Second-line in HFrEF per 2023 in symptomatic NYHA II–IV patients with sinus rhythm, HR ≥75 bpm, EF ≤35%. Added to standard therapy (ARNI/ACEi, β-blockers, aldosterone antagonists, SGLT2 inhibitors) when β-blockers are contraindicated or HR remains high on maximum tolerated dose. SHIFT showed 18% reduction in cardiovascular death or HF hospitalization. Starting dose 5 mg twice daily, titrated to 7.5 mg twice daily.
Only in HFrEF patients with sinus rhythm and HR ≥75 bpm on optimal foundation therapy.
Used in stable angina in patients with sinus rhythm and resting HR ≥70 bpm intolerant to or inadequately controlled on β-blockers. SIGNIFY in non-HF patients raised cardiovascular death and non-fatal MI by 18% – since then, angina-only indications are restricted to patients without alternatives.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
F
Athletic endurance
Not recommended
+
Ivabradine is a selective sinus node If-channel inhibitor that reduces heart rate. It is prescribed for stable angina and heart failure with reduced ejection fraction ( 2024). In sports circles, ivabradine is occasionally promoted for pulse control during cardio in people without heart failure. In healthy athletes, no clinical studies of prophylactic use exist; such prescription can mask cardiovascular symptoms and is dangerous. The drug has specific risks: bradycardia, phosphenes (flashes of bright light in the visual field, in 14% of patients), atrial fibrillation, and conduction disturbances. Ivabradine is on the WADA Prohibited List in competition. If ivabradine was prescribed to an athlete for training, consider seeking a second opinion.
AStrong evidence – first or second line in international guidelines
BRecommended in selected cases
CStudy data contradict each other
DBenefit not proven, no documented harm
FDocumented harm, or risk without benefit
Mechanism of action
A selective and specific inhibitor of the If («funny») current in sinoatrial node pacemaker cells. Reduces diastolic depolarization slope – lowers heart rate without affecting myocardial contractility, AV conduction, ventricular repolarization, or BP. BEAUTIFUL and SHIFT meta-analyses showed resting HR reduction of 8–10 bpm. CYP3A4-metabolized, half-life 11 hours.
Safety
Contraindications
Ivabradine hypersensitivity
Resting HR under 70 bpm at baseline
Cardiogenic shock
Acute myocardial infarction
Severe hypotension (BP under 90/50)
Severe hepatic impairment
Sick sinus syndrome, sinoatrial block
Third-degree AV block
Pacemaker-dependent rhythm
Unstable or acute heart failure
Concomitant strong CYP3A4 inhibitors
Pregnancy and lactation
Serious adverse effects
Severe bradycardia and AV block
Atrial fibrillation (30% increased risk)
Heart failure decompensation
Cardiovascular events in non-HF patients (SIGNIFY)
Common adverse effects
Luminous phenomena in vision (phosphenes) – 14%, reversible
Bradycardia
Headache
Dizziness
Atrioventricular extrasystoles
Pregnancy: can you take Ivabradine?
Contraindicated. Animal studies show embryo-fetal defects. Reliable contraception is required in women of reproductive age.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Practical notes
Timing and administration
Take twice daily with food – meals raise bioavailability by 20%. Check HR before each titration: target resting HR 50–60 bpm. With HR under 50 or bradycardia symptoms (dizziness, fatigue), reduce dose or stop. Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) raise ivabradine levels 7–8 fold – combination contraindicated. Grapefruit juice doubles exposure.
Drug–nutrient interactions
Grapefruit juice
Grapefruit juice inhibits CYP3A4, and in the Procoralan SmPC it doubled ivabradine exposure. More drug slows the heart too much: dizziness, tiredness, fainting. The SmPC lists grapefruit juice among combinations not recommended and says to avoid it.
In the liver and gut, a single enzyme, CYP3A4 (cytochrome P450 3A4), breaks down ivabradine, and clarithromycin strongly inhibits this enzyme (ivabradine and clarithromycin summaries of product characteristics, SmPCs). When the two are taken together, ivabradine levels in the blood rise, and high levels can lead to excessive bradycardia (ivabradine SmPC, European Medicines Agency, ). The documents give no figures for clarithromycin itself. Figures exist for other strong inhibitors: ketoconazole 200 mg once daily and the macrolide antibiotic josamycin 1 g twice daily raised mean ivabradine plasma exposure 7- to 8-fold (ivabradine SmPC, EMA). The second mechanism involves the QT interval. Clarithromycin prolongs QT on its own, and the slower heart rate caused by ivabradine can worsen this prolongation and lead to a serious arrhythmia (clarithromycin and ivabradine SmPCs, EMA).
