Carvedilol Tablets USP 12.5mg Taj Pharma

Name of the medicinal product

Carvedilol Tablets USP 3.125mg Taj Pharma
Carvedilol Tablets USP 6.25mg Taj Pharma
Carvedilol Tablets USP 12.5mg Taj Pharma
Carvedilol Tablets USP 25mg Taj Pharma

Qualitative and quantitative composition

a) Carvedilol Tablets USP 3.125mg Taj Pharma
Each film coated tablet contains:
Carvedilol USP 3.125mg
Excipients: Q.S.

b) Carvedilol Tablets USP 6.25mg Taj Pharma
Each film coated tablet contains:
Carvedilol USP 6.25mg
Excipients: Q.S.

c) Carvedilol Tablets USP 12.5mg Taj Pharma
Each film coated tablet contains:
Carvedilol USP 12.5mg
Excipients: Q.S.

d) Carvedilol Tablets USP 25mg Taj Pharma
Each film coated tablet contains:
Carvedilol USP 25mg
Excipients: Q.S.

Excipient(s) with known effect: Each tablet contains 28.625mg of lactose monohydrate and 0.625mg of sucrose.

For the full list of excipients, see section 6.1.

Pharmaceutical form

Film-coated tablet.
Film-coated tablets white to off-white in colour.

Clinical particulars

Therapeutic indications

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

Posology and method of administration

Oral use.

Essential Hypertension

Carvedilol Taj Pharma may be used for the treatment of hypertension alone or in combination with other antihypertensives, especially thiazide diuretics. Once daily dosing is recommended, however the recommended maximum single dose is 25mg and the recommended maximum daily dose is 50mg.

Adults:

The recommended initial dose is 12.5mg once a day for the first two days. Thereafter, the treatment is continued at the dose 25mg/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 12.5mg 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.

Chronic stable angina pectoris:

A twice-daily regimen is recommended.

Adults

The recommended initial dosage is 12.5mg twice a day for the first two days. Thereafter, the treatment is continued at the dose 25mg 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 100mg a day divided into two doses (twice daily).

Elderly

The recommended initial dose is 12.5mg twice daily for two days. Thereafter, the treatment is continued at the dose 25mg twice daily, which is the recommended maximum daily dose.

Heart Failure:

Carvedilol Taj Pharma 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 (see section 4.3).

The initial dose is 3.125mg 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 6.25mg twice a day, then up to 12.5mg twice a day and finally up to 25mg twice a day. The dosage should be increased to the highest tolerable level.

The recommended maximum dosage is 25mg twice a day for patients with a body weight of less than 85 kg, and 50mg twice a day for patients with a body weight above 85 kg, provided that the heart failure is not severe. A dose increase to 50mg 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). Worsening of heart failure or fluid retention is treated by increasing the dose of diuretic, and the dose of Carvedilol Taj Pharma should not be increased until the patient is stabilized. 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 Taj Pharma dose or temporarily discontinue treatment altogether. Even in these cases, Carvedilol Taj Pharma dose titration can often be successfully continued.

Renal function, thrombocytes and glucose (in case of NIDDM and/or IDDM) should be monitored regularly during dose titration. However, after dose titration the frequency of monitoring can be reduced.

If Carvedilol Taj Pharma has been withdrawn for more than two weeks, the therapy should be reinitiated with 3.125mg twice a day and increased gradually according to the above recommendations.

Renal insufficiency

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

Moderate hepatic dysfunction

Dose adjustment may be required.

Paediatric population (< 18 years)

Carvedilol Taj Pharma is not recommended for the use in children below 18 years of age due to insufficient data on the efficacy and safety of Carvedilol Taj Pharma.

Elderly

Elderly patients may be more susceptible to the effects of Carvedilol Taj Pharma and should be monitored more carefully.

As with other beta-blockers and especially in patients with coronary disease, the withdrawal of Carvedilol Taj Pharma should be done gradually (see section 4.4).

Methods of administration

The tablets should be taken with the adequate supply of fluid. It is recommended that heart failure patients take their Carvedilol Taj Pharma medication with food to allow the absorption to be slower and the risk of orthostatic hypotension to be reduced.

Contraindications

Hypersensitivity to the Carvedilol Taj Pharma or to any of the excipients of Carvedilol Taj Pharma listed in section 6.1.
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 (see section 4.4).
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 (see section 4.5).

Special warnings and precautions for use

Warnings to be considered particularly in heart failure patients

In chronic heart failure patients Carvedilol Taj Pharma 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 Taj Pharma 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 Taj Pharma medication. The Carvedilol Taj Pharma dose should not be increased before symptoms due to the worsening of heart failure or hypotension due to vasodilatation are under control.

Reversible deterioration of renal function has been observed during Carvedilol Taj Pharma 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 Taj Pharma. If significant worsening of renal function occurs, the Carvedilol Taj Pharma dose must be reduced or therapy must be discontinued.

In patients with chronic heart failure treated with digitalis, Carvedilol Taj Pharma should be given with caution, as digitalis and Carvedilol Taj Pharma both lengthen the AV conduction time (see section 4.5).

Other warnings as regards Carvedilol Taj Pharma and beta-blockers in general

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 Taj Pharma in these patients, although the alpha-blocking activity of Carvedilol Taj Pharma may prevent such symptoms. However, caution should be taken in the administration of Carvedilol Taj Pharma 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 Taj Pharma if the expected improvement outweighs the possible risk. Patients should be monitored closely in the initial phase, and titration of Carvedilol Taj Pharma and Carvedilol Taj Pharma dose should be reduced in case of bronchospasms.

Carvedilol Taj Pharma 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 Taj Pharma. Therefore, close monitoring of diabetic patients receiving Carvedilol Taj Pharma is required by means of regular blood glucose measurements, especially during dose titration, and adjustment of antidiabetic medication as necessary (see section 4.5). Blood glucose levels should also be closely monitored after a longer period of fasting.

Carvedilol Taj Pharma may mask features (symptoms and signs) of thyrotoxicosis.

Carvedilol Taj Pharma 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 Taj Pharma dose should be reduced.

When Carvedilol Taj Pharma is used concomitantly with calcium channel blocking agents such as verapamil and diltiazem or with other antiarrhythmics, specifically amiodarone, the patient’s blood pressure and ECG have to be monitored. Intravenous co-administration should be avoided (see section 4.5).

Cimetidine should be administered only with caution concomitantly as effects of Carvedilol Taj Pharma may be increased (see section 4.5).

Persons wearing contact lenses should be advised of a possible reduction of the secretion of lacrimal fluid.

Care should be taken in administrating Carvedilol Taj Pharma to patients with a history of serious hypersensitivity reactions and in those undergoing desensitisation 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 Taj Pharma 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 (see section 5.2).

Since there is limited clinical experience, Carvedilol Taj Pharma should not be administered in patients with labile or secondary hypertension, orthostasis, acute inflammatory heart disease, haemodynamic 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 Taj Pharma 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 Taj Pharma 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. Newer studies suggest however, a benefit of beta-blockers in preventing perioperative cardiac morbidity and reduction of the incidence of cardiovascular complications.

As with other beta-blockers, Carvedilol Taj Pharma should not be discontinued abruptly. This applies in particular to patients with ischaemic heart disease. Carvedilol Taj Pharma 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 Taj Pharma 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.

Interaction with other medicinal products and other forms of interaction

Antiarrhythmics.

Isolated cases of conduction disturbance (rarely compromised haemodynamics) have been reported, if oral Carvedilol Taj Pharma and oral diltiazem verapamil and/or amiodarone are given concomitantly. 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 Taj Pharma, 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.

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 Taj Pharma should be done under close supervision as heart failure and severe hypotension have been reported.

Nitrates.

Increased hypotensive effects.

Cardiac glycosides.

