INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
CARLOC 12.5 (Tablets)
CARLOC 25 (Tablets)

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

CARLOC 12.5 (Tablets)
CARLOC 25 (Tablets)

COMPOSITION:
CARLOC 12.5: Each tablet contains carvedilol 12.5 mg.
CARLOC 25: Each tablet contains carvedilol 25.0 mg.

PHARMACOLOGICAL CLASSIFICATION:
A 7.1.3 Other hypotensives.

PHARMACOLOGICAL ACTION:
Pharmacodynamics: Congestive Heart Failure (CHF):
Although the benefits of carvedilol in congestive heart failure (CHF) have been proven in numerous studies, the basis for these effects is not established.
A US multicentre program, comprising four concurrent multicentre, double-blind, placebo-controlled studies, initially enrolled 1197 patients with stable symptomatic CHF (NYHA class II-IV), who were then challenged with a low dose of carvedilol (3,125 mg or 6,25 mg twice daily) for 2 to 4 weeks to determine tolerability. Subsequently 1094 of these patients were randomised to double-blind treatment with either carvedilol (n=696) or placebo. These patients were assigned to one of four treatment protocols on the basis of their exercise capacity. The objective was to evaluate total mortality or hospitalisation for cardiovascular reasons. The average duration of therapy on carvedilol was 6.5 months, extending to 15 months. All patients in the study had symptomatic CHF for at least 3 months and ejection fractions <35%, despite 2 months treatment with diuretics and an angiotensin -converting enzyme (ACE) inhibitor (if tolerated), with or without digoxin, hydralazine or nitrates. The cause of the CHF was mostly ischemic left ventricular dysfunction or non-ischemic cardiomyopathy. Exclusion criteria included a major cardiovascular event or a major surgical procedure within 3 months of the study, uncorrected, primary valvular disease, active myocarditis, severe arrhythmias, clinically significant hepatic or renal disease and certain medications.
The overall mortality rate was 7.8% in the placebo group and 3.2% in the carvedilol group, an absolute risk reduction of 4.6% or a relative risk reduction of 65% (95% Cl, 39-80%, p <0.001). In addition, carvedilol therapy led to a relative risk reduction of 36% (95% Cl, 14-53%, p=0.004) in cardiovascular hospitalisations (13% incidence in the carvedilol group versus 21% in the placebo group). Furthermore, there was also a reduction in the risk of death from progressive heart failure, as well as a reduction in the risk of sudden death. Improvement in the patients' well-being in the carvedilol group was indicated by a change in the CHF NYHA class from baseline to endpoint. The overall between-group difference in distributions was significant (p<0.001). This was also indicated by patient and physician global assessments, where patients rated their condition as improved in 78% of the carvedilol group and 63% in the placebo group (p values from 0.001 to 0.032 over 4 studies). However, exercise tolerance was not significantly improved. Worsening heart failure during treatment was less frequent in the carvedilol group than in the placebo group.
A multicentre study, performed in Australia and New Zealand, enrolled 443 patients with stable symptomatic CHF (NYHA class I - III) to determine tolerability of a low dose of carvedilol (3.125 mgor 6.25 mg twice daily) for 2 to 4 weeks. 415 of these patients were then randomized to continued treatment with carvedilol, up to 25 mg twice daily (n=207), or matching placebo (n=208). The symptomatic CHF was due to ischemic left ventricular dysfunction with an ejection fraction <45%. Exclusion criteria included current NYHA class IV CHF, severe arrhythmias, coronary event or procedure within 4 weeks prior to study, significant valvular disease, certain medications, COPD, and significant hepatic or renal impairment.The average duration of therapy on carvedilol was 16.1 months.
The overall mortality rate was 13.9% in the placebo group and 10.1% in the carvedilol group, an absolute risk reduction of 3.8%, corresponding to a non-statistically significant relative risk reduction of 29% (95% Cl, 24-59%, p = 0.231). Carvedilol therapy also led to a relative risk reduction of 28% (95% Cl, 1-48%, p = 0.044) in cardiovascular hospitalisations (31% versus 40% in the carvedilol and placebo groups, respectively). Patient well-being, according to the NYHA class or Specific Activity Scale rating, as well as exercise tolerance, were no different between the 2 groups.
Pharmacodynamics: Hypertension:
Carvedilol is an effective antihypertensive agent due to its vasodilating (alpha1-adrenoreceptor blocker) and non-selective beta-blocking properties in the same dose range.
Studies have shown carvedilol to be a competitive non-selective antagonist of both beta1- and beta2-adreno-receptors. This leads to reduction in cardiac output and reduction of exercise-induced and beta2-tachycardia. The beta-blockade also suppresses the renin-angiotensin-aldosterone system. Carvedilol has no intrinsic sympathomimetic activity.
Carvedilol causes vasodilatation primarily due to its selective blockade of alpha1-adrenoreceptors. This leads to a reduction in peripheral vascular resistance. The alpha-blockade also attenuates the pressor effects of phenylephrine.
Clinical studies with carvedilol have shown that the combination of beta-blockade and vasodilation (alpha-blockade) results in a number of desirable hemodynamic and metabolic effects, including the following:

•	When compared to conventional beta-blocking agents, which lack additional vasodilating activity, carvedilol causes a smaller reduction in the resting heart rate. Myocardial function is therefore maintained, as well as peripheral blood flow.
•	Carvedilol has little or no effect on serum electrolytes, cholesterol, triglycerides, high density lipoproteins or low density lipoproteins, and although the plasma renin activity is reduced significantly, renal function is not affected.

Pharmacokinetics:
Carvedilol is absorbed from the gastro-intestinal tract and extensively metabolized in the liver, primarily by aromatic ring oxidation and glucuronidation. Absolute bio-availability is about 25% due to the considerable first-pass metabolism. Peak plasma concentration occurs approximately 1 hour after administration. Protein binding, especially to albumin, is more than 98%. The absorption rate of carvedilol is slowed by food, but the bio-availability appears not to be affected (taking CARLOC with food could therefore minimize the risk of orthostatic hypotension). The elimination half-life is 6-10 hours and excretion is mainly in the bile, with a small part (about 15%) excreted via the kidneys.
The plasma level of carvedilol is an average of about 50% higher in the elderly, compared with younger patients. The plasma levels of carvedilol are 5 times higher inpatients suffering from cirrhosis of the liver, than in healthy subjects. Although the metabolites of carvedilol are excreted mainly in the bile, the role of the active metabolites excreted by the kidneys (about 15%) cannot be totally ignored when renal impairment exists.

INDICATIONS:

-	Treatment of mild to moderate essential hypertension.
-	Treatment of mild to moderate stable symptomatic heart failure of ischemic or cardiomyopathic origin often in conjunction with standard therapy. Carvedilol has previously been used in patients unable to tolerate an ACE inhibitor and also in those not receiving digitalis.

CONTRA-INDICATIONS:
Hypersensitivity to carvedilol.
Carvedilol should not be prescribed to patients suffering from bronchospasm or asthma, or patients with a history of obstructive airways disease, bronchitis and chronic respiratory disease. Carvedilol is contraindicated in the following conditions: 2nd and 3rd degree atrioventricular block, severe bradycardia (<50/minute), New York Heart Association (NYHA) Class IV decompensated heart failure requiring intravenous inotropic support, cardiogenic shock, sick sinus syndrome (including sino-atrial block), hepatic impairment, metabolic acidosis, peripheral vascular disease, Raynaud's phenomenon and severe hypotension (systolic BP <85 mmHg). Carvedilol should not be prescribed to patients suffering from allergic conditions involving the airways e.g. asthma, allergic rhinitis or glottis oedema.
Carvedilol should not be used during pregnancy and lactation. Administration to pregnant mothers shortly before giving birth, or duringlabour, may result in the newborn infant being born hypotonic, collapsed and hypoglycaemic.
Safety and efficacy in children have not been established.

WARNINGS:
Patients with pheochromocytoma should never receive carvedilol without receiving alpha-adrenoreceptor blocking therapy beforehand or concomitantly. It is important to make sure that adequate clinical control has been achieved inpatients with CHF before carvedilol therapy is initiated, and then with great caution.

DOSAGE AND DIRECTIONS FOR USE:
Essential hypertension:
ADULTS:
Initial dose: 6.25 mg twice daily, for 1 to 2 weeks
Maintenance dose: 12.5 mg twice daily
or
Initial dose: 12.5 mg once daily, for two days
Maintenance dose: 25 mg once daily.
At doses higher than 25 mg the incidence of side-effects increases significantly with only a marginal increase in efficacy.

