Ivabradine - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

Overview:

Ivabradine is a medication used to treat heart failure and inappropriate sinus tachycardia in adults. It is available as an oral tablet and oral solution. It lowers heart rate by effectively and selectively suppressing the cardiac pacemaker current that regulates the heartbeat. The United States Food and Drug Administration (FDA) approved Ivabradine for the treatment of heart failure on April 15, 2015.

How Does Ivabradine Work?

Ivabradine is classified under the class of medications called hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers. It acts by blocking these channels, which block the pacemaker current, which regulates the heartbeat. In other words, Ivabradine slows down the heart rate and enables the heart to pump more blood.

Dosage:

• The starting dose of Ivabradine is 5 mg, twice daily.

• The doctor may adjust the dose based on the response and heart rate.

• The maximum daily dose of Ivabradine is 7.5 mg.

Always talk to the doctor for instructions to follow during drug therapy, and it is important to follow the treatment plan strictly.

What Are the Drug Warnings and Precautions?

• Fetal Toxicity: Animal studies have shown that Ivabradine has the potential to cause harm to the unborn baby. Hence, effective contraception is recommended for women who are in therapy with the drug. The physician should be informed if the patient is pregnant or intends to get pregnant while on therapy with the drug.

• Conduction Disturbances: Ivabradine is associated with conduction disturbances and sinus arrest. The patients should specifically inform the doctor if they are taking other medications like Digoxin, Diltiazem, Verapamil, or Amiodarone, as they may exacerbate this effect.

• Atrial Fibrillation: Ivabradine may cause atrial fibrillation (very rapid heart rhythm that may lead to clots). Hence, monitoring of the heart rhythm is recommended while on drug therapy.

For Patients:

What Is Heart Failure?

Heart failure is when the heart is unable to pump enough blood to meet the body’s requirements. It is a serious condition that may be fatal. The heart does not necessarily stop beating in the event of cardiac failure. It indicates that the heart is not functioning as it should be.

Heart failure is a common condition, especially in older adults. In the U.S., it is also one of the main reasons for hospitalization, and there are more than 5.7 million adults who suffer from heart failure. About 970,000 persons receive a diagnosis of heart failure each year. Heart failure can be mild, moderate, or severe and is caused by a number of reasons. Shortness of breath, exhaustion, swelling in the legs and ankles, and trouble sleeping are a few signs of this illness. The patient should see a doctor immediately if they believe they may be exhibiting heart failure symptoms. There are numerous options for treating heart failure, which is a condition that is treatable.

Learn More About Ivabradine:

Before Starting Ivabradine:

When and Why to Take Ivabradine?

Ivabradine is a prescription drug used for the treatment of chronic heart failure (heart rate greater than or equal to 75 beats per minute) and symptomatic stable angina (manifests as chest pain). The drug should be taken only as per the order of the doctor. Speak with the doctor or pharmacist if an experience with the drug has a stronger or weaker effect than being informed. Also, contact the pharmacist or physician in case of any queries.

How Effective Is Ivabradine?

Studies have shown that Ivabradine decreased fatal or non-fatal heart attack-related hospital admissions in patients with heartbeats of 70 or higher. It has also been shown to improve heart function and clinical outcomes in patients with chronic heart failure.

Things to Inform the Doctor Before Taking Ivabradine:

Do let the doctor know if any of the following conditions are present while taking Ivabradine:

• If the patient experiences persistent atrial fibrillation, a form of irregular heartbeat, palpitations, an increase in chest discomfort, or an abnormality on an electrocardiogram, the patient may have heart rhythm issues (ECG).

• If the patient has signs like fatigue, lightheadedness, or shortness of breath (this could indicate that the heart is also slowing down).

• If the patient experiences atrial fibrillation symptoms, which include a difficult-to-measure pulse rate at rest that is very high (above 110 beats per minute).

• If the patient recently experienced a stroke.

• If the patient gets mild to moderate hypotension.

• If the patient has uncontrolled high blood pressure, particularly following a change in the antihypertensive drugs.

• If the patient suffers from any chronic retinal eye diseases.

• If the patient suffers from any kidney disease.

• If the patient has any liver disease.

• If the patient is currently taking medications for fungal infections (such as Ketoconazole, Fluconazole), macrolide antibiotics (such as Clarithromycin, Erythromycin, etc.), medications to treat HIV infections (such as Nelfinavir, Ritonavir), Diltiazem, Verapamil (used for high blood pressure).

Starting Ivabradine:

How Is Ivabradine Given?

• The tablets may be taken with food.

• For the oral solution of Ivabradine, empty the entire contents of the drug's ampule in a medication cup and measure the dose with an oral syringe. Discard any unused solution. Do not keep it to use for a second time.

• In case of queries, contact a healthcare professional immediately.

