Composition and excipients:

1-Each F.C. tablet of Carvilol 3.125 contains: Carvedilol 3.125 mg.

2-Each F.C. tablet of Carvilol 6.25 contains: Carvedilol 6.25 mg.

3-Each F.C. tablet of Carvilol 12.5 contains: Carvedilol 12.5 mg.

4-Each F.C. tablet of Carvilol 25 contains: Carvedilol 25 mg.

Pharmacodynamic properties:

Carvedilol is a vasodilatory 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 beta-blockade.

Pharmacokinetic properties:

Absorption: 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%.

Distribution: The plasma protein binding is about 98 to 99%.

Metabolism: Carvedilol is extensively metabolized in the liver to several metabolites, which are excreted primarily in bile.

Elimination: The average half-life of elimination of carvedilol is approximately 6 hours. Elimination is mainly via the bile, and excretion mainly via the faeces. A minor part is eliminated renally in the form of various metabolites.

Indications:

• Essential hypertension
• Chronic stable angina pectoris
• Adjunctive treatment of moderate to severe stable chronic heart failure

Posology and method of administration:

1. Essential Hypertension:

• Carvedilol may be used for the treatment of hypertension alone or in combination with other antihypertensive, especially thiazide diuretics.
• Once daily dosing is recommended, however the recommended maximum single dose is 25 mg and the recommended maximum daily dose is 50 mg.
• Adults: The recommended initial dose is 12.5 mg once a day for the first two days. Thereafter, the treatment is continued at the dose 25 mg/day.
• If necessary, the dose may be further increased gradually at intervals of two weeks or more rarely.
• Elderly: The recommended initial dose in hypertension is 12.5 mg once a day, which may also be sufficient for continued treatment. However, if the therapeutic response is inadequate at this dose, the dose may be further increased gradually at intervals of two weeks or more rarely.

2. Chronic stable angina pectoris:

• A twice-daily regimen is recommended.
• Adults: The recommended initial dosage is 12.5 mg twice a day for the first two days. Thereafter, the treatment is continued at the dose 25 mg twice a day. If necessary, the dose may be further increased gradually at intervals of two weeks or more rarely to the recommended maximum dose of 100 mg a day divided into two doses (twice daily).
• Elderly: The recommended initial dose is 12.5 mg twice daily for two days. Thereafter, the treatment is continued at the dose 25 mg twice daily, which is the recommended maximum daily dose.

3. Heart Failure:

• Carvedilol is given in moderate to severe heart failure in addition to conventional basic therapy with diuretics, ACE inhibitors, digitalis, and/or vasodilators. The patient should be clinically stable (no change in NYHA-class, no hospitalisation due to heart failure) and the basic therapy must be stabilized for at least 4 weeks prior to treatment. Additionally the patient should have a reduced left ventricular ejection fraction and heart rate should be > 50 bpm and systolic blood pressure > 85 mm Hg.
• The initial dose is 3.125 mg twice a day for two weeks. If this dose is tolerated, the dose may be increased slowly with intervals of not less than two weeks up to 6.25 mg twice a day, then up to 12.5 mg twice a day and finally up to 25 mg twice a day. The dosage should be increased to the highest tolerable level.
• The recommended maximum dosage is 25 mg twice a day for patients with a body weight of less than 85 kg, and 50 mg twice a day for patients with a body weight above 85 kg, provided that the heart failure is not severe.
• A dose increase to 50 mg twice daily should be performed carefully under close medical supervision of the patient.
• Transient worsening of symptoms of heart failure may occur at the beginning of treatment or due to a dose increase, especially in patients with severe heart failure and/or under high dose diuretic treatment. This does usually not call for discontinuation of treatment, but dose should not be increased.
• The patient should be monitored by a physician/cardiologist for two hours after starting treatment or increasing the dose.
• Before each dose increase, an examination should be performed for potential symptoms of worsening heart failure or for symptoms of excessive vasodilatation (e.g. renal function, body weight, blood pressure, heart rate and rhythm).
• If bradycardia appears or in case of lengthening of AV conduction, the level of digoxin should first be monitored. Occasionally it may be necessary to reduce the carvedilol dose or temporarily discontinue treatment altogether. Even in these cases, carvedilol dose titration can often be successfully continued.
• Renal function, thrombocytes and glucose should be monitored regularly during dose titration. However, after dose titration the frequency of monitoring can be reduced.
• If carvedilol has been withdrawn for more than two weeks, the therapy should be reinitiated with 3.125 mg twice a day and increased gradually according to the above recommendations.
• Elderly: Elderly patients may be more susceptible to the effects of carvedilol and should be monitored more carefully.

