Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cardiac therapy, other cardiac preparations, ATC code: C01EB17.

Mechanism of action

Ivabradine is a pure heart rate lowering agent, acting by selective and specific inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarisation.

Ivabradine can interact also with the retinal current Ih which closely resembles cardiac If. It participates in the temporal resolution of the visual system, by curtailing the retinal response to bright light stimuli. Under triggering circumstances (e.g. rapid changes in luminosity), partial inhibition of Ih by ivabradine underlies the luminous phenomena that may be occasionally experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field (see section 4.8).

Pharmacodynamic effects
The main pharmacodynamic property of ivabradine in humans is a specific dose dependent reduction in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend towards a plateau effect which is consistent with a reduced risk of severe bradycardia below 40 bpm (see section 4.8).
At usual recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise. This leads to a reduction in cardiac workload and myocardial oxygen consumption.
Ivabradine does not influence intracardiac conduction, contractility (no negative inotropic effect) or ventricular repolarisation:
- in clinical electrophysiology studies, ivabradine had no effect on atrioventricular or intraventricular conduction times or corrected QT intervals;
- in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) between 30 and 45%), ivabradine did not have any deleterious influence on LVEF.

Clinical efficacy and safety

The antianginal and anti-ischaemic efficacy of ivabradine was studied in five double-blind randomised trials (three versus placebo, and one each versus atenolol and amlodipine). These trials included a total of 4,111 patients with chronic stable angina pectoris, of whom 2,617 received ivabradine.

Ivabradine 5 mg twice daily was shown to be effective on exercise test parameters within 3 to 4 weeks of treatment. Efficacy was confirmed with 7.5 mg twice daily. In particular, the additional benefit over 5 mg twice daily was established in a reference-controlled study versus atenolol: total exercise duration at trough was increased by about 1 minute after one month of treatment with 5 mg twice daily and further improved by almost 25 seconds after an additional 3-month period with forced titration to 7.5 mg twice daily. In this study, the antianginal and anti-ischaemic benefits of ivabradine were confirmed in patients aged 65 years or more. The efficacy of 5 and 7.5 mg twice daily was consistent across studies on exercise test parameters (total exercise duration, time to limiting angina, time to angina onset and time to 1 mm ST segment depression) and was associated with a decrease of about 70% 
in the rate of angina attacks. The twice-daily dosing regimen of ivabradine gave uniform efficacy over 24 hours.

In a 889-patients randomised placebo-controlled study, ivabradine given on top of atenolol 50 mg o.d. showed additional efficacy on all ETT parameters at the trough of drug activity (12 hours after oral intake).

In a 725-patients randomised placebo-controlled study, ivabradine did not show additional efficacy on top of amlodipine at the trough of drug activity (12 hours after oral intake) while an additional efficacy was shown at peak (3-4 hours after oral intake).

Ivabradine efficacy was fully maintained throughout the 3- or 4-month treatment periods in the efficacy trials. There was no evidence of pharmacological tolerance (loss of efficacy) developing during treatment nor of rebound phenomena after abrupt treatment discontinuation. The antianginal and anti-ischaemic effects of ivabradine were associated with dose-dependent reductions in heart rate and with a significant decrease in rate pressure product (heart rate x systolic blood pressure) at rest and during exercise. The effects on blood pressure and peripheral vascular resistance were minor and not clinically significant.

A sustained reduction of heart rate was demonstrated in patients treated with ivabradine for at least one year (n = 713). No influence on glucose or lipid metabolism was observed.

The antianginal and anti-ischaemic efficacy of ivabradine was preserved in diabetic patients (n = 457) with a similar safety profile as compared to the overall population.

A large outcome study, BEAUTIFUL, was performed in 10917 patients with coronary artery disease and left ventricular dysfunction (LVEF<40%) on top of optimal background therapy with 86.9% of patients receiving beta-blockers. The main efficacy criterion was the composite of cardiovascular death, hospitalization for acute MI or hospitalization for new onset or worsening heart failure. The study showed no difference in the rate of the primary composite outcome in the ivabradine group by comparison to the placebo group (relative risk ivabradine:placebo 1.00, p=0.945).
In a post-hoc subgroup of patients with symptomatic angina at randomisation (n=1507), no safety signal was identified regarding cardiovascular death, hospitalization for acute MI or heart failure (ivabradine 12.0% versus placebo 15.5%, p=0.05).

A large outcome study, SIGNIFY, was performed in 19102 patients with coronary artery disease and without clinical heart failure (LVEF > 40%), on top of optimal background therapy. A therapeutic scheme higher than the approved posology was used (starting dose 7.5 mg b.i.d. (5 mg b.i.d, if age ≥ 75 years) and titration up to 10 mg b.i.d). The main efficacy criterion was the composite of cardiovascular death or non-fatal MI. The study showed no difference in the rate of the primary composite endpoint (PCE) in the ivabradine group by comparison to the placebo group (relative risk ivabradine/placebo 1.08, p=0.197).
Bradycardia was reported by 17.9 % of patients in the ivabradine group (2.1% in the placebo group). Verapamil, diltiazem or strong CYP 3A4 inhibitors were received by 7.1% of patients during the study.
A small statistically significant increase in the PCE was observed in a pre-specified subgroup of patients with angina patients in CCS class II or higher at baseline (n=12049) (annual rates 3.4% versus 2.9%, relative risk ivabradine/placebo 1.18, p=0.018), but not in the subgroup of the overall angina population in CCS class ≥ I (n=14286) (relative risk ivabradine/placebo 1.11, p=0.110).
The higher than approved dose used in the study did not fully explain these findings.


The SHIFT study was a large multicentre, international, randomised double-blind placebo controlled outcome trial conducted in 6505 adult patients with stable chronic CHF (for ≥ 4 weeks), NYHA class II to IV, with a reduced left ventricular ejection fraction (LVEF ≤ 35%) and a resting heart rate ≥ 70 bpm.
Patients received standard care including beta-blockers (89 %), ACE inhibitors and/or angiotensin II antagonists (91 %), diuretics (83 %), and anti-aldosterone agents (60 %). In the ivabradine group, 67% of patients were treated with 7.5 mg twice a day. The median follow- up duration was 22.9 months. Treatment with ivabradine was associated with an average reduction in heart rate of 15 bpm from a baseline value of 80 bpm. The difference in heart rate between ivabradine and placebo arms was 10.8 bpm at 28 days, 9.1 bpm at 12 months and 8.3 bpm at 24 months.

The study demonstrated a clinically and statistically significant relative risk reduction of 18% in the rate of the primary composite endpoint of cardiovascular mortality and hospitalisation for worsening heart failure (hazard ratio: 0.82, 95%CI [0.75;0.90] – p<0.0001) apparent within 3 months of initiation of treatment. The absolute risk reduction was 4.2%. The results on the primary endpoint are mainly driven by the heart failure endpoints, hospitalisation for worsening heart failure (absolute risk reduced by 4.7 %) and deaths from heart failure (absolute risk reduced by 1.1 %).

Treatment effect on the primary composite endpoint, its components and secondary endpoints 
Ivabradine         Placebo         Hazard ratio      p-value
(N=3241)         (N=3264)          [95% CI] n (%)            n (%)
Primary composite endpoint        793 (24.47)      937 (28.71)    0.82 [0.75; 0.90]   <0.0001 Components of the composite:                        449 (13.85)      491 (15.04)    0.91 [0.80; 1.03]    0.128 - CV death                        514 (15.86)      672 (20.59)    0.74 [0.66; 0.83]   <0.0001 - Hospitalisation for worsening HF
Other secondary endpoints:
- All cause death                503 (15.52)       552 (16.91)    0.90 [0.80; 1.02]     0.092 - Death from HF                   113 (3.49)        151 (4.63)    0.74 [0.58;0.94]      0.014 - Hospitalisation for any        1231 (37.98)     1356 (41.54)    0.89 [0.82;0.96]      0.003 cause                            977 (30.15)      1122 (34.38)    0.85 [0.78; 0.92]    0.0002 - Hospitalisation for CV reason


The reduction in the primary endpoint was observed consistently irrespective of gender, NYHA class, ischaemic or non-ischaemic heart failure aetiology and of background history of diabetes or hypertension.

In the subgroup of patients with HR ≥ 75 bpm (n=4150), a greater reduction was observed in the primary composite endpoint of 24 % (hazard ratio: 0.76, 95%CI [0.68;0.85] – p<0.0001) and for other secondary endpoints, including all cause death (hazard ratio: 0.83, 95%CI [0.72;0.96] – p=0.0109) and CV death (hazard ratio: 0.83, 95%CI [0.71;0.97] – p=0.0166).
In this subgroup of patients, the safety profile of ivabradine is in line with the one of the overall population.


