Ivabradine (Coralan, Ivabrid, Corlanor) acts on the SA node resulting in decreasing the heart rate.

Ivabradine Indications:

• It is used to reduce the risk of hospitalization for heart failure in the following groups of patients:
  • Adult patients with stable, symptomatic (NYHA class II to III according to the ACC/AHA/HFSA heart failure guidelines) chronic heart failure with a left ventricular ejection fraction of 35% or less,
  • Patients who are in sinus rhythm with a resting heart rate of 70 beats per minute or more and have contraindications to a beta-blocker or are on maximally tolerated doses of beta-blockers.

• Off Label indications of Ivabradine in Adults:

  • Inappropriate sinus tachycardia
  • Patients with Stable angina

Ivabradine dose in Adults:

Ivabradine Dose in the treatment of Heart failure:

• 5 mg orally two times a day (or 2.5 mg two times a day in patients with conduction defects or at risk of developing symptomatic bradycardia)
• The dose is titrated after two weeks to achieve a heart rate of 50 - 60 bpm.
• The maximum dose is 7.5 mg two times a day.

• How to adjust the Ivabradine dose?

  • If the heart rate is greater than 60 bpm:

    • Increase the dose by 2.5 mg two times a day to the maximum dose of 7.5 mg two times a day.

  • If the heart rate is 50 to 60 bpm:

    • Maintain the same dose

  • If the heart rate is less than 50 bpm or the patient develops symptoms of bradycardia:

    • Decrease the dose by 2.5 mg two times a day
    • Patients who are already on a low dose (2.5 mg two times a day) should discontinue the treatment.

Ivabradine Dose in the treatment of inappropriate sinus tachycardia:

• 5 mg orally two times a day
• The usual maintenance dose is 7.5 mg two times a day.
• It may be used in combination with a beta-blocker like metoprolol in patients who are refractory to ivabradine monotherapy.

Ivabradine dose in patients with stable angina:

• Adults younger than 75 years of age:

  • 2.5 - 5 mg orally two times a day initially.
  • The dose is titrated up in increments of 2.5 mg every 3 to 4 weeks if the patient continues to have symptoms and the heart rate is greater than 60 bpm.
  • The maximum dose is 7.5 mg two times a day.
• If despite treatment for 3 months or more, the symptoms of angina persist, the treatment may be discontinued.
• Treatment may also be discontinued if the symptoms of angina are limited and clinically significant heart rate reduction does not occur within three months of therapy.
• Patients who develop symptomatic bradycardia or the heart rate drops to less than 50 bpm, the dose should be reduced to 2.5 mg two times a day (or discontinue if already taking 2.5 mg two times a day).
• The heart rate should be monitored after dose adjustments
• Patients who remain symptomatic may be initiated on a low-dose beta-blocker or a dihydropyridine calcium channel blocker such as slow-release nifedipine, amlodipine, or felodipine

Ivabradine dose in Children:

Ivabradine Dose in the treatment of Heart failure and dilated cardiomyopathy:

• Infants ≥6 months, Children, and Adolescents <18 years:

  • Weight less than 40 kgs:

    • 0.05 mg/kg/dose two times a day.
    • The dose may be increased every 2 weeks by 0.05 mg/kg/dose.
    • The dose is increased to achieve a 20% reduction in heart rate (without inducing bradycardia) or if the maximum dose is reached.
    • The Maximum dose is 2 mg/kg/dose two times a day in children less than one year of age and 3 mg/kg/dose two times a day up to a maximum of 7.5 mg/dose two times a day in children older than 1 year of age.

  • Ivabradine dosage adjustment for bradycardia:

    • Patients who develop bradycardia should decrease the dose to 0.02 mg/kg/dose two times a day or decrease the dose to the previous dose.

• Weight greater than 40 kgs:

  • 2.5 mg two times a day.
  • The dose may be increased every 2 weeks by 2.5 mg as tolerated.
  • The dose is increased until a 20% reduction in heart rate (without inducing bradycardia) is achieved or the maximum dose of 7.5 mg/dose two times a day is reached.

  • Dosage adjustment for bradycardia:

    • Decrease the dose to the previously tolerated dose.

Adolescents older than 18 years of age:

• 5 mg orally two times a day or 2.5 mg two times a day in patients who may develop symptomatic bradycardia including those with a history of conduction defects.
• The dose is adjusted after 2 weeks to achieve a resting heart rate between 50 and 60 beats per minute or until the maximum dose of 7.5 mg two times a day is reached.

• Dosage adjustment based on resting heart rate:

  • If the heart rate is greater than 60 bpm:

    • Increase the dose by 2.5 mg two times a day to the maximum dose of 7.5 mg two times a day.

  • If the heart rate is 50 to 60 bpm:

    • Maintain the same dose

  • If the heart rate is less than 50 bpm or the patient develops symptoms of bradycardia:

    • Decrease the dose by 2.5 mg two times a day
    • Patients who are already on a low dose (2.5 mg two times a day) should discontinue the treatment.

Pregnancy Risk Factor: D/X  

• If Ivabradine is given to pregnant women, it may cause fetal harm.
• Effective contraception should be recommended for females with reproductive potential.
• Patients who are taking the drug should be closely monitored for any decompensation, particularly during the first trimester.

