BETAXOLOL: 638 Adverse Event Reports & Safety Profile

DESCRIPTION: Betaxolol hydrochloride is a ß 1 -selective (cardioselective) adrenergic receptor blocking agent available as 10-mg and 20-mg tablets for oral administration. Betaxolol hydrochloride is chemically described as 2-propanol, 1- [4-[2-(cyclopropylmethoxy) ethyl] phenoxy]-3-[(1-methylethyl) amino]-, hydrochloride, (±)-. It has the following chemical structure: Each tablet for oral administration contains 10 mg or 20 mg of betaxolol hydrochloride equivalent to 8.94 mg or 17.88 mg of betaxolol respectively. In addition, each tablet contains the following inactive ingredients, hypromellose, anhydrous lactose, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium starch glycolate, stearic acid and titanium dioxide. Betaxolol hydrochloride is a water-soluble white crystalline powder with a molecular formula of C 18 H 29 NO 3

• HCl and a molecular weight of 343.9. It is freely soluble in water, ethanol, chloroform, and methanol, and has a pKa of 9.4.

Chemical

Structure

INDICATIONS AND USAGE Betaxolol Hydrochloride Ophthalmic Solution has been shown to be effective in lowering intraocular pressure and is indicated in the treatment of ocular hypertension and chronic open-angle glaucoma. It may be used alone or in combination with other anti-glaucoma drugs. In clinical studies, Betaxolol Hydrochloride Ophthalmic Solution was safely used to lower intraocular pressure in 47 patients with both glaucoma and reactive airway disease who were followed for a mean period of 15 months. However, caution should be used in treating patients with severe reactive airway disease or a history of asthma.

DOSAGE AND ADMINISTRATION: The initial dose of betaxolol tablets, USP in hypertension is ordinarily 10 mg once daily either alone or added to diuretic therapy. The full antihypertensive effect is usually seen within 7 to 14 days. If the desired response is not achieved the dose can be doubled after 7 to 14 days. Increasing the dose beyond 20 mg has not been shown to produce a statistically significant additional antihypertensive effect; but the 40-mg dose has been studied and is well tolerated. An increased effect (reduction) on heart rate should be anticipated with increasing dosage. If monotherapy with betaxolol tablets, USP does not produce the desired response, the addition of a diuretic agent or other antihypertensive should be considered (see PRECAUTIONS, Drug Interactions ).

Dosage Adjustments For Specific

Patients: Patients with renal failure: In patients with renal impairment, clearance of betaxolol declines with decreasing renal function. In patients with severe renal impairment and those undergoing dialysis, the initial dose of betaxolol tablets, USP is 5 mg once daily. If the desired response is not achieved, dosage may be increased by 5 mg/day increments every 2 weeks to a maximum dose of 20 mg/day. Patients with hepatic disease: Patients with hepatic disease do not have significantly altered clearance. Dosage adjustments are not routinely needed. Elderly patients: Consideration should be given to reduction in the starting dose to 5 mg in elderly patients. These patients are especially prone to beta-blocker-induced bradycardia, which appears to be dose related and sometimes responds to reductions in dose. Cessation of therapy: If withdrawal of betaxolol tablets, USP therapy is planned, it should be achieved gradually over a period of about 2 weeks. Patients should be carefully observed and advised to limit physical activity to a minimum.

BETOPTIC S is contraindicated in patients with: sinus bradycardia greater than a first degree atrioventricular (AV) block cardiogenic shock patients with overt cardiac failure hypersensitivity to any component of this product Hypersensitivity to any component of this product. ( 4 ) Sinus bradycardia, second or third degree atrioventricular (AV) block, overt cardiac failure, and cardiogenic shock. ( 4 )

ADVERSE REACTIONS Most adverse reactions have been mild and transient and are typical of beta-adrenergic blocking agents, eg, bradycardia, fatigue, dyspnea, and lethargy. Withdrawal of therapy in U.S. and European controlled clinical trials has been necessary in about 3.5% of patients, principally because of bradycardia, fatigue, dizziness, headache, and impotence. Frequency estimates of adverse events were derived from controlled studies in which adverse reactions were volunteered and elicited in U.S. studies and volunteered and/or elicited in European studies. In the U.S., the placebo-controlled hypertension studies lasted for 4 weeks, while the active-controlled hypertension studies had a 22- to 24-week double-blind phase. The following doses were studied: betaxolol—5, 10, 20, and 40 mg once daily; atenolol—25, 50, and 100 mg once daily; and propranolol—40, 80, and 160 mg b.i.d. Betaxolol, like other beta-blockers, has been associated with the development of antinuclear antibodies (ANA) (e.g., lupus erythematosus). In controlled clinical studies, conversion of ANA from negative to positive occurred in 5.3% of the patients treated with betaxolol, 6.3% of the patients treated with atenolol, 4.9% of the patients treated with propranolol, and 3.2% of the patients treated with placebo. Betaxolol adverse events reported with a 2% or greater frequency, and selected events with lower frequency, in U.S. controlled studies are: Dose Range Body System/Adverse Reaction Betaxolol (N=509) 5-40 mg q.d.* (%) Propranolol (N=73) 40-160 mg b.i.d. (%) Atenolol (N=75) 25-100 mg q.d. (%) Placebo (N=109) (%)

