Bravadin 5mg coated film pills N28
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Active ingredients
Ivabradin
Release form
Pills
Composition
1 tab. Ivabradine hydrobromide 8.796 mg, which corresponds to the content of Ivabradine 5 mg. Excipients: lactose monohydrate — 96.954 mg, microcrystalline cellulose — 30 mg, povidone — 9 mg, croscarmellose sodium — 3 mg, colloidal silicon dioxide — 0.75 mg, magnesium stearate — 1.5 mg. including hypromellose 71.714%, titanium dioxide (E171) 15.936%, talc 6.972%, propylene glycol 4.98%, iron dye yellow oxide (E172) 0.332%, iron dye red oxide (E 172) 0.066%.
Pharmacological effect
Antianginal agent. The mechanism of action lies in the selective and specific inhibition of If channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate 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. The main pharmacodynamic property of ivabradine is a specific, dose-dependent decrease in heart rate. Analysis of the dependence of the decrease in heart rate at a dose of more than 20 mg 2 times / day revealed a tendency to achieve a plateau effect, which reduces the risk of developing severe, poorly tolerated bradycardia (heart rate less than 40 beats / min). When used in recommended doses, the decrease in heart rate is about 10-15 beats / min at rest and during exercise. As a result, the work of the heart is reduced and myocardial oxygen demand is reduced. Ivabradine is also able to interact with the Ih channels of the retina, similar to If channels of the heart. Ih channel is involved in the occurrence of a temporary change in the resolution of the visual system, because reduces retinal response to bright light stimuli. Under provoking circumstances (for example, a quick change of brightness), Ivabradine partially inhibits the electrical impulse Ih, which sometimes in some patients leads to light sensations (phosphenes), which are described as a short-term sensation of increased brightness in a limited part of the visual field. Against the background of the use of ivabradine in patients with CHF II-IV functional class according to the NYHA classification with LVEF less than 35%shows a clinically and statistically significant decrease in the relative risk of complications (death rate from cardiovascular diseases and a decrease in the hospitalization rate due to increased symptoms of CHF) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed after 3 months from the start of therapy.
Pharmacokinetics
The pharmacokinetics of ivabradine in a dose of 0.5 to 24 mg is linear. After ingestion, ivabradine is rapidly and almost completely absorbed from the gastrointestinal tract. Cmax in plasma is reached approximately 1 hour after ingestion on an empty stomach. Bioavailability is approximately 40%, due to the effect of the first passage through the liver. Eating increases the absorption time by about 1 hour and increases the concentration in the blood plasma by 20-30%. Plasma protein binding - about 70% .Vd is about 100 liters. Plasma Cssmax after prolonged use at the recommended dose of 5 mg 2 times / day is approximately 20 ng / ml (CV = 29%). The average Css in plasma is 10 ng / ml (CV = 38%). Ivabradine is extensively metabolized in the liver and intestines by oxidation in the presence of CYP3A4 isoenzyme. The main active metabolite is the N-desmethylated derivative (S18982), its part accounting for 40% of the dose of the parent compound. Metabolism of the active metabolite of ivabradine also occurs in the presence of the CYP3A4 isoenzyme. Ivabradine's T1 / 2 is 2 hours (70-75% AUC) and the effective T1 / 2 is 11 hours. The total clearance is about 400 ml / min, the renal clearance is about 70 ml / min. Excretion of metabolites occurs at the same rate with urine and feces. About 4% of the ingested dose is excreted in the urine unchanged. In patients with renal insufficiency (CK 15-60 ml / min), changes in pharmacokinetic parameters are minimal due to the low participation of renal clearance (about 20%) in the total elimination of ivabradine and its main metabolite S18982. In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale), the AUC of ivabradine and its active metabolite is 20% more than during normal liver function.
Indications
1. Stable angina. Therapy of stable angina in adult patients with normal sinus rhythm: with intolerance or contraindications to the use of beta-blockers in combination with beta-blockers with inadequate control of stable angina on the background of the optimal dose of beta-blocker. 2. Chronic heart failure.To reduce the incidence of cardiovascular complications (mortality from cardiovascular diseases and hospitalization due to increased symptoms of chronic heart failure (CHF)) in patients with CHF, with sinus rhythm and heart rate of at least 70 beats / min.
