Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: Milpharm Limited, Ares, Odyssey Business Park, West End Road, South Ruislip HA4 6QD, United Kingdom
Pharmacotherapeutic group: Alpha and beta blocking agents
ATC code: C07AG02
Carvedilol is a vasodilatory non-selective beta-blocker, which reduces the peripheral vascular resistance by selective alpha1-receptor blockade and suppresses the renin-angiotensin system through non-selective beta-blockade. Plasma renin activity is reduced and fluid retention is rare.
Carvedilol has no intrinsic sympathomimetic activity (ISA). Like propranolol, it has membrane stabilising properties.
Carvedilol is a racemate of two stereoisomers. Both enantiomers were found to have alpha-adrenergic blocking activity in animal models. 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-blocking agents. 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, often observed with beta-blockers, are rarely seen. In hypertensive patients carvedilol increases the plasma norepinephrine concentration.
In prolonged treatment of patients with angina, carvedilol has been seen to have an anti-ischaemic effect and to alleviate pain. Haemodynamic studies demonstrated that carvedilol reduces ventricular pre- and after-load with consequent improvement in left ventricular systolic and diastolic function without substantial changes in the cardiac output In patients with left ventricular dysfunction or congestive heart failure, carvedilol has a favourable effect on haemodynamics and left ventricular ejection fraction and dimensions.
Carvedilol has no negative effect on the serum lipid profile or electrolytes. The ratio of HDL (high-density lipoproteins) and LDL (low-density lipoproteins) remains normal and in hypertensive patients with dyslipidaemia favourable effects on the serum lipids have been reported after six months of oral therapy.
Renal impairment Several open studies have shown that carvedilol is an effective agent in patients with renal hypertension. The same is true in patients with chronic renal failure or those on haemodialysis or after renal transplantation. Carvedilol causes a gradual reduction in blood pressure both on dialysis and non-dialysis days, and the blood pressure-lowering effects are comparable with those seen in patients with normal renal function. On the basis of results obtained in comparative trials on haemodialysed patients, it was concluded that carvedilol was more effective than calcium channel blockers and was better tolerated.
In two studies, Carvedilol 25mg b.i.d. was compared with other anti-anginal drugs of recognised value in patients with chronic stable exertional angina. The dose regimens that were chosen were those widely used in clinical practice. Both trials had a double-blind, parallel group design. The primary objective was total exercise time (TET).
| Report no: | Control (dose) | Patient numbers carvedilol/comparator drug | Duration of treatment |
|---|---|---|---|
| 060 | Verapamil (120mg t.i.d.) | 126/122 | 12 weeks |
| 061 | ISDN s.r. (40mg b.i.d.) | 93/94 | 12 weeks |
The results of both trials clearly demonstrated that for TET at trough blood drug levels after 12 weeks of therapy there was no statistically significant difference between treatment groups. However the risk ratios obtained from the Cox proportional hazards model showed a trend in favour of carvedilol indicating that on average carvedilol was 114% as effective as verapamil (90% CI: 85-152%) and 134% as effective as ISDN (90%CI: 96-185%). This was also true for time to angina (TTA) and ST-segment depression (TST) at trough. The increase in TET was about 50 seconds in all groups; the improvements for TTA and TST were about 30 seconds, which is clinically relevant.
In study 060, 48h Holter monitoring data measurements demonstrated a reduction of number and duration of STsegment depressions (silent myocardial ischaemia) in both treatment groups. Carvedilol also decreased premature atrial and ventricular contractions (PAC, PVC), couplets and runs.
Carvedilol is rapidly absorbed after oral administration. In healthy subjects, maximum serum concentration is achieved approximately 1 hour after administration. The absolute bioavailability of carvedilol in humans is approximately 25%.
There is a linear relationship between dose and serum concentrations of carvedilol. Food intake did not affect the bioavailability or the maximum serum concentration, although the time needed to reach maximum serum concentration is prolonged.
Following oral administration of a 25 mg capsule to healthy subjects, carvedilol is rapidly absorbed with a peak plasma concentration Cmax of 21 mg/L reached after approximately 1.5 hour (tmax). The Cmax values are linearly related to the dose. Following oral administration, carvedilol undergoes extensive first pass metabolism that results in an absolute bioavailability of about 25% in healthy male subjects. Carvedilol is a racemate and the S ( - ) enantiomer appears to be metabolized more rapidly than the R ( + ) enantiomer, showing an absolute oral bioavailability of 15% compared to 31% for the R ( + ) enantiomer. The maximal plasma concentration of R-carvedilol is approximately 2 fold higher than that of S-carvedilol.
