Source: Health Sciences Authority (SG) Revision Year: 2023 Publisher: <u>France:</u> Les Laboratoires Servier, 50, rue Carnot, 92284 Suresnes cedex, France <u>Singapore:</u> Servier Singapore Pte Ltd, 67 Ubi Avenue 1, #06-09 StarHub Green, Singapore 408942
Pharmacotherapeutic group: Beta blocking agents, other combinations
ATC code: C07FX06
Carvedilol is a vasodilating non-selective beta-blocker, which reduces the peripheral vascular resistance by selective alpha 1-receptor blockade and suppresses the renin-angiotensin system through non-selective betablockade.
Plasma renin activity is reduced and fluid retention is rare.
Carvedilol has no intrinsic sympathomimetic activity. Like propranolol, it has membrane-stabilising
properties. Carvedilol is a racemate of two stereoisomers. Both enantiomers were found to have alpha-adrenergic blocking characteristics in animal experiments. Non-selective beta1- and beta2- adrenoceptor blockade is attributed mainly to the S(-) enantiomer.
The antioxidant properties of carvedilol and its metabolites have been demonstrated in in vitro and in vivo animal studies and in vitro in a number of human cell types.
In hypertensive patients, a reduction in blood pressure is not associated with a concomitant increase in peripheral resistance, as observed with pure beta-blockers. The heart rate is slightly decreased. Stroke volume remains unchanged. Renal blood flow and renal function remain normal, as does peripheral blood flow. Therefore, cold extremities, which often occur with beta-blockers, are rarely seen. In hypertensive patients, carvedilol increases the plasma norepinephrine concentration.
In prolonged treatment of patients with angina pectoris, carvedilol has been seen to have an anti-ischaemic effect and to alleviate pain. Haemodynamic studies have demonstrated that carvedilol reduces ventricular preand after-load.
In patients with left ventricular dysfunction or congestive heart failure, carvedilol has a favourable effect on haemodynamics and the left ventricular ejection fraction and its dimensions. Carvedilol reduces mortality and the need for cardiovascular hospitalisation in patients with heart failure.
Carvedilol has no negative effect on the serum lipid profile or electrolytes. The ratio of high-density lipoproteins and low-density lipoproteins remains normal.
Clinical studies have shown that a balance between vasodilation and the beta-blocking effect of carvedilol causes the following haemodynamic and metabolic effects:
In a large multi-centre, double-blind, placebo-controlled study on mortality (COPERNICUS), 2,289 patients presenting with severe, ischaemic or non-ischaemic, chronic stable heart failure on standard therapy were randomised, either on carvedilol (1,156 patients) or on placebo (1,133 patients). Patients had left ventricular systolic dysfunction with an average ejection fraction of less than 20%. All-cause mortality was reduced by 35% - 19.7% in the placebo group – to 12.8% in the carvedilol group (Cox proportional hazards, P=0.00013). The benefit of carvedilol on mortality was consistent in all sub-populations studied. Sudden death was reduced by 41% in the carvedilol group (4.2% versus 7.8%). The combined secondary assessment parameters in terms of mortality or hospitalisations due to heart failure, mortality or cardiovascular hospitalisations, and mortality or all-cause hospitalisations all improved significantly in the carvedilol group in relation to the placebo group (31%, 27% and 24% reductions respectively, P=0.00004). The incidence of severe secondary effects in the study was lower in the carvedilol group (39% versus 45.4%). At the start of treatment, the incidence of aggravated heart failure was similar in the two groups. The incidence of aggravated heart failure during the study was lower in the carvedilol group (14.5% versus 21.1%).
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).
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:
The anti-anginal 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 anti-anginal 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 an 889-patients randomised placebo-controlled study, ivabradine given on top of atenolol 50 mg once daily 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).