An increase of steady state digoxin levels by approximately 16% and of digitoxin by approximately 13% has been seen in hypertensive patients in connection with the concomitant use of Carvedilol Taj Pharma and digoxin. Monitoring of plasma digoxin concentrations is recommended when initiating, discontinuing or adjusting treatment with Carvedilol Taj Pharma.

Other antihypertensive medicines.

Carvedilol Taj Pharma 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.

Modest increases in mean trough cyclosporine concentrations were observed following the initiation of Carvedilol Taj Pharma treatment in 21 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 with 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 interindividual variability in the dose adjustments required, it is recommended that cyclosporine concentrations be monitored closely after initiation of Carvedilol Taj Pharma 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 hypoglycaemia may be masked. In diabetic patients regular monitoring of blood glucose levels is necessary.

Clonidine.

In case of withdrawal of both Carvedilol Taj Pharma and clonidine, Carvedilol Taj Pharma should be withdrawn several days before the stepwise withdrawal of clonidine.

Inhalational anaesthetics.

Caution is advised in case of anaesthesia due to synergistic, negative inotrope and hypotensive effect of Carvedilol Taj Pharma and certain anaesthetics.

NSAIDs, estrogens and corticosteroids.

The antihypertensive effect of Carvedilol Taj Pharma 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 Taj Pharma as serum Carvedilol Taj Pharma concentrations may be reduced by the first agents and increased by the enzyme inhibitors.

Rifampicin reduced plasma concentrations of Carvedilol Taj Pharma 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 Taj Pharma may be reduced, or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels may be increased. However, based on the relatively small effect of cimetidine on Carvedilol Taj Pharma drug levels, the likelihood of any clinically important interaction is minimal.

Sympathomimetics with alpha-mimetic and beta-mimetic effects.

Risk of hypertension and excessive bradycardia.

Ergotamine.

Vasoconstriction increased.

Neuromuscular blocking agents.

Increased neuromuscular block.

Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Carvedilol Taj Pharma in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Beta-blockers reduce placental perfusion which may result in intrauterine fetal death and immature and premature deliveries. In addition, adverse reactions (especially hypoglycaemia, hypotension, bradycardia, respiratory depression and hypothermia) may occur in the fetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Carvedilol Taj Pharma 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 new-born has to be monitored for the first 2-3 days of life.

BreastfeedingCarvedilol Taj Pharma is lipophilic and according to results from studies with lactating animals, Carvedilol Taj Pharma and its metabolites are excreted in breast milk and, therefore, mothers receiving Carvedilol Taj Pharma should not breast-feed.

Effects on ability to drive and use machines

This medicinal product has minor influence on the ability to drive and use machines. Some individuals may have reduced alertness especially on initiation and adjustment of medication.

Undesirable effects

(a) Summary of the safety profile

The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia.

(b) Tabulated list of adverse reactions

The risk of most adverse reactions associated with Carvedilol Taj Pharma is similar across all indications.

Exceptions are described in subsection (c).

Frequency categories are as follows:

Very common ≥ 1/10

Common ≥ 1/100 and < 1/10

Uncommon ≥ 1/1,000 and < 1/100

Rare ≥ 1/10,000 and < 1/1,000

Very rare < 1/10,000

Infections and infestations

Common: Bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection

Blood and lymphatic system disorders

Common: Anaemia

Rare: Thrombocytopaenia

Very rare: Leukopenia

Immune system disorders

Very rare: Hypersensitivity (allergic reaction)

Metabolism and nutrition disorders

Common: Weight increase, hypercholesterolaemia, impaired blood glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes

Psychiatric disorders

Common: Depression, depressed mood

Uncommon: Sleep disorders, confusion

Nervous system disorders

Very common: Dizziness, headache

Uncommon: Presyncope, syncope, paraesthesia

Eye disorders

Common: Visual impairment, lacrimation decreased (dry eye), eye irritation

Cardiac disorders

Very common: Cardiac failure

Common: Bradycardia, oedema, hypervolaemia, fluid overload

Uncommon: Atrioventricular block, angina pectoris

Vascular disorders

Very common: Hypotension

Common: Orthostatic hypotension, disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Reynaud’s phenomenon)

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients

Rare: Nasal congestion

Gastrointestinal disorders

Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain

Rare: dry mouth

Hepatobiliary disorders

Very rare: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyltransferase (GGT) increased

Skin and subcutaneous tissue disorders

Uncommon: Skin reactions (e.g. allergic exanthema, dermatitis, urticaria, pruritus, psoriatic and lichen planus like skin lesions and increased sweating), alopecia

Very rare: Severe cutaneous adverse reactions (e.g. Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis)

Musculoskeletal and connective tissue disorders

Common: Pain in extremities

Renal and urinary disorders

Common: Renal failure and renal function abnormalities in patients with diffuse vascular disease and/or underlying renal insufficiency, micturition disorders

Very rare: Urinary incontinence in women

Reproductive system and breast disorders

Uncommon: Erectile dysfunction

General disorders and administration site conditions

Very common: Asthenia (fatigue)

Common: Pain

(c) Description of selected adverse reactions

Dizziness, syncope, headache and asthenia are usually mild and are more likely to occur at the beginning of treatment.

In patients with congestive heart failure, worsening cardiac failure and fluid retention may occur during up-titration of Carvedilol Taj Pharma dose (see section 4.4).

Cardiac failure is a commonly reported adverse event in both placebo and Carvedilol Taj Pharma-treated patients (14.5% and 15.4% respectively, in patients with left ventricular dysfunction following acute myocardial infarction).

Reversible deterioration of renal function has been observed with Carvedilol Taj Pharma therapy in chronic heart failure patients with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or underlying renal insufficiency (see section 4.4).

As a class, beta-adrenergic receptor blockers may cause latent diabetes to become manifest, manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.

Carvedilol Taj Pharma may cause urinary incontinence in women which resolves upon discontinuation of the medication.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Overdose

Symptoms and signs

In the event of overdose, 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

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

Atropine can be used for excessive bradycardia, while to support ventricular function intravenous glucagon, or sympathomimetics (dobutamine, isoprenaline) are recommended. If positive inotropic effect is required, phosphodiesterase inhibitors (PDE) should be considered. If peripheral vasodilation dominates the intoxication profile then norfenephrine or noradrenaline should be administered with continuous monitoring of the circulation. In the case of drug-resistant bradycardia, pacemaker therapy should be initiated.

For bronchospasm, β-sympathomimetics (as aerosol or intravenous) should be given, or aminophylline may be administered intravenously by slow injection or infusion. In the event of seizures, slow intravenous injection of diazepam or clonazepam is recommended.

Carvedilol Taj Pharma 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, i.e. until the patient’s condition has stabilised, as a prolongation of elimination half-life and redistribution of Carvedilol Taj Pharma from deeper compartments are to be expected.

Pharmacological properties
- Pharmacodynamic properties

Pharmacotherapeutic group: Alpha and beta blocking agents..

Carvedilol Taj Pharma 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. Plasma renin activity is reduced and fluid retention is rare.

Carvedilol Taj Pharma has no intrinsic sympathomimetic activity (ISA). Like propranolol, it has membrane stabilising properties.

Carvedilol Taj Pharma 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 Taj Pharma 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 Taj Pharma increases the plasma norepinephrine concentration.

In prolonged treatment of patients with angina, Carvedilol Taj Pharma has been seen to have an anti-ischaemic effect and to alleviate pain. Haemodynamic studies demonstrated that Carvedilol Taj Pharma reduces ventricular pre- and after-load. In patients with left ventricular dysfunction or congestive heart failure, Carvedilol Taj Pharma has a favourable effect on haemodynamics and left ventricular ejection fraction and dimensions.

Carvedilol Taj Pharma 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.