Children and adolescents (< 18 years): Carvedilol is not recommended for the use in children below 18 years of age.

Moderate hepatic dysfunction: Dose adjustment may be required.

Renal insufficiency: Dosage must be determined for each patient individually, but according to pharmacokinetic parameters  ,there is no evidence that dose adjustment of carvedilol in patients with renal impairment is necessary.

Methods of administration: It is recommended that heart failure patients take their carvedilol medication with food to allow the absorption to be slower and the risk of orthostatic hypotension to be reduced.

Contraindications:

• Hypersensitivity to the carvedilol or to any of the excipients of the preparation.
• Heart failure belonging to NYHA Class IV of the heart failure classification with marked fluid retention or overload requiring intravenous inotropic treatment.
• Chronic obstructive pulmonary disease with bronchial obstruction.
• Clinically significant hepatic dysfunction.
• Bronchial asthma.
• AV block, degree II or III (unless a permanent pacemaker is in place).
• Severe bradycardia (<50 bpm).
• Sick sinus syndrome (incl. sino-atrial block).
• Cardiogenic shock.
• Severe hypotension (systolic blood pressure below 85 mmHg).
• Prinzmetal’s angina.
• Untreated phaeochromocytoma.
• Metabolic acidosis.
• Severe peripheral arterial circulatory disturbances.
• Concomitant intravenous treatment with verapamil or diltiazem.

Warnings and precautions:

• In chronic heart failure patients, carvedilol should be administered principally in addition to diuretics, ACE inhibitors, digitalis and/or vasodilators. Initiation of therapy should be under the supervision of a hospital physician. Therapy should only be initiated, if the patient is stabilized on conventional basic therapy for at least 4 weeks. Patients with severe heart failure, salt and volume depletion, elderly or patients with low basic blood pressure should be monitored for approximately 2 hours after the first dose or after dose increase as hypotension may occur. Hypotension due to excessive vasodilatation is initially treated by reducing the dose of the diuretic. If symptoms still persist, the dose of any ACE inhibitor may be reduced. At the start of therapy or during up-titration of Carvedilol worsening of heart failure or fluid retention may occur. In these cases, the dose of diuretic should be increased. However, sometimes it will be necessary to reduce or withdraw Carvedilol medication. The carvedilol dose should not be increased before symptoms due to the worsening of heart failure or hypotension due to vasodilatation are under control.
• The withdrawal of carvedilol should be done gradually.
• Reversible deterioration of renal function has been observed during carvedilol therapy in heart failure patients with low blood pressure (systolic < 100 mm Hg), ischaemic heart disease and generalized atherosclerosis, and/or underlying renal insufficiency. In heart failure patients with these risk factors, renal function should be monitored during dose titration of carvedilol. If significant worsening of renal function occurs, the carvedilol dose must be reduced or therapy must be discontinued.
• Agents with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal’s variant angina. There is no clinical experience with carvedilol in these patients, although the alpha-blocking activity of carvedilol may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal’s variant angina.
• Patients with a chronic obstructive pulmonary disease with a tendency towards bronchospasms who are not treated with oral or inhalation medicine should only be given carvedilol if the expected improvement outweighs the possible risk. Patients should be monitored closely in the initial phase, and titration of carvedilol and carvedilol dose should be reduced in case of bronchospasms.
• Carvedilol may mask symptoms and signs of acute hypoglycaemia. Impaired blood glucose control may occasionally occur in patients with diabetes mellitus and heart failure in connection with the use of carvedilol. Therefore, close monitoring of diabetic patients receiving carvedilol is required by means of regular blood glucose measurements, especially during dose titration, and adjustment of antidiabetic medication as necessary. Blood glucose levels should also be closely monitored after a longer period of fasting. The blood sugar-lowering effect of insulin and oral diabetic medicines may be intensified.
• Carvedilol may mask features (symptoms and signs) of thyrotoxicosis.
• Carvedilol may cause bradycardia. If there is a decrease in pulse rate to less than 55 beats per minute, and symptoms associated with bradycardia occur, the carvedilol dose should be reduced.
• Persons wearing contact lenses should be advised of a possible reduction of the secretion of lacrimal fluid.
• Care should be taken in administrating carvedilol to patients with a history of serious hypersensitivity reactions and in those undergoing desensitization therapy as beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.
• Cautions should be exercised when prescribing beta-blockers to patients with psoriasis since skin reactions may be aggravated.
• Carvedilol should be used with caution in patients with peripheral vascular diseases, as beta-blockers may aggravate symptoms of the disease. The same also applies to those with Raynaud’s syndrome, as there may be exacerbation or aggravation of symptoms.
• Patients, who are known as poor metabolizers of debrisoquine, should be closely monitored during initiation of therapy.
• Since there is limited clinical experience, carvedilol should not be administered in patients with labile or secondary hypertension, orthostatic, acute inflammatory heart disease, hemodynamic relevant obstruction of heart valves or outflow tract, end-stage peripheral arterial disease, concomitant treatment with α1-receptor antagonist or α2-receptor agonist.
• In patients with phaeochromocytoma, an initial treatment with alpha-blockers should be started before using any beta-blocker. Although carvedilol exercises alpha and beta blockade there is not sufficient experience in this disease, therefore caution should be advised in these patients.
• Because of its negative dromotropic action, carvedilol should be given with caution to patients with first-degree heart block.
• Beta-blockers reduce the risk of arrhythmias at anasthesia, however the risk of hypotension may be increased as well. Caution should therefore be observed with the use of certain anaesthetic medicines.
• As with other beta-blockers, carvedilol should not be discontinued abruptly. This applies in particular to patients with ischaemic heart disease. Carvedilol therapy must be discontinued gradually within two weeks, e.g. by reducing the daily dose to half every three days. If necessary, at the same time replacement therapy should be initiated to prevent exacerbation of angina pectoris.
• Carvedilol contains lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, sucrase-isomaltase insufficiency should not take this medicine.
• This medicinal product has minor influence on the ability to drive and use machines.

Pregnancy:

There are no adequate data from the use of carvedilol in pregnant women. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Carvedilol should not be used during pregnancy unless clearly necessary, that is if the potential benefit for the mother outweighs the potential risk for the fetus/neonate .The treatment should be stopped 2-3 days before expected birth. If this is not possible, the newborn has to be monitored for the first 2-3 days of life.

Lactation:

Carvedilol and its metabolites are excreted in breast milk and, therefore, mothers receiving carvedilol should not breast-feed.

Drug Interaction:

Antiarrhythmics: As with other beta-blockers, ECG and blood pressure should be monitored closely when concomitantly administering calcium-channel-blockers of the verapamil and diltiazem type due to the risk of AV conduction disorder or risk of cardiac failure (synergetic effect). Close monitoring should be done in case of co-administration of carvedilol, and amiodarone therapy (oral) or class I antiarrhythmics. Bradycardia, cardiac arrest, and ventricular fibrillation have been reported shortly after initiation of beta-blocker treatment in patients receiving amiodarone. There is a risk of cardiac failure in case of class Ia or Ic antiarrhythmics concomitant intravenous therapy. Intravenous co-administration should be avoided.

Concomitant treatment with reserpine, guanethidine, methyldopa, guanfacine and monoamine oxidase inhibitors (exception MAO-B inhibitors): can lead to additional decrease in heart rate and hypotension, monitoring of vital signs is recommended.

Dihydropyridines: The administration of dihydropyridines and carvedilol should be done under close supervision as heart failure and severe hypotension have been reported.

