INFORMATION FOR HEALTH PROFESSIONALS
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Corgard is available as 40 mg and 80 mg tablets of nadolol. The tablets are white to off-white, round and biconvex. The 40 mg tablet is unscored with SQUIBB and 207 engraved on one side; the diameter is 8.5mm. The 80 mg tablet is scored on one side with SQUIBB and 241; the diameter is 11mm.
Corgard (nadolol) is a nonselective beta-adrenergic receptor blocking agent.
Corgard blocks the response to beta adrenergic stimulation by specifically competing with adrenergic receptor agonists for available beta-1 and beta-2 receptor sites. At beta-1 adrenergic receptor sites - located chiefly in cardiac muscle - it inhibits the chronotropic and inotropic responses of the heart; in the bronchial and vascular musculature, it occupies beta-2 adrenergic receptor sites, thus inhibiting brochodilation and vasodilation. Corgard has neither intrinsic sympathomimetic activity, nor membrane stabilising action. Animal and human studies show that Corgard slows the sinus rate and depresses AV conduction. Corgard has low lipophilicity as determined by octanol/water partition coefficient (0.71). The extent to which it crosses the blood-brain barrier is limited compared with the less hydrophilic beta adrenergic blockers and may contribute to a lower incidence of CNS side effects.
The mechanism of the antihypertensive effects of beta-adrenergic receptor blocking agents has not been established. While cardiac output and arterial pressure are reduced by nadolol therapy, renal haemodynamics are stable, with preservation of renal blood flow and glomerular filtration rate.
By blocking catecholamine-induced increases in the heart rate, the velocity and extent of myocardial contraction, and in blood pressure, Corgard® (nadolol) generally reduces the oxygen requirements of the heart at any given level of effort, making it useful for many patients in the long-term management of angina pectoris. On the other hand, nadolol can increase oxygen requirements by increasing left ventricular fibre length and end diastolic pressure, particularly in patients with heart failure.
Although beta-adrenergic receptor blockade is useful in treatment of angina and hypertension, there are situations in which sympathetic stimulation is vital, and beta-adrenergic blocker therapy not appropriate. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen AV block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction in patients subject to bronchospasm, and may interfere with endogenous or exogenous bronchodilators in such patients.
The mechanism of the antimigraine effect of Corgard has not been established.
The Class II antiarrhythmic activity of beta blockers is primarily due to its selectively blocking β-adrenergic modulation of the atrioventricular node, which increases the effective refractory period of the AV node.
Beta-adrenergic blockade controls symptoms associated with hyperthyroidism, including tremor, anxiety and muscle weakness.
Absorption of Corgard (nadolol) after oral dosing is variable, averaging about 30 percent. Peak serum concentrations of nadolol usually occur in three to four hours after oral administration and the presence of food in the gastrointestinal tract does not affect the rate or extent of nadolol absorption. Approximately 30 percent of the nadolol present in serum is reversibly bound to plasma protein.
Unlike many other beta-adrenergic blocking agents, nadolol is not metabolised by the liver and is excreted unchanged, principally by the kidneys.
The half-life of therapeutic doses of nadolol is about 20-24 hours, permitting once-daily dosage. Because nadolol is excreted predominantly in the urine, its half-life increases in the presence of renal impairment (see Precautions, Dosage And Administration ). Steady-state serum concentrations of nadolol are attained in six to nine days with once daily dosage in persons with normal renal function. Because of variable absorption and different individual responsiveness, the proper dosage should be determined by titration.
Corgard is indicated for:
The management of hypertension. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.
The management of patients with angina pectoris.
The treatment of cardiac tachyarrhythmias.
The prophylactic management of both common and classic migraine headache.
The symptomatic treatment of hyperthyroidism and for the preoperative preparation of patients for thyroidectomy. It may be used with conventional antithyroid therapy.
The dosage of Corgard must be individualised and may be administered without regard to meals.
The usual initial dose is 40 mg Corgard (nadolol) once daily whether it is used alone or in addition to diuretic therapy. The dosage may be gradually increased in 40 mg and 80 mg increments until an optimum response is obtained. The usual maintenance dose is 80 - 120 mg, administered once daily. Doses up to 240 or 320 mg administered once daily may be needed.
An initial dose of 40 mg once daily. Dosage may be gradually increased by 40 mg increments at weekly intervals until an adequate response is obtained or excessive bradycardia occurs. Although individual patients may respond at various dosage levels, most patients will respond to 160 mg or less per day.
An initial dose of 40 mg once daily. Dosage may be increased by 40 mg increments at weekly intervals to a maximum dose of 160 mg. If bradycardia occurs, dose should be reduced to 40 mg once daily.