Pharmacokinetic properties

Absorption

Carvedilol Taj Pharma is rapidly absorbed after oral administration. In healthy subjects, maximum serum concentration is achieved approximately 1 hour after administration. The absolute bioavailability of Carvedilol Taj Pharma in humans is approximately 25%.

There is a linear relationship between dose and serum concentrations of Carvedilol Taj Pharma. Food intake did not affect the bioavailability or the maximum serum concentration, although the time needed to reach maximum serum concentration is prolonged.

Distribution

Carvedilol Taj Pharma 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.

Biotransformation

In humans and in animal species studied, Carvedilol Taj Pharma 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 Taj Pharma 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 Taj Pharma. The three active metabolites have a weak vasodilating activity, compared with Carvedilol Taj Pharma. 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 Taj Pharma.

Elimination

The average half-life of elimination of Carvedilol Taj Pharma 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.

Pharmacokinetics in Special Populations

Patients with renal impairment

In some of the hypertensive patients with moderate to severe renal impairment (creatinine clearance < 30 ml/min), an increase in plasma Carvedilol Taj Pharma 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 Taj Pharma 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 Taj Pharma dosage (see section 4.2).

Patients with liver failure

In patients with liver cirrhosis, the systemic availability of Carvedilol Taj Pharma is increased 80% due to reduced first pass effect. Therefore, Carvedilol Taj Pharma is contraindicated in patients with clinically manifest hepatic impairment (see section 4.3 Contraindications).

Use in elderly

Age had a statistically significant effect on pharmacokinetic parameters of Carvedilol Taj Pharma 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.

Use in pediatrics

The available information on pharmacokinetics in subjects younger than 18 years is limited.

Diabetic patients

In hypertensive patients with type 2 diabetes was not observed effect of Carvedilol Taj Pharma 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 Taj Pharma had no statistically significant influence on the glucose tolerance test. In nondiabetic hypertensive patients with altered insulin sensitivity (Syndrome X), Carvedilol Taj Pharma increased insulin sensitivity. The same results were observed in hypertensive patients with type 2 diabetes.

Heart failure

In a study in 24 patients with heart failure, the clearance of R-and S-Carvedilol Taj Pharma was significantly lower than previously estimated in healthy volunteers. These results suggested that the pharmacokinetics of R-and S-Carvedilol Taj Pharma is significantly altered by heart failure.

Preclinical safety data

Carvedilol Taj Pharma demonstrated no mutagenic or carcinogenic potential.

High doses of Carvedilol Taj Pharma 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.

Pharmaceutical particulars
- List of excipients

Tablet core
Lactose monohydrate, Silica colloidal anhydrous, Crospovidone (Type A), Crospovidone (Type B), Povidone 30, Sucrose, Magnesium stearate

Tablet coating
Macrogol 400, Polysorbate 80, Titanium dioxide, Hypromellose

Incompatibilities

Not applicable

Shelf life

2 years

Special precautions for storage

Do not store above 30 ° C.

Nature and contents of container

PVC / PE / PVDC – Aluminum:
Package sizes: 5, 7, 10, 14, 15, 20, 28, 30, 40, 50, 56, 60, 90, 98, 100, 120, 150, 200, 250, 300, 400 and 500 film-coated tablets.
Package sizes: 30, 50, 60, 100, 250 and 500 film-coated tablets

Not all pack sizes may be marketed.

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)Monday through Saturday 9:00 a.m. to 7:00 p.m. EST E-mail: tajgroup@tajpharma.com

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4

What is in this leaflet:

What Carvedilol Taj Pharma is and what it is used for
What you need to know before you take Carvedilol Taj Pharma
How to take Carvedilol Taj Pharma
Possible side effects
How to store Carvedilol Taj Pharma
Contents of the pack and other information

1. What Carvedilol Taj Pharma is and what it is used for

Carvedilol Taj Pharma belongs to a group of medicines called beta-blockers that work by relaxing and widening the blood vessels. This makes it easier for your heart to pump blood around the body and reduces blood pressure and strain on your heart.