Things to Do After Starting Ivabradine:

• Inform the doctor if any side effects are experienced.

• Regularly follow up with the doctor at scheduled appointments for necessary interventions.

What Are the Side Effects of Ivabradine?

Medications often are associated with side effects which are undesirable effects of the medications. The extent and reaction of side effects vary among individuals. Hence, it is important to assess the experience of any side effects after taking the medication. Inform the doctor if any of the below-mentioned effects are experienced for the necessary medical intervention:

Common Side Effects:

• Luminous visual phenomenon (short-lived increases in brightness, typically brought on by abrupt changes in light intensity). A halo, colored flashes, picture breakdown, or numerous images are some ways to characterize them. Usually occurring within the first two months of therapy, they may then recur often and disappear throughout or after therapy.

• Alteration in how the heart works (symptoms include a heart rate slowdown). They are most common during the first two to three months of treatment.

• Patients have commonly experienced adverse effects like headache, lightheadedness, foggy or blurry vision, and uncontrolled blood pressure.

• The uncommon side effects include double vision, impaired vision, vertigo, palpitations, extracardiac beats, low blood pressure, dyspnea (difficulty breathing), nausea, abdominal pain, skin rash, muscle spasms, fatigue, and weakness, as well as excess of eosinophils (a type of white blood cell), high uric acid levels, elevated creatinine in the blood (a breakdown product of muscle), and abnormal ECG heart tracing, are all symptoms.

Serious Side Effects:

• Allergic reaction to the drug, which includes rashes, redness, itching, breathlessness, etc.

• Swelling of the tongue, face, or throat; difficulty breathing or swallowing; and dizziness.

• Abnormal heartbeat perception and irregular, fast heartbeat.

The serious effects should be reported to the doctor, and emergency care should be taken.

What Should Be Done if a Dose Is Missed?

If a dose of Ivabradine is missed, take the medication as soon as it is remembered and continue with the normal dosing regimen. However, if it is almost time for the next dose, skip the previous one and continue as scheduled. Avoid taking double doses of the drug to make up for a missed dose. In case of queries, contact the pharmacist or the doctor.

What Should Be Done to Treat Ivabradine Overdose?

Avoid taking the tablet more than the advised dosage. Only take the number of tablets the doctor specified on the pharmacy label. Inform the doctor immediately if an overdose happens, or visit the local accident and emergency department.

How to Store Ivabradine?

• Store Ivabradine at room temperature between 15 to 30 degrees Celsius.

• Keep the tablets away from children and pets.

• Avoid disposing of medications in wastewater or household garbage. Talk to the pharmacist about how to dispose of expired medications. These measures will aid in environmental protection.

Avoid Self-Medication:

Avoid taking this drug without a prescription, do not recommend it to others, and do not take it on someone else's advice. Different people react to medications differently, and some may even react worse. Make a list of all the prescriptions and non-prescription that are being taken whenever consulting a doctor, and take the medication only as instructed by a qualified healthcare professional.

For Doctors:

Indication:

Ivabradine is indicated for:

• To lower the risk of hospitalization in adult patients with stable, symptomatic chronic heart failure and a decreased left ventricular ejection fraction due to heart failure.

• For treating pediatric patients six months or older with heart failure (stable symptomatic) due to dilated cardiomyopathy.

Dosing of Ivabradine:

Dosing Considerations:

• Renal Impairment, CrCl Greater Than 15 mL/min: No adjustment required

• Mild to Moderate Hepatic Impairment (Child-Pugh A and B): No adjustment required

• Severe Hepatic Impairment (Child-Pugh C): Use contraindicated

• Geriatric Patients (75 Years or Older) With Chronic Stable Angina: Consider 2.5 mg orally twice daily when added to beta-blocker therapy.

• History of Conduction Defects or When Bradycardia Could Lead To Hemodynamic Compromise in Adult Chronic Heart Failure: Initiate at 2.5 mg orally twice daily and titrate based on heart rate.

• Resting Heart Rate Less Than 50 Beats per Minute During Therapy in Chronic Stable Angina: Consider 2.5 mg orally twice daily when added to beta-blocker therapy.

Pharmacology:

Mechanism of Action:

Ivabradine reduces spontaneous pacemaker activity at the cardiac sinus node by blocking the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel to selectively inhibit I(f)-current, thus reducing the heart rate. Ventricular repolarization and myocardial contractility are not affected.

Pharmacodynamics:

Ivabradine reduces the heart rate in a dose-dependent manner. The baseline heart rate determines the extent of the effect (i.e., greater reduction in the heart rate occurs in subjects with higher baseline heart rates). At the prescribed doses, both at rest and during exercise, the heart rate is reduced by about ten bpm. Heart rate reduction analysis showing dose vs. impact shows a plateau effect at doses > 20 mg twice daily. Ivabradine does not result in rate-corrected QT prolongation, although it does lengthen the uncorrected QT interval with decreased heart rate.

