Corgard Tablets 80mg

The tablets contain Nadolol 80.0mg.

Tablet.

White, capsule-shaped, biconvex tablet engraved “80” on one side and with a break line on the other side.

Corgard is indicated in the management of:

Angina Pectoris:

For the long-term management of patients with angina pectoris by continuous medication.

Hypertension:

For the long-term management of essential hypertension, either alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

Arrhythmias:

For the treatment of cardiac tachyarrhythmias.

Migraine:

For the prophylactic management of migraine headache. The efficacy of Corgard in the treatment of a migraine attack that has already started has not been established, and Corgard is not indicated for such use.

Thyrotoxicosis:

For the relief of the symptoms of hyperthyroidism and the pre- operative preparation of patients for surgery. Nadolol may be used in conjunction with conventional antithyroid therapy.

Adults:

Dosage should be titrated gradually with at least a week between increments to assess response; individuals show considerable variation in their response to beta-adrenergic blockade.

Corgard may be given in a once daily dosage without regard to meals. The dosage interval should be increased when creatinine clearance is below 50ml/min/1.73m².

If Corgard is to be discontinued, reduce dosage over a period of at least two weeks (see warnings).

Children:

Safety and effectiveness in children have not been established.

Elderly:

In elderly patients a low initial dose should be used so that sensitivity to side-effects may be assessed.

Renal or hepatic impairment

As with all drugs patients with impaired renal or hepatic function should be monitored.

• Bronchial asthma or a history of asthma

• Sinus bradycardia

• Greater than first degree atrioventricular conduction block

• Cardiogenic shock

• Right ventricular failure secondary to pulmonary hypertension

• Overt cardiac failure (see 4.4 – Special warnings and special precautions for use)

• Previously demonstrated hypersensitivity to nadolol

Warnings

Exacerbation of Ischaemic Heart Disease Following Abrupt Withdrawal

Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina, hypertension, and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered nadolol, particularly in patients with ischaemic heart disease, the dosage should be gradually reduced over a period of one to two weeks, and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, nadolol administration should be re-instituted promptly (at least temporarily), and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognised, it may be prudent not to discontinue nadolol therapy abruptly, even in patients under treatment for hypertension alone.

Patients with a History of Cardiac Failure - Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and beta-blockade may worsen failure.

Although beta-blockers including nadolol should be avoided in overt congestive heart failure, they can be cautiously used, if necessary, in patients with a history of heart failure who are well compensated (usually with digitalis and diuretics). Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.

Patients Without a History of Heart Failure - Continued depression of the myocardium with beta blockade over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending heart failure, the patient should be fully digitalised and/or treated with diuretics, and the response observed closely.

If cardiac failure continues despite adequate digitalisation and diuresis, Corgard should be withdrawn (gradually, if possible).

Major Surgery - Beta-blockade impairs the ability of the heart to respond to reflex stimuli and may increase the risks of general anaesthesia and surgical procedures, resulting in protracted hypotension or low cardiac output. It has generally been suggested that beta blocker therapy should be withdrawn several days prior to surgery. Recognition of the increased sensitivity to catecholamines of patients recently withdrawn from beta-blocker therapy, however, has made this recommendation controversial. If possible, beta-blockers including nadolol should be withdrawn well before surgery takes place.

In no circumstances should beta-blockers be discontinued prior to surgery in patients with phaeochromocytoma or thyrotoxicosis.

In the event of emergency surgery, the anaesthesiologist should be informed that the patient is on beta-blocker therapy. The effects of nadolol can be reversed by administration of beta-receptor agonists such as isoprenaline or dobutamine. However, such patients may be subject to protracted severe hypotension. Difficulty in restarting and maintaining the heart beat has also been reported with beta-adrenergic receptor blocking agents.

(An exception to the above paragraph is thyroid surgery—see under 'Thyrotoxicosis' in section 4.1 Indications and section 4.2 Posology and method of administration).

Nonallergic Bronchospasm (e.g. chronic bronchitis, emphysema) - Patients with bronchospastic diseases should not, in general, receive beta-blockers since they may block bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta receptors.

(NOTE: Corgard is contra-indicated in asthmatic patients.)

Diabetes and Hypoglycaemia - Beta-adrenergic blockade may prevent the appearance of warning signs and symptoms (e.g. tachycardia and blood pressure changes) of acute hypoglycaemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycaemia; therefore, it may be necessary to adjust the dose of anti-diabetic drugs.

Occasionally causes hypoglycaemia, even in non-diabetic patients, e.g., neonates, infants, children, elderly patients, patients on haemodialysis or patients suffering from chronic liver disease and patients suffering from overdose. Severe hypoglycaemia associated with nadolol has rarely presented with seizures and/or coma in isolated patients.

Skin Rashes - There have been reports of skin rashes (including a psoriasiform type) and/or ocular changes (conjunctivitis and `dry eye') associated with the use of beta-adrenergic blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when the treatment was withdrawn. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Cessation of the therapy with a beta-adrenergic blocker should be gradual.

Treatment for Anaphylactic Reaction - While taking beta-blockers, patients with a history of severe anaphylactic reaction may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

(NOTE: Epinephrine combined with non cardio-selective beta blockers such as nadolol can cause a hypertensive episode followed by bradycardia.)

Thyrotoxicosis - Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism (e.g. tachycardia). Abrupt withdrawal of nadolol in thyroid patients can precipitate thyroid storm.

Precautions

Occasionally, beta-blockade with drugs such as nadolol may produce hypotension and/or marked bradycardia, resulting in vertigo, syncope or orthostatic hypotension.

Impaired Renal or Hepatic Function - Nadolol should be used with caution in patients with impaired renal or hepatic function (see section 4.2 Posology and method of administration).

Carcinogenesis, Mutagenesis, Impairment of Fertility - In chronic oral toxicologic studies lasting one to two years, nadolol did not produce any significant toxic effects in mice, rats, or dogs. In two-year oral carcinogenic studies in rats and mice, nadolol did not produce any neoplastic, pre-neoplastic, or non-neoplastic pathologic lesions. In fertility and general reproductive performance studies in rats, nadolol caused no adverse effects.

General anaesthetics - Those which cause myocardial depression such as chloroform, cyclopropane, trichloroethylene and ether should be avoided as the patient may be subject to protracted severe hypotension. (see Major Surgery in section 4.4 Special warnings and special precautions for use).

Myocardial depressants such as lidocaine and procainamide may subject the patient to protracted severe hypotension.

Adrenoceptor Stimulants - Beta-adrenoceptor stimulants such as isoprenaline and verapamil, or alpha-adrenoceptor stimulants such as noradrenaline and adrenaline, will reverse the hypotensive effects and increase vasoconstrictor activity.

Catecholamine Depleting Drugs - Additive effects may occur with nadolol; monitor closely for evidence of hypotension and/or excessive bradycardia (e.g. vertigo, syncope, postural hypotension).

Antihypertensives (e.g. neurone-blocking drugs, vasodilators, diuretics) Additive hypotensive effect.

Clonidine - If Corgard and clonidine are given concurrently, clonidine should not be discontinued until several days after Corgard withdrawal.

Antidiabetic drugs (oral agents and insulin) - Hypoglycaemia or hyperglycaemia; adjust dosage of anti-diabetic drug accordingly (see Diabetes and Hypoglycaemia in section 4.4 Special warnings and special precautions for use).

Monoamine oxidase inhibitors (MAOIs) - Isolated cases of bradycardia have occurred during concurrent use of beta blockers and MAOIs.

Antimuscarinic agents - May counteract the bradycardia caused by beta blockers.

Calcium-channel blockers - Calcium channel blockers generally potentiate the pharmacologic effects of beta-blockers. Patients taking both agents should be carefully monitored for adverse cardiovascular events.

Other antiarrhythmic agents - Additive or antagonistic effects may occur with nadolol.

Lidocaine, IV - Significant reduction of lidocaine clearance can occur when a beta blocker is administered concurrently.

Non-steroidal anti-inflammatory agents (NSAIDs) - The antihypertensive effects of beta blockers may be reduced during concurrent administration of indometacin and possibly other NSAIDs.

Phenothiazines and other antipsychotic agents - Additive antihypertensive effects have occurred with other beta blockers when they were given concurrently with phenothiazines or haloperidol.

Vasoconstrictor Agents - Effects with nadolol can be additive (e.g. with ergot alkaloids).

Pregnancy

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies with nadolol, evidence of embryo- and foetotoxicity was found in rabbits, but not in rats or hamsters, at doses 5 to 10 times greater (on a mg/kg basis) than the maximum indicated human dose. No teratogenic potential was observed in any of these species.

Nadolol should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Neonates whose mothers are receiving nadolol at parturition have exhibited bradycardia, hypoglycaemia, and associated symptoms.

Lactation

Nadolol is excreted in human milk. Because of the potential for adverse effects in nursing infants, a decision should be made whether to discontinue nursing or to discontinue therapy, taking into account the importance of nadolol to the mother.

There are no studies on the effect of this medicine on the ability to drive. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or fatigue may occur.

Most adverse effects have been mild and transient and have rarely required withdrawal of therapy. The percentages given below were based on a population of 1440 patients taking nadolol in clinical trials.

Cardiovascular:

Bradycardia (heart rate <60 BPM) occurs commonly in nadolol-treated patients; heart rate <40 BPM and/or symptomatic bradycardia occurred in approximately 2% of patients; Symptoms of peripheral vascular insufficiency, usually of the Raynaud type (approximately 2%);

Cardiac failure, hypotension, and rhythm/conduction disturbances (about 1%). Single instances of first-degree and third-degree heart block have been reported; intensification of AV block is a known effect of beta-blockers (see also section 4.3 Contra-indications, and section 4.4 Special warnings and special precautions for use).

Central Nervous System:

Dizziness or fatigue has been reported in approximately 2% of patients; paraesthesias, sedation, and change in behaviour have each been reported in approximately 0.6% of patients. Light-headedness, insomnia and cold extremities have also been reported.

Gastrointestinal:

Nausea, diarrhoea, abdominal discomfort, constipation, vomiting, indigestion, anorexia, bloating and flatulence have been reported in 0.1% to 0.5% of patients.

Respiratory:

Bronchospasm has been reported in approximately 0.1% of patients (see section 4.3 Contraindications and section 4.4 Special warnings and precautions for use).

Endocrine:

Hypoglycaemia in neonates, infants, children, elderly patients, patients on haemodialysis, patients on concomitant anti-diabetic therapy, patients with prolonged fasting and patients with chronic liver disease has been reported (see section 4.4).

Miscellaneous:

Each of the following has been reported in 0.1% to 0.5% of patients: rash; pruritus; headache; dry mouth, eyes or skin; impotence or decreased libido; facial swelling; weight gain; slurred speech; cough; nasal stuffiness; sweating; tinnitus; blurred vision. Reversible alopaecia has been reported infrequently.

The events listed below have also occurred with nadolol and/or other beta-adrenergic blocking agents; however, no causal relationship to nadolol was established:

Central Nervous System - Reversible depression progressing to catatonia; visual disturbances; hallucinations; an acute reversible syndrome characterised by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychologic tests.

Gastrointestinal - Mesenteric arterial thrombosis; ischaemic colitis; elevated liver enzymes.

Haematologic - Agranulocytosis; thrombocytopaenic or non-thrombocytopaenic purpura.

Allergic - Fever combined with aching, and sore throat; laryngospasm; respiratory distress.

Miscellaneous - Pemphigoid rash; hypertensive reaction in patients with pheochromocytoma; sleep disturbances; Peyronie's disease.