Ivabradine use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• It should not be used during breastfeeding because of the possible harm it can cause to the fetus.

Ivabradine dose in renal impairment:

• CrCl of 15 mL/minute or more:

  • Adjustment in the dose is not necessary.

• CrCl of less than 15 mL/minute:

  • It has not been studied in severe renal disease.
  • The manufacturer has not recommended any dosage adjustment.

Ivabradine dose in liver disease:

• Mild or moderate impairment (Child-Pugh class A or B):

  • Adjustment in the dose is not necessary.

• Severe impairment (Child-Pugh class C):

  • It has not been studied in severe hepatic impairment and should be avoided in severe hepatic impairment.

Side Effects of Ivabradine:

• Cardiovascular:

  • Bradycardia
  • Hypertension
  • Atrial fibrillation
  • Heart block
  • Sinoatrial arrest

• Central nervous system:

  • Phosphene

Contraindication to Ivabradine Include:

• Acute decompensated heart failure
• Hypotension in patients with clinically significant symptoms
• Sick sinus syndrome
• Sinoatrial block
• Third-degree AV Block (except for patients with a functioning demand Pacemaker)
• Significant bradycardia
• Hepatic impairment severe
• Pacemaker dependence
• Use with strong CYP3A4 inhibitors in conjunction
• Hypersensitivity to any drug or component of the formulation
• Patients with congenital long QT syndrome may have a prolonged QT interval
• Cardiogenic shock
• Acute myocardial injury
• Concomitant use of verapamil or diltiazem
• Pregnancy
• Breastfeeding
• Women who are pregnant or have recently given birth to children should not use contraceptives.
• Galactose intolerance,
• Glucose-galactose malabsorption, or
• The Lapp lactase defect

Warnings and precautions

• Atrial fibrillation:

  • There may be an increase in the risk of atrial fibrillation from using it.
  • If atrial fibrillation occurs, the patient should be closely monitored. Treatment may be stopped.

• Conduction disturbances and Bradycardia:

  • Before and after treatment, it is important to monitor your heart rate.
  • Bradycardia may occur in patients who are already at high risk for QT prolongation, which can lead to severe ventricular arrhythmias such as torsade-de-pointes.
  • Concomitant use with other drugs may increase your risk of QTc prolongation.
  • Bradycardia is more common in patients who have sinus node dysfunction, bundle block, heart blocks and patients using other negative chronotropic medications such as verapamil and digoxin.
  • The concurrent use of verapamil and diltiazem should be avoided.
  • It is also important to avoid it in sick sinus syndromes, sinoatrial block and third-degree AVP block.
  • If the heart rate drops below 50 beats per minute or if bradycardia develops, treatment should be stopped immediately.
  • It should not be used in patients who have bradycardia or baseline symptoms.
  • Patients at high risk for bradycardia, such as those with baseline conduction problems, should receive a lower initial dose.

• Visual function

  • Patients might notice transient brightness or halos, image degradation, color bright lights, multiple images, or other symptoms.
  • These visual symptoms are common in patients who have received treatment within the first two weeks.
  • These symptoms can be resolved with continued treatment. However, in some cases, it is necessary to stop the treatment.

Ivabradine: Drug Interaction

Monitor:

• Heart rate should be monitored before the initiation of the treatment and before increasing or decreasing the dose
• Heart rate should be specially monitored in patients who are on concomitant other negative chronotropic medicines such as amiodarone, beta-blockers, or digoxin.
• Monitor blood pressure, cardiac rhythm for atrial fibrillation.

How to administer Ivabradine?

• It should be administered orally with food.
• Adults who can not swallow may be administered an oral solution.
• The oral solution is made by mixing the contents of the ampoule in a medication cup
• A calibrated syringe should be used to measure the calculated dose. Any unused solution should be discarded.

Mechanism of action of Ivabradine:

• It acts as a selective inhibitor of funny channels in the SA node (sinoatrial).
• The diastolic polarization is prolonged by inhibition of the fchannels.
• This causes the SA node to fire slower.
• It decreases heart rate, but not myocardial contractility or relaxation.
• It also blocks the retinal I current, which can cause vision problems known as phosphenes. 
• Patients may experience transient brightness, halos or image decomposition as well as multiple images that are visible in phosphenes.

70% of the drug's total value is unknown.protein-bound. It is extensively metabolized in the intestines by the liver via CYP3A4 and to the potent, active metabolite N–desmethylated derivative (S18982), which is also metabolized using CYP3A4. It has been abioavailabilityMore than 40%, and an effectivehalf-life eliminationIt takes approximately 6 hours. It takes approximately 6 hours to get there peak plasma concentrationThe time spent in fasting is approximately one hour. If taken with food, it can be extended to two hours. TheExcretionThe drug is primarily ingested via urine and feces.

Ivabradine Brand Names (International):

• Corlanor
• Lancora
• Apredonav
• Bixebra
• Bradipect
• Bredinal
• Brediwal
• Corabid
• Coralan
• Coraxan
• Corlentor
• Ilibrift
• Inevica
• Ivabenor
• Ivacard
• Ivanor
• Procoralan
• Raenom
• Savapran
• Siftus

Ivabradine brand Names in Pakistan:

Ivatab Sivab Coralen Ivaset