Vacodil

Carvedilol.

6.25 mg: Each film-coated tablet contains: Carvedilol 6.25 mg.
25 mg: Each film-coated tablet contains: Carvedilol 25 mg.

Pharmacology: Pharmacodynamics: Mechanism of action: Carvedilol is a multiple action adrenergic receptor blocker with alpha1, beta1 and beta2 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 alpha-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 beta-adrenergic receptor blocking properties are non-selective for the beta1 and beta2-adrenoceptors and are associated with the levorotatory S(-) enantiomer.
Carvedilol has no intrinsic sympathomimetic activity and (like propranolol) it has membrane stabilizing properties. Carvedilol suppresses the renin-angiotensin-aldosterone system through beta-blockade, which reduces the release of renin, thus making fluid retention rate. Carvedilol reduces the peripheral vascular resistance via selective blockade of alpha1-adrenoceptors. Carvedilol attenuates the increase in blood pressure induced by phenylephrine, an alpha1-adrenoceptor agonist, but not that induced by angiotensin II.
Carvedilol has no adverse effect on the lipid profile. A normal ratio of high-density lipoproteins to low density lipoproteins (HDL/LDL) is maintained.
Efficacy: Clinical studies showed the following results for carvedilol.
Hypertension: Carvedilol lowers blood pressure in hypertensive patients by a combination of beta-blockade and alpha1 mediated vasodilation.
A 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 the carotid artery is not compromised by carvedilol. There is a reduced incidence of cold extremities and early fatigue during physical activity. 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, 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 over activity. It also decreases the myocardial preload (pulmonary artery pressure and pulmonary capillary wedge pressure) and after load (total peripheral resistance).
Chronic heart failure: Carvedilol significantly reduces all cause mortality and the need for cardiovascular hospitalization. Carvedilol also increases ejection fraction and improves symptoms in patients with ischemic or non-ischemic chronic heart failure. The effect of carvedilol is dose dependent.
Pharmacokinetics: Absorption: Following oral administration, carvedilol is rapidly absorbed. In healthy volunteers the maximum serum concentration is reached after approximately one hour. The absolute bioavailability of carvedilol in humans is approximately 25%.
Distribution: Carvedilol is a highly lipophilic compound, approximately 98% to 99% bound to plasma proteins. The distribution volume approximately 2L/kg.
Metabolism: In humans, carvedilol is extensively metabolized into a variety of metabolites that are eliminated mainly in the bile. The first-pass effect after oral administration amounts to about 60-75%. Enterohepatic circulation of the parent substance has been shown in animals
Carvedilol is metabolized extensively by the liver and glucuronidation is one of the major reactions. Demethylation and hydroxylation at the phenol ring produce 3 metabolites with beta-adrenergic receptor blocking activity. Compared to carvedilol, the three active metabolites are about 10 times lower than that of the parent substance. Two of the hydroxyl-carbazole metabolites of carvedilol are extremely potent antioxidants, demonstrating a 30- to 80-fold greater potency than carvedilol.
Elimination: The average elimination half-life of carvedilol is approximately 6 hours. Plasma clearance is approximately 500-700 ml/min. The primary route of excretion is via the feces. Elimination is mainly biliary. A minor part is eliminated via the kidneys in the form of various metabolites.
Pharmacokinetics in special populations: Patients with renal impairment: The autoregulatory blood supply is preserved and the glomerular filtration is unchanged during chronic treatment with carvedilol.
In patients with hypertension and renal insufficiency, the area under plasma level-time curve, elimination half-life and maximum plasma concentration does not change significantly. Renal excretion of the unchanged drug decreases in the patients with renal insufficiency; however, changes in pharmacokinetic parameters are modest.
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, probably due to its high plasma protein binding.
On the other basis of results obtained in comparative trials on hemodialysed patients, it was concluded that carvedilol was more effective than calcium channel blockers and was better tolerated.
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 dysfunction (see Contraindications).
Geriatric use: The pharmacokinetics of carvedilol is hypertensive patients were not affected by age.
Pediatric use: There is limited data available on pharmacokinetics in people younger than 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, glycolated 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 improved the insulin sensitivity. The same results were found in hypertensive patients with non-insulin dependent diabetes.

Hypertension: Vacodil is indicated primarily for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents (e.g. calcium channel blockers, diuretics).
Treatment of angina pectoris.
Treatment of symptomatic chronic heart failure: Vacodil is indicated for the treatment of symptomatic chronic heart failure (CHF) to reduce mortality and cardiovascular hospitalizations, improve patient well-being and slow the progression of the disease.
Vacodil may be used as adjunct to standary therapy, but may also be used in those patients unable to tolerate an ACE inhibitor, or those who are not receiving digitalis, hydralazine or nitrate therapy.

Duration of treatment: Treatment with carvedilol is a long-term therapy. Treatment should not be stopped abruptly but rather gradually reduced at weekly intervals. This is particularly important in the case of patients with concomitant coronary heart disease.
Essential hypertension: The recommended dose for initiation of therapy is 12.5 mg once a day for the first 2 days. Thereafter, the recommended dosage is 25 mg once a day. If necessary, the dosage may subsequently be increased at intervals of at least two weeks to the recommended maximum daily dose of 50 mg given once daily or in divided doses (twice daily).
Angina pectoris: The recommended dose for initiation of therapy is 12.5 mg twice a day for the first 2 days. Thereafter, the recommended dosage is 25 mg twice a day. If necessary, the dosage may thereafter be increased at intervals of at least two weeks, up to the recommended maximum daily dose of 100 mg given in divided doses (twice daily).
Symptomatic, stable, chronic heart failure: Dosage must be tailored to suit the individual and closely monitored by a physician during up-titration.
For those patients receiving digitalis, diuretics and ACE inhibitors, dosing of these drugs should be stabilized before initiation of Vacodil treatment.
The recommended dose for initiation of therapy is 3.125 mg twice daily for 2 weeks. If this dose is tolerated, the dose may thereafter be increased, at intervals of not less than two weeks, to 6.25 mg, 12.5 mg and 25 mg twice daily. Doses should be increased to the highest level tolerated by the patient.
The maximum recommended dose is 25 mg twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85 kg (187 lbs) in patients with mild or moderate CHF weighing more than 85 kg; the maximum recommended dose if 50 mg twice daily.
Before each dose increase, the patient should be evaluated by the physician for symptoms of vasodilation or worsening heart failure.
Transient worsening of heart failure or fluid retention should be treated with increased doses of diuretics. Occassionally, it may be necessary to lower the dose of Vacodil and, in rare cases, temporarily discontinue Vacodil treatment.
If Vacodil treatment is discontinued for more than one week, therapy should be recommended at a lower dose level (twice daily) and up-titrated in line with the previously mentioned dosing recommendation. If Vacodil is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg in line with the previously mentioned dosing recommendation.
Symptoms of vasodilation may be managed initially by a reduction in the dose of diuretics. If symptoms persist, the dose of ACE inhibitor (if used) may be reduced, followed by a reduction in the dose of carvedilol if necessary. Under these circumstances, the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized.
Special dosage instructions: Renal impairment: Available pharmacokinetic data in patients with varying degrees of renal impairment (including renal failure) suggest no changes in Vacodil dosing recommendation are warranted in patients with moderate to severe renal insufficiency.
Hepatic impairment: Vacodil is contraindicated in patients with clinical manifestations of liver dysfunction (see Contraindications).
Elderly: There is no evidence to support dose adjustment.
Method of administration: Oral.

