Dilatrend®

Dilatrend®

This is a medicament
A medicament is a product which affects your health, and its consumption contrary to instructions is dangerous for you. Follow strictly the doctor’s prescription, the method of use and the instructions of the pharmacist who sold the medicament. The doctor and the pharmacist are experts in medicine, its benefits and risks. Do not by yourself interrupt the period of treatment prescribed for you. Do not repeat the same prescription without consulting your doctor.

Mechanism of action and pharmacodynamics
Carvedilol is a multiple action-adrenergic receptor blocker with 1-, 1- and -2-adrenergic receptor blockade properties. Carvedilol has been shown to have organ-protective effects. Carvedilol is a potent antioxidant and a scavenger of reactive oxygen radicals. Carvedilol is racemic, and both R(+)- and S(-)-enantiomers have the same ¬-adrenergic receptor blocking properties and antioxidant properties. Carvedilol has antiproliferative effects on human vascular smooth muscle cells. A decrease in oxidative stress has been shown in clinical studies by measuring various markers during chronic treatment of patients with carvedilol. Carvedilol’s -adrenergic receptor blocking properties are non-selective for the 1- and 2-adrenoceptors and are associated with the laevorotatory S(-)-enantiomer. Carvedilol has no intrinsic sympathomimetic activity and (like propranolol) it has membrane stabilising properties. Carvedilol suppresses the renin-angiotensin-aldosterone system through beta¬blockade, which reduces the release of renin, thus making fluid retention rare. Carvedilol reduces peripheral vascular resistance via selective blockade of 1-adrenoceptors. Carvedilol attenuates the increase in blood pressure induced by phenylephrine, an 1-adrenoceptor agonist, but not that induced by angiotensin II. Carvedilol has no adverse effect on lipid profile. A normal ratio of high-density lipoproteins to low-density lipoproteins (HDL/LDL) is maintained.

Clinical efficacy

Hypertension: Carvedilol lowers blood pressure in hypertensive patients by a combination of beta¬blockade and alpha1¬mediated vasodilation. The reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as observed with pure beta¬blocking agents. Heart rate is slightly decreased. Renal blood flow and renal function are maintained in hypertensive patients. Carvedilol has been shown to maintain stroke volume and reduce total peripheral resistance. Blood supply to distinct organs and vascular beds including kidneys, skeletal muscles, forearms, legs, skin, brain or carotid arteries is not compromised by carvedilol. Cold extremities and early fatigue during physical activity occur rarely. The long-term effect of carvedilol on hypertension is documented in several double-blind controlled studies.

Coronary heart disease: In patients with coronary heart disease, carvedilol has demonstrated anti-ischemic (improved total exercise time, exercise time to 1 mm ST segment depression and time to angina) and anti-anginal properties that were maintained during long-term treatment. Acute hemodynamic studies have demonstrated that carvedilol significantly decreases myocardial oxygen demand and sympathetic activity. It also decreases ventricular preload (pulmonary artery pressure and pulmonary capillary wedge pressure) and afterload (total peripheral resistance).

Pharmacodynamics and clinical studies in the indication ‘Treatment of mild to severe heart failure’
Studies on mild to moderate heart failure: The cause of the beneficial effects of Dilatrend® in heart failure has not been elucidated. Two placebo-controlled studies compared the acute hemodynamic effects of Dilatrend® with baseline measurements in 59 and 49 patients with NYHA class II–IV heart failure who were receiving diuretics, ACE inhibitors and digitalis. Significant reductions in blood pressure, pulmonary arterial pressure, pulmonary capillary pressure and heart rate were found. Initial effects on cardiac output, stroke volume index and peripheral vascular resistance were slight and variable. The studies reassessed the hemodynamic effects after 12–14 weeks. Dilatrend® significantly reduced blood pressure, pulmonary arterial pressure, right atrial pressure, peripheral vascular resistance and heart rate, whereas stroke volume index increased. In 839 patients with NYHA class II–III heart failure treated for 26–52 weeks in the four American placebo-controlled studies, left ventricular ejection fraction as measured by radionuclide ventriculography increased by an average of 8 ejection fraction units in the Dilatrend®-treated patients compared to 2 ejection fraction units in the placebo-controlled patients. This effect of the treatment was significant in each of the studies. An American double-blind placebo-controlled stratified study programme included 1094 patients with NYHA class II–III heart failure and an ejection fraction of ¬0.35 (696 patients randomised to the carvedilol group). Most of the patients had been treated with digitalis, diuretics and ACE inhibitors before the start of the study. The patients were assigned to the individual treatment plans on the basis of their exercise tolerance. A double-blind placebo-controlled study performed in Australia and New Zealand included 415 patients with less severe heart failure (half of the patients randomised to the carvedilol group). All the protocols excluded patients expected to need a heart transplant during the 6–12-month period of double-blind treatment. All the randomised patients had shown good tolerance to carvedilol during a 2-week period of treatment with 6.25 mg twice daily. In each study a primary endpoint was either progression of heart failure or exercise tolerance or quality of life (Minnesota Living with Heart Failure Questionnaire). In these studies numerous secondary endpoints were defined, e.g. NYHA class, general well-being as assessed by physician and patient, and cardiovascular-related hospitalisations. Mortality was not a predefined endpoint in any of the studies, but was analysed in all the studies. Other analyses that were not planned in advance were overall death rate and total and cardiovascular-related hospitalisations. Where the primary endpoint of a study showed no significant benefit of treatment, the attribution of significance with respect to the other results is complex and the values concerned must be interpreted with caution. The results of the American and Australian-New Zealand studies were as follows:

Reduction of progression of heart failure: An American multicentre study with 366 patients had as its primary endpoint total cardiovascular-related mortality, cardiovascular-related hospitalisations and increase in medication for heart failure. Progression of heart failure was reduced by 47% (p=0.008) during a mean follow-up period of 7 months. In the Australian-New Zealand study, mortality and total hospitalisations fell by 25% over 18–24 months. In the three largest American studies, mortality and total hospitalisations fell by
19%, 39% and 49%, these figures being nominally statistically significant in the latter two studies. The results of the Australian-New Zealand study were borderline in terms of statistical significance.

Functional measures: NYHA class was not a primary endpoint in any, but was a secondary endpoint in all, of the multicentre studies. All the studies identified at least a trend towards an improvement in NYHA class. Exercise tolerance was the primary endpoint in three studies, and in none of these was a significant effect identified.

Subjective measures: Quality of life as assessed by a standardised questionnaire (primary endpoint of one study) was not influenced by carvedilol. Nevertheless, it was shown that general well-being as assessed both by the physician and by the patient improved significantly.

Studies on severe heart failure: In a large multicentre, placebo-controlled, double-blind mortality study (COPERNICUS), 2289 patients with stable severe chronic heart failure of ischemic or non-ischemic origin who received standard therapy were randomly assigned to treatment with either carvedilol (1133 patients) or placebo (1156 patients). The patients suffered from impaired left ventricular systolic function and had a mean ejection fraction of 19.8% in the placebo group and 19.9% in the carvedilol group. Mortality regardless of cause was reduced by 35% from 19.7% per patient year in the placebo group to 12.8% per patient year in the carvedilol group (Cox proportional hazards model, p=0.00013). The occurrence of sudden cardiac death was reduced by 41% in the carvedilol group (5.3% vs 8.9%).

Results of the COPERNICUS study:

The combined secondary endpoints ‘mortality or hospitalisation due to heart failure’, ‘mortality or hospitalisation due to cardiovascular disease’ and ‘mortality or hospitalization regardless of cause’ were all significantly lower in the carvedilol group than in the placebo group (reduction by 31%, 27% and 24% respectively per patient year, p<0.00004 in all cases). The incidence of severe adverse events during the study was lower in the carvedilol group (39.0% vs 45.4%). During the first 90 days the incidence of deterioration of heart failure was similar in the carvedilol and placebo groups (15.4% vs 14.8%). The incidence of serious deterioration of heart failure during the study was lower in the carvedilol group (14.6% vs 21.6%).

Pharmacokinetics

Absorption
Dilatrend® is rapidly absorbed following oral administration. Carvedilol is a substrate of the intestinal efflux transporter P-glycoprotein, which plays a major role in the bioavailability of certain drugs. The maximum plasma concentration is reached after approximately 1–2 hours. There is pronounced first-pass metabolism, and absolute bioavailability is approximately 25% (12–49%). The first-pass extraction is stereospecific, the bioavailability of the R-enantiomer (alpha1-blocking activity) being approximately 2.5 times higher than that of the S-enantiomer (beta- and alpha1-blocking activity). Simultaneous food intake does not influence bioavailability, however the tmax is delayed. Dilatrend® is highly lipophilic. When used as directed, Dilatrend® is unlikely to accumulate during long-term treatment.

Distribution
Steady-state volume of distribution (VDss) is approximately 2 l/kg. Dilatrend® is 98% bound to plasma proteins.