Cardiovascular

Bradycardia (heart rate <50 BPM) Symptomatic bradycardia Edema 8.1 0.8 1.8 4.1 1.4 0 12.0 0 0 0 0

1.8 Central Nervous System Headache Dizziness Fatigue Lethargy 6.5 4.5 2.9 2.8 4.1 11.0 9.6 4.1 5.3 2.7 4.0 2.7 15.6 5.5 0

0.9 Psychiatric Insomnia Nervousness Bizarre dreams Depression 1.2 0.8 1.0 0.8 8.2 1.4 2.7 2.7 2.7 2.7 1.3 4.0 0 0 0 0 Autonomic Impotence 1.2† 0 0 0 Respiratory Dyspnea Pharyngitis Rhinitis Upper respiratory infection 2.4 2.0 1.4 2.6 2.7 0 0 0 1.3 4.0 4.0 0 0.9 0.9 0.9

5.5 Gastrointestinal Dyspepsia Nausea Diarrhea 4.7 1.6 2.0 6.8 1.4 6.8 2.7 4.0 8.0 0.9 0

0.9 Musculoskeletal Chest pain Arthralgia 2.4 3.1 1.4 0 2.7 4.0 0.9

1.8 Skin Rash 1.2 0 0 0 *Five patients received 80 mg q.d. †N=336 males; impotence is a known possible adverse effect of this pharmacological class. Of the above adverse reactions associated with the use of betaxolol, only bradycardia was clearly dose related, but there was a suggestion of dose relatedness for fatigue, lethargy, and dyspepsia.

In

Europe, the placebo-controlled study lasted for 4 weeks, while the comparative studies had a 4-52-week double-blind phase. The following doses were studied: betaxolol 20 and 40 mg once daily and atenolol 100 mg once daily.

From

European controlled hypertension clinical trials, the following adverse events reported by 2% or more patients and selected events with lower frequency are presented: Dose Range Body System/Adverse Reaction Betaxolol (N=155) 20-40 mg q.d. (%) Atenolol (N=81) 100 mg q.d. (%) Placebo (N=60) (%)

Cardiovascular

Bradycardia (heartrate <50 BPM) Symptomatic bradycardia Palpitation Edema Cold extremities 5.8 1.9 1.9 1.3 1.9 5.0 2.5 3.7 1.2 0 0 0 1.7 0 0 Central Nervous System Headache Dizziness Fatigue Asthenia Insomnia Paresthesia 14.8 14.8 9.7 7.1 5.0 1.9 9.9 17.3 18.5 0 3.7 2.5 23.3 15.0 0 16.7 3.3 0 Gastrointestinal Nausea Dyspepsia Diarrhea 5.8 3.9 1.9 1.2 7.4 3.7 0 3.3 0 Musculoskeletal Chest pain Joint pain Myalgia 7.1 5.2 3.2 6.2 4.9 3.7 5.0 1.7

3.3 The only adverse event whose frequency clearly rose with increasing dose was bradycardia. Elderly patients were especially susceptible to bradycardia, which in some cases responded to dose-reduction (see Precautions ). The following selected (potentially important) adverse events have been reported at an incidence of less than 2% in U.S. controlled and open, long-term clinical studies, European controlled clinical trials, or in marketing experience. It is not known whether a causal relationship exists between betaxolol and these events; they are listed to alert the physician to a possible relationship: Autonomic: flushing, salivation, sweating. Body as a whole: allergy, fever, malaise, pain, rigors. Cardiovascular: angina pectoris, arrhythmia, atrioventricular block, heart failure, hypertension, hypotension, myocardial infarction, thrombosis, syncope. Central and peripheral nervous system: ataxia, neuralgia, neuropathy, numbness, speech disorder, stupor, tremor, twitching. Gastrointestinal: anorexia, constipation, dry mouth, increased appetite, mouth ulceration, rectal disorders, vomiting, dysphagia. Hearing and Vestibular: earache, labyrinth disorders, tinnitus, deafness. Hematologic: anemia, leucocytosis, lymphadenopathy, purpura, thrombocytopenia. Liver and biliary: increased AST, increased ALT. Metabolic and nutritional: acidosis, diabetes, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia, hypokalemia, weight gain, weight loss, thirst, increased LDH. Musculoskeletal: arthropathy, neck pain, muscle cramps, tendonitis. Psychiatric: abnormal thinking, amnesia, impaired concentration, confusion, emotional lability, hallucinations, decreased libido. Reproductive disorders: Female: breast pain, breast fibroadenosis, menstrual disorder; Male: Peyronie&apos;s disease, prostatitis. Respiratory: bronchitis, bronchospasm, cough, epistaxis, flu, pneumonia, sinusitis. Skin: alopecia, eczema, erythematous rash, hypertrichosis, pruritus, skin disorders. Special senses: abnormal taste, taste loss. Urinary system: cystitis, dysuria, micturition disorder, oliguria, proteinuria, abnormal renal function, renal pain. Vascular: cerebrovascular disorder, intermittent claudication, leg cramps, peripheral ischemia, thrombophlebitis. Vision: abnormal lacrimation, abnormal vision, blepharitis, ocular hemorrhage, conjunctivitis, dry eyes, iritis, cataract, scotoma.

Potential Adverse Effects

Although not reported in clinical studies with betaxolol, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and may be considered potential adverse effects of betaxolol: Central nervous system: Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability with slightly clouded sensorium, and decreased performance on neuropsychometric tests. Allergic: Fever combined with aching and sore throat, laryngospasm, respiratory distress. Hematologic: Agranulocytosis, thrombocytopenic purpura, and nonthrombocytopenic purpura. Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis. Metabolic: Hypoglycemia. Miscellaneous: Raynaud's phenomena. There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs. The reported incidence is small, and in most cases, the symptoms have cleared when treatment was withdrawn. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Patients should be closely monitored following cessation of therapy. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with betaxolol during investigational use and extensive foreign experience. However, dry eyes have been reported.

AND PRECAUTIONS Systemic Absorption : Same adverse reactions found with systemic administration of beta-adrenergic receptor inhibitors may occur with topical ophthalmic administration. ( 5.1 )

Cardiac

Failure : Discontinue treatment at the first signs of cardiac failure. ( 5.2 )

Diabetes

Mellitus : Beta-adrenergic receptor inhibitors may mask the signs and symptoms of acute hypoglycemia. Administer with caution in diabetic patients subject to hypoglycemia. ( 5.3 ) Thyrotoxicosis : Beta-adrenergic receptor inhibitors may mask certain clinical signs (e.g., tachycardia) or hyperthyroidism. ( 5.4 )

5.1 Systemic Absorption As with many topically applied ophthalmic drugs, this drug is absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic receptor inhibitors may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and death due to cardiac failure, have been reported with topical application of beta-adrenergic receptor inhibitors.

5.2 Cardiac Failure BETOPTIC S has been shown to have a minor effect on heart rate and blood pressure in clinical studies. Caution should be used in treating patients with a history of cardiac failure or heart block. Treatment with BETOPTIC S should be discontinued at the first signs of cardiac failure.

5.3 Diabetes Mellitus Beta-adrenergic receptor inhibitors should be administered with caution in patients subject to hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor inhibitors may mask the signs and symptoms of acute hypoglycemia.

5.4 Thyrotoxicosis Beta-adrenergic receptor inhibitors may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic receptor inhibitors, which might precipitate a thyroid storm.

5.5 Muscle Weakness Beta-adrenergic receptor inhibitors have been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).

5.6 Surgical Anesthesia The necessity or desirability of withdrawal of beta-adrenergic receptor inhibitors prior to major surgery is controversial. Beta-adrenergic receptor inhibitors impair the ability of the heart to respond to beta adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor inhibitors have experienced protracted, severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. In patients undergoing elective surgery, consider gradual withdrawal of beta-adrenergic receptor inhibitors. If necessary during surgery, the effects of beta-adrenergic receptor inhibitors may be reversed by sufficient doses of adrenergic agonists.

5.7 Bronchospasm and Obstructive Pulmonary Disease Caution should be exercised in the treatment of glaucoma patients with excessive restriction of pulmonary function. There have been reports of asthmatic attacks and pulmonary distress during betaxolol treatment. Although rechallenges of some such patients with ophthalmic betaxolol has not adversely affected pulmonary function test results, the possibility of adverse pulmonary effects in patients sensitive to beta-adrenergic receptor inhibitors cannot be ruled out.

