Coraxan, 7.5 mg 56 pcs

Coraxan is a heart rhythm slowing drug whose mechanism of action consists in 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 may also interact with Ih channels of the retina, similar to If channels of the heart, which are involved in causing temporary changes in the visual perception system by altering the retinal response to bright light stimuli.

In provocative circumstances (e.g., a rapid change in brightness in the visual field), partial inhibition of Ih 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 characteristic of ivabradine is the ability to dose-dependently decrease heart rate (HR).

Indications

Stable angina pectoris
The therapy of stable angina pectoris in patients with normal sinus rhythm:
– In intolerance or contraindications to the use of beta-adrenoblockers
– In combination with beta-adrenoblockers in inadequate control of stable angina against optimal dose of beta-adrenoblocker

Chronic heart failure

To reduce the incidence of cardiovascular complications (cardiovascular mortality and hospitalization due to worsening symptoms of CHF) in patients with chronic heart failure, with sinus rhythm and HR of at least 70 bpm./min.

Active ingredient

Composition

1 7.5 mg tablet contains:

the active ingredient:

Ivabradine hydrochloride 8.085 mg, which corresponds to 7.5 mg of base.

excipients:

Lactose monohydrate 61.215 mg,

Magnesium stearate 0.5 mg,

corn starch 20 mg,

maltodextrin 10 mg,

colloidal anhydrous silica 0.20 mg.

Shell:

. Glycerol 0.08740 mg, hypromellose 1.45276 mg, iron oxide yellow dye (E172) 0.01457 mg, iron oxide red dye (E172) 0.00485 mg, macrogol 6000 0.09276 mg, magnesium stearate 0.08740 mg, titanium dioxide (E171) 0.26026 mg.

How to take, the dosage

Coraxan should be taken orally 2 times a day, in the morning and evening with meals.

Stable angina pectoris. Recommended initial dose of the preparation is 10 mg per day (1 tablet of 5 mg two times per day).
Depending on the therapeutic effect, after 3-4 weeks of using the drug the daily dose can be increased up to 15 mg (1 tablet of 7.5 mg two times per day). If during the treatment by Coraxan HR at rest falls below 50 BPM, or if the patient experiences bradycardia-related symptoms (such as dizziness, increased fatigability or marked BP decrease), it is necessary to decrease Coraxan dosage (for example, to 2.5 mg (1/2 5 mg tablet) 2 times per day). If on decreasing the dose of Coraxan the HR is still less than 50 bpm, or there are still symptoms of marked bradycardia, the drug should be discontinued.

Chronic heart failure. Recommended initial dose of Coraxan is 10 mg per day (1 tablet of 5 mg twice a day).
After two weeks of use the daily dose of Coraxan may be increased up to 15 mg (1 tablet of 7.5 mg twice a day) if resting HR is stable over 60 bpm. If HR is stable less than 50 bpm or in case of bradycardia symptoms, such as dizziness, increased fatigability or arterial hypotension, the dose may be decreased to 2.5 mg (1/2 tablet of 5 mg) 2 times per day.
If the resting heart rate is within the range of 50-60 beats/min, it is recommended to use the preparation Coraxan in a dose of 5 mg twice a day./min or if bradycardia symptoms are noted in the patient, the drug dose should be decreased for patients receiving Coraxan in dose of 5 mg 2 times per day or 7.5 mg 2 times per day.
If resting heart rate is steadily greater than 60 bpm in patients receiving Coraxan 2.5 mg (1/2 tablet of 5 mg) 2 times daily or 5 mg 2 times daily, the drug dose may be increased.
If heart rate is less than 50 bpm or if patient has sustained bradycardia symptoms, the drug should be stopped.

In patients aged 75 years and older the recommended starting dose of Coraxan is 2.5 mg (1/2 tablet of 5 mg) twice daily. Thereafter, the dose of the drug may be increased.

Renal dysfunction. Recommended dose for patients with CKD more than 15 ml/min is 10 mg per day (1 tablet 5 mg 2 times per day). Taking this medicine dose can be increased up to 15 mg (1 tablet of 7.5 mg two times per day).
Because of lack of clinical data concerning Coraxan use in patients with IQ less than 15 ml/min, the preparation should be used with caution.

Hepatic impairment. In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale) the usual dosage regimen is recommended. The recommended starting dose for Coraxan is 10 mg per day (1 tablet of 5 mg 2 times per day). After 3-4 weeks of use, depending on the therapeutic effect, the dose may be increased to 15 mg (1 tablet of 7.5 mg 2 times per day).

