Carvedilol is a vasodilating non-selective beta-blocker, which reduces the peripheral vascular resistance by selective alpha1-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 beta2adrenoceptor 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.
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.
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.
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. 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 rate and extent of absorption of ivabradine and carvedilol from carvedilol/ivabradine fixed-dose combination 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.
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.
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.
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.
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.
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.
No preclinical studies have been performed with the carvedilol/ivabradine combination.
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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