An initial dose of 40-80 mg once daily. Dosage may be gradually increased in 40 mg increments until optimum migraine prophylaxis is achieved. The usual maintenance dose is 80 to 160 mg administered once daily. After 4 to 6 weeks at the maximum dose if a satisfactory response is not obtained, therapy with nadolol should be discontinued; withdrawing the medicine gradually over a period of 2 weeks.
An initial dose of 80 mg once daily. If after 1 to 2 weeks control of clinical symptoms has not been fully achieved, the dose may be increased to 160 mg. Corgard may be used with antithyroid medicines. For the preparation of patients for partial thyroidectomy, nadolol should be administered in conjunction with potassium iodide for a period of 10 days prior to surgery. Nadolol should be administered on the morning of the surgery. Postoperatively, nadolol dosage should be slowly reduced and then withdrawn once the patient has been stabilised.
Corgard® is excreted from the kidneys; consequently dosage should be adjusted in cases of severe impairment of renal function. Some reduction in dosage may also be appropriate for the elderly since decreased kidney function is a physiological consequence of aging, and Corgard® excretion would be expected to decrease with advancing age.
Safety and effectiveness have not been established.
Increased blood levels of Corgard occur in the presence of renal failure. Although non-renal elimination does occur, dosage adjustments are necessary in this patient group. The following dose intervals are suggested :
Nadolol is excreted unchanged, principally by the kidneys. The following dose adjustments are recommended in patients with renal impairment.
| Creatinine Clearance (ml/min/1.73m²) |
Dosage Interval (hours) |
|---|---|
| > 50 | 24 |
| 31 - 50 | 24-36 |
| 10-30 | 24-48 |
| < 10 | 40-60 |
Corgard can be removed from the general circulation by haemodialysis.
Corgard is contraindicated in:
Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and beta-adrenergic blockade may worsen failure.
Although beta-adrenergic blockers 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.
Continued depression of the myocardium with beta-adrenergic 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).
Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-adrenergic 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.
(e.g., chronic bronchitis, emphysema) - Patients with Bronchospastic diseases should not, in general, receive Beta-Adrenergic Blockers, since they may block bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta receptors.
Beta-adrenergic blockers and calcium antagonists potentiate the depressant action of each other on the myocardium and reinforce the tendency of each other to impair AV conduction. Therefore they should be used together with great caution.
Impairment of peripheral circulation may result with beta blockade as systemic vascular resistance may rise at rest and during exercise.
Beta-adrenergic 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-adrenergic blocker therapy should be withdrawn several days prior to surgery. Recognition of the increased sensitivity to catecholamines of patients recently withdrawn from beta-adrenergic blocker therapy, however, has made this recommendation controversial. If possible, beta-adrenergic blockers should be withdrawn well before surgery takes place. In the event of emergency surgery, the anesthetist should be informed that the patient is on beta-adrenergic blocker therapy. The effects of nadolol can be reversed by administration of beta-adrenergic receptor agonists such as isoprenaline, dopamine, dobutamine, or noradrenaline. 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 Indications: Hyperthyroidism and Dosage And Administration: Hyperthyroidism ).
In patients with diabetes, especially labile diabetes, or with a history of episodes of spontaneous hypoglycaemia, the medicine should be given with caution since beta-adrenergic blockade may mask some important premonitory signs of acute hypoglycaemia, e.g. tachycardia and blood pressure changes.
Beta-adrenergic blockade also reduces the release of insulin in response to hyperglycaemia; therefore, it may be necessary to adjust the dose of antidiabetic drugs.
Beta- adrenoreceptors are involved in the regulation of lipid as well as carbohydrate metabolism. While some beta-adrenergic blockers have been found to cause increased plasma levels of triglycerides there is considerable conflicting data on the other effects of beta-adrenergic blockade on lipid metabolism. The long term clinical significance of the effect of beta-adrenergic blockers on lipid metabolism is not known.
Beta-adrenergic blockade may mask certain clinical signs (e.g. tachycardia) of hyperthyroidism. Abrupt withdrawal of nadolol in thyroid patients can precipitate thyroid storm.
Nadolol should be used with caution in patients with impaired renal function (see Dosage And Administration ).
While taking beta-adrenergic 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 adrenaline used to treat allergic reaction.
(Note: Adrenaline combined with non cardio-selective beta-adrenergic blockers such as nadolol can cause a hypertensive episode followed by bradycardia).
In chronic oral toxicologic studies (one to two years) in mice, rats and dogs, nadolol did not produce any significant toxic effects. In two-year oral carcinogenic studies in rats and mice, nadolol did not produce any neoplastic, preneoplastic, or nonneoplastic pathologic lesions. In fertility and general reproductive performance studies in rats, nadolol caused no adverse effects.
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.
There are no adequate and well-controlled studies in pregnant women. 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.
Nadolol is excreted in human milk. Because of the potential for adverse effects in breast fed infants, a decision should be made whether to discontinue breastfeeding or to discontinue therapy taking into account the importance of Corgard (nadalol) to the mother.
Safety and efficacy in children have not been established.
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.
Bradycardia with heart rates of less than 50 beats per minute occurs commonly and heart rates below 40 beats per minute and/or symptomatic bradycardia were seen in about 2% of patients. Symptoms of peripheral vascular insufficiency, usually of the Raynaud type, have occurred in approximately 2% of patients. Cardiac failure, hypotension and rhythm/conduction disturbances have each recurred in about 1% of patients. Single instances of first-degree and third-degree heart block have been reported; intensification of AV block is a known effect of beta-adrenergic blockers (see also Contraindications, Warnings And Precautions ).
Dizziness or fatigue has been reported in approximately 2% of patients; paresthesias, sedation, and change in behaviour have each been reported in approximately 0.6% of patients.
Brochospasm has been reported in approximately 0.1% of patients (see Contraindications and Warnings).
Nausea, diarrhoea, abdominal discomfort, constipation, vomiting, indigestion, anorexia, bloating and flatulence have been reported in 0.1% to 0.5% of patients.
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 alopecia 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.
Reversible depression progressing to catatonia; visual disturbances; hallucinations; and 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.
Mesenteric arterial thrombosis; ischaemic colitis; elevated liver enzymes.
Agranulocytosis; thrombocytopenic or nonthrombocytopenic purpura.
Fever combined with aching and sore throat; laryngospasm; respiratory distress.
Pemphigoid rash; hypertensive reaction in patients with pheochromocytoma; sleep disturbances; Peyronie's disease.
When administered concurrently, the following may interact with beta-adrenergic receptor blocking agents:
Beta blockers may exaggerate the hypotension induced by general anaesthetics (see Warnings, Major Surgery).
Hypoglycaemia or hyperglycaemia; adjust dosage of antidiabetic drug accordingly (see Warnings, Diabetes and Hypoglycaemia).
May counteract the bradycardia caused by beta-adrenergic blockers.
Calcium channel blockers generally potentiate the pharmacologic effects of beta-adrenergic blockers. Patients taking both agents should be carefully monitored for adverse cardiovascular events. (see Warnings & Precautions ).
Additive effects; monitor closely for hypotension and/or excessive bradycardia (e.g., vertigo, syncope, postural hypotension).
Additive or antagonistic effects may occur.
Carefully determine additive effects.
Significant reduction of lignocaine clearance can occur when beta-adrenergic blockers are administered concurrently.
Isolated cases of bradycardia have occurred during concurrent use of beta-adrenergic blockers and MAOIs.
The antihypertensive effects of beta-adrenergic blockers may be reduced during concurrent administration of indomethacin and possibly other NSAIDs.
Additive antihypertensive effects have occurred with other beta-adrenergic blockers when they were given concurrently with phenothiazines or haloperidol.
Effects can be additive, e.g., with ergot alkaloids.
Adrenaline and noradrenaline should not be given to patients receiving nadolol as severe vasoconstriction may occur due to action on the α adrenergic receptors while the β adrenergic receptors are blocked.
In addition to gastric lavage, the following measures should be employed, as appropriate. In determining the duration of corrective therapy, take note of the long duration of the effect of nadolol.
Administer atropine (0.25 to 1.0 mg). If there is no response to vagal blockade, administer isoprenaline cautiously.
Administer a digitalis glycoside and diuretic. It has been reported that glucagon may also be useful in this situation.
If fluid administration is ineffective, administer vasopressors such as dopamine, dobutamine, noradrenaline or isoprenaline.
Administer a beta2-agonist agent and/or a theophylline derivative.
Nadolol can be removed from the general circulation by haemodialysis.
Store below 30°C.
Protect from moisture.
Prescription Medicine
Tablets 40mg and 80mg; blister packs of 30.
Nil.
Bristol-Myers Squibb( NZ ) Ltd
Stanway Business Park
Tower 2, Level 1
646 Great South Road
Ellerslie, AUCKLAND
NEW ZEALAND
Telephone: (09) 571 5250; Toll Free: 0800 80 40 80
13 January 1995
CORGARD6c