Symptoms and signs of intoxication: In the event of overdosage, there may be severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest. There may also be respiratory problems, bronchospasm, vomiting, disturbed consciousness and generalized seizures.
Treatment of intoxication: In additional to general procedures, the vital parameters must be monitored corrected, if necessary, under intensive care conditions. The following supportive therapies can be used: Patients should be placed in the supine position.
Atropine: 0.5 to 2 mg i.v. then 2 to 5 mg/h as a long term infusion (to support cardiovascular function).
Sympathomimetics according to body-weight and effect: dobutamine, isoprenaline, orciprenaline or adrenaline. If positive inotropic effect is required, phosphodiesterase inhibitors (PDE) e.g. milrinone should be considered.
If peripheral vasodilation dominates the intoxication profile then norfenephrine or noradrenaline should be administered with continuous monitoring of the circulatory conditions.
In the case of drug-resistance bradycardia, pacemaker therapy should be initiated.
Glucagon: Initially 1 to 10 mg i.v. then 2 to 5 mg/h as a long-term infusion (to support cardiovascular function).
Treatment of bronchospams: For bronchospasm, beta-sympathomimetics (as aerosol or i.v.) or aminophylline i.v. should be given.
Treatment of seizures: In the event of seizures, slow i.v. injection of diazepam or clonazepam is recommended.
Important note: In case of severe intoxication with shock, supportive treatment must be continued for a sufficiently long period, as a prolongation of elimination half-life and redistribution of carvedilol from deeper compartments are to be expected. The duration of the supportive/antidote therapy depends on the severity of the overdosage. The supportive treatment should be therefore be continued until the patient's condition has stabilized.

Vacodil must not be used in patients with hypersensitivity to carvedilol or any component of the product; unstable/decompensate heart failure; clinically manifest liver dysfunction.
As with other beta-blockers, Vacodil must not be used in patients with: 2nd and 3rd degree AV block (unless a permanent pacemaker is in place); Severe bradycardia (<50 bpm); Sick sinus syndrome (including sino-atrial block); Severe hypotension (systolic blood pressure <85 mmHg); Cardiogenic shock; History of bronchospasm or asthma.

Chronic heart failure: In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of Vacodil. If such symptoms occur, diuretics should be increased and the Vacodil dose should not be advanced until clinical stability resumes. Occassionally, it may be necessary to lower the Vacodil dose or, in rare cases, temporarily discontinue it. Such episodes do not preclude subsequent successfully titration of Vacodil, Vacodil should be used with caution in combination with digitalis glycosides, as both drugs slow AV conduction.
Renal function in chronic heart failure: Reversible deterioration of renal has been observed with Vacodil therapy in chronic heart failure patients with low blood pressure (systolic BP <100 mmHg, ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency).
Chronic obstructive pulmonary disease: Vacodil should be used with caution, in patients with chronic obstructive pulmonary disease (COPD) with a bronchospastic component who are not receiving oral or inhaled medication, and only if the potential benefit outweighs the potential risk.
In patients with a tendency to bronchospasm, respiratory distress can occur as a result of a possible increase in airway resistance. Patients should be closely monitored during initiation and up-titration of Vacodil and the dose of Vacodil should be reduced if any evidence of bronchospasm is observed during treatment.
Diabetes: Care should be taken in the administration of Vacodil to patients with diabetes mellitus, as the early signs and symptoms of acute hypoglycemia may be masked or attenuated. In chronic heart failure patients with diabetes, the use of Vacodil may be associated with worsening control of blood glucose.
Peripheral vascular disease: Vacodil should be used with caution in patients with peripheral vascular disease as beta-blockers can precipitate or aggravate symptoms of arterial insufficiency.
Raynaud's phenomenon: Vacodil should be used with caution in patients suffering from peripheral circulatory disorders (e.g. Raynaud's phenomenon) as there may be exacerbation of symptoms.
Thyrotoxicosis: Vacodil, like other agents with beta-blocking properties, may obscure the symptoms of thyrotoxicosis.
Anesthesia and major surgery: Caution should be exercised in patients undergoing general surgery, because of the synergistic negative inotropic effects of Vacodil and anesthetic drugs.
Bradycardia: Vacodil may induce bradycardia. If the patient's pulse rate decreases to less than 55 beats per minute, the dosage of Vacodil should be reduced.
Hypersensitivity: Care should be taken in administering Vacodil to patients with a history of serious hypersensitivity reactions, and in those undergoing desensitization therapies, as beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.
Psoriasis: Patients with a history of psoriasis associated with beta-blocker therapy should take Vacodil only after consideration of the risk-benefit ratio.
Concomitant use of calcium channel blockers: Careful monitoring of ECG and blood pressure is necessary in patients receiving concomitant therapy with calcium channel blockers of the verapamil or diltiazem type or other antiarrhythmic drugs.
Pheochromocytoma: In patients with pheochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Although Vacodil has both alpha- and beta-blocking pharmacological activities, there is no experience with its use in this condition. Caution should therefore be taken in the administration of Vacodil of patients suspected of having pheochromocytoma.
Prinzmetal's variant angina: Agents with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There is no clinical experience with Vacodil in these patients although the alpha-blocking activity of Vacodil may prevent such symptoms. Caution should: however, be taken in the administration of Vacodil to patients suspected of having Prinzmetal's variant angina.
Contact lenses: Wearers of contact lenses should bear in mind the possibility of reduced lacrimation.
Withdrawal syndrome: Vacodil treatment should not be discontinued abruptly, particularly in patients suffering from ischemic heart disease. The withdrawal of Vacodil should be gradual (over a period of two weeks).
Effects on ability to drive and use machines: No studies have been performed on the effects of Vacodil on patient's fitness to drive or operate machinery.
Because of individually variable reactions (e.g. dizziness, tiredness), the ability to drive, operate machinery, or work without firm support may be impaired. This applies particularly at the start of treatment, after dose increases, on changing products, and in combination with alcohol.
Use in Children: safety and efficacy have not yet been established.

Pregnancy: Beta-blockers reduce placental perfusion, which may result in intrauterine fetal death, and immature and premature deliveries. In addition, adverse effects (especially hypoglycemia and bradycardia) may occur in the fetus and neonate. There may be an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. There is no evidence from animal studies that Vacodil has any teratogenic effects.
There is no adequate clinical experience with Vacodil in pregnanct women.
Vacodil should be used during pregnancy unless the potential benefit outweighs the potential risk.
Lactation: Animal studies demonstrated that Vacodil or its metabolites are excreted in breast milk. It is not known whether Vacodil is excreted in human milk. Breast-feeding is therefore not recommended during administration of Vacodil.

Adverse Event (AE) frequency: AE's occuring at ≥10% are described as very common;
AE's occurring at ≥1% and <10% are described as common;
AE's occurring at ≥0.1% and <1% are described as uncommon;
AE's occurring at ≥0.01% and <0.1% are described as rare;
AE's occurring at ≥0.01% are described as very rare including isolated cases.
The frequency of adverse experiences is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia.
Undesirable effects in chronic heart failure: Adverse experiences most frequently observed in the Vacodil group in clinical trials in chronic heart failure patients and not seen at an equivalent incidence among placebo treated patients are described as follows.
Central nervous system: Very common: dizziness, headaches are usually mild and occur particularly at the start of treatment. Asthenia (including fatigue) also occurs very commonly.
Cardiovascular system: Common: bradycardia, postural hypotension, hypotension, edema (including generalized, peripheral, dependent and genital edema, edema of the legs, hypervolemia and fluids overload).
Uncommon: syncope (including presyncope), AV block and cardiac failure during uptitration.
Gastro-intestinal system: Commonly, nausea, diarrhea and vomiting.
Hematology: Rare, thrombocytopenia.
Leucopenia has been reported in isolated cases.
Metabolic: Commonly, weight increase and hypercholesterolemia. Hyperglycemia, hypoglycemia and worsening control of blood glucose are also common in patients with pre-exisitng diabetes mellitus (see Precautions).
Others: Commonly, vision abnormalities. Rarely, renal failure and renal function abnormalities in patients with diffuse vascular disease and/or impairment renal function (see Precautions).
Undesirable effects in hypertension and the long term management of coronary heart disease: The profile of adverse events associated with the use of Vacodil in the treatment of hypertension and the long-term management of coronary heart disease is consistent with that observed in chronic heart failure. The incidence of adverse events in these patient populations is lower, however, Adverse experiences reported in clinical trials in patients with hypertension and coronary heart diseases are: Central nervous system: Commonly, dizziness, headaches and fatigue, which are usually mild and occur particularly at the beginning of treatment. Uncommonly, depressed mood, sleep disturbances, paresthesia.
Cardiovascular system: Commonly, bradycardia, postural hypotension and uncommonly syncope, especially at the beginning of treatment. Uncommonly, disturbances of peripheral circulation (cold extremities, PVD, exacerbation of intermittent claudication and Raynauds phenomenon), AV block, angina pectoris (including chest pain), symptoms of heart failure and peripheral edema.
Respiratory system: Commonly, asthma and dyspnea in predisposed patients. Rarely, stuffy nose.
Gastro-intestinal system: Commonly, gastro-intestinal upset (with symptoms such as nausea, abdominal pain, diarrhea). Uncommonly, constipation and vomiting.
Skin and appendages: Uncommonly, skin reactions (e.g. allergic exanthema, dermatitis, urticaria and pruritus).
Blood chemistry and hematology: Isolated cases of increases in ALAT, ASAT and gamma GT, thrombocytopenia and leucopenia.
Others: Commonly, pain in the extremities. Commonly, reduced lacrimation and eye irritation. Uncommon cases of sexual impotence and disturbed vision. Rarely, dryness of the mouth and disturbances of micturition.
Isolated cases of allergic reactions have been reported.
Class effect: Due to the beta-blocking properties, it is also possible for latent diabetes mellitus to become manifest, manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.