ELDERLY:
Usual dose: 12.5 mg once daily
If necessary the dosage may be increased, as tolerated, at intervals of at least 2 weeks, to 25 mg once daily or in divided doses.

Heart failure (in conjunction with standard therapy):
To reduce the incidence of orthostatic effects, carvedilol should be taken with food to slow the rate of absorption. The overall bio-availability of carvedilol is not affected by food.
It is advised that the dosage be individualised and that the patient be closely monitored by a medical practitioner experienced in the management of heart failure, during dose titration.        .
The dosing of digitalis, diuretics and/or angiotensin-converting enzyme (ACE) inhibitors, should be stabilised in those patients on these agents, before carvedilol is initiated.
ADULTS:
Initial dose: 3.125 mg twice daily for at least two weeks.
Increase to: 6.25 mg twice daily for two weeks.
Increase to: 12.5 mg twice daily for two weeks.
Maintenance dose: 25 mg twice daily for patients weighing <85 kg (maximum dose).
Increase to: 50 mg twice daily for patients weighing >85 kg (maximum dose).
An interval of at least two weeks should be allowed after each dose increase. The dose should be increased to the highest dose tolerated by the patient. Before the dosage is increased, the patient should be evaluated for symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure and fluid retention should be treated with higher doses of diuretics. It may however be necessary to reduce the carvedilol dosage or to discontinue carvedilol therapy temporarily in some cases.
Should treatment be discontinued for two weeks or more, it is advised that therapy be reinstated at 3.125 mg twice daily for two weeks and the dosage then increased in line with the abovementioned dosage instructions. Symptoms of vasodilation (headache, dizziness, postural hypotension) may initially be managed by decreasing the dose of the diuretics. Should the symptoms persist, however, the dose of the ACE inhibitor (if applicable) may be reduced, followed by a reduction in the dose of carvedilol, if still required. All symptoms of vasodilation or worsening heart failure must be stabilised before the dose of carvedilol is increased again, in line with the recommended dosage instructions.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS.
Side-effects:
The following side-effects may occur:
Cardiovascular:: Postural hypotension and bradycardia can occur. Exacerbation of peripheral vascular disease, development of Raynaud's phenomenon (due to unopposed arteriolar alpha-sympathetic activation), and even peripheral gangrene may be precipitated.
Congestive cardiac failure can be precipitated or worsened, especially during dose titration. Heart block may be precipitated in patients with underlying cardiac disorders. Chest pain, generalized oedema and syncope have also been reported.
Respiratory: Bronchoconstriction, wheeze and dyspnoea may occur in patients with asthma, bronchitis and other chronic pulmonary diseases.
Gastro-intestinal and hepatobiliary: Diarrhoea, nausea, vomiting, constipation, abdominal cramps and hepatic injury (elevated transaminases) have been reported.
General: Vague fatigue and malaise, which is usually mild and occurs particularly after initiation of therapy. Stuffy nose, fever and weight gain occurs rarely.
Urogenital: Sexual impotence, reduced libido, hematuria, urine retention and deterioration of renal function in patients with CHF.
Metabolic: Hypoglycemia has been reported rarely.
Musculoskeletal: Muscle weakness, muscle cramps, myopathies and cold extremities. Neuropsychiatric: This may range from vague fatigue and malaise, insomnia, vivid dreams and nightmares, to overt psychosis. Other CNS effects include headache, dizziness, depression, hallucinations and confusion. Paresthesia (including tingling of the scalp) and peripheral neuropathy have also been reported.
Haematological: Non-thrombocytopenic purpura, thrombocytopenia, agranulocytosis, transient eosinophilia and leucopenia.
Dermatological: Allergic skin reactions, reversible alopecia, stomatitis and angioedema. Psoriasis may be aggravated or induced by carvedilol.
Special senses: Decreased lacrimation, blurred vision, ocular pain and transient hearing loss have been reported.
