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Raenom instruction for use

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Raenom is an antianginal medication that slows heart rate. The mechanism of action of Ivabradine is selective and specific inhibition of If channels of the sinus node, controlling spontaneous diastolic depolarization in the sinus node and regulating heart rate.
Ivabradine has a selective effect on the sinus node, without affecting the duration of the impulses along the atrial, atrioventricular and intraventricular pathways, as well as myocardial contractility and ventricular repolarization.
Ivabradine can also interact with the Ih channels of the retina of the eye, similar in structure to the If channels of the heart, participating in the mechanisms of the temporal adaptation of the visual perception system by changing the response of the retina to bright light stimuli.
Under provoking circumstances (for example, a sharp change in the intensity of illumination in the visual field), partial inhibition of Ih channels by ivabradine leads to the phenomenon of a change in light perception (photopsia). The photopsy is characterized by a transient change in brightness in a limited zone of the visual field.
The main pharmacological effect of ivabradine is dose-dependent decrease in heart rate. Analysis of the dependence of the HR decrease on the dose of the drug was carried out with a gradual increase in the dose of ivabradine to 20 mg 2 times / day and revealed a tendency to achieve a plateau effect (no increase in the therapeutic effect with a further increase in the drug dose), which reduces the risk of severe bradycardia (HR less than 40 beats per minute
When using the drug in recommended doses, the degree of decrease in heart rate depends on its initial value and is approximately 10-15 beats / min, both at rest and during physical exertion, as a result, the heart’s work and myocardial oxygen demand are reduced.
Ivabradine does not affect intracardiac conduction, myocardial contractility (does not have a negative inotropic effect) and the process of ventricular repolarization. In clinical electrophysiological studies, ivabradine did not affect the duration of the impulses along the atrioventricular or intraventricular pathways, as well as the corrected QT intervals.
In studies in patients with left ventricular dysfunction (LVEF 30-45%), it was shown that ivabradine does not affect myocardial contractility.

Pharmacokinetics

Ivabradine is a S-enantiomer with no signs of bioconversion (according to in vivo studies). The main active metabolite is the N-desmethylated derivative of ivabradine.
After ingestion, ivabradine is rapidly and almost completely absorbed from the gastrointestinal tract. Cmax in plasma is achieved within 1 h after ingestion on an empty stomach. Bioavailability is approximately 40% due to the "first pass" effect through the liver. Meal increases absorption time approximately for 1 h and increases concentration in a blood plasma from 20% to 30%. To reduce the variability of the concentration of the drug is recommended to be taken simultaneously with a meal.
Plasma protein binding is approximately 70%. Vd in equilibrium - about 100 liters. Cmax in plasma with long-term use at the recommended dose of 5 mg 2 times / day is approximately 22 ng / ml (coefficient of variation = 29%). The mean Css in plasma is 10 ng / ml (coefficient of variation = 38%).
Ivabradine pharmacokinetics is linear in the dose range from 0.5 to 24 mg.
Ivabradine is predominantly metabolized in the liver and intestines by oxidation with the participation of the CYP3A4 isoenzyme. The main active metabolite is the N-desmethylated derivative (S 18982), which accounts for 40% of the dose of ivabradine. Metabolism of the active metabolite of ivabradine also occurs with the involvement of the CYP3A4 isoenzyme. Ivabradine has a low affinity for the CYP3A4 isoenzyme, does not induce or inhibit it. In this regard, it is unlikely that ivabradine influences the metabolism or concentration of substrates of CYP3A4 isoenzyme in plasma. At the same time, the simultaneous use of ivabradine with powerful inhibitors or inducers of cytochrome P450 can significantly affect the concentration of ivabradine in the blood plasma.
T1 / 2 ivabradine is, on average, 2 hours (70-75% AUC), effective T1 / 2 is 11 hours. Total clearance is approximately 400 ml / min, renal clearance is about 70 ml / min. Excretion of metabolites occurs at the same rate through the kidneys and intestines. About 4% of the accepted dose is excreted by the kidneys unchanged.