(Also see Precautions).
Pharmacokinetic interactions: Digoxin: Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Both digoxin and carvedilol slow AV conduction. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol.
Insulin or oral hypoglycemic: Agents with beta-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemic. The signs of hypoglycemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycemic, regular monitoring of blood glucose is therefore recommended.
Inducers and inhibitors of hepatic metabolism: Rifampicin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30% but caused no change in Cmax. Care may be required in those patients receiving inducers of mixed function oxidases e.g. rifampicin, as serum levels of carvedilol may be reduced, or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels of carvedilol may be increased.
However, based on the relatively small effect of cimetidine on carvedilol drug levels, the likelihood of any clinically important interaction is minimal.
Catecholamine-depleting agents: Patients taking both agents with beta-blocking properties and a drug that can deplete catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.
Cyclosporine: Modest increased in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On average, the dose of cyclosporine was reduced about 20% in these patients. Due to wide inter-individual variability in the dose adjustment required. It is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
Verapamil, diltiazem, or other antiarrhythmics: In combination with carvedilol can increase the risk of AV conduction disturbances (see Precautions).
Pharmacodynamic interactions: Clonidine: Concomitant administration of clonidine with agents with beta-blocking properties may potentiate blood-pressure and heart-rate-lowering effects. When concomitant treatment with agents with beta-blocking properties and clonidine to be terminated, the beta-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
Calcium channel blockers (see Precautions): Isolated cases of conduction disturbances (rarely with hemodynamic compromise) have been observed when carvedilol is co-administerd with diltiazem. As with other agents with beta-blocking properties. If carvedilol is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
As with other agents with beta-blocking activity, carvedilol may potentiate the effect of other concomitantly administered drugs that are anti-hypertensive in action (e.g. alpha1-receptor antagonist) or have hypotension as part of their adverse effect profile.
Careful attention must be paid during anesthesia to the synergistic negative inotropic and hypotensive effects of carvedilol and anesthesia drugs.
Certain sedatives (barbiturates, phenothiazines) and drugs for treating depression (tricyclic antidepressant), vasodilating drugs and alcohol may intesify the blood pressure lowering effect.

Store below 30°C. Store in the original container (sensitive to light).
Shelf-Life: 36 months.

Beta-Blockers

C07AG02 - carvedilol ; Belongs to the class of alpha and beta blocking agents. Used in the treatment of cardiovascular diseases.

B