Special precautions:
Carvedilol should be given to patients with congestive heart failure only after adequate clinical control has been achieved, and only then with great caution especially if the heart failure is controlled with digitalis, diuretics and/or ACE inhibitors (both digitalis and carvedilol slow AV conduction).
Before the dosage is increased, the patient should be evaluated for symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure and fluid retention should be treated with increased doses of diuretics. It may be necessary to lower the carvedilol dosage or to discontinue carvedilol therapy temporarily in some cases. In these cases titration of carvedilol can resume once clinical stability has been achieved.
All symptoms of vasodilation or worsening heart failure must be stabilised before the dose of carvedilol is increased in line with the recommended dose instructions. (see "Dosage and directions for use").
It is of the greatest importance that the anaesthetist be informed that a beta-blocker is being taken by the patient, prior to anaesthesia. Carvedilol therapy should be discontinued 48 hours prior to anaesthesia. If this is not possible, an agent such as atropine may be administered to counter increases in vagal tone.
In the peri-operative period it is generally unwise to reduce the dosage, as there may be danger of aggravation of angina pectoris or of hypertension. A patient's normal tachycardiac response to hypovolaemia or blood loss may be obscured during and after surgery. Particular caution should be taken in this regard.
Safety during long-term administration has not been demonstrated. Adverse reactions are more common in patients with renal decompensation. A dose reduction is necessary in elderly patients and in some patients suffering from renal dysfunction.
Abrupt discontinuation of therapy may cause exacerbation of angina pectoris in patients suffering from ischemic heart disease. Discontinuation of therapy should be gradual (over a period of 1 to 2 weeks) and patients should be advised to limit the extent of their physical activity during the period that the medicine is being tapered.
Patients with pheochromocytoma should receive alpha-adrenoreceptor blocking therapy beforehand or concomitantly.
There is no clinical experience in the use of carvedilol in patients suffering from Prinzmetal's variant angina. Caution is advised as carvedilol may provoke chest pain in patients suspected of suffering from this disease.
Carvedilol may cause bradycardia. A dose reduction is advised should the pulse rate drop to <55 beats/ minute.
Early signs of acute hypoglycaemia may be masked or attenuated by the administration of carvedilol to diabetics. Caution is advised when carvedilol is prescribed to diabetic patients. A dose reduction of anti-diabetic medication or insulin, may be necessary in patients with CHF and diabetes, as carvedilol can cause deterioration of glucose control.
The symptoms of hyperthyroidism may be masked by carvedilol.
When dizziness or related symptoms are experienced, the patient should be advised not to drive or operate machinery
Wearers of contact lenses should be informed that there maybe a reduction in lacrimation.
Psoriasis may be aggravated.
Patients with a history of anaphylaxis to an antigen may be more reactive to repeated challenge with the antigen while taking carvedilol.
The following CHF patients on carvedilol maybe at risk of reversible deterioration of renal function: hypotensive patients (systolic BP <100mmHg), ischemic heart disease, diffuse vascular disease and/or underlying renal impairment. CHF patients with the above risk factors should have their renal function monitored during the upward titration of carvedilol, which should be discontinued or reduced when the renal function deteriorates.
Caution should be used when carvedilol is initiated or titrated upwards in patients with asthma, chronic bronchitis or COPD due to the danger of bronchospasm. These patients should be monitored closely and the dose reduced or discontinued in the event of any sign of bronchospasm.
Carvedilol can precipitate or aggravate claudication in patients with peripheral vascular disease. The symptoms of Raynaud's phenomenon may also be exacerbated.