Carvedilol Taj Pharma is used: –

for the treatment of high blood pressure (hypertension),
for the treatment of chest pain that occurs when the arteries that supply your heart with blood carrying oxygen are narrowed which results in less oxygen reaching your heart muscles (angina),
for the treatment of weakening of the heart muscle (heart failure), in combination with other medicines.

What you need to know before you take Carvedilol Taj Pharma

DO NOT TAKE Carvedilol Taj Pharma:

if you are allergic to Carvedilol Taj Pharma or any of the other ingredients of this medicine (listed in section 6).
if you have a history of wheezing due to asthma or other lung diseases,
if you have been told you have very severe heart failure and you have fluid retention (swelling) which is being treated with injections of medicines into your veins (intravenously),
if you have liver disease,
if you have been told that you have a very slow heartbeat,
if you have very low blood pressure,
if you have been told you have a condition called Prinzmetal’s angina,
if you have phaeochromocytoma (a tumour of the adrenal gland causing high blood pressure) which is not being treated,
if you are suffering from serious disturbances in the body’s acid-base balance (metabolic acidosis),
if you have very poor blood circulation in the hands and feet resulting in coldness and pain in them,
if you have a particular conduction defect of the heart (called an AV heart block Grade II or III (unless a pacemaker is fitted) or a SA block),
if you are currently being treated with injections of verapamil or diltiazem (used in the treatment of high blood pressure or heart problems),

If any of these apply to you, do not take Carvedilol Taj Pharma.

Warnings and precautions

Talk to your doctor or pharmacist before taking Carvedilol Taj Pharma:

have been told you suffer from any other heart problems,
have or have ever had any problems with your liver, kidneys or thyroid,
have diabetes. Carvedilol Taj Pharma may hide your usual symptoms of low blood sugar,
have a skin condition known as psoriasis,
have poor circulation affecting hands, feet or lower legs, or Raynaud’s phenomenon,
have or have ever had a serious allergic reaction or you are undergoing allergic desensitization therapy for any type of severe allergy,
wear contact lenses because Carvedilol Taj Pharma may cause the eyes to be drier than normal.

Other medicines and Carvedilol Taj Pharma

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

The administration of Carvedilol Taj Pharma:

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription or herbal medicines.

Take particular care and tell your doctor or pharmacist, if you are taking any of the following medicines:

medicines used to treat an irregular heartbeat (e.g. diltiazem, verapamil or amiodarone),
nitrate medicines for angina (e.g. isosorbide mononitrate or glyceryl trinitrate),
medicines used to treat heart failure (e.g. Digoxin),
any other medicine used to treat high blood pressure (e.g. doxazosin, reserpine, amlodipine or indoramin),
medicines used to treat depression or other mental health conditions (e.g. fluoxetine, tricyclic antidepressants, barbiturates,
phenothiazines, haloperidol or monoamine oxide inhibitors (MAOIs),
medicines used to prevent your body rejecting organs after transplant operations (e.g. ciclosporin),
medicines to reduce blood sugar such as oral antidiabetic medicines or insulin,
medicines used to reduce blood pressure or to treat migraine (e.g. clonidine or ergotamine),
certain painkilling agents such as non-steroidal anti-inflammatory medicines (NSAIDs) (e.g. ibuprofen or diclofenac),
medicines used for hormone replacement therapy (e.g. estrogens),
corticosteroids used to suppress inflammatory or allergic reactions (e.g. prednisolone),
medicines used to treat bacterial infections (e.g. rifampicin or erythromycin),
medicines used to treat stomach ulcers, heartburn and acid reflux (e.g. cimetidine),
medicines used to treat fungal infections (e.g.. ketoconazole),
medicines sometimes used in decongestant cough and cold remedies (e.g. ephedrine or pseudoephedrine)

If you need to have an anaesthetic for an operation, tell your hospital doctor you are taking Carvedilol Taj Pharma.

Carvedilol Taj Pharma with food, drink and alcohol

You should take Carvedilol Taj Pharma with water.