Indications for use

The drug Raenom is used for stable angina:
Therapy of stable angina in patients with normal sinus rhythm:
- with intolerance or the presence of contraindications to the use of beta-blockers;
- in combination with beta-blockers with inadequate control of symptoms of stable angina pectoris on the background of the optimal dose of beta-blocker.
The drug Raenom used in chronic heart failure:
- to reduce the incidence of cardiovascular complications (mortality from cardiovascular diseases and hospitalization due to worsening of CHF) in patients with chronic heart failure, with sinus rhythm and heart rate of at least 70 beats / min.

Mode of application

The drug Raenom taken orally 2 times / day, morning and evening, during the meal.
The decision to start therapy and dose titration should be made with regular monitoring of heart rate, ECG.
With stable angina, the recommended initial dose of the drug is 10 mg / day (1 tab. 5 mg 2 times / day) for patients aged less than 75 years. After 3-4 weeks of the drug, depending on the therapeutic effect, the daily dose may be increased to 15 mg (1 tab. 7.5 mg 2 times / day).
If, during therapy with Raenom, the heart rate decreases to less than 50 beats / min or the patient develops symptoms associated with bradycardia (such as dizziness, fatigue, or a marked reduction in blood pressure), the dose of Raenom should be reduced (for example, to 2.5 mg (1/2 tab. 5 mg) 2 times / day). If, at lower doses of the drug, the heart rate remains below 50 beats / min or the symptoms of severe bradycardia persist, Raenom should be discontinued.
If, against the background of therapy, the symptoms of angina pectoris persist for 3 months, treatment with the drug should be stopped.
In chronic heart failure, the recommended initial dose of Raenom is 10 mg / day (1 tablet. 5 mg 2 times / day) for patients less than 75 years old. Treatment should be initiated only in patients with stable CHF. After 2 weeks of use, the daily dose of the drug Raenom can be increased to 15 mg (1 tab. 7.5 mg 2 times / day) if the heart rate at rest is stable over 60 beats / min.
If the heart rate is stable no more than 50 beats / min or in the event of the appearance of symptoms of bradycardia, such as dizziness, fatigue or hypotension, the dose can be reduced to 2.5 mg (1/2 tablet 5 mg) 2 times / day .
If the value of the heart rate is in the range from 50 to 60 beats / min, it is recommended to use the drug Raenom at a dose of 5 mg 2 times / day.
If in the course of therapy the heart rate at rest is consistently less than 50 beats / min or if the patient has symptoms of severe bradycardia, for patients taking the drug in a dose of 5 mg 2 times / day or 7.5 mg 2 times / day, the dose of the drug should be reduced.
If patients receiving the drug Raenom at a dose of 2.5 mg (1/2 tab. 5 mg) 2 times / day or 5 mg 2 times / day, the heart rate at rest is stable over 60 beats / min, the dose of the drug can be increased .
If the heart rate is not more than 50 beats per minute or the patient has symptoms of bradycardia, the use of Raenom should be stopped.
For patients aged 75 years and older, the recommended initial dose of the drug is 2.5 mg (1/2 tab. 5 mg) 2 times / day. In the future, may increase the dose of the drug.
In patients with CC more than 15 ml / min, the recommended initial dose of the drug is 10 mg / day (1 tablet. 5 mg 2 times / day). After 3-4 weeks of the drug, depending on the therapeutic effect, the daily dose may be increased to 15 mg (1 tab. 7.5 mg 2 times / day). In patients with QA less than 15 ml / min, the drug should be used with caution (due to insufficient clinical data).
Patients with mild hepatic insufficiency (up to 7 points on the Child-Pugh scale) are recommended to prescribe the drug Raenom in the usual dose. The recommended initial dose of the drug is 10 mg / day (1 tab. 5 mg 2 times / day). After 3-4 weeks of the drug, depending on the therapeutic effect, the daily dose may be increased to 15 mg (1 tab. 7.5 mg 2 times / day). Caution must be exercised when Raenom is used in patients with moderate hepatic insufficiency (7–9 points on the Child-Pugh scale). Raenom is contraindicated in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale), since there is no data on the use of ivabradine in this group of patients (a significant increase in plasma ivabradine concentration can be expected).

Side effects of Raenom

The most frequent side effects of ivabradine, bradycardia, and photopsia were dose-dependent in nature and were due to the mechanism of its pharmacological action.
Adverse adverse reactions are represented by system-organ classes according to the MedDRA classification and with the frequency of occurrence: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000); frequency unknown (insufficient data to estimate development frequency).
On the part of the nervous system: often - headache (especially in the first month of therapy), dizziness, possibly associated with bradycardia; infrequently - vertigo, muscle spasms; frequency unknown - syncope, possibly associated with bradycardia.
From the organ of vision: very often - changes in light perception (photopsia1); often - blurred vision; frequency unknown - diplopia, visual disturbances.
Since the cardiovascular system: often - bradycardia2, AV-blockade I degree, ventricular premature beats, short-term increase in blood pressure; infrequently - palpitations, supraventricular premature beats, prolongation of the QT interval on the ECG; very rarely - atrial fibrillation, AV-blockade II-III degree, CCCU; frequency is unknown - excessive reduction in blood pressure, possibly associated with bradycardia.
The following are adverse events identified in clinical studies that occurred with the same frequency in both the group of patients receiving ivabradine and the control group, which suggests their connection with the disease as such, and not with taking ivabradine: sinus arrhythmia, angina pectoris, including unstable angina, atrial fibrillation, myocardial ischemia, myocardial infarction and ventricular tachycardia.
On the part of the respiratory system: infrequently - shortness of breath.
On the part of the digestive system: rarely - nausea, constipation, diarrhea.
From the musculoskeletal system: infrequently - muscle spasms.
Allergic reactions: frequency is unknown - skin rash, itching, erythema, angioedema, urticaria.
From the laboratory and instrumental studies: infrequently - hyperuricemia, eosinophilia, increased serum creatinine concentration.
Other: frequency is unknown - asthenia, fatigue, malaise, possibly associated with bradycardia.
1 Photopsia - a transient change in brightness in a limited zone of the visual field. As a rule, such phenomena are provoked by a sharp change in the intensity of illumination in the zone of the visual field. Most often the photopsia appeared in the first 2 months of therapy, followed by repetition. The severity of photopsia, as a rule, was mild or moderate. Photopsy disappeared during therapy or after its completion.
2 Bradycardia was observed more frequently in the first 2-3 months of therapy, and only some patients developed severe bradycardia with a heart rate of not more than 40 beats / min.

Contraindications

Contraindications to the use of the drug Raenom are: bradycardia (heart rate at rest less than 60 beats / min (before treatment)); cardiogenic shock; acute myocardial infarction; severe hypotension (systolic blood pressure less than 90 mm Hg. Art. and diastolic blood pressure less than 50 mm Hg. Art.); severe hepatic insufficiency (more than 9 points on the Child-Pugh scale); SSSU; sinoatrial blockade; the presence of an artificial pacemaker; unstable angina; AV block III degree; simultaneous use with potent inhibitors of CYP3A4 isoenzyme, such as antifungal agents of the azole group (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin for oral administration, josamycin, telithromycin), HIV protease inhibitors (HIV inhibitor (nelfinavir), ritonavir))))), a proteolase inhibitor of HIV (nelfinavir), a reditavir))))). simultaneous use with slow calcium channel blockers (BCCA), which reduce heart rate, such as verapamil or diltiazem; pregnancy; lactation period (breastfeeding); use in women of reproductive age who do not use reliable methods of contraception; age up to 18 years (the efficacy and safety of the drug in this age group has not been studied); lactase deficiency, lactose intolerance, glucose / galactose malabsorption syndrome; Hypersensitivity to ivabradine or any of the auxiliary components of the drug.
With caution should be prescribed the drug for moderate liver failure (less than 9 points on the Child-Pugh scale); severe renal failure (CC less than 15 ml / min); congenital prolongation of the QT interval; simultaneous use of drugs that prolong the QT interval; simultaneous use of moderate inhibitors and inducers of CYP3A4 and grapefruit juice; simultaneous use with potassium-sparing diuretics; asymptomatic left ventricular dysfunction; AV blockade II degree; a recent stroke; CHF IV functional class according to NYHA classification; retinal pigment degeneration (retinitis pigmentosa); hypotension; patients over the age of 75 years.