Pharmacokinetics:

Absorption:

Under fasting conditions, Ivabradine reaches its peak plasma concentrations about an hour after oral administration. It has a 40 % absolute oral bioavailability due to first-pass liver and gastrointestinal elimination. Food causes an hour-long delay in absorption and a 20 % to 40 % increase in plasma exposure. It is best to prescribe the drug along with food.

Distribution:

Ivabradine is around 70 % plasma protein bound, and the steady-state distribution volume is about 100 L.

Metabolism:

Ivabradine undergoes extensive metabolism in the liver and intestines by CYP3A4 enzyme-mediated oxidation. The main metabolite is the N-demethylated derivative, which circulates at quantities around 40 % of those of Ivabradine and is equivalent to ivabradine. The CYP3A4 enzyme also breaks down the N-demethylated derivative. Plasma levels of ivabradine decrease during the course of two hours for the distribution half-life and six hours or so for the effective half-life.

Excretion:

Ivabradine has a 24 L/h total clearance, 4.2 L/h renal clearance, and 4 % of an oral dosage is excreted unaltered in urine. The drug is excreted in the feces and urine.

Active Ingredient:

The active ingredient in the Ivabradine tablet is Ivabradine.

Inactive Ingredient:

The inactive ingredients include

• Hypromellose.

• Lactose monohydrate.

• Magnesium stearate.

• Maize starch.

• Maltodextrin.

• Polyethylene glycol 6000.

• Red iron oxide.

• Titanium dioxide.

Toxicity:

Clinical Toxicology:

It is anticipated that overdose effects are similar to adverse effects reported at therapeutic doses, including severe and prolonged bradycardia and conduction disturbances.

• Management of Mild to Moderate Toxicity:

Treatment is symptomatic and supportive.

• Management of Severe Toxicity:

Treatment is symptomatic and supportive. Treat bradycardia with Atropine; if unresponsive, use beta-adrenergic agonists (for example, Isoproterenol). Consider temporary pacemaker insertion. Therapeutic doses of Ivabradine may cause bradycardia, and bradycardia may increase the risk of QT interval prolongation. Concomitant use of Ivabradine and other drugs that prolong the QT interval may increase the risk of rapid heart rhythm (torsades de pointes). Treat torsades de pointes with IV magnesium sulfate and correct electrolyte abnormalities.

Warnings and Precautions:

Cardiovascular:

• Patients without a working demand pacemaker should not use this medication with second-degree AV block.

• Use is not advised in individuals with demand pacemakers set to 60 bpm or higher.

• Atrial fibrillation risk increased; monitoring advised; stop using if it develops.

• Adult patients have reported bradycardia; risk is raised by sinus node dysfunction, conduction abnormalities, and cardiac dyssynchrony; monitoring is advised if used in conjunction with other negatively chronotropic drugs.

• Adult individuals have been known to get sinus arrest and heart block.

• Pediatric individuals have been documented to experience bradycardia and first-degree heart block; a dose change may be required.

Adults' QT prolongation risk increased with bradycardia; in patients with risk factors, this may result in severe ventricular arrhythmias (including torsade de pointes).

Concurrent Use:

• Avoid use with Verapamil or Diltiazem. Avoid use with CYP3A4 inducers or moderate CYP3A4 inhibitors.

Reproductive:

• Appropriate contraception is required with use in females of reproductive potential.

Contraindications:

Ivabradine is contraindicated in the following conditions:

• Acute decompensated heart failure.

• Clinically significant hypotension or bradycardia.

• Concomitant use with strong CYP3A4 inhibitors.

• Pacemaker-dependent patients.

• Severe hepatic impairment.

• Sick sinus syndrome, sinoatrial block, or third-degree atrioventricular block, except in case of a functioning demand pacemaker.

Clinical Studies:

10,917 adult patients with coronary artery disease, decreased left ventricular systolic function (ejection fraction 40 %), and resting heart rate of 60 bpm participated in the randomized, double-blind, placebo-controlled trial. Patients were taking traditional cardiovascular drugs at stable doses for at least one month and had stable heart failure and angina symptoms for at least three months.

For patients receiving beta-blockers, neither therapy nor achieving any precise dose targets was required by the protocol. Ivabradine or placebo was randomly assigned to patients at the beginning of the trial. Depending on tolerability and resting heart rate, the dose can be adjusted from 5 mg twice daily to 7.5 mg twice daily.

The primary goal was the time to first cardiovascular death, acute myocardial infarction hospitalization, or hospitalization for new-onset or worsening heart failure. None of the patients was class IV; most were NYHA classes II (61.4 %) or III (23.2 %). Ivabradine had a median follow-up of 19 months. However, it had no discernible impact on the main composite outcome.

