Concomitant use of carvedilol with other beta-blockers in the form of eye drops may cause an increase in adverse effects, with beta-blockers presenting a particular risk of excessive bradycardia. |
| Barbiturates | Concomitant administration of carvedilol with barbiturates can lead to a reduced efficacy of carvedilol due to enzyme induction. |
Specific drug-drug interaction studies have shown no clinically significant effect of the following medicinal products on pharmacokinetics and pharmacodynamics of ivabradine: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG CoA reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlodipine, lacidipine), digoxin and warfarin. In addition, there was no clinically significant effect of ivabradine on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics of aspirin.
In pivotal phase III clinical trials, the following medicinal products were routinely combined with ivabradine with no evidence of safety concerns: angiotensin converting enzyme inhibitors, angiotensin II antagonists, beta-blockers, diuretics, anti-aldosterone agents, short and long acting nitrates, HMG CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics, aspirin and other anti-platelet medicinal products.
Interaction studies have only been performed in adults.
Women of child-bearing potential should use appropriate contraceptive measures during treatment (see section 4.3).
Based on existing data with the individual components, the use of Carivalan is contraindicated during pregnancy (see section 4.3).
There are insufficient data on the use of carvedilol in pregnant women. Experimental animal studies have shown reproductive toxicity (see section 5.3). The potential risk use in humans is unknown. Beta-blockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia, hypotension, respiratory depression and hypothermia) may occur in the foetus and neonate. There may be an increased risk of cardiac and pulmonary complications in the neonate during the postnatal period. There are no or limited amount of data from the use of ivabradine in pregnant women.
Animal studies with ivabradine have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects (see section 5.3). The potential risk for humans is unknown.
Carivalan is contraindicated during breast-feeding (see section 4.3).
Animal studies have shown that carvedilol or its metabolites are excreted in the breast milk. It is not known whether carvedilol is excreted in the human breast milk.
Animal studies indicate that ivabradine is excreted in milk. Women that need treatment with ivabradine should stop breast-feeding and choose for another way of feeding their child.
There are no clinical data on fertility with the use of Carivalan.
Studies with carvedilol have shown impaired fertility in adult female rats. Studies in rats with ivabradine shown no effect on fertility in males and females (see section 5.3).
Based on existing data with the individual components, the use of Carivalan may affect the ability to drive or use machinery.
Due to variability of individual reactions on carvedilol (such as dizziness, fatigue or decreased alertness), the ability to drive or operate machinery may be impaired. This is particularly true at the start of treatment, when the dose is increased, during the switch to a new preparation, or when taken together with alcohol.
Ivabradine may affect the patient’s ability to drive. Patients should be warned that ivabradine may cause transient luminous phenomena (consisting mainly of phosphenes). Luminous phenomena may occur in situations when there are sudden variations in light intensity, especially when driving at night. Ivabradine has no influence on the ability to use machines. However, in post-marketing experience, cases of impaired driving ability due to visual symptoms have been reported.
For carvedilol, the frequency of undesirable effects is not dose-dependent, with the exception of dizziness, visual disturbances and bradycardia.
For ivabradine, the most common adverse reactions, luminous phenomena (phosphenes) and bradycardia are dose-dependent and related to the pharmacological effect of the medicinal product.
The following undesirable effects have been observed during treatment with carvedilol and ivabradine given separately and ranked under the MedDRA classification by body system and under heading of frequency using the following convention: 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); not known (cannot be estimated from the available data).
| MedDRA System Organ Class | Undesirable effects | Frequency | |
|---|---|---|---|
| Carvedilol | Ivabradine | ||
| Infections and infestations | Bronchitis | Common | - |
| Pneumonia | Common | - | |
| Upper respiratory tract infections | Common | - | |
| Urinary tract infections | Common | - | |
| Blood and lymphatic system disorders | Anaemia | Common | - |
| Eosinophilia | - | Uncommon | |
| Thrombocytopenia | Rare | - | |
| Leukopenia | Very rare | - | |
| Immune system disorders | Allergic reactions (hypersensitivity) | Very rare | - |
| Metabolism and nutrition disorders | Hypercholesterolaemia | Common | - |
| Deterioration in glycaemic control (hyperglycaemia or hypoglycaemia) in patients with pre-existing diabetes | Common | - | |
| Diabetes mellitus | Common | - | |
| Hyperuricaemia | - | Uncommon | |
| Psychiatric disorders | Depressive mood, depression | Common | - |
| Sleep disorders, nightmares | Uncommon | - | |
| Confusion | Uncommon | - | |
| Nervous system disorders | Headache | Very common | Common |
| Dizziness | Very common | Common | |
| Syncope | Uncommon | Uncommon | |
| Presyncope | Uncommon | - | |
| Paraesthesia | Uncommon | - | |
| Eye disorders | Luminous phenomena (phosphenes) | - | Very Common |
| Visual impairment | Common | Uncommon | |
