ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Sectral is well tolerated in properly selected patients. Mostadverse reactions have been mild, not required discontinuation oftherapy, and tended to decrease as duration of treatment increases. The following table shows the frequency of treatment-relatedside effects derived from controlled clinical trials in patients withhypertension, angina pectoris, and arrhythmia. These patients receivedSectral, propranolol, or hydrochlorothiazide as monotherapy, or placebo. TOTAL VOLUNTEERED AND ELICITED (U.S.STUDIES)Body System/Adverse ReactionSECTRAL(N=1002)%Propranolol(N=424)%Hydrochloro-thiazide(N=178)%Placebo(N=314)%Cardiovascular Chest Pain2441 Edema2241Central Nervous System Depression2131 Dizziness67122 Fatigue1117104 Headache69134 Insomnia3651 Abnormal dreams2301Dermatologic Rash2241 Gastrointestinal Constipation4270 Diarrhea4551 Dyspepsia4631 Flatulence3471 Nausea4630Genitourinary Micturition(frequency)319<1Musculoskeletal Arthralgia2132 Myalgia2140Respiratory Cough1120 Dyspnea4642 Rhinitis214<1Special Senses Abnormal Vision2230 The following selected (potentially important) side effects wereseen in up to 2% of Sectral patients:Cardiovascular: hypotension,bradycardia, heart failure.Central Nervous System: anxiety,hyper/hypoesthesia, impotence.Dermatological: pruritus.Gastrointestinal: vomiting,abdominal pain. Genitourinary: dysuria, nocturia.Liver and Biliary System: smallnumber of cases of liver abnormalities (increased SGOT, SGPT, LDH) havebeen reported in association with acebutolol therapy. In some casesincreased bilirubin or alkaline phosphatase, fever, malaise, dark urine,anorexia, nausea, headache, and/or other symptoms have been reported. Insome of the reported cases, the symptoms and signs were confirmed byrechallenge with acebutolol. The abnormalities were reversible uponcessation of acebutolol therapy.Musculoskeletal: back pain, jointpain.Respiratory: pharyngitis,wheezing. Special Senses: conjunctivitis,dry eye, eye pain.Autoimmune: In extremely rareinstances, systemic lupus erythematosus has been reported. The incidence of drug-related adverse effects (volunteered andsolicited) according to Sectral dose is shown below. (Data from 266hypertensive patients treated for months on constant dose.) Body System400 mg/day(N=132)800 mg/day(N=63)1200 mg/day(N=71)Cardiovascular5%2%1%Gastrointestinal3%3%7%Musculoskeletal2%3%4%Central Nervous System9%13%17%Respiratory1%5%6%Skin1%2%1%Special Senses2%2%6%Genitourinary2%3%1%. Potential Adverse Events. In addition, certain adverse effects not listed abovehave been reported with other -blocking agents andshould also be considered as potential adverse effects ofSectral. Central NervousSystem: Reversible mental depression progressing tocatatonia (an acute syndrome characterized by disorientation fortime and place), short-term memory loss, emotional lability,slightly clouded sensorium, and decreased performance(neuropsychometrics). Cardiovascular:Intensification of AV block (see CONTRAINDICATIONS). Allergic: Erythematousrash, fever combined with aching and sore throat, laryngospasm,and respiratory distress. Hematologic:Agranulocytosis, nonthrombocytopenic, and thrombocytopenicpurpura. Gastrointestinal:Mesenteric arterial thrombosis and ischemic colitis. Miscellaneous: Reversiblealopecia and Peyronies disease. The oculomucocutaneous syndromeassociated with the -blocker practolol has not beenreported with Sectral during investigational use and extensiveforeign clinical experience.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Hypertension. Sectral is indicated for the management of hypertensionin adults. It may be used alone or in combination with otherantihypertensive agents, especially thiazide-type diuretics.. Ventricular Arrhythmias. Sectral is indicated in the management of ventricularpremature beats; it reduces the total number of premature beats,as well as the number of paired and multiform ventricularectopic beats, and R-on-T beats.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment ofFertility:. Chronic oral toxicity studies in rats and mice, employing doselevels as high as 300 mg/kg/day, which is equivalent to 15 times themaximum recommended (60 kg) human dose, did not indicate carcinogenicpotential for Sectral. Diacetolol, the major metabolite of Sectral inman, was without carcinogenic potential in rats when tested at doses ashigh as 1800 mg/kg/day. Sectral and diacetolol were also shown to bedevoid of mutagenic potential in the Ames Test. Sectral, administeredorally to two generations of male and female rats at doses of up to 240mg/kg/day (equivalent to 12 times the maximum recommended therapeuticdose in 60-kg human) and diacetolol, administered to two generationsof male and female rats at doses of up to 1000 mg/kg/day, had nosignificant impact on reproductive performance or fertility.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Sectral is cardioselective, -adrenoreceptor blockingagent, which possesses mild intrinsic sympathomimetic activity (ISA) inits therapeutically effective dose range. Pharmacodynamics. 1-cardioselectivity has beendemonstrated in experimental animal studies. In anesthetizeddogs and cats, Sectral is more potent in antagonizingisoproterenol-induced tachycardia (1) thanin antagonizing isoproterenol-induced vasodilatation(2).In guinea pigs and cats, it is morepotent in antagonizing this tachycardia than in antagonizingisoproterenol- induced bronchodilatation(2). ISA of Sectral has been demonstratedin catecholamine-depleted rats by tachycardia induced byintravenous administration of this agent. membrane-stabilizingeffect has been detected in animals, but only with highconcentrations of Sectral. Clinical studies have demonstrated1-blocking activity at the recommendeddoses by: a) reduction in the resting heart rate and decrease inexercise-induced tachycardia; b) reduction in cardiac output atrest and after exercise; c) reduction of systolic and diastolicblood pressures at rest and postexercise; d) inhibition ofisoproterenol-induced tachycardia. The 1-selectivity of Sectral hasalso been demonstrated on the basis of the following vascularand bronchial effects: Vascular Effects: Sectral has less antagonistic effