COMPOSITION CORGARETIC-80 tablets contain 80 mg of nadolol; 2,3 Cis-1,2,3,4- tetrahydro-5- [2-hydroxy-3- (tert-butyl-amino) propoxy] -2,3- naphthalenediol in combination with 5 mg bendroflumethiazide; 3-benzyl-3,4-dihydro-6- (trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide.
CORGARETIC-40 tablets contain 40 mg of nadolol; 2,3 Cis-1,2,3,4- tetrahydro-5- [2-hydroxy-3- (tert-butyl-amino) propoxy] -2,3- naphthalenediol in combination with 5 mg bendroflumethiazide; 3-benzyl-3,4-dihydro-6- (trifluoromethyl)-2H-1,2,4-benzothia diazine-7-sulphonamide 1,1-dioxide.
PHARMACOLOGICAL CLASSIFICATION Category A 7.1.3 Other Hypotensives
PHARMACOLOGICAL ACTION CORGARETIC is an antihypertensive which combines nadolol, a non-selective beta-adrenergic receptor blocking agent, and bendroflumethiazide, a diuretic/antihypertensive.
Nadolol and bendroflumethiazide produce an additive therapeutic effect in reducing elevated blood pressure.
CONTRA-INDICATIONS ALLERGY TO ANY OF THE COMPONENTS
Nadolol is contra-indicated for patients with bronchial asthma; chronic respiratory diseases; allergic rhinitis during the pollen season; sinusbradycardia; cardiogenic shock and all degrees of heart block greater than first degree AV block and bradycardia less than 50 per minute; right ventricular failure secondary to pulmonary hypertension; congestive heart failure (see Warnings); patients receiving adrenergic-augmenting psychotropic drugs (including MAO inhibitors), and during a two-week withdrawal period from such drugs, peripheral vascular diseases and Raynaud's phenomenon; heart failure; renal failure and hepatic failure.
Caution should be exercised when transferring a patient from clonidine. The withdrawal of clonidine may result in the release of large amounts of catacholamines 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.
IMPORTANT: Exacerbation of angina and myocardial infarction have occurred after abrupt discontinuation of therapy with nadolol in patients with angina pectoris or other evidence of coronary artery insufficiency. When discontinuing chronically administered nadolol in such patients, the dosage should be gradually reduced over a period of at least two weeks and the patient should be carefully monitored. Patients should be advised to limit the extent of their physical activity during the period that the medicine is being discontinued. If angina markedly worsens or acute coronary insufficiency develops, re-institute nadolol promptly at least temporarily. In addition, warn patients with angina pectoris against abrupt discontinuation of nadolol.
Because coronary artery disease is common and may be unrecognized, 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. If cardiac failure continues despite adequate digitalization and diuresis, CORGARETIC 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 anesthesia and surgical procedures, resulting in protracted hypotension or low cardiac output.
If possible, beta-blockers including nadolol should be withdrawn well before surgery. In the event of emergency surgery, the anesthesiologist should be informed that the patient is on beta-blocker therapy.
Thiazides may increase the responsiveness to tubocurarine. Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema)- PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD NOT, IN GENERAL, RECEIVE BETA-BLOCKERS. (NOTE: CORGARETIC is contraindicated in asthmatic patients), since it may block bronchodilatation produced by endogenous or exogenous catecholamine stimulation of beta- (B2) receptors. Diabetes and Hypoglycaemia- Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (pulse rate and 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 antidiabetic medication. Thyrotoxicosis- Beta-blockade may mask certain clinical signs (eg tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might precipitate a thyroid storm. Response to treatment for anaphylactic reaction- While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens 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. Pregnancy- The safety of nadolol in human pregnancy has not been established. Use of any drug in pregnancy or women of childbearing potential requires that the possible risk to mother and/or foetus be weighed against the expected therapeutic benefit. Neonates whose mothers are receiving nadolol at parturition have exhibited bradycardia, hypoglycemia, and associated symptoms. Nadolol is excreted in human milk. Caution should be exercised when nadolol is administered to a nursing woman.
BENDROFLUMETHIAZIDE Bendroflumethiazide may be additive or may potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lithium generally should not be given with diuretics; diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Pregnancy- Bendroflumethiazide crosses the placental barrier and appears in cord blood. The use of bendroflumethiazide in pregnant women requires that the anticipated benefit be weighed against possible hazards to the foetus. These hazards include foetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. Nursing Mothers - Bendroflumethiazide appears in breast milk. If use of the drug is deemed essential, the patient should stop nursing.
DOSAGE AND DIRECTIONS FOR USE Dosage must be individualised.
Bendroflumethiazide is usually given as a dose of 5 to 10 mg per day. The initial dose of nadolol is 40 to 80 mg daily and may gradually be increased in increments of 40 to 80 mg until an optimum response is obtained. The usual effective dose is 80 to 160 mg.
One or two CORGARETIC tablets once daily can be used to administer up to 160 mg of nadolol and 10 mg of bendroflumethiazide. For doses of nadolol in excess of 160 mg, the combination product may not be appropriate because an excessive dose of the thiazide component may be administered . Dosage adjustment in Renal Failure- Absorbed nadolol is excreted principally by the kidneys and, although nonrenal elimination does occur, dosage adjustments are necessary in patients with renal impairment. The following dose intervals are recommended:
more than 50
31 - 50
24 - 36
CORGARETIC would not be appropriate for patients with severe renal impairment, since loop diuretics (eg, furosemide) would be preferred to a thiazide in such patients. Elderly- Some reduction in dosage may be appropriate for the elderly, since decreased kidney function is a physiological consequence of aging. Children- Safety and effectiveness of CORGARETIC have not been established.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS NADOLOL
Adverse reactions due to nadolol include: Cardiovascular Marked bradycardia; symptoms of peripheral vascular insufficiency (usually of the Raynauds type); cold extremities; severe peripheral vascular insufficiency may be precipitated; lightheadedness; cardiac failure, hypotension and rhythm/conduction disturbances. Single incidences of first-degree and third-degree heart block have been reported. Intensification of AV-block is a known effect of beta-blockers.
In certain patients the interaction between beta-blockers and digitalis may produce profound bradycardia.
Orthostatic hypotension may be potentiated by coadministration with certain other drugs (e.g. alcohol, barbiturates, narcotics, other antihypertensive medication - See drug interactions). Central Nervous System Dizziness, fatigue, paresthesias, sedation, change in behaviour, sleeplessness, vivid dreams and nightmares to overt psychosis. Gastrointestinal Nausea, diarrhoea, abdominal discomfort, constipation, vomiting, indigestion, anorexia, bloating and flatulence. Respiratory Bronchoconstriction Other 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, hypoglycaemia, skeletal muscle weakness. Severe peripheral muscular disease and even peripheral gangrene may be precipitated. Reversible alopecia has been reported.
Safety during long term administration has not been demonstrated. Adverse reactions are more common in patients with renal decompensation.
Patients with phaeochromocytoma usually require treatment with an alpha-adrenergic blocker.
Occasionally, beta-blockade with drugs such as nadolol may produce hypotension and/or marked bradycardia resulting in vertigo, syncopal attacks, or orthostatic hypotension. Nadolol should be given with caution to patients who have first degree heart block.
Laboratory parameters should be observed at intervals. The drug should be used with caution in patients with impaired renal or hepatic function.
Central nervous System Vertigo, paresthesia, headache, and xanthopsia. Gastro-intestinal Epigastric pain, anorexia, gastric irritation, nausea, vomiting, diarrhoea, constipation. Jaundice (intrahepatic cholestatic jaundice), hepatitis and sialoadenitis occasionally occur. Pancreatitis has been reported. Hematologic Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, and aplastic anemia. Dermatologic-Hypersensitivity Purpura, exfoliative dermatitis, pruritus, ecchymosis, urticaria, necrotizing angiitis (vasculitis, cutaneous vasculitis), respiratory distress including pneumonitis, fever, and anaphylactic reactions occasionally occur in bendroflumethiazide-treated patients; photosensitivity and rash have been reported.
Toxic effects such as hypochloraemic alkalosis have occurred. In patients with severe congestive heart failure who are very oedematous, a low salt syndrome may occur, particularly with large doses in conjunction with restricted salt in the diet.
Patients receiving diuretics should be observed for clinical signs of thiazide induced fluid or electrolyte imbalance.
Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance may include: dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances, such as nausea and vomiting. Hypokalemia may develop. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis and non-depolarising muscle relaxants.
Any chloride deficit is generally mild and usually does not require specific treatment.
The antihypertensive effect of thiazide diuretics may be enhanced in the postsympathectomy patients.
If progressive renal impairment becomes evident, a careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing the diuretic component of therapy.
Thiazides may decrease serum protein-bound iodine levels. Muscles spasm, weakness, or restlessness are not uncommon in patients on bendroflymethiazide; hyperglycemia, glycosuria, metabolic acidosis in diabetic patients, hyperuricemia, and allergic glomerulonephritis also occasionally occur.
The plasma uric acid is frequently elevated and in susceptible patients may be associated with attacks of gout. Borderline renal and/or hepatic insufficiency may be unpredictably aggravated.
Increased concentrations of blood ammonia have been reported.
Insulin requirements in diabetic patients may be increased, decreased or unchanged. Latent diabetes mellitus may become manifest during bendroflumethiazide administration.
Bendroflumethiazide should be used with caution in patients with impaired hepatic or renal function or with diabetes mellitus. The patient should be carefully observed for signs of fluid and electrolyte imbalance.
Bendroflumethiazide should be used with caution in patients with impaired hepatic functions or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
In cirrhosis of the liver, deterioration of mental function including the onset of coma has been reported.
Bendroflumethiazide should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotaemia. Cumulative effects of the drug may develop in patients with impaired renal function.
Pathologic changes in the parathyroid gland with hypercalcaemia and hypophosphataemia have been observed in a few patients during prolonged thiazide therapy.
Thiazides have been shown to increase the urinary excretion of magnesium. Special Precaution The normal dose should be reduced in elderly patients, or in patients suffering from renal dysfunction; in the perioperative period it is generally unwise to reduce the dosage to which the patient is accustomed, as there may be danger of aggravation of angina pectoris or of hypertension.s
Alcohol, barbiturates, or narcotics- Potentiation of orthostatic hypotension may occur with bendroflumethiazide. Amphotericin B, corticosteroids, or corticotropin (ACTH)- Bendroflumethiazide may intensify electrolyte imbalance, particularly hypokalemia. Anesthetics (general)- Beta-blockers may exaggerate the hypotension induced by general anesthetics. Anticoagulants (oral: e.g. warfarin, coumarin)- Either of the components of CORGARETIC may alter their effects. Antidiabetic drugs (oral agents and insulin)- Hypoglycemia has been associated with nadolol, and hyperglycemia with both nadolol and bendroflumethiazide; adjust dosage of antidiabetic drug accordingly. Antigout medications- Bendroflumethiazide may raise the level of blood uric acid. 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. Calcium salts- Increased serum levels due to decreased excretion may occur with bendroflumethiazide. Cardiac glycosides- Enhanced possibility of digitalis toxicity with hypokalemia has been associated with bendroflumethiazide. Catecholamine-depleting drugs - Additive effects may occur. Cholestyramine resin and colestipol HCl- May delay or decrease absorption of bendroflumethiazide. CORGARETIC should be taken at least one hour before or four to six hours after these medications. Diazoxide- Enhanced hyperglycemic, hyperuricemic, and antihypertensive effects may occur with bendroflumethiazide. Other antiarrhythmic agents- Additive or antagonistic effects may occur with nadolol. Other antihypertensive agents (eg, ganglionic or peripheral adrenergic blocking agents) - May potentiate their effects. Lidocaine, IV- Significant reduction of lidocaine clearance can occur when a beta blocker is administered concurrently. Lithium salts- Bendroflumethiazide may enhance lithium toxicity due to reduced renal clearance. Avoid concurrent use. MAO inhibitors- Hypotensive effects are enhanced. Methenamine- Bendroflumethiazide may possibly decrease effectiveness due to alkalinization of the urine. Nondepolarizing muscle relaxants and preanesthetics - Effects of these agents may be potentiated. Non-steroidal anti-inflammatory agents (NSAIDs)- The antihypertensive effects of both nadolol and bendroflumethiazide may be reduced in some patients during concurrent administration of indomethacin and possibly other NSAIDs. Also, in some patients, the administration of the nonsteroidal anti-inflammatory agent can reduce the diuretic and natriuretic effects of diuretics. Phenothiazines and other antipsychotic agents- Additive antihypertensive effects have occurred with phenothiazines. Pressor amines (e.g. norepinephrine)- Bendroflumethiazide may be associated with decreased arterial responsiveness to a pressor agent; however, the decrease is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Use caution in patients taking both CORGARETIC and pressor amines who undergo surgery. If possible, discontinue CORGARETIC one week prior to surgery. (See also WARNINGS: Major Surgery). Vasoconstrictor Agents- Effects with nadolol can be additive. Laboratory Test Interactions- Thiazides such as bendroflumethiazide should be discontinued before carrying out tests for parathyroid function.
Bendroflumethiazide may cause a decrease in serum protein-bound iodine levels without signs of thyroid disturbance.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT In the event of overdosage, nadolol may cause excessive bradycardia, cardiac failure, hypotension, or bronchospasm. In addition to the expected diuresis, overdosage of bendroflumethiazide may produce varying degrees of lethargy which may progress to coma with minimal depression of respiration and cardiovascular function and without significant serum electrolyte changes or dehydration. The mechanism of thiazide-induced CNS depression is unknown. Gastrointestinal irritation may occur. 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 hemodialysis. 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 isoproterenol cautiously. Cardiac Failure- Administer to 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, levarterenol or isoproterenol. There is some pharmacological evidence that levarterenol (norepinephrine) is the drug of choice. Brochospasm- Administer a beta-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.
Treatment for overdose of the bendroflumethiazide component in CORGARETIC is essentially supportive; in thiazide overdose, cathartics should be avoided, since they tend to enhance the loss of fluid and electrolytes.
IDENTIFICATION CORGARETIC-80: Round 9,5 mm diameter biconvex white to bluish white tablets with dark blue specks, having a bisect bar on one side. May have the word 'SQUIBB' and the number 284 on the reverse.
CORGARETIC-40: Round 8,7 mm diameter biconvex white to bluish white tablets with dark blue specks, having a bisect bar on one side. May have the word 'SQUIBB' and the number 283 on the reverse.
PRESENTATION Bottles of 30 tablets.
STORAGE INSTRUCTIONS Store at room temperature not exceeding 25°C.
Avoid excessive heat.
KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBER CORGARETIC-80: Q/7.1.3/130
NAME AND BUSINESS ADDRESS OF APPLICANT BRISTOL-MYERS SQUIBB (PTY) LTD*
47 Van Buuren Road
DATE OF PUBLICATION OF THIS PACKAGE INSERT NOVEMBER 1995
*Authorised user of the TM CORGARETIC.
Updated on this site: July 2005
Source: Pharmaceutical Industry