Pregnancy

The use of the drug Raenom contraindicated in pregnancy. At the moment there is not enough data on the use of ivabradine in pregnancy. In preclinical studies of ivabradine, embryotoxic and teratogenic effects were detected.
Women of reproductive age should use reliable methods of contraception during the period of treatment with Raenom.
The use of the drug Raenom contraindicated during lactation. Information on the allocation of ivabradine with breast milk is not available. Animal studies have shown that ivabradine is excreted in breast milk.

Interaction with other drugs

Unwanted combinations
Drugs that prolong the QT interval
- antiarrhythmic drugs that prolong the QT interval (for example, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone);
- drugs that prolong the QT interval, not related to antiarrhythmic drugs (for example, pimozide, ziprasidone, sertindol, mefloquine, halofantrine, pentamidine, cisapride, erythromycin for intravenous administration).
The simultaneous use of ivabradine and these drugs should be avoided, since a decrease in heart rate can cause an additional lengthening of the QT interval. If necessary, the simultaneous use of these drugs should be carefully monitored ECG.
CYP3A4 isoenzyme
Ivabradine is metabolized in the liver with the participation of the CYP3A4 isoenzyme and is a very weak inhibitor of this cytochrome. Ivabradine has no significant effect on the metabolism and plasma concentration of other substrates (potent, moderate and weak inhibitors) of the CYP3A4 isoenzyme. At the same time, inhibitors and inducers of the CYP3A4 isoenzyme can interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. It was found that CYP3A4 isoenzyme inhibitors increase, and CYP3A4 isoenzyme inducers reduce the concentration of ivabradine in the blood plasma.
Increasing plasma plasma concentrations of ivabradine may increase the risk of developing bradycardia.

Contraindications

Potent inhibitors of isoenzyme CYP3A4
Simultaneous use of ivabradine with powerful inhibitors of the isoenzyme CYP3A4, such as antifungal agents of the azoles group (ketoconazole, itraconazole); macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin); HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone are contraindicated.
Potent inhibitors of CYP3A4 isoenzyme - ketoconazole (200 mg 1 time / day) or josamycin (1 g 2 times / day) - increase the average concentration of ivabradine in the blood plasma by 7-8 times.
Moderate inhibitors of isoenzyme CYP3A4
Simultaneous use of ivabradine and diltiazem or verapamil (drugs that slow heart rate) in healthy volunteers and patients was accompanied by an increase in AUC of ivabradine by a factor of 2-3 and an additional decrease in heart rate by 5 beats / min. The use of these combinations is contraindicated.