Metabolism
In all animal species studied and also in humans, Dilatrend® is almost completely broken down in the liver by oxidation and conjugation to a variety of metabolites. The oxidative metabolism of carvedilol is stereoselective. The R-enantiomer is predominantly metabolised by CYP2D6 and CYP1A2, while the S-enantiomer is mainly metabolised by CYP2C9 and to a lesser extent by CYP2D6. Other CYP450 isoenzymes involved in the metabolism of carvedilol include CYP3A4, CYP2E1 and CYP2C19. The peak plasma concentration of R-carvedilol is approximately twice that of S-carvedilol. The R-enantiomer is predominantly metabolised by hydroxylation. In poor metabolisers of CYP2D6 (sparteine/debrisoquine-type) there may be an increase in the plasma concentration of carvedilol, mainly the R¬enantiomer, leading to an increase in alpha-blocking activity. Demethylation and hydroxylation at the phenol ring result in the formation of three active metabolites with beta-blocking activity. In animals, the 4’-hydroxyphenol metabolite is approximately 13 times more potent than Dilatrend® in terms of beta-blockade. Compared to Dilatrend®, the three principal metabolites exhibit weak vasodilating activity. Plasma levels (Cmax) of the active metabolites after 1 hour were as follows: M2 3.9 ng/ml, M4 4.1 ng/ml, M5 3.3 ng/ml (approximately 20% those of carvedilol: Cmax 49 ng/ml). In addition, two hydroxycarbazole metabolites are very potent antioxidants, having a 30–80 times greater activity in this respect than Dilatrend®.

Elimination
The half-life of Dilatrend® after oral administration is approximately 6–10 hours. Plasma clearance is 590 ml/min. Elimination is predominantly biliary and via the feces. Less than 2% of unaltered substance is eliminated via the urine, approximately 15% in the form of metabolites.

Pharmacokinetics in special patient populations

Patients with renal impairment: Glomerular filtration and autoregulation of renal perfusion are unaffected during chronic treatment with carvedilol. No significant changes in elimination half-life or maximum plasma concentration are observed in hypertensive patients with renal insufficiency. However, the AUC is increased by 40–50% in patients with renal impairment. Renal excretion of the parent substance is decreased in patients with renal insufficiency; however, change in pharmacokinetic parameters is modest. 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 dialysis or after renal transplantation. After oral administration of 10 mg Dilatrend®, plasma concentration reached a maximum after 1–5 hours both on dialysis days and on ‘dialysis-free’ days. After 24 hours the substance could no longer be detected in plasma. 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. Carvedilol is not eliminated during dialysis because it does not cross the dialysis membrane, possibly due to its high plasma protein binding. Data from comparative studies in hemodialysis patients show that carvedilol is more effective than diltiazem in silent ischemia.
Patients with hepatic impairment: In patients with cirrhosis of the liver, the systemic availability of the drug is increased by up to 80% because of a reduction in the first-pass effect. Therefore, carvedilol is contraindicated in patients with clinically manifest liver failure (see Contraindications about replica oris watches).
Heart failure patients: 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 suggest that the pharmacokinetics of R- and S-carvedilol are significantly altered by heart failure.
Elderly patients: The pharmacokinetics of Dilatrend® are affected by patient age. Plasma levels of Dilatrend® are approximately 50% higher in older than in younger patients. The Cmax and AUC may be elevated in elderly patients. In such cases the dose should be adjusted.
Children and adolescents: Only limited data are available on pharmacokinetics in patients under 18 years of age.
Diabetic patients: In hypertensive patients with non-insulin-dependent diabetes no influence of carvedilol on fasting or post-prandial blood glucose concentration, glycosylated hemoglobin A1 or need for change of the dose of antidiabetic agents was found. In patients with non-insulin-dependent diabetes, carvedilol had no statistically significant influence on the glucose tolerance test. In hypertensive non-diabetic patients with impaired insulin sensitivity (syndrome X) carvedilol induced a modest improvement in insulin sensitivity. The same results were found in hypertensive patients with non-insulin dependent diabetes.

Preclinical Data
In carcinogenicity studies conducted in rats and mice, employing dosages up to 75 mg/kg/day and 200 mg/kg/day respectively (38 to 100 times the maximum recommended human dose [MRHD]), carvedilol had no carcinogenic effect. Carvedilol was not mutagenic in in vitro or in vivo mammalian tests and non-mammalian tests. Administration of carvedilol to pregnant rats at maternally toxic doses (≥ 200 mg/kg, ≥¬100 times MRHD) resulted in impairment of fertility (poor mating, fewer corpora lutea, implants and embryonic responses). Doses >60 mg/kg (>30 times MRHD) caused delays in the growth/ development of offspring. Embryotoxicity (increased post-implantation deaths) was observed, but no malformations, in rabbits and rats at doses of 75 mg/kg and 200 mg/kg, respectively (38 to 100 times MRHD).

Correct method of administration
The tablets should be taken with an adequate amount of liquid. It is not necessary to take the tablets with meals, however patients with heart failure should take the tablets with food in order to slow the rate of absorption and reduce the incidence of orthostatic effects. Treatment with Dilatrend® is generally long-term therapy. It should not be stopped abruptly, but must be tapered off over a number of days (e.g. by halving the dose every three days). This is particularly important in patients who also have coronary artery disease.



Presentation:

Dilatrend® scored tablets: Tablets containing 6.25 mg Carvedilol

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