In a 1,277-patients randomised placebo-controlled study, ivabradine demonstrated a statistically significant additional efficacy on response to treatment (defined as a decrease of at least 3 angina attacks per week and/or an increase in the time to 1 mm ST segment depression of at least 60 seconds during a treadmill ETT) on top of amlodipine 5 mg once daily or nifedipine GITS 30 mg once daily. at the trough of drug activity (12 hours after oral ivabradine intake) over a 6-week treatment period (Odds ratio = 1.3, 95% CI [1.0–1.7]; p=0.012). Ivabradine did not show additional efficacy on secondary endpoints of ETT parameters at the trough of drug activity while an additional efficacy was shown at peak (3-4 hours after oral ivabradine 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 anti-anginal 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 anti-anginal 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 10,917 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 myocardial infarction or heart failure (ivabradine 12.0% versus placebo 15.5%, P=0.05). From this subgroup, a post analysis in patients treated with carvedilol at baseline (n=254) showed similar results (ivabradine 8.4% versus placebo 17.9%, HR: 0.40, 95% CI [0.19;0.83]).
A large outcome study, SIGNIFY, was performed in 19,102 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 twice daily (5 mg twice daily, if age ≥75 years) and titration up to 10 mg twice daily). The main efficacy criterion was the composite of cardiovascular death or non-fatal myocardial infarction. The study showed no difference in the rate of the primary composite endpoint 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 primary composite endpoint was observed in a pre-specified subgroup of patients with angina patients in CCS class II or higher at baseline (n=12,049) (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=14,286) (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 6,505 adult patients with stable chronic heart failure (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 (N=3,241) n (%) | Placebo (N=3,264) n (%) | Hazard ratio [95% CI] | P-value | |
|---|---|---|---|---|
| Primary composite endpoint | 793 (24.47) | 937 (28.71) | 0.82 [0.75; 0.90] | <0.0001 |
| Components of the composite | ||||
| CV death Hospitalisation for worsening HF | 449 (13.85) 514 (15.86) | 491 (15.04) 672 (20.59) | 0.91 [0.80; 1.03] 0.74 [0.66; 0.83] | 0.128 <0.0001 |
| Other secondary endpoints | ||||
| All cause death Death from HF Hospitalisation for any cause Hospitalisation for CV reason | 503 (15.52) 113 (3.49) 1,231 (37.98) 977 (30.15) | 552 (16.91) 151 (4.63) 1,356 (41.54) 1,122 (34.38) | 0.90 [0.80; 1.02] 0.74 [0.58;0.94] 0.89 [0.82;0.96] 0.85 [0.78; 0.92] | 0.092 0.014 0.003 0.0002 |
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.
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).
In the subgroup of patients with heart rate ≥75 bpm (n=4,150), 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 cardiovascular 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 heart rate ≥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]).
In the subgroup of patients receiving carvedilol at baseline (n=2596), a significant relative risk reduction was observed on the primary composite endpoint in the ivabradine group as compared to the placebo group (HR: 0.80, 95% CI [0.68;0.94]). In the subgroup of patients with HR ≥75 bpm and receiving carvedilol at baseline (n=1654), a consistent trend was observed (HR: 0.79, 95% CI [0.65;0.95]).
In a 97-patient randomised placebo-controlled study, the data collected during specific ophthalmologic investigations, aiming at documenting the function of the cone and rod systems and the ascending visual pathway (i.e. electroretinogram, static and kinetic visual fields, colour vision, visual acuity), in patients treated with ivabradine for chronic stable angina pectoris over 3 years, did not show any retinal toxicity.
The long-term effects of ivabradine on growth, puberty and general development as well as the long-term efficacy of therapy with ivabradine in childhood to reduce cardiovascular morbidity and mortality have not been studied.
The rate and extent of absorption of ivabradine and carvedilol from Carivalan are not significantly different, respectively, from the rate and extent of absorption of ivabradine and carvedilol when taken alone as monotherapy.
The absolute bioavailability of carvedilol administered orally is approximately 25%. Maximum plasma concentration is achieved approximately 1 hour after administration. There is a linear relationship between dose and plasma concentrations. In patients with a slow debrisoquine hydroxylation, carvedilol’s plasma concentration increased by a factor of 2 to 3, compared with rapid metabolisers of debrisoquine. Food intake does not affect bioavailability, although it takes longer to reach maximum plasma concentration.