Combinations that require caution

The use of ivabradine in combination with other moderate inhibitors of the CYP3A4 isoenzyme (for example, fluconazole) is possible provided that the heart rate at rest is more than 60 beats / min. The recommended initial dose of ivabradine is 2.5 mg 2 times / day. Heart rate control is required.
Simultaneous use with CYP3A4 isoenzyme inducers, such as rifampicin, barbiturates, phenytoin, and herbal remedies containing Hypericum perforatum (Hypericum perforatum), can lead to a decrease in plasma concentration and Ivabradine activity and require a higher dose of Ivabradine. With the joint use of ivabradine and preparations containing St. John's wort, it was noted a twofold decrease in the AUC of ivabradine. During the period of drug therapy by Raenom, whenever possible, use of drugs and products containing St. John's wort should be avoided.
It is necessary to use the drug with caution simultaneously with potassium-sparing diuretics (thiazide group diuretics and “loop” diuretics), since hypokalemia may increase the risk of developing arrhythmias. Since Ivabradine can cause bradycardia, a combination of hypokalemia and bradycardia is a predisposing factor for the development of a severe form of arrhythmia, especially in patients with the syndrome of lengthening the QT interval, both congenital and caused by exposure to any substances.

Combined use with other drugs

The absence of a clinically significant effect on the pharmacodynamics and pharmacokinetics of Ivabradine with the simultaneous use of the following drugs: proton pump inhibitors (omeprazole, lansoprazole), PDE5 inhibitors (for example, sildenafil), HMG-CoA reductase inhibitors (for example, simvastatin), BMKK - a series (for example, amlodipine, lacidipine), digoxin and warfarin.
Ivabradine has not been shown to have a clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, the pharmacokinetics and pharmacodynamics of digoxin, warfarin and the pharmacodynamics of acetylsalicylic acid.
Ivabradine used in combination with ACE inhibitors, angiotensin II receptor, beta-blockers, diuretics, aldosterone antagonists, nitrates short and long-acting inhibitors of HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, hypoglycemic agents for oral administration, acetylsalicylic acid and other antiplatelet agents. The use of the above medicines was not accompanied by a change in the safety profile of the therapy.
Other interactions requiring caution when used together
While taking grapefruit juice, there was a twofold increase in the concentration of ivabradine in the blood plasma. During the period of drug therapy by Raenom, the use of grapefruit juice should be avoided whenever possible.

Overdose

Symptoms of drug overdose Raenom: an overdose of ivabradine can lead to severe and prolonged bradycardia.
Treatment: Therapy of severe bradycardia - symptomatic, is carried out in specialized departments. In the case of the development of bradycardia in combination with impaired hemodynamic parameters, symptomatic treatment is given with IV injection of beta-adrenomimetics, such as isoprenaline. If necessary, it is possible to produce an artificial pacemaker.

Storage conditions

The drug Raenom should be stored in its original packaging to protect from moisture, out of the reach of children at a temperature not exceeding 30 ° C. Shelf life - 2 years.

Composition of Raenom

1 tablet Raenom contains: ivabradine hydrobromide 8.795 mg, which corresponds to the content of ivabradine 7.5 mg.
Excipients: lactose - 41.675 mg, mannitol - 44.53 mg, maltodextrin - 3 mg, croscarmellose sodium - 1 mg, colloidal silicon dioxide - 0.5 mg, magnesium stearate - 0.5 mg.
The composition of the shell: Opadra pink - 3 mg (polyvinyl alcohol - 1.05 mg, talc - 0.716 mg, titanium dioxide - 0.705 mg, macrogol-3350 - 0.36 mg, methacrylic acid copolymer (type C) - 0.12 mg, iron dye yellow oxide - 0.038 mg, iron dye red oxide - 0.007 mg, sodium bicarbonate - 0.004 mg)

Additionally

Ivabradine is not effective in treating or preventing arrhythmias. Its effectiveness decreases with the development of tachyarrhythmias (for example, ventricular or supraventricular tachycardia). Raenom is not recommended for patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with the function of the sinus node.
During Raenom therapy, patients should be clinically monitored for atrial fibrillation (paroxysmal or permanent). According to clinical indications (for example, worsening of the course of stenocardia, the appearance of a sensation of heartbeat, irregular heart rhythm), an ECG should be included in the current control.
The risk of developing atrial fibrillation may be higher in patients with CHF who take Raenom. Atrial fibrillation was more common among patients who took amiodarone or class I antiarrhythmic drugs simultaneously with ivabradine. Patients with CHF and intraventricular conduction disorders (blockade of the left or right leg of the bundle of His) and ventricular dyssynchrony should be controlled.