If you are taking Carvedilol Taj Pharma to treat heart failure, you should take this medicine with water at your mealtime (see section 3 ‘How to take Carvedilol Taj Pharma)

Do not drink alcohol whilst taking

Carvedilol Taj Pharma as it might worsen the effects of alcohol.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, do not take this medicine until you have talked to your doctor. Consult your doctor immediately if you become pregnant while taking this medicine.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

You may experience dizziness or tiredness whilst taking Carvedilol Taj Pharma. This is more likely to occur when you first begin treatment, or when the dose is increased. If this occurs, you should not drive or operate machinery. You should avoid drinking alcohol, as it may make these symptoms worse. If you are concerned or want more information, you should talk to your doctor.

Carvedilol Taj Pharma contains lactose and sucrose (types of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

How to take Carvedilol Taj Pharma

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Carvedilol Taj Pharma should be swallowed with a drink of water.

High blood pressure

Adults: The usual starting dose is

12.5mg once a day for the first two days. After this, the dose is increased to 25mg once a day. If necessary, your doctor may gradually increase the dose further at intervals of two weeks or more.

The maximum recommended daily dose is 50mg (the maximum recommended single dose is 25mg).

Elderly: Your doctor will usually start you on 12.5mg once a day and continue with this dose for the length of your treatment. If necessary, your doctor may increase your dose gradually at intervals of two weeks or more.

Angina

Adults: The usual starting dose is

12.5mg twice a day for the first two days. After this, the dose is increased to 25mg twice a day. If necessary, your doctor may gradually increase the dose further at intervals of two weeks or more to a maximum of 100mg a day in two doses.

Elderly: The recommended starting dose is 12.5mg twice a day for two days.

After this, the dose may be increased to 25mg twice a day, which is the recommended maximum daily dose.

Heart failure

Adults and elderly: For the treatment of stable heart failure, the tablets should be taken twice a day, in the morning and in the evening, and should be taken with food in order to reduce the risk of side effects.

The starting dose is 3.125mg twice a day for two weeks. Your doctor will then gradually increase the strength of tablets you take at intervals of two weeks or more until you receive the dose that suits you best.

If you weigh less than 85 kg, the maximum recommended dose of Carvedilol Taj Pharma is 25mg twice a day, if you weigh more than 85 kg, your doctor may increase your dose to 50mg twice a day.

For the treatment of heart failure, it is recommended that your treatment with Carvedilol Taj Pharma is started and carefully monitored by a hospital specialist.

If you have stopped taking Carvedilol Taj Pharma for more than two weeks, you will need to return to the starting dose and increase the dose gradually again.

Sometimes, your heart failure may worsen while taking Carvedilol Taj Pharma, particularly at the start of your treatment.

This may result in increased symptoms (e.g. tiredness, shortness of breath) and signs of fluid retention (e.g. weight gain and swelling of the legs).

If your symptoms or condition worsen whilst taking Carvedilol Taj Pharma you should tell your doctor, as he or she may need to change the dose of your other medications or of Carvedilol Taj Pharma.

While taking Carvedilol Taj Pharma, make sure that you continue with your other treatments for heart failure as advised by your doctor.

Patients with liver problems

Depending on your condition, your doctor may reduce your dose compared to those recommended above.

Children and adolescents (under 18 years old)

Carvedilol Taj Pharma are not recommended in this age group.

If you take more Carvedilol Taj Pharma than you should

If you accidentally take too many tablets, contact your doctor immediately or go to the nearest hospital casualty department. You may feel dizzy, sick, faint, breathless/wheezy, very drowsy, or experience convulsions.

If you forget to take Carvedilol Taj Pharma

If you forget to take a dose, do not worry. Take another as soon as you remember, provided it is not nearly time for your next dose. Take your next tablet at the normal time, but do not take a double dose to make up for a forgotten tablet.

If you stop taking Carvedilol Taj Pharma

Do not suddenly stop taking Carvedilol Taj Pharma before you have spoken to your doctor about it. You may have side effects if you suddenly stop the tablets. Your doctor will tell you how to reduce the dosage gradually and then stop this medicine. If you are also taking a medicine called clonidine, never stop either treatment unless told to by your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The frequency of possible side effects is shown in the table below:

The majority of side effects are dose-related and disappear when the dose is reduced or the treatment discontinued. Some side effects can occur at the beginning of treatment and resolve spontaneously as the treatment continues.

Very common: may affect more than 1 in 10 people

Dizziness
Headache
Tiredness
Low blood pressure
Heart failure

Common: may affect up to 1 in 10 people

Bronchitis, pneumonia, upper respiratory tract infection
Infections of the urinary tract
Low numbers of red blood cells
Increase in weight
Elevated cholesterol levels
Loss of control of blood sugar in people with diabetes
Depression, depressed mood
Visual disturbance
Reduced lacrimation, eye irritation
Slow heart rate
Oedema (swelling of the body or parts of the body), fluid overload, increased volume of blood in the body
Dizziness when standing up quickly
Problems with blood circulation (signs include cold hands and feet), hardening of the arteries (atherosclerosis) worsening of symptoms in patients with Raynaud’s disease (fingers or toes turn first bluish, then whitish, and then reddishb together with pain) or claudication (pain in the legs which worsens when walking)
Asthma and breathing problems
Fluid accumulation in the lungs
Diarrhoea
Malaise, vomiting, stomach pains, indigestion
Pains (e.g. in the arms and legs)
Acute renal insufficiency and disturbances in renal function in patients with hardening of the arteries and/or impaired renal function
Difficulty in passing urine

Uncommon: may affect up to 1 in 100 people

Sleep disturbance
Confusion
Fainting
Abnormal sensation
Disturbances in the heart’s conduction system, angina pectoris (including chest pain)
Certain skin reactions (e.g. allergic dermatitis, hives, itching and skin inflammation, increased sweating, psoriatic or lichen planus like skin lesions)
Hair loss
Impotence

Rare: may affect up to 1 in 1,000 people

Lowered blood platelet count (thrombocytopenia)
Mouth dryness (dryness of the mouth)
Stuffy nose

Very rare: may affect up to 1 in 10,000 people

Low numbers of white blood cells
Allergic reactions
Changes in the liver function test
Involuntary leakage of urine in women (urinary incontinence).
skin rash, which may blister, and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge – erythema multiforme)
a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals
(Stevens-Johnson syndrome)
a more severe form, causing extensive peeling of the skin (more than 30% of the body surface – toxic epidermal necrolysis)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

How to store Carvedilol Taj Pharma

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of that month.
Do not store above 30º C.

Do not throw awat any medicines via wastewater or household waste.
Ask your pharmacist how to throw away medicines you no longer use.
These measures will help protect the environment.

Contents of the pack and other information

What Carvedilol Taj Pharma contains

The active substance is Carvedilol Taj Pharma. Each tablet contains 3.125mg, 6.25mg, 12.5mg or 25mg Carvedilol Taj Pharma.
The other ingredients are: lactose monohydrate, silica colloidal anhydrous, crospovidone (Type A), crospovidone (Type B), povidone 30, sucrose, magnesium stearate

Tablet coating: macrogol 400, polysorbate 80, titanium Dioxide, hypromellose

What Carvedilol Taj Pharma looks like and contents of the pack

Film-coated tablet
Carvedilol Taj Pharma 3.125mg,6.25mg, 12.5mg and 25mg film-coated tablets
Each Film-coated tablets white to off-white in colour Blister:
Package sizes: 5, 10, 15, 30, 40, 50, 56, 60, 90, 98, 100, 120, 150, 200, 250, 300, 400 and 500 filmcoated tablets.
Package sizes: 30, 50, 60, 100, 250 and 500 film-coated tablets

It is possible that not all presentations are marketed.

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Carvedilol Tablets USP 12.5mg Taj Pharma