5.8 Atopy/Anaphylaxis While taking beta-adrenergic receptor inhibitors, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

5.9 Angle-Closure Glaucoma In patients with angle-closure glaucoma, the immediate treatment objective is to reopen the angle. This may require constricting the pupil. Betaxolol has little or no effect on the pupil and should not be used alone in the treatment of angle-closure glaucoma.

5.10 Vascular Insufficiency Because of potential effects of beta-adrenergic receptor inhibitors on blood pressure and pulse, these inhibitors should be used with caution in patients with vascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow or Raynaud’s phenomenon develop following initiation of therapy with BETOPTIC S, alternative therapy should be considered.

5.11 Bacterial Keratitis Bacterial keratitis may occur with use of multiple dose containers of topical ophthalmic products when these containers are inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Instruct patients on appropriate instillation techniques <span class="opacity-50 text-xs">[see Patient Counseling Information (17)]</span> .

5.12 Choroidal Detachment Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy.

5.13 Contact Lens Wear The preservative in BETOPTIC S, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of BETOPTIC S but may be reinserted 15 minutes after instillation <span class="opacity-50 text-xs">[see Patient Counseling Information (17)]</span> .

PRECAUTIONS: General: Beta-adrenoceptor blockade can cause reduction of intraocular pressure. Since betaxolol hydrochloride is marketed as an ophthalmic solution for treatment of glaucoma, patients should be told that betaxolol tablets, USP may interfere with the glaucoma-screening test. Withdrawal may lead to a return of increased intraocular pressure. Patients receiving beta-adrenergic blocking agent orally and beta-blocking ophthalmic solutions should be observed for potential additive effects either on the intraocular pressure or on the known systemic effects of beta-blockade. The value of using beta-blockers in psoriatic patients should be carefully weighed since they have been reported to cause an aggravation in psoriasis.

Impaired

Hepatic or Renal Function: Betaxolol tablets, USP is primarily metabolized in the liver to metabolites that are inactive and then excreted by the kidneys; clearance is somewhat reduced in patients with renal failure but little changed in patients with hepatic disease. Dosage reductions have not routinely been necessary when hepatic insufficiency is present (see Dosage and Administration ) but patients should be observed. Patients with severe renal impairment and those on dialysis require a reduced dose. (See Dosage and Administration ).

Information For

Patients: Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of betaxolol tablets, USP therapy without the physician’s advice. Although cardiac failure rarely occurs in appropriately selected patients, patients being treated with beta-adrenergic blocking agents should be advised to consult a physician at the first sign or symptom of failure. Patients should know how they react to this medicine before they operate automobiles and machinery or engage in other tasks requiring alertness. Patients should contact their physician if any difficulty in breathing occurs, and before surgery of any type. Patients should inform their physicians, ophthalmologist, or dentists that they are taking betaxolol tablets, USP. Patients with diabetes should be warned that beta-blockers may mask tachycardia occurring with hypoglycemia.