Carvedilol is highly lipophilic. Plasma protein binding is about 98 to 99%. The distribution volume is around 2 L/kg. The first-pass effect after oral administration is around 60-75%.
Carvedilol is extensively metabolised to various metabolites which are excreted primarily via bile. The first pass metabolism after oral administration is about 60-75%. The enterohepatic circulation of the parent substance has been demonstrated in animals.
Carvedilol is metabolised in the liver, mainly through oxidation of the aromatic ring and glucuronidation. Demethylation and hydroxylation at the phenol ring produce three active metabolites with beta-blocking activity. These three active metabolites have a weak vasodilating effect, compared with carvedilol. According to preclinical studies, the beta-blocking activity of the metabolite 4-hydroxyphenol is approximately 13 times higher than that of carvedilol. However, the metabolite concentrations in humans are about 10 times lower than that of carvedilol. Two of the carbazole-hydroxy metabolites of carvedilol are extremely potent antioxidants, making them 30 – 80 times stronger than carvedilol.
The oxidative metabolism of carvedilol is stereoselective. R-enantiomer is primarily metabolised by CYP2D6 and CYP1A2, while S-enantiomer is primarily metabolised by CYP2C9 and to a lesser extent by CYP2D6. Other CYP450 isoenzymes participating in carvedilol metabolism include CYP3A4, CYP2E1 and CYP2C19. Maximum plasma concentration of R-carvedilol in plasma is approximately twice the concentration of Scarvedilol. R-enantiomer is metabolised mainly via hydroxylation. In the slow metabolisers of CYP2D6, an increase of carvedilol concentration in plasma may occur, mainly of the R-enantiomer, leading to the increase of the alpha-blocking activity.
The average half-life of elimination of carvedilol varies between 6 and 10 hours. The plasma clearance is approximately 590 mL/min. Elimination is mainly via bile. Excretion is mainly via faeces. A minor part is eliminated renally in the form of metabolites.
The pharmacokinetics of carvedilol is dependent on age. Plasma carvedilol levels are around 50% higher in the elderly than in young people.
In a study involving patients with liver cirrhosis, the bioavailability of carvedilol was four times higher and the maximum plasma concentration five times higher and the distribution volume three times higher than in healthy subjects.
In some hypertensive patients with moderate (creatinine clearance 20-30 mL/min) or severe (creatinine clearance <20 mL/min) renal impairment, an increase in plasma carvedilol concentrations of approximately 40-55% was seen compared to patients with normal renal function. However, there was a large variation in the results.
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 Ndesmethylated derivative of ivabradine has been identified as the main active metabolite in humans.
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).
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.
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).
Ivabradine is eliminated with a main half-life of 2 hours (70-75% of the AUC) in plasma and an effective halflife 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.
The kinetics of ivabradine is linear over an oral dose range of 0.5–24 mg.
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).
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).
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).
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).
No preclinical studies have been performed with the Carivalan.
Non-clinical studies on safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity revealed no special hazard for humans. In reproductive toxicity studies, impaired fertility, embryotoxicity (increased post-implantation loss, decreased fetal body weight and delayed skeletal development) and increased neonatal mortality at one week post-partum were observed at high doses.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Reproductive toxicity studies showed no effect of ivabradine on fertility in male and female rats. When pregnant animals were treated during organogenesis at exposures close to therapeutic doses, there was a higher incidence of foetuses with cardiac defects in the rat and a small number of foetuses with ectrodactylia in the rabbit.
In dogs given ivabradine (doses of 2, 7 or 24 mg/kg/day) for one year, reversible changes in retinal function were observed but were not associated with any damage to ocular structures. These data are consistent with the pharmacological effect of ivabradine related to its interaction with hyperpolarisation-activated Ih currents in the retina, which share extensive homology with the cardiac pacemaker If current. Other long-term repeat dose and carcinogenicity studies revealed no clinically relevant changes.
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