Contraindications
Hypersensitivity to ivabradine or any of the auxiliary components of the drug Bravadin. Bradycardia (heart rate at rest less than 60 beats / min (before treatment)). Cardiogenic shock. Acute myocardial infarction. Severe arterial hypotension (systolic blood pressure (BP) less than 90 mm Hg and diastolic blood pressure less than 50 mm Hg). Severe liver failure (more than 9 points on the Child-Pugh scale). Sick sinus syndrome. Sinoatrial blockade. Unstable or acute heart failure. The presence of an artificial pacemaker working in the mode of constant stimulation. Unstable angina. Atrioventricular block (AV) III degree. The simultaneous use of potent inhibitors of cytochrome P450 ZA4, such as antifungals group azoles (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin for oral, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone. Pregnancy and breastfeeding period. 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. Precautions: moderately severe liver failure (less than 9 points on the Child-Pugh scale), severe renal failure (CC less than 15 ml / min), congenital lengthening of the interval, simultaneous use of drugs (LS), prolonging the interval, simultaneous use of moderate inhibitors and inducers of CYP3A4 isoenzyme and grapefruit juice, asymptomatic left ventricular dysfunction, AV block II, recently suffered a stroke, retinal pigmentosa (retinitis pigmentosa), hypotension, CHF IV function NYHA classification, concurrent use with “slow” calcium channel blockers (BCCA), which reduce heart rate (verapamil or diltiazem), concurrent use with non-calcium-sparing diuretics.
Precautionary measures
On the part of the senses: very often - changes in light perception (photopsia), often - blurred vision, infrequently - vertigo, unspecified frequency - diplopia, blurred vision. Since the cardiovascular system: often - bradycardia, AV-block I degree, ventricular premature beats, short-term increase in blood pressure, rarely - palpitations, supraventricular premature beats, very rarely - atrial fibrillation, AV-blockade II and III degrees, SSSUA unspecified frequency - marked reduction in blood pressure, possibly associated with bradycardia. On the part of the digestive system: rarely - nausea, constipation, diarrhea. On the part of the central nervous system: often - headache (especially in the first month of therapy), dizziness, possibly associated with bradycardia, unspecified frequency - fainting, possibly associated with bradycardia. On the part of the respiratory system: infrequent - shortness of breath.
Use during pregnancy and lactation
Contraindicated use during pregnancy and lactation (breastfeeding).
Dosage and administration
Inside, twice a day (morning and evening) during the meal. 1. Stable angina: The recommended initial dose is 10 mg per day (1 tablet 5 mg twice a day). After 3-4 weeks of therapy, the dose may be increased to 15 mg per day (1 tablet of 7.5 mg twice a day), depending on the therapeutic effect. If during the use of the drug Bravadin, the heart rate is less than 50 beats / min, or the patient has symptoms associated with bradycardia (dizziness, fatigue or a pronounced decrease in blood pressure), the dose of the drug Bravadin should be reduced to 2.5 mg (1 / 2 pills of 5 mg twice a day. Therapy with Bravadin should be discontinued if, at a lower dose of the drug Bravadin, the heart rate remains below 50 beats / min or the symptoms of severe bradycardia persist. 2. Chronic heart failure: The recommended initial dose is 10 mg per day (1 tablet of 5 mg twice a day). After 2 weeks of therapy, the dose may be increased to 15 mg per day (1 tablet of 7.5 mg twice a day), if the heart rate is at rest more stable than 60 beats / min, or reduced to 2.5 mg (1 / 2 pills of 5 mg twice a day, if the heart rate is consistently less than 50 beats / min or the patient has symptoms associated with bradycardia (dizziness, fatigue or a pronounced decrease in blood pressure). If the value of the heart rate is in the range of 50-60 beats / min, it is recommended to use the drug Bravadin at a dose of 5 mg twice a day.If during the use of the drug Bravadin, the heart rate at rest decreases to less than 50 beats / min or the patient has symptoms associated with bradycardia, for patients receiving the drug Bravadin 5 mg twice a day or 7.5 mg twice a day, The dose of the drug should be reduced. If patients receiving the drug Bravadin at a dose of 2.5 mg (1/2 tablet 5 mg) twice a day or 5 mg twice a day, the heart rate at rest is more stable than 60 beats / min, the dose of the drug Bravadin can be is increased. If the heart rate remains less than 50 beats per minute or the patient has symptoms associated with bradycardia, treatment with Bravadin should be stopped. Patients older than 75 years: Patients aged 75 years and older should begin