Symptoms
Excessive bradycardia shows as a resting heart rate below 50 beats per minute, dizziness, fatigue and low blood pressure (ivabradine summary of product characteristics, European Medicines Agency, ). Sinus arrest and heart block can occur (Corlanor label, US Food and Drug Administration, ). The QT interval on the electrocardiogram (ECG) can lengthen, and a severe ventricular arrhythmia, including torsade de pointes, may follow (ivabradine and clarithromycin summaries of product characteristics). The risk is higher in people who also take other QT-prolonging drugs (Corlanor label, FDA).
Management
The combination is contraindicated on both sides. The ivabradine summary of product characteristics (SmPC) lists clarithromycin among the strong inhibitors of the enzyme CYP3A4 (cytochrome P450 3A4) that must not be taken with ivabradine (European Medicines Agency, , sections 4.3 and 4.5). The clarithromycin SmPC lists ivabradine among contraindicated drugs (Spanish Agency of Medicines and Medical Devices, AEMPS, 4.3 and 4.5). The US ivabradine label also contraindicates strong CYP3A4 inhibitors and gives clarithromycin as an example (US Food and Drug Administration, , sections 4 and 7.1). So during a course of clarithromycin, choose another antibiotic or pause ivabradine (this follows from the contraindication in both labels). The documents give no interval after clarithromycin before ivabradine can be restarted. When choosing the antibiotic, note that oral erythromycin, josamycin and telithromycin are also contraindicated with ivabradine, and drugs that prolong the QT interval should be avoided with it (ivabradine SmPC, EMA, sections 4.3–4.5). Clarithromycin itself is contraindicated with a history of QT prolongation and with low potassium or magnesium (clarithromycin SmPC, AEMPS, 4.3). Avoid it in clinically significant bradycardia (clarithromycin label, FDA, 5.2). If the drugs have already been taken together, stop one of them and monitor the heart rate and electrocardiogram (ECG). With a resting heart rate below 50 beats per minute or symptoms of bradycardia, reduce the ivabradine dose, and if bradycardia persists, stop ivabradine (ivabradine SmPC, EMA, 4.2 and 4.4). Treat severe bradycardia in a specialised unit. If it compromises the circulation, give intravenous beta-stimulants such as isoprenaline, and use temporary cardiac pacing if that is not enough (ivabradine SmPC, EMA, 4.9). Before restarting ivabradine, measure the resting heart rate several times, by ECG or 24-hour monitoring, and do not start the drug below 70 beats per minute (ivabradine SmPC, EMA, 4.3 and 4.4).
Diltiazem is a moderate inhibitor of CYP3A4, the enzyme that clears ivabradine. When the two are taken together, ivabradine exposure (area under the concentration curve, AUC) rises 2–3-fold (ivabradine SmPC, ). Both drugs slow the heart. Ivabradine slows the sinus node; diltiazem prolongs the refractory periods of the atrioventricular node and can cause bradycardia or second- or third-degree atrioventricular block (diltiazem SmPC). Together they lower the heart rate by a further 5 beats per minute beyond the effect of ivabradine alone and worsen conduction disturbances (ivabradine SmPC, EMA; Corlanor label, ).
Symptoms
Bradycardia: resting pulse below 50 beats per minute, dizziness, fatigue, low blood pressure (ivabradine SmPC, ). Sinus arrest and atrioventricular block with fainting can occur (Corlanor label, ; diltiazem SmPC). Marked bradycardia raises the risk of QT prolongation and torsade de pointes, especially with other QT-prolonging drugs (Corlanor label, FDA).