Drug

Interactions: The following drugs have been coadministered with betaxolol tablets, USP and have not altered its pharmacokinetics: cimetidine, nifedipine, chlorthalidone, and hydrochlorothiazide. Concomitant administration of betaxolol tablets, USP with the oral anticoagulant warfarin has been shown not to potentiate the anticoagulant effect of warfarin. Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with a beta-adrenergic receptor blocking agent plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Should it be decided to discontinue therapy in patients receiving beta-blockers and clonidine concurrently, the beta-blocker should be discontinued slowly over several days before the gradual withdrawal of clonidine. Literature reports suggest that oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function. Hypotension, AV conduction disturbances, and left ventricular failure have been reported in some patients receiving beta-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen. Hypotension was more likely to occur if the calcium antagonist were a dihydropyridine derivative, e.g., nifedipine, while left ventricular failure and AV conduction disturbances, including complete heart block, were more likely to occur with either verapamil or diltiazem. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta blockers. Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects. Disopyramide has been associated with severe bradycardia, asystole and heart failure when administered with beta blockers. Particular care should be taken when using anesthetic agents which depress the myocardium, such as ether, cyclopropane, and trichloroethylene (see Warnings, Major Surgery ). Risk of anaphylactic reaction: Although it is known that patients on beta-blockers may be refractory to epinephrine in the treatment of anaphylactic shock, beta-blockers can, in addition, interfere with the modulation of allergic reaction and lead to an increased severity and/or frequency of attacks. Severe allergic reactions including anaphylaxis have been reported in patients exposed to a variety of allergens either by repeated challenge, or accidental contact, and with diagnostic or therapeutic agents while receiving beta-blockers. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime studies with betaxolol HCl in mice at oral dosages of 6, 20, and 60 mg/kg/day (up to 90 x the maximum recommended human dose [MRHD] based on 60 kg body weight) and in rats at 3, 12, or 48 mg/kg/day (up to 72 x MRHD) showed no evidence of a carcinogenic effect. In a variety of in vitro and in vivo bacterial and mammalian cell assays, betaxolol HCl was nonmutagenic. Betaxolol did not adversely effect fertility or mating performance of male or female rats at doses up to 256 mg/kg/day (380 x MRHD). Pregnancy: Pregnancy Category C. In a study in which pregnant rats received betaxolol at doses of 4, 40, or 400 mg/kg/day, the highest dose (600 x MRHD) was associated with increased postimplantation loss, reduced litter size and weight, and an increased incidence of skeletal and visceral abnormalities, which may have been a consequence of drug-related maternal toxicity. Other than a possible increased incidence of incomplete descent of testes and sternebral reductions, betaxolol at 4 mg/kg/day and 40 mg/kg/day (6 x MRHD and 60 x MRHD) caused no fetal abnormalities. In a second study with a different strain of rat, 200 mg betaxolol/kg/day (300 x MRHD) was associated with maternal toxicity and an increase in resorptions, but no tetratogenicity. In a study in which pregnant rabbits received doses of 1, 4, 12, or 36 mg betaxolol/kg/day (54 x MRHD), a marked increase in postimplantation loss occurred at the highest dose, but no drug-related teratogenicity was observed. The rabbit is more sensitive to betaxolol than other species because of higher bioavailability resulting from saturation of the first-pass effect. In a peri- and postnatal study in rats at doses of 4, 32, and 256 mg betaxolol/kg/day (380 x MRHD), the highest dose was associated with a marked increase in total litter loss within 4 days postpartum. In surviving offspring, growth and development were also affected. There are no adequate and well-controlled studies in pregnant women. Betaxolol tablets, USP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Beta-blockers reduce placental perfusion, which may result in intrauterine fetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycemia and bradycardia) may occur in fetus. Neonatal period The beta-blocker action persists in the neonate for several days after birth to a treated mother: there is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Bradycardia, respiratory distress and hypoglycemia have also been reported. Accordingly, attentive surveillance of the neonate (heart rate and blood glucose for the first 3 to 5 days of life) in a specialized setting is recommended.

Nursing

Mothers: Since betaxolol is excreted in human milk in sufficient amounts to have pharmacological effects in the infant, caution should be exercised when betaxolol tablets, USP is administered to a nursing mother.

Pediatric

Use: Safety and effectiveness in pediatric patients have not been established.

Elderly

Patients: Betaxolol tablets, USP may produce bradycardia more frequently in elderly patients. In general, patients 65 years of age and older had a higher incidence rate of bradycardia (heart rate <50 BPM) than younger patients in U.S. clinical trials. In a double-blind study in Europe, 19 elderly patients (mean age = 82) received betaxolol tablets, USP 20 mg daily. Dosage reduction to 10 mg or discontinuation was required for 6 patients due to bradycardia (See Dosage and Administration ).

Drug Interactions The following drugs have been coadministered with betaxolol and have not altered its pharmacokinetics: cimetidine, nifedipine, chlorthalidone, and hydrochlorothiazide. Concomitant administration of betaxolol with the oral anticoagulant warfarin has been shown not to potentiate the anticoagulant effect of warfarin. Catecholamine-depleting drugs (eg, reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with a beta-adrenergic receptor blocking agent plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Should it be decided to discontinue therapy in patients receiving beta-blockers and clonidine concurrently, the beta-blocker should be discontinued slowly over several days before the gradual withdrawal of clonidine. Literature reports suggest that oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function. Hypotension, AV conduction disturbances, and left ventricular failure have been reported in some patients receiving beta-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen. Hypotension was more likely to occur if the calcium antagonist were a dihydropyridine derivative, eg, nifedipine, while left ventricular failure and AV conduction disturbances, including complete heart block, were more likely to occur with either verapamil or diltiazem. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta blockers. Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects. Disopyramide has been associated with severe bradycardia, asystole and heart failure when administered with beta blockers. Particular care should be taken when using anesthetic agents which depress the myocardium, such as ether, cyclopropane, and trichloroethylene (see Warnings, Major surgery ).