Description
Coraxan Pharmacodynamics
Ivabradine is a heart rhythm slowing drug whose mechanism of action is the selective and specific inhibition of If channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate the heart rate (HR). Ivabradine has a selective effect on the sinus node without affecting the timing of impulse conduction along the intraatrial, atrial-ventricular and intraventricular conduction pathways, as well as on myocardial contractility and ventricular repolarization. Ivabradine can also interact with h channels of the retina, similar to It channels of the heart, involved in the occurrence of temporary changes in the system of visual perception by changing the response of the retina to bright light stimuli. Under provocative circumstances (e.g., rapid brightness change in the visual field), partial inhibition of h channels by ivabradine causes the phenomenon of changes in light perception (photopsia). Photopsia is characterized by a transient change in brightness in a limited area of the visual field (see section “Side effects”).
The main pharmacological feature of ivabradine is the ability of dose-dependent pacing (HR). Analysis of the dependence of HR slowness on the drug dose was carried out with gradual increase of ivabradine dose up to 20 mg twice a day and revealed a tendency to reach the “plateau” effect (no increase of therapeutic effect with further increase of the dose), which reduces the risk of bradycardia (HR under 40 bpm) (see section “Side effects”).
When prescribing the drug in recommended doses, the degree of HR shortening depends on its initial value and is about 10-15 beats/min at rest and during physical activity. As a result, cardiac performance decreases and myocardial oxygen demand decreases.
Indications
Symptomatic therapy of stable angina pectoris
Symptomatic therapy of stable angina pectoris in ischemic heart disease in adult patients with normal sinus rhythm and heart rate not less than 70 bpm:
-when beta-adrenoblockers are intolerant or contraindicated
-in combination with beta-adrenoblockers at inadequate control of stable angina against optimal dose of beta-adrenoblocker
Therapy of chronic heart failure
Therapy of chronic heart failure class P-IV according to NYHA classification with systolic dysfunction in patients with sinus rhythm and heart rate of at least 70 bpm in combination with standard therapy, which includes therapy with beta-adrenoblockers, or in case of intolerance or presence of contraindications to beta-adrenoblockers use.
Contraindications
Hypersensitivity to ivabradine or any of the excipients of the drug;
Resting heart rate less than 70 bpm (before treatment);
Cardiogenic shock;
Acute myocardial infarction;
Severe arterial hypotension (systolic BP less than 90 mmHg and diastolic BP less than 50 mmHg);
Severe hepatic insufficiency (more than 9 points on the Child-Pugh scale);
Sinus node weakness syndrome;
Sinoatrial block;
Unstable or acute heart failure;
Presence of an artificial pacemaker operating in continuous stimulation mode;
Unstable angina pectoris;
Atrioventricular (AV) block of P and C degree;
Concomitant use with potent isoenzyme inhibitors of cytochrome P450 CA4 system, such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, jozamicin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see “Pharmacokinetics and pharmacokinetics” sections). Pharmacokinetics” and “Interaction with other medicinal products”);
Concomitant use with verapamil or diltiazem, which are moderate CYP3A4 inhibitors with the ability to reduce heart rate (see section “Interaction with other medicinal products”);
Pregnancy, breastfeeding and use in women of childbearing age who do not observe reliable contraceptive measures (see section “Use in pregnancy and breastfeeding”);
– Age up to 18 years old (efficacy and safety of the drug in this age group have not been established);
Lactase deficiency, lactose intolerance, glucose-galactose
malabsorption syndrome.
Dosage and administration regimen
- Coraxan® should be taken orally 2 times daily, in the morning and in the evening with a meal (see section “Pharmacokinetics”).
- Symptomatic therapy of stable angina pectoris
Before initiating therapy or deciding on dose titration, heart rate should be determined by one of the following methods: serial heart rate measurement, ECG, or 24-hour ambulatory observation. - Starting dose of Coraxan® should not exceed 5 mg 2 times daily in patients younger than 75 years old.
- If symptoms persist within 3-4 weeks and if the initial dose is well tolerated and resting HR remains over 60 beats per minute, the dose can be increased to the next level in patients receiving Coraxan® at a dose of 2.5 mg 2 times daily or 5 mg 2 times daily. The maintenance dose of Coraxan® should not exceed 7.5 mg twice daily.
- Coraxan® use should be discontinued if symptoms of angina pectoris do not subside, if improvement is insignificant, or if no clinically significant decrease of HR is observed during 3 months of therapy.
- If during the treatment by Coraxan® HR slows down to values less than 50 BPM at rest, or if patient shows symptoms associated with bradycardia (such as dizziness, increased fatigability or marked BP decrease), Coraxan® dose should be decreased up to 2.5 mg (1/2 of 5 mg tablet) twice daily. HR should be controlled after dose lowering (see sect. “Cautionary Note”). If at dose lowering the drug Coraxan® HR remains less than 50 bpm, or bradycardia symptoms persist, the drug should be discontinued.
- Chronic heart failure.
This therapy should be started only in patients with stable chronic heart failure.
Recommended initial dose of Coraxan® is 10 mg per day (1 tablet of 5 mg 2 times per day). - After two weeks of Coraxan® use daily dose can be increased up to 15 mg (1 tablet of 7.5 mg 2 times per day), if resting heart rate is stably more than 60 beats/min. If HR is steadily lower than 50 bpm or in case of bradycardia symptoms, such as dizziness, increased fatigability or arterial hypotension, the dose may be reduced to 2.5 mg (1/2 tablet of 5 mg) 2 times per day.
- If HR is within 50 to 60 bpm, the recommended maintenance dose of Coraxan® is 5 mg 2 times per day.
- If during Coraxan® therapy use, resting HR is stably less than 50 bpm, or if bradycardia symptoms are observed in a patient, the dose of Coraxan® should be decreased to lower one for patients receiving Coraxan® in dose of 5 mg 2 times per day or 7.5 mg 2 times per day.
- If resting HR stably more than 60 bpm in patients treated with Coraxan® in dose of 2.5 mg (1/2 tablet of 5 mg) 2 times daily or 5 mg 2 times daily, the dose of Coraxan® can be increased.
- If HR remains less than 50 bpm, or if bradycardia symptoms persist, the use of Coraxan® should be discontinued (see section “Cautionary Note”). Administration in patients older than 75 years old
- Recommended initial dose for Coraxan® is 2.5 mg (1/2 tablet 5 mg) twice daily for patients aged 75 or more. The dose of Coraxan® may be increased in future.
- Renal dysfunction.
Recommended initial dose for Coraxan® is 10 mg per day (1 tablet 5 mg 2 times daily) in patients with CKD over 15 ml/min (see section “Pharmacokinetics”). After 3-4 weeks of use, depending on the therapeutic effect, the dose of Coraxan® can be increased to 15 mg (1 tablet of 7.5 mg twice daily). - Due to insufficient clinical data on Coraxan® administration in patients with CKD less than 15 ml/min, the drug should be used with caution.
- Liver function impairment.
For patients with mild hepatic impairment, the usual dosage regimen is recommended.
Caution should be exercised when using Coraxan® in patients with moderate hepatic impairment (Child-Pugh score 7-9). - Coraxan® is contraindicated in patients with severe hepatic impairment (over 9 Child-Pugh scores), because Coraxan® has not been studied in such patients (a significant increase in plasma concentrations can be expected) (see sections “Contraindications” and “Pharmacokinetics”).