Management
The combination is contraindicated from both sides: the ivabradine SmPC () forbids use with diltiazem and verapamil, and the diltiazem SmPC forbids use with ivabradine (section 4.3 of both). The labels require avoiding concomitant use (ivabradine and diltiazem labels, FDA). If a calcium channel blocker is needed, the ivabradine SmPC notes no safety problems with dihydropyridines such as amlodipine (ivabradine SmPC, EMA). If a patient already takes both, one of them is stopped and heart rate and ECG (electrocardiogram) are monitored. With a resting heart rate below 50 beats per minute or symptoms of bradycardia the ivabradine dose is reduced; if bradycardia persists, ivabradine is stopped (ivabradine SmPC, EMA). Ivabradine is not started with a resting heart rate below 70 beats per minute (ivabradine SmPC, EMA).
In the liver and gut, a single enzyme, CYP3A4 (cytochrome P450 3A4), breaks down ivabradine, and itraconazole strongly inhibits this enzyme (ivabradine and itraconazole summaries of product characteristics, SmPCs). When the two are taken together, ivabradine levels in the blood rise, and high levels can lead to excessive bradycardia (ivabradine SmPC, European Medicines Agency, ). The documents give no figures for itraconazole itself. Ketoconazole, another azole antifungal, raised mean ivabradine plasma exposure 7- to 8-fold at 200 mg once daily (ivabradine SmPC, EMA). Itraconazole keeps acting after the last dose. Its plasma levels take 7–14 days to become almost undetectable, and even longer in liver cirrhosis or with other CYP3A4 inhibitors (itraconazole SmPC). A second risk concerns the heart itself. Itraconazole has a negative inotropic effect and has been linked to cases of congestive heart failure, while ivabradine is also used in chronic heart failure (itraconazole and ivabradine SmPCs).
Symptoms
Excessive bradycardia shows as a resting heart rate below 50 beats per minute, dizziness, fatigue and low blood pressure (ivabradine summary of product characteristics, European Medicines Agency, ). Sinus arrest and heart block can occur (Corlanor label, US Food and Drug Administration, ). Marked bradycardia raises the risk of QT interval prolongation and severe ventricular arrhythmia, including torsade de pointes (Corlanor label, FDA). Signs of congestive heart failure during itraconazole treatment: shortness of breath, swelling of the feet, ankles or legs, sudden weight gain, increased tiredness, coughing up white or pink mucus, fast heartbeat, waking up at night more than usual (Sporanox label, FDA).
Management
The combination is contraindicated on both sides. The ivabradine summary of product characteristics (SmPC) lists itraconazole among the strong inhibitors of the enzyme CYP3A4 (cytochrome P450 3A4) that must not be taken with ivabradine (European Medicines Agency, , sections 4.3 and 4.5). The itraconazole SmPC lists ivabradine among contraindicated drugs (Spanish Agency of Medicines and Medical Devices, AEMPS, 4.3 and 4.5). The US labels of both drugs also contraindicate the combination (US Food and Drug Administration, ). So during itraconazole treatment, pause ivabradine or choose another antifungal (this follows from the contraindication in both labels). When choosing another antifungal, note that strong CYP3A4 inhibitors are contraindicated with ivabradine (ivabradine label, FDA, 4). With moderate inhibitors, start ivabradine only at 2.5 mg twice daily, with a resting heart rate above 70 beats per minute and heart rate monitoring (ivabradine SmPC, EMA, 4.5), or avoid these inhibitors altogether (ivabradine label, FDA, 7.1). The ban covers the whole itraconazole course and two weeks after its last dose (itraconazole SmPC, AEMPS, 4.5, and FDA label). Restart ivabradine no earlier than that, and only if the resting heart rate is at least 70 beats per minute on several measurements, an electrocardiogram (ECG) or 24-hour monitoring (ivabradine SmPC, EMA, 4.3 and 4.4). Ivabradine is also used in chronic heart failure (ivabradine SmPC, EMA, 4.1). Itraconazole is contraindicated in current or past heart failure, except in life-threatening or other serious infections. Stop it if signs of heart failure appear during treatment (itraconazole SmPC, AEMPS, 4.3 and 4.4). If the drugs have already been taken together, stop one of them and monitor the heart rate and ECG. With a resting heart rate below 50 beats per minute or symptoms of bradycardia, reduce the ivabradine dose, and if bradycardia persists, stop ivabradine (ivabradine SmPC, EMA, 4.2 and 4.4). Treat severe bradycardia in a specialised unit. If it compromises the circulation, give intravenous beta-stimulants such as isoprenaline, and use temporary cardiac pacing if that is not enough (ivabradine SmPC, EMA, 4.9).