INTERACTIONS:
Warning:

Caution should be exercised when transferring a patient from clonidine. The withdrawal of clonidine may result in the release of large amounts of catecholamines which may give rise to a hypertensive crisis. If beta-blockers are administered in these circumstances, the unopposed alpha receptor stimulation may potentiate this effect. If a beta-blocker and clonidine are given concurrently, the clonidine should not be discontinued until several days after the withdrawal of the beta-blocker, as severe rebound hypertension may occur. It can be dangerous to administer this medicine concomitantly with the following medicines: hypoglycaemic agents (see "Precautions"), phenothiazines and various anti-arrhythmic agents (see below). Such drug-drug interactions can have life-threatening consequences. Special note: Digitalisation of patients receiving long-term beta-blocking therapy may be necessary if congestive, cardiac failure is likely to develop. This combination may be considered despite the potentiation of negative chronotropic effects of the two medicines. Careful control of the dosages and of the individual patient's response (and notably pulse rate), is essential in this situation.

Anaesthetic agents causing myocardial depression, such as cyclopropane and trichloroethylene, should be avoided.
Carvedilol should be avoided in combination with cardio-depressant calcium channel blockers such as verapamil and diltiazem.
The hypotensive effects of carvedilol are antagonized by non-steroidal anti-inflammatory agents (NSAIDS). Carvedilol may potentiate antidiabetic agents such as insulin or the sulfonylureas.
Myocardial depressant agents, including anti-arrhythmics eg. disopyramide, procainamide, lignocaine and phenytoin, may cause potentiation of the negative inotropic effect on the heart, as well as potentiation of the AV conduction time when used concurrently with carvedilol.
Enzyme inhibitors, such as quinidine may affect the metabolism and pharmacokinetics of carvedilol.
Reserpine and other medicines which can deplete catecholamines, such as adrenergic neuron blocking agents (e.g. guanethidine and bethanidine), may cause hypotension and/or severe bradycardia.
Beta-adrenoreceptor stimulating agents, such as isoprenaline, diminish the effects of carvedilol.
Alpha-adrenoreceptor stimulating agents such as noradrenaline and mixed alpha and beta-adrenoreceptor stimulating agents, such as adrenaline, may enhance the peripheral vasoconstrictor effects of carvedilol and may reverse the hypotensive effects dangerously.
Rifampicin may decrease the systemic availability of carvedilol.
Digoxin levels should be monitored when carvedilol dosages are changed.
Concurrent therapy with cimetidine may result in a 30% increase in the systemic bioavailability of carvedilol, but has no affect on the Cmax.
Hydralazine and alcohol may increase the plasma concentration of carvedilol by delaying the hepatic metabolism of carvedilol.
Carvedilol may potentiate the hypotensive effect of other antihypertensives or other agents that may cause hypotension as part of their side-effect profile.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Overdosage may lead to bradycardia, severe hypotension, heart failure, cardiogenic shock and cardiac arrest. These patients may also present with bronchospasm, vomiting, seizures and disturbed consciousness.
Placing the patient in a supine position will improve the blood supply to the brain. Gastric lavage can be useful shortly after ingestion of the medicine.
Bradycardia and severe hypotension should be treated with intravenous atropine. Incremental doses of up to 3 mg should he given immediately. If necessary, this should be followed up by a slow intravenous infusion of isoprenaline. If further measures are required, noradrenaline may be preferable in restoring circulation. The recommended starting dose for noradrenaline is 5-10 mcg given intravenously, and should be repeated according to the patient's response. Alternatively it may be given by intravenous infusion at a rate of 5 mcg/minute until a response is achieved. Adrenaline or dobutamine can also be used. In the case of therapy-resistant bradycardia, pacemaker therapy should be performed.
In severe overdosage the following regime may be preferred:
Initially 1-10 mg glucagon intravenously, followed by intravenous infusion at a rate of 2-2.5 mg/hour.
Bronchospasm should be treated with beta-agonists and intravenous aminophylline, and cardiac failure with digitalis and diuretics.
Peripheral vasodilation may be treated with noradrenaline with continuous monitoring of the circulation. In the event of seizures, diazepam or clonazepam may be given by slow intravenous injection.
Special note: Since a prolonged elimination half-life of carvedilol can be expected due to release from deeper compartments, treatment with antidotes must be continued for a sufficiently long period of time when there are symptoms of shock, following severe intoxication with carvedilol.

IDENTIFICATION:

CARLOC 12.5:	Cream coloured, circular, biconvex tablets with cross break-line on one side and plain on the ether.
CARLOC 25:	Light red coloured, circular biconvex tablets with cross break-line on one side and plain on the other.

PRESENTATION:

CARLOC 12.5:	30 or 60 tablets per pack in blister strips of 10 tablets.
CARLOC 25:	30 or 60 tablets per pack in blister strips of 10 tablets.

STORAGE INSTRUCTIONS:
Store in well closed containers, below 25°C.
Protect from light.
Keep the blisters in the outer carton until required for use.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:

CARLOC 12.5:	34/7.1.3/0433
CARLOC 25:	34/7.1.3/0434

NAME OF BUSINESS AND ADDRESS OF APPLICANT:
Cipla Medpro (Pty) Ltd
Rosen Heights, Pasita Street, Rosen Park, Bellville 7530

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
April 2003

© 2003 CIPLA MEDPRO (PTY) LTD

144XB 2

New addition to this site: November 2004
Source: Community Pharmacy
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