treatment with a lower dose. The recommended starting dose is 2.5 mg (1/2 tablet 5 mg) twice a day. In the future, the dose may be increased. Renal dysfunction: Patients with impaired renal function (CC more than 15 ml / min) do not require dose adjustment. The recommended initial dose is 10 mg per day (1 tablet 5 mg twice a day). After 3-4 weeks of therapy, the dose may be increased to 15 mg per day (1 tablet of 7.5 mg twice a day). In connection with the lack of clinical data, the drug Bravadin should be used with caution in patients with QA less than 15 ml / min. Impaired liver function: Dose adjustment is not required in patients with a mild degree of liver failure (up to 7 on the Child-Pugh scale). Care should be taken when using the drug Bravadin in patients with moderate hepatic insufficiency (7-9 points on the Child-Pugh scale). For patients with severe liver failure (more than 9 points on the Child-Pugh scale), the use of the drug Bravadin is contraindicated. Children and adolescents: Safety and effectiveness of ivabradine in children and adolescents under the age of 18 years have not been established.
Side effects
The use of ivabradine has been studied in clinical studies involving almost 14,000 patients. The most frequent side effects were dose-dependent in nature and were associated with the mechanism of action of ivabradine. The classification of the incidence of side effects of the World Health Organization (WHO): very often ≥1 / 10, often from ≥1 / 100 to rarely from ≥1 / 1000 to rarely from ≥1 / 10000 to very rarely of the frequency unknown can not be estimated on the basis of available data. In each group, undesirable effects are presented in order of decreasing severity. - Disorders of the organ of vision: very often a change in light perception (photopsia).Often blurred vision. - Disturbances from an organ of hearing and labyrinth disturbances. Uncommon: vertigo- Violations of the heart and blood vessels, uncontrolled blood pressure, bradycardia, AV block of I degree (long PQ interval on the electrocardiogram (ECG)), ventricular premature beats, rarely palpitations, supraventricular arrhythmias, marked reduction in blood pressure may be associated with bradycardia , very rarely atrial fibrillation, AV block II and III degree, sick sinus syndrome. - Nervous system disorders, often headache (especially during the first month of therapy), dizziness, possibly associated with dikardiey, fainting, possibly related to bradycardia. Disturbances from the respiratory system, organs of the chest and mediastinum. Infrequently: shortness of breath. Violations of the skin and subcutaneous tissues. Infrequently, angioedema, skin rash, rarely pruritus, erythema, urticaria. - Disorders from the gastrointestinal tract. Infrequently nausea, constipation, diarrhea. Disorders of the musculoskeletal and connective tissue. Muscle spasms. General disorders and disorders at the injection site, asthenia, fatigue, possibly associated with bradycardia. Rarely, malaise, possibly associated with bradycardia. Laboratory and instrumental data: infrequent hyperuricemia, eosinophilia, increased plasma creatinine concentration, prolongation of the QT interval on an ECG. A change in light perception (photopsia) was noted in 14.5% of patients and was described as a transient change in brightness in a limited area of the visual field. As a rule, such phenomena were provoked by a sharp change in the intensity of illumination in the zone of the visual field. In general, photopsia appeared in the first two months of therapy, followed by repetition. The severity of photopsia, as a rule, was mild or moderate. Photopsia was stopped with continued therapy (77.5% of cases) or after its completion. In less than 1% of patients, photopsy was the cause of failure of therapy. ** Bradycardia was observed in 3.3% of patients, especially in the first 2-3 months of therapy, 0.5% of patients developed severe bradycardia with a heart rate less than or equal to 40 beats / min
Interaction with other drugs
When combined with the use ivabradine drugs that increase the interval QT (quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin / v), possibly increased deceleration of heart rate and additional lengthening the QT interval.If necessary, simultaneous therapy should be carefully monitored ECG indicators (such combinations are not recommended). Ivabradine is metabolized in the liver with the participation of the CYP3A4 isoenzyme and is a very weak inhibitor of this isoenzyme. Ivabradine has no significant effect on the metabolism and plasma concentration of other substrates (strong, moderate and weak inhibitors) of cytochrome CYP3A4. 