In vitro studies have shown that carvedilol is a substrate of the efflux transporter P-glycoprotein. The role of P-glycoprotein in the disposition of carvedilol was also confirmed in vivo in healthy subjects. Food does not affect bioavailability, residence time or the maximum serum concentration, although the time to reach maximum serum concentration is delayed.
Carvedilol is highly lipophilic. The plasma protein binding is about 98 to 99%. The volume of distribution is approximately 2 l/kg and increases in patients with liver cirrhosis.
In humans and in animal species studied, carvedilol is extensively metabolized to several metabolites which are excreted primarily in bile. The first pass effect after oral administration is about 60-75%. The enterohepatic circulation of the parent substance was demonstrated in animals.
Carvedilol is extensively metabolized in the liver, glucuronidation being one of the main reactions. The demethylation and hydroxylation at the phenol ring produce 3 active metabolites with blocking activity of beta-adrenergic receptors.
According to preclinical studies, the beta-blocking activity of the metabolite 4-hydroxyphenol is approximately 13 times higher than that of carvedilol. The three active metabolites have a weak vasodilating activity, compared with carvedilol. In humans, their concentrations are about 10 times lower than the parent substance. Two of the carbazole-hydroxy metabolites are extremely potent antioxidants, showing a potency 30-80 times that of carvedilol.
The average half-life of elimination of carvedilol is approximately 6 hours. The plasma clearance is approximately 500-700 ml/min. Elimination is mainly via the bile, and excretion mainly via the faeces. A minor part is eliminated renally in the form of various metabolites.
Following a single oral administration of 50 mg carvedilol, around 60% are secreted into the bile and eliminated with the faeces in the form of metabolites within 11 days. Following a single oral dose, only about 16% are excreted into the urine in form of carvedilol or its metabolites. The urinary excretion of unaltered drug represents less than 2%. After intravenous infusion of 12.5 mg to healthy volunteers, the plasma clearance of carvedilol reaches around 600 mL/min and the elimination half-life around 2.5 hours. The elimination half-life of a 50 mg capsule observed in the same individuals was 6.5 hours corresponding indeed to the absorption half-life from the capsule. Following oral administration, the total body clearance of the S-carvedilol is approximately two times larger than that of the R-carvedilol.
In some of the hypertensive patients with moderate to severe renal impairment (creatinine clearance <30 ml/min), an increase in plasma carvedilol concentrations of approximately 40-50% was seen compared to patients with normal renal function. Peak plasma concentrations in patients with renal insufficiency increased also by an average of 10-20%. However, there was a large variation in the results. Since carvedilol is primarily excreted via the faeces, significant accumulation in patients with renal impairment is unlikely.
In patients with moderate to severe renal impairment there is no need to modify carvedilol dosage (see section 4.2).
In patients with liver cirrhosis, the systemic availability of carvedilol is increased 80% due to reduced first pass effect. Therefore, carvedilol is contraindicated in patients with clinically manifest hepatic impairment (see section 4.3 Contraindications).
Age had a statistically significant effect on pharmacokinetic parameters of carvedilol in hypertensive patients. A study in elderly hypertensive patients showed no difference between the adverse event profile of this group and younger patients. Another study involving elderly patients with coronary artery disease showed no difference in reported adverse reactions vs. those that were reported by younger patients.
The available information on pharmacokinetics in subjects younger than 18 years is limited.
In hypertensive patients with type 2 diabetes was not observed effect of carvedilol on blood glucose (fasting or postprandial) and glycosylated haemoglobin A1, it was not necessary to change the dose of antidiabetic drugs.
In patients with type 2 diabetes, carvedilol had no statistically significant influence on the glucose tolerance test. In nondiabetic hypertensive patients with altered insulin sensitivity (Syndrome X), carvedilol increased insulin sensitivity. The same results were observed in hypertensive patients with type 2 diabetes.
In a study in 24 patients with heart failure, the clearance of R-and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results suggested that the pharmacokinetics of R-and S-carvedilol is significantly altered by heart failure.
Carvedilol demonstrated no mutagenic or carcinogenic potential.
High doses of carvedilol impaired fertility and affected pregnancy in rats (increased resorptions). Decreased fetal weight and delayed skeletal development were also seen in rats. Embryotoxicity (increased post-implantation loss) occurred in rats and rabbits.
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