| Irritation of the eye | Common | - | |
| Blurred vision | - | Common | |
| Reduced lacrimation | Common | - | |
| Diplopia | - | Uncommon | |
| Ear and labyrinth disorders | Vertigo | - | Uncommon |
| Cardiac disorders | Heart failure | Very common | - |
| Bradycardia | Common | Common | |
| Pulmonary oedema | Common | - | |
| Oedema (including generalised and peripheral oedema and swelling of the genital area and feet, hypervolaemia and fluid retention) | Common | - | |
| AV 1st degree block (ECG prolonged PQ interval) | - | Common | |
| Ventricular extrasystoles | - | Common | |
| Atrial fibrillation | - | Common | |
| Angina pectoris | Uncommon | - | |
| Palpitations | - | Uncommon | |
| Supraventricular extrasystoles | - | Uncommon | |
| AV-block | Uncommon | - | |
| AV 2nd degree block | - | Very Rare | |
| AV 3rd degree block | - | Very Rare | |
| Sick sinus syndrome | - | Very Rare | |
| Vascular disorders | Hypotension | Very common | Uncommon (possibly related to bradycardia) |
| Postural hypotension | Common | - | |
| Disturbances of peripheral circulation (cold extremities, PVD, exacerbation of intermittent claudication and Raynauds phenomenon) | Common | - | |
| Uncontrolled blood pressure | - | Common | |
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | Common | Uncommon |
| Asthma in predisposed patients | Common | - | |
| Nasal congestion | Rare | - | |
| Wheezing | Rare | - | |
| Gastrointestinal disorders | Nausea | Common | Uncommon |
| Diarrhoea | Common | Uncommon | |
| Abdominal pain | Common | Uncommon* | |
| Vomiting | Common | - | |
| Dyspepsia | Common | - | |
| Constipation | Uncommon | Uncommon | |
| Dry mouth | Rare | - | |
| Skin and subcutaneous tissue disorders | Skin reactions (such as allergic exanthema, dermatitis, urticaria, pruritus and increased sweating) | Uncommon | - |
| Reactions similar to lichen planus, psoriasis or psoriasiform exanthema (occurring several weeks up to years after the start of treatment). Existing lesions may worsen. | Uncommon | - | |
| Alopecia | Uncommon | - | |
| Angioedema | - | Uncommon | |
| Rash | - | Uncommon | |
| Erythema | - | Rare | |
| Pruritus | - | Rare | |
| Urticaria | - | Rare | |
| Severe skin reactions (such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) | Very rare | - | |
| Musculoskeletal and connective tissue disorders | Pain in extremities | Common | - |
| Gout | Common | - | |
| Muscle spasms | - | Uncommon | |
| Renal and urinary disorders | Renal failure and renal function abnormality in patients with diffuse vascular disease and/or underlying renal insufficiency | Common | - |
| Micturition disorders | Common | - | |
| Urinary incontinence in women | Very rare | - | |
| General disorders and administration site conditions | Asthenia, fatigue | Very common | Uncommon |
| Pain | Common | - | |
| Malaise (possibly related to bradycardia) | - | Rare | |
| Investigations | Weight gain | Common | - |
| Blood creatinine increased | - | Uncommon | |
| ECG prolonged QT interval | - | Uncommon | |
| Increase in the transaminases ALT, AST and GGT | Very rare | - | |
| Reproductive system and breast disorders | Impotence, erectile dysfunction | Uncommon | - |
* Frequency calculated from clinical trials for adverse events detected from spontaneous report.
Dizziness, syncope, headache and debility are generally mild and are more likely to occur at the start of treatment.
Cardiac failure is an event commonly reported both in patients treated with placebo and in patients treated with carvedilol (14.5% and 15.4% respectively, in patients with left ventricular dysfunction following acute myocardial infarction).
A reversible deterioration in renal function has been observed during treatment with carvedilol in patients with chronic cardiac insufficiency with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or basal renal insufficiency (see point 4.4).
Non-selective beta-blockers in particular may cause latent diabetes to become manifest, manifest diabetes to be aggravated and blood glucose control to be impaired. The glucose balance may also be slightly upset during treatment with carvedilol, but this does not happen often.
Carvedilol may cause urinary incontinence in women. The problem is resolved once treatment is discontinued.
Luminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient enhanced brightness in a limited area of the visual field. They are usually triggered by sudden variations in light intensity. Phosphenes may also be described as a halo, image decomposition (stroboscopic or kaleidoscopic effects), coloured bright lights, or multiple images (retinal persistency). The onset of phosphenes is generally within the first two months of treatment after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity. All phosphenes resolved during or after treatment, of which a majority (77.5%) resolved during treatment. Fewer than 1% of patients changed their daily routine or discontinued the treatment in relation with phosphenes.
Bradycardia was reported by 3.3% of patients particularly within the first 2 to 3 months of treatment initiation. 0.5% of patients experienced a severe bradycardia below or equal to 40 bpm.
In the SIGNIFY study, atrial fibrillation was observed in 5.3% of patients taking ivabradine compared to 3.8% in the placebo group. In a pooled analysis of all the Phase II/III double blind controlled clinical trials with a duration of at least 3 months including more than 40,000 patients, the incidence of atrial fibrillation was 4.86% in ivabradine treated patients compared to 4.08% in controls, corresponding to a hazard ratio of 1.26, 95% CI [1.15-1.39].
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.
Not applicable.
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