Use in patients with bradycardia

Ivabradine is contraindicated if, before initiating therapy, the heart rate at rest is less than 60 beats / min. If, during therapy, the heart rate decreases to less than 50 bpm / min, or the patient has symptoms associated with bradycardia (such as dizziness, fatigue, or hypotension), the dose should be reduced. If, at lower doses of the drug, the heart rate remains less than 50 beats per minute or if symptoms associated with bradycardia persist, then Raenom should be stopped.

Combined use as part of antianginal therapy

The use of the drug Raenom together with BMCC, slower heart rate, such as verapamil or diltiazem, is contraindicated. With the combined use of ivabradine with nitrates and BMCA, derivatives of the dihydropyridine series, such as amlodipine, no changes in the safety profile of the therapy were noted. It is not established that the combined use with BMKK increases the effectiveness of ivabradine.
It is not recommended to prescribe the drug Raenom immediately after a stroke, because data on the use of the drug in this period are not available.

Visual Perception Functions

Ivabradine affects the function of the retina. To date, no toxic effects of ivabradine on the retina have been identified. However, there is no data on the effect of ivabradine on the retina with prolonged use (over 1 year). If there is a violation of visual functions that are not described in this manual, you should consider stopping the drug Raenom. Patients with retinal pigment degeneration (retinitis pigmentosa) should take Raenom with caution.
Raenom should be administered with caution to patients with arterial hypotension (due to insufficient clinical data).
Raenom is contraindicated in severe hypotension (systolic blood pressure less than 90 mm Hg. Art. And diastolic blood pressure less than 50 mm Hg. Art.).

Atrial fibrillation (atrial fibrillation) - cardiac arrhythmias

An increase in the risk of developing severe bradycardia against the background of the use of ivabradine during pharmacological cardioversion to restore sinus rhythm has not been proven. However, due to insufficient data, if possible, to delay the planned electrical cardioversion, Raenom should stop taking the drug 24 hours before it is given.
Use in patients with congenital long QT interval syndrome or in patients taking drugs prolonging the QT interval
The drug Raenom should not be used for congenital long QT syndrome, as well as in combination with drugs that can lengthen the QT interval. If necessary, the simultaneous use of such drugs requires strict ECG monitoring. The decrease in heart rate due to the use of the drug by Raenom can aggravate the prolongation of the QT interval, which, in turn, can trigger the development of a severe form of arrhythmia, in particular, polymorphic ventricular tachycardia of the "pirouette" type.

Hypertensive patients requiring a switch to another antihypertensive drug

When changing antihypertensive therapy in patients with CHF who take the drug Raenom, monitoring of blood pressure is required at appropriate intervals.

Chronic heart failure

Before deciding on the use of drug Raenom heart failure should be stable. Care should be taken when using the drug Raenom in patients with CHF IV functional class according to the NYHA classification due to limited data on the use of the drug in this category of patients.

Hepatic insufficiency moderate

With moderately severe liver failure (less than 9 points on the Child-Pugh scale), Raenom therapy should be carried out with caution.

Severe renal failure

In cases of severe renal failure (CC less than 15 ml / min), Raenom therapy should be carried out with caution.

Excipients

Raenom contains lactose, therefore it is not recommended for patients with lactase deficiency, lactose intolerance and glucose / galactose malabsorption syndrome.

Influence on ability to drive motor transport and control mechanisms

Ivabradine does not affect the ability to drive vehicles and perform work that requires a high rate of psychomotor reactions. However, one should remember about the possibility of photopsy with a sharp change in the intensity of illumination, especially when driving at night.

Terms of sell

You don't need a prescription to buy Raenom.