Nitrates: Increased hypotensive effects.

Cardiac glycosides: Monitoring of plasma digoxin concentrations is recommended when initiating, discontinuing or adjusting treatment with carvedilol. In patients with chronic heart failure treated with digitalis, carvedilol should be given with caution, as digitalis and carvedilol both lengthen the AV conduction time.

Other antihypertensive medicines: Carvedilol may potentiate the effects of other concomitantly administered antihypertensives (e.g. α1-receptor antagonists) and medicines with antihypertensive adverse reactions such as barbiturates, phenothiazines, tricyclic antidepressants, vasodilating agents and alcohol.

Cyclosporin: Due to wide interindividual variability in the dose adjustments 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.

Antidiabetics including insulin: The blood sugar-lowering effect of insulin and oral diabetic medicines may be intensified. Symptoms of hypoglycemia may be masked. In diabetic patients regular monitoring of blood glucose levels is necessary.

Clonidine: In case of withdrawal of both carvedilol and clonidine, carvedilol should be withdrawn several days before the stepwise withdrawal of clonidine.

Inhalational anesthetics: Caution is advised in case of anaesthesia due to synergistic, negative inotrope and hypotensive effect of carvedilol and certain anaesthetics.

NSAIDs, estrogens and corticosteroids: The antihypertensive effect of carvedilol is decreased due to water and sodium retention.

Medicines inducing or inhibiting cytochrome P450 enzymes: Patients receiving medicines that induce (e.g. rifampicin and barbiturates) or inhibit (e.g. cimetidine, ketoconazole, fluoxetine, haloperidol, verapamil, erythromycine) cytochrome P450 enzymes have to be monitored closely during concomitant treatment with carvedilol as serum carvedilol concentrations may be reduced by the first agents and increased by the enzyme inhibitors .Cimetidine should be administered only with caution concomitantly as effects of carvedilol may be increased.

Sympathomimetics with alpha-mimetic and beta-mimetic effects: Risk of hypertension and excessive bradycardia.

Ergotamine: Vasoconstriction increased.

Neuromuscular blocking agents: Increased neuromuscular block.

Undesirable effects:

Very common: Dizziness, headache, Cardiac failure, Hypotension, Asthenia (fatigue).

Common: Bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection, Anaemia, Weight increase, hypercholesterolaemia, impaired blood glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes, Depression, depressed mood, Visual impairment, lacrimation decreased (dry eye), eye irritation, Bradycardia, oedema, hypervolaemia, fluid overload, Orthostatic hypotension, disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Reynaud’s phenomenon), Dyspnoea, pulmonary oedema, asthma in predisposed patients, Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain, Pain in extremities, Renal failure and renal function abnormalities in patients with diffuse vascular disease and/or underlying renal insufficiency, micturition disorders, Pain.

Uncommon: Sleep disorders, confusion, Presyncope, syncope, paraesthesia, Atrioventricular block, angina pectoris, Skin reactions (e.g. allergic exanthema, dermatitis, urticaria, pruritus, psoriatic and lichen planus like skin lesions and increased sweating), alopecia, Erectile dysfunction.

Overdose:

In the event of overdose, there may be severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest.

Treatment: In addition to general supportive treatment, the vital parameters must be monitored and corrected, if necessary, under intensive care conditions.

Carvedilol is highly protein-bound. Therefore, it cannot be eliminated by dialysis.

In cases of severe overdose with symptoms of shock, supportive treatment must be continued for a sufficiently long period.

How supplied:                                                               

1-A pack containing 20 F.C. tablets of Carvilol 3.125.

2-A pack containing 20 F.C. tablets of Carvilol 6.25.

3-A pack containing 20 F.C. tablets of Carvilol 12.5.

4-A pack containing 20 F.C. tablets of Carvilol 25.

5-A pack containing 50 F.C. tablets of Carvilol 3.125.

6-A pack containing 50 F.C. tablets of Carvilol 6.25.

7-A pack containing 50 F.C. tablets of Carvilol 12.5.

8-A pack containing 50 F.C. tablets of Carvilol 25.