In the event of overdosage, nadolol may cause excessive bradycardia, cardiac failure, hypotension, or bronchospasm.

Transitory increase in BUN has been reported, and serum electrolyte changes may occur, especially in patients with impaired renal function.

Treatment

Nadolol can be removed from the general circulation by haemodialysis. In determining the duration of corrective therapy, note must be taken of the long duration of the effect of nadolol.

In addition to gastric lavage, the following measures should be employed, as appropriate:

Excessive Bradycardia - Administer atropine (0.25 to 1.0 mg). If there is no response to vagal blockade, administer isoprenaline cautiously.

Cardiac Failure - Administer a digitalis glycoside and diuretic. It has been reported that glucagon may also be useful in this situation.

Hypotension - If fluid administration is ineffective, administer vasopressors such as dopamine, dobutamine or adrenaline.

Bronchospasm - Administer a beta-2-agonist agent and/or a theophylline derivative.

Stupor or coma - Supportive therapy as warranted.

Gastrointestinal Effects - Symptomatic treatment as needed.

BUN and/or Serum Electrolyte Abnormalities - Institute supportive measures as required to maintain hydration, electrolyte balance, respiration, and cardiovascular and renal function.

Nadolol is a beta-adrenergic receptor blocking agent with a prolonged activity, permitting once-daily dosage in angina, hypertension, cardiac arrhythmias, the prophylaxis of migraine, and the relief of hyperthyroid symptoms.

Nadolol is not metabolised. It has no membrane stabilising or intrinsic sympathomimetic activity, and its only effect on the autonomic nervous system is one of beta-adrenergic blockade. Nadolol is nonselective.

Receptor blockade by nadolol results in protection from excessive inappropriate sympathetic activity. Nadolol reduces the number and severity of attacks of angina pectoris by blocking response to catecholamine stimulation and thus lowers the oxygen requirement of the heart at any given level of effort.

Nadolol reduces both supine and erect blood pressure. Like other beta-blockers nadolol exerts an antiarrhythmic action. Nadolol has been shown to reduce the rapid ventricular response which accompanies atrial fibrillation/flutter by slowing conduction through the A-V node. Beta-blockade is of particular value in arrhythmias caused by increased levels of, or sensitivity of the heart to, circulating catecholamines, e.g. arrhythmias associated with phaeochromocytoma, thyrotoxicosis, or exercise. Nadolol is effective in reducing ventricular premature beats in selected patients.

Nadolol exerts an effect in the prophylaxis of migraine by a mechanism which may involve prevention of vasoconstriction in the area served by the internal carotid artery and prevention of excessive adrenergic vasodilation in the external carotid artery.

Nadolol alleviates the symptoms of thyrotoxicosis and provides symptomatic control before and during thyroid surgery.

Beta-blocking agents have been shown in large scale studies to reduce mortality by preventing reinfarction and sudden death in patients surviving their first myocardial infarction.

About 30 percent of an oral dose of Corgard is absorbed. Peak serum concentrations usually occur in 3 to 4 hours after drug administration. The presence of food in the gastrointestinal tract does not affect the rate or extent of Corgard absorption. Approximately 30 percent of the Corgard present in serum is reversibly bound to plasma protein. Unlike most available beta-blocking agents, Corgard is not metabolised, and is excreted unchanged principally by the kidneys. The serum half-life of therapeutic doses of Corgard is relatively long, ranging from 20 to 24 hours (permitting once daily dosage). A significant correlation between minimum steady-state serum concentrations of Corgard and total oral daily dose has been demonstrated in hypertensive patients; however, the observed dose-response range is wide and proper dosage requires individual titration.

None stated.

The tablets also contain microcrystalline cellulose and magnesium stearate.

Not applicable.

36 months.

Do not store above 25^oC.

PVC/aluminium foil blister packs in cartons containing 28 tablets.

None stated.

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

PL 11723/0100.

24 November 1995/23 September 2004

January 2009

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