CYP3A4 is the only enzyme that clears ivabradine. Verapamil is a moderate CYP3A4 inhibitor and also slows the sinus rhythm on its own. In interaction studies verapamil or diltiazem raised ivabradine exposure 2- to 3-fold (AUC) and lowered the heart rate by a further 5 beats per minute (ivabradine SmPC, , section 4.5). The two effects add up: more ivabradine in the blood plus a second rate-lowering drug on top.
Symptoms
Marked bradycardia: resting heart rate below 50 beats per minute, dizziness, fatigue, hypotension (ivabradine SmPC, , section 4.4). Conduction disturbances: sinoatrial or atrioventricular block, sinus arrest (ivabradine label, section 5.3). A slow rate prolongs the QT interval and may end in ventricular arrhythmia, including torsade de pointes, especially when the patient also takes QT-prolonging drugs (ivabradine SmPC, EMA, section 4.4; FDA label, section 5.3).
Management
The combination is contraindicated in both labels: the ivabradine SmPC (, section 4.3) names verapamil and diltiazem, and the verapamil SmPC (AEMPS, 4.3) names ivabradine. The contraindication in the ivabradine SmPC has no dose condition, and the label of prolonged-release verapamil also says to avoid the combination (verapamil ER label, FDA). If the patient needs ivabradine, replace verapamil: the ivabradine SmPC reports no safety problems with nitrates, dihydropyridine calcium antagonists such as amlodipine, or beta-blockers (EMA, 4.4 and 4.5); with beta-blockers monitor the heart rate (ivabradine FDA label, 7.2). If verapamil itself is needed, for example for supraventricular tachycardia, stop ivabradine. Before starting ivabradine measure the resting heart rate repeatedly, by ECG or 24-hour monitoring, and do not start it below 70 beats per minute (EMA, 4.3 and 4.4). If the patient has already taken the two drugs together, reduce the ivabradine dose or stop it when the resting rate falls below 50 or bradycardia symptoms appear (EMA, 4.4). The US labels are softer but point the same way: both the ivabradine label (FDA, 5.3 and 7.1) and the verapamil label (FDA, Drug Interactions) say to avoid coadministration.
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»
«moderados del CYP3A4 (ej. fluconazol) puede plantearse a la dosis inicial de 2,5 mg, dos veces al día, siempre que la frecuencia cardíaca en reposo sea superior a 70 lpm y con monitorización de la…»
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»
«Negative Chronotropes: Most patients receiving ivabradine will also be treated with a beta-blocker. The risk of bradycardia increases with concomitant administration of drugs that slow heart rate…»
«Ivabradina: el uso concomitante con ivabradina está contraindicado debido al descenso adicional en la frecuencia cardíaca de diltiazem con ivabradina (ver sección 4.3).»
«CONTRAINDICATIONS: Coadministration of pimozide, quinidine or ivabradine with voriconazole tablets is contraindicated because increased plasma concentrations of these drugs can lead to QT…»
«Drug Interactions: Ivabradine: Concurrent use of diltiazem increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and…»
«Drug Interactions:: Ivabradine: Concurrent use of verapamil increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid coadministration of verapamil and…»
Ivabradine is evaluated for the following indications with varying evidence strength: Heart failure (evidence tier A), Stable angina (evidence tier B), Athletic endurance (evidence tier F). See the full indication matrix with dosing and citations above on this page.
What are the side effects of Ivabradine?+
Common side effects of Ivabradine (≥ 1 in 100): Luminous phenomena in vision (phosphenes) – 14%, reversible, Bradycardia, Headache, Dizziness, Atrioventricular extrasystoles. See the Safety section for uncommon and serious reactions.
Is Ivabradine safe during pregnancy?+
Contraindicated. Animal studies show embryo-fetal defects. Reliable contraception is required in women of reproductive age.
Is Ivabradine compatible with breastfeeding?+
Contraindicated during lactation.
Who should not take Ivabradine?+
Ivabradine is contraindicated in: Ivabradine hypersensitivity; Resting HR under 70 bpm at baseline; Cardiogenic shock; Acute myocardial infarction; Severe hypotension (BP under 90/50). Full list in the Safety section.
Official sources
Direct links to regulator labels. Open in a new tab.