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 has been found that CYP3A4 isoenzyme inhibitors increase, while CYP3A4 isoenzyme inducers decrease plasma concentrations of ivabradine. Increasing plasma plasma concentrations of ivabradine may increase the risk of developing bradycardia. Concurrent use is contraindicated with strong inhibitors of the CYP3A4 isoenzyme, such as antifungal agents of the azoles group (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), inhibitors (nelfinavir, i), I, I, I, I, I, I, I, I, I, I, I, my, my, my, my, my, my, my, my, my, my, my, my, ivabradine in the blood plasma and the risk of developing excessive bradycardia. Simultaneous use of ivabradine and moderate inhibitors of CYP3A4 isoenzyme diltiazem or verapamil (means that slows heart rate) in healthy volunteers and patients was accompanied by an increase in AUC of ivabradine by 2-3 times and an additional reduction in heart rate by 5 beats / min. These combinations are not recommended. CYP3A4 isoenzyme inducers, such as rifampicin, barbiturates, phenytoin, and herbal preparations containing Hypericum perforatum, which contain St. John's wort, when used together with ivabradine, can lead to a decrease in blood concentration and Ivabradine activity (may require a higher dose). 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 application of ivabradine, the use of herbal preparations containing St. John's wort should be reduced. The use of ivabradine in combination with other moderate inhibitors of the isoenzyme CYP3A4 (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.It should be used with caution ivabradine with non-Pallic diuretics (thiazide and loop diuretics), because hypokalemia may increase the risk of arrhythmia. 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. When using grapefruit juice on the background of the use of ivabradine, there was an increase in the concentration of ivabradine in the blood by 2 times. In the period of therapy with ivabradine, the use of grapefruit juice should be reduced.
special instructions
Caution should be used for moderate liver failure (less than 9 points on the Child-Pugh scale); severe renal failure (KK less than 15 ml / min); congenital prolongation of the QT interval; simultaneously with the medication, extending the QT interval (risk of developing severe ventricular arrhythmias such as pirouette); concomitantly with the administration of moderate inhibitors and inducers of CYP3A4 isoenzymes and grapefruit juice; with AV block II degree; recent stroke; retinal pigment degeneration (retinitis pigmentosa); hypotension; chronic heart failure IV functional class according to the NYHA classification; while taking blockers of slow calcium channels that reduce heart rate, such as verapamil or diltiazem; simultaneously with the intake of non-calcium-saving diuretics. Ivabradine is not effective for the treatment or prevention of arrhythmias. Its effectiveness falls on the background of the development of tachyarrhythmias (for example, ventricular or supraventricular paroxysmal tachycardia). Not recommended for patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with the function of the sinus node. During therapy with ivabradine, it is recommended to regularly monitor the patient's condition for the development of atrial fibrillation (paroxysmal or permanent). In case of clinical indications (for example, worsening of the course of stenocardia, the appearance of a sensation of heartbeat, irregular heart rhythm), an ECG should be monitored regularly.The risk of developing atrial fibrillation may be higher in patients with chronic heart failure who take ivabradine. Atrial fibrillation was more common among patients who took amiodarone or class I antiarrhythmic drugs simultaneously with ivabradine. Before deciding on the use of ivabradine, the course of heart failure must be stable. Patients with chronic heart failure and disorders of intraventricular conduction (blockade of the left or right bundle of the His bundle) and ventricular dyssynchrony require constant medical monitoring. There is no evidence of an increased risk of developing severe bradycardia in patients receiving ivabradine while restoring sinus rhythm during pharmacological cardioversion. However, due to the lack of sufficient data, if possible, to delay the planned electrical cardioversion, the reception of ivabradine should be stopped 24 hours before its implementation. A decrease in heart rate due to ivabradine may aggravate the prolongation of the QT interval, which, in turn, may trigger the development of a severe form of arrhythmia, in particular, polymorphic ventricular tachycardia such as pirouette. Impact on the ability to drive vehicles and control mechanisms: During the period of treatment, the patient should be careful when engaging in potentially hazardous activities that require high-speed psychomotor reactions in situations where sudden changes in illumination can occur, especially at night.