Interaction

Pharmacodynamic Interactions

Not recommended combinations

The QT interval prolonging drugs (e.g. quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone).

The non-cardiovascular QT interval lengthening drugs (e.g., pimozide, ziprasidone, certindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin by IV).

The concomitant use with drugs that prolong the QT interval may increase heart rate slowing, so close cardiac monitoring should be performed if concomitant use is necessary.

Pharmacokinetic interaction

Cytochrome P4503A4 (CYP3A4). Ivabradine is metabolized in the liver by enzymes of cytochrome P450 system (CYP3A4) and is a very weak inhibitor of this cytochrome. Ivabradine has no significant effect on the metabolism and plasma concentrations of other cytochrome CYP3A4 substrates. At the same time, CYP3A4 inhibitors and inducers interact with ivabradine and affect its metabolism and pharmacokinetic properties. CYP3A4 cytochrome inhibitors have been found to increase and CYP3A4 cytochrome inducers to decrease the plasma concentrations of ivabradine. Increasing the plasma concentration of ivabradine increases the risk of severe bradycardia.

Contraindicated combinations

Concomitant use with strong cytochrome P450 inhibitors, such as antifungal agents of azole group (ketoconazole, itraconazole), antibiotics from macrolide group (clarithromycin, oral erythromycin, jozamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone, ketoconazole (in a dose of 200 mg once daily) or jozamycin (in a dose of 1 g twice daily), increase average plasma concentrations of ivabradine by 7-8 times.

Not recommended combinations

Moderate CYP3A4 inhibitors. The combined use of ivabradine and the heart rate-limiting agents diltiazem or verapamil was well tolerated by patients and was accompanied by a 2-3-fold increase in ivabradine concentration, with an additional heart rate slowing of about 5 bpm.

This combination is not recommended.

Combinations requiring caution when using

Moderate CYP3A4 inhibitors. Concomitant use of ivabradine with other CYP3A4 inhibitors (e.g., fluconazole) should be started with an initial dose of 2.5 mg twice daily. If HR is less than 60 bpm, careful monitoring of HR is necessary.

Grapefruit juice. A 2-fold increase in ivabradine blood concentrations has been observed with grapefruit juice. Grapefruit juice should be minimized during therapy with ivabradine.

CYP3A4 inducers such as rifampicin, barbiturates, phenytoin and herbal preparations containing Hypericum perforatum when used together may decrease the blood concentration and activity of ivabradine and require a higher dose of ivabradine. During therapy with ivabradine, the use of drugs and products containing St. John’s wort should be minimized.

Combined use with other drugs

It has been demonstrated that there is no clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradine of the following drugs: Proton pump inhibitors (omeprazole, lansoprazole), phosphodiesterase-5 inhibitors (sildenafil), HMG-CoA reductase inhibitors (simvastatin), dihydropyridine-type BCA derivatives (amlodipine, lacidipine), digoxin and warfarin.

Ivabradine has been shown to have no clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, latsidipine, pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics of acetylsalicylic acid.

In the pilot phase III study, the use of the following drugs had no specific restrictions, so they can be prescribed in combination with ivabradine without special precautions: ACE inhibitors, angiotensin II receptor antagonists, diuretics, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral hypoglycemic agents, acetylsalicylic acid and other antithrombotic agents.

Special Instructions

Heart rhythm disorders
Coraxan is ineffective in the treatment or prevention of arrhythmias. Its effectiveness decreases against the background of the development of tachyarrhythmias (e.g. ventricular or supraventricular tachycardia). The drug is not recommended for patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with sinus node function.
During therapy, patients should be clinically monitored for atrial fibrillation (paroxysmal or permanent). If clinically indicated (e.g., worsening angina, palpitations, irregular heart rhythm), ECG should be included in ongoing monitoring.

The use in patients with bradycardia
Coraxan is contraindicated if the resting HR is less than 60 bpm before therapy. If during the treatment the resting HR falls below 50 BPM or the patient has bradycardia-related symptoms (such as dizziness, increased fatigue or hypotension), the drug dose should be decreased. If the HR remains less than 50 bpm or bradycardia-related symptoms persist when the drug dose is reduced, Coraxan should be discontinued.

Combined use as part of antianginal therapy
The use of Coraxan together with HR-relieving BMCCs such as verapamil or diltiazem is not recommended. When combining ivabradine with nitrates and dihydropyridine-type BMCCs such as amlodipine, no changes in the safety profile of the therapy have been observed. Combined use with BMCC has not been found to increase the efficacy of ivabradine.

Stroke
It is not recommended to prescribe the drug immediately after a stroke, since there are no data on the use of the drug during this period.

Visual functions
Coraxan affects retinal function. No toxic effects of ivabradine on the retina have been identified to date, but the effects of the drug on the retina during long-term use (>1 year) are unknown to date. In case of visual impairment not described in these instructions, discontinuation of Coraxan should be considered. Coraxan should be used with caution in patients with retinal pigmentary degeneration (retinitis pigmentosa).

Auxiliary excipients
The drug contains lactose; therefore Coraxan is not recommended for patients with lactase deficiency, lactose intolerance or glucose-galactose malabsorption syndrome.

Arterial hypotension
Because of insufficient clinical data the drug should be used with caution in patients with arterial hypotension.

Atrial fibrillation (atrial fibrillation) – cardiac arrhythmias
There is no evidence of increased risk of bradycardia with Coraxan in restoring sinus rhythm during pharmacological cardioversion. However, due to insufficient data, when electrical cardioversion can be delayed, Coraxan should be discontinued 24 hours prior to cardioversion.

Performance in patients with congenital long QT interval syndrome or patients receiving drugs prolonging the QT interval
Coraxan should not be administered in congenital long QT interval syndrome and also in combination with drugs prolonging the QT interval. Strict ECG monitoring is necessary if such therapy is necessary.

Moderate hepatic impairment
Therapy with Coraxan should be performed with caution in moderate hepatic impairment (less than 9 points by Child-Pugh score).

Severe renal impairment
In severe renal impairment (CKI less than 15 ml/min), therapy with Coraxan should be used with caution.

Contraindications

Side effects

Visually:
Very common: changes in light perception (photopsia): noted in 14.5% of patients and described as a transient change in brightness in a limited area of the visual field. As a rule, such phenomena were provoked by an abrupt change of illumination intensity in the visual field zone. Generally, photopsia appeared in the first two months of treatment with subsequent recurrence. The severity of photopsia was usually mild to moderate. The occurrence of photopsia ceased during continuation of therapy (in 77.5% of cases) or after its completion. In less than 1% of patients, the occurrence of photopsia was a reason for discontinuing treatment.
Often: blurred vision.

Cardiovascular system disorders:
Often: bradycardia: in 3.3% of patients, especially during the first 2-3 months of the therapy; 0.5% of patients had severe bradycardia with heart rate not more than 40 beats/min; AV block of 1st degree; ventricular extrasystole.
Infrequent: palpitation, supraventricular extrasystole.
Unspecified frequency: arterial hypotension, possibly associated with bradycardia
The following adverse events identified in clinical trials occurred with equal frequency in both the patient group receiving ivabradine and the comparison group, suggesting their association with the disease itself and not with ivabradine administration: sinus arrhythmia; angina pectoris, including unstable angina; atrial fibrillation; myocardial ischemia; myocardial infarction; and ventricular tachycardia.

Digestive system disorders: infrequent: nausea, constipation, diarrhea.

Central nervous system disorders:
Often: headache, especially in the first month of therapy; dizziness, possibly associated with bradycardia.
Infrequent: shortness of breath, vertigo, muscle spasms.
Unspecified frequency: fainting, possibly associated with bradycardia.

Laboratory measures: infrequent: hyperuricemia, eosinophilia, increased plasma creatinine concentration.

Skin and subcutaneous fat: skin rash, itching, erythema, angioedema, urticaria.

General disorders and symptoms: asthenia, increased fatigue, malaise, possibly associated with bradycardia.

Overdose

Symptoms: severe and prolonged bradycardia.

The treatment of severe bradycardia should be symptomatic and carried out in specialized departments. If bradycardia occurs in conjunction with hemodynamic disturbances, symptomatic treatment with intravenous beta-adrenomimetic agents, such as isoprenaline, is indicated.
An artificial pacemaker may be inserted if necessary.

Pregnancy use

The drug Coraxan is contraindicated for use in pregnancy. Currently, there are insufficient data on the use of the drug during pregnancy. Preclinical studies of ivabradine showed embryotoxic and teratogenic effects.

The use of Coraxan during lactation is contraindicated. There are no data on penetration of ivabradine into breast milk.

Similarities