Drug Interactions:

The common drug-drug interactions of Ivabradine are as follows:

• Alfuzosin.

• Amiodarone.

• Amisulpride.

• Amitriptyline.

• Anagrelide.

• Apomorphine.

• Aprepitant.

• Aripiprazole.

• Belzutifan.

• Buprenorphine.

• Buserelin.

• Carbamazepine.

• Ceritinib.

• Chloroquine.

• Chlorpromazine.

• Citalopram.

• Clofazimine.

• Clomipramine.

• Clothiapine.

• Clozapine.

• Crizotinib.

• Cyclobenzaprine.

• Dabrafenib.

• Dasatinib.

• Degarelix.

• Delamanid.

• Desipramine.

• Deslorelin.

• Deutetrabenazine.

• Ebastine.

• Efavirenz.

• Encorafenib.

• Entrectinib.

• Enzalutamide.

• Eribulin.

• Erythromycin.

• Escitalopram.

• Famotidine.

• Fedratinib.

• Felbamate.

• Fexinidazole.

• Fingolimod.

• Flecainide.

• Fluoxetine.

• Formoterol.

• Fosaprepitant.

• Foscarnet.

• Fosnetupitant.

• Fosphenytoin.

• Fostemsavir.

• Galantamine.

• Gatifloxacin.

• Gemifloxacin.

• Glasdegib.

• Gonadorelin.

• Goserelin.

• Halofantrine.

• Haloperidol.

• Histrelin.

• Hydroquinidine.

• Hydroxychloroquine (probable)

• Hydroxyzine.

• Ibutilide.

• Iloperidone.

• Imatinib.

• Imipramine.

• Letermovir.

• Leuprolide.

• Levofloxacin.

• Lofexidine.

• Lorlatinib.

• Lumacaftor.

• Lumefantrine.

• Macimorelin.

• Mefloquine.

• Methadone.

• Metronidazole.

• Mifepristone.

• Mirtazapine.

• Mitotane.

• Mizolastine.

• Mobocertinib.

• Moxifloxacin.

• Nafarelin.

• Netupitant.

• Nilotinib.

• Norfloxacin.

• Octreotide.

• Olanzapine.

• Ondansetron.

• Osilodrostat.

• Osimertinib.

• Oxaliplatin.

• Ozanimod.

• Pacritinib.

• Paliperidone.

• Panobinostat.

• Paroxetine.

• Pasireotide.

• Pazopanib.

• Pentamidine.

• Perphenazine.

• Phenytoin.

• Pimavanserin.

• Pitolisant.

• Ponesimod.

• Probucol.

• Procainamide.

• Prochlorperazine.

• Quetiapine.

• Quinidine.

• Quinine.

• Ranolazine.

• Ribociclib.

• Rifampin.

• Risperidone.

• Selpercatinib.

• Sertindole.

• Sertraline.

• Sevoflurane.

• Siponimod.

• Sodium Phosphate.

• Solifenacin.

• Sorafenib.

• Sotalol.

• St John's Wort.

• Sulpiride.

• Sunitinib.

• Tacrolimus.

• Tamoxifen.

• Telavancin.

• Trazodone.

• Trimipramine.

• Triptorelin.

• Vandetanib.

• Vardenafil.

• Vemurafenib.

• Venlafaxine.

• Verapamil.

• Vilanterol.

• Vinflunine.

• Voclosporin.

• Vorinostat.

• Zuclopenthixol.

Other Specifications:

Ivabradine in Pregnant Women:

When administered, Ivabradine has been documented to cause harm to the fetus according to animal studies. Ivabradine has not been adequately studied in pregnant women under well-controlled settings to determine any potential concerns. Inform an expectant mother of any possible fetal risk.

Ivabradine in Lactating Women:

There is no evidence on whether Ivabradine passes through breast milk in humans, its effects on breastfed infants, or how the medication affects the production of milk. However, research on animals has revealed that rat milk contains ivabradine. Breastfeeding is not advised due to the potential risk Corlanor exposure poses to nursing infants.

Ivabradine in Pediatric Patients:

Pharmacokinetic, pharmacodynamic, and evidence from well-controlled trials of Ivabradine in adult patients all support the safety and efficacy of the drug in pediatric patients (age six months to less than 18 years old).

Ivabradine in Patients With Hepatic Impairment:

Ivabradine requires no specific dosing adjustments in patients with mild to severe impairment. However, the use of the drug is not advised for use in patients with severe hepatic impairment because an increase in systemic exposure is anticipated (Child-Pugh C).

Ivabradine in Patients With Renal Impairment:

No dosage adjustment is necessary for Ivabradine in patients with renal impairment.