A significant effect was observed on the primary composite endpoint in the overall group of patients receiving beta blocker therapy (hazard ratio: 0.85, 95%CI [0.76;0.94]). In the subgroup of patients with HR ≥ 75 bpm and on the recommended target dose of beta-blocker, no statistically significant benefit was observed on the primary composite endpoint (hazard ratio: 0.97, 95%CI [0.74;1.28]) and other secondary endpoints, including hospitalisation for worsening heart failure (hazard ratio: 0.79, 95% CI [0.56;1.10]) or death from heart failure (hazard ratio: 0.69, 95% CI [0.31;1.53]).

There was a significant improvement in NYHA class at last recorded value, 887 (28%) of patients on ivabradine improved versus 776 (24%) of patients on placebo (p=0.001).

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Coralan in all subsets of the paediatric population in the treatment of angina pectoris.
The European Medicines Agency has deferred the obligation to submit the results of studies with Coralan in one or more subsets of the paediatric population in the treatment of chronic heart failure (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Under physiological conditions, ivabradine is rapidly released from tablets and is highly water-soluble (>10 mg/ml). Ivabradine is the S-enantiomer with no bioconversion demonstrated in vivo. The N-desmethylated derivative of ivabradine has been identified as the main active metabolite in humans.

Absorption and bioavailability
Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma level reached in about 1 hour under fasting condition. The absolute bioavailability of the film-coated tablets is around 40%, due to first-pass effect in the gut and liver.
Food delayed absorption by approximately 1 hour, and increased plasma exposure by 20 to 30 %. The intake of the tablet during meals is recommended in order to decrease intra- individual variability in exposure (see section 4.2).

Distribution
Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady-state is close to 100 l in patients. The maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is 22 ng/ml (CV=29%).
The average plasma concentration is 10 ng/ml (CV=38%) at steady-state.

Biotransformation
Ivabradine is extensively metabolised by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. The major active metabolite is the N-desmethylated derivative (S 18982) with an exposure about 40% of that of the parent compound. The metabolism of this active metabolite also involves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4 induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma concentrations. Inversely, potent inhibitors and inducers may substantially affect ivabradine plasma concentrations (see section 4.5).

Elimination
Ivabradine is eliminated with a main half-life of 2 hours (70-75% of the AUC) in plasma and an effective half-life of 11 hours. The total clearance is about 400 ml/min and the renal 
clearance is about 70 ml/min. Excretion of metabolites occurs to a similar extent via faeces and urine. About 4% of an oral dose is excreted unchanged in urine.

Linearity/non linearity
The kinetics of ivabradine is linear over an oral dose range of 0.5 – 24 mg.

Special populations
- Older people: no pharmacokinetic differences (AUC and Cmax) have been observed between elderly (≥ 65 years) or very elderly patients (≥ 75 years) and the overall population (see section 4.2).
- Renal impairment: the impact of renal impairment (creatinine clearance from 15 to 60 ml/min) on ivabradine pharmacokinetic is minimal, in relation with the low contribution of renal clearance (about 20 %) to total elimination for both ivabradine and its main metabolite S 18982 (see section 4.2).
- Hepatic impairment: in patients with mild hepatic impairment (Child Pugh score up to 7) unbound AUC of ivabradine and the main active metabolite were about 20% higher than in subjects with normal hepatic function. Data are insufficient to draw conclusions in patients with moderate hepatic impairment. No data are available in patients with severe hepatic impairment (see sections 4.2 and 4.3).

Pharmacokinetic/pharmacodynamic (PK/PD) relationship
PK/PD relationship analysis has shown that heart rate decreases almost linearly with increasing ivabradine and S 18982 plasma concentrations for doses of up to 15-20 mg twice daily. At higher doses, the decrease in heart rate is no longer proportional to ivabradine plasma concentrations and tends to reach a plateau. High exposures to ivabradine that may occur when ivabradine is given in combination with strong CYP3A4 inhibitors may result in an excessive decrease in heart rate although this risk is reduced with moderate CYP3A4 inhibitors (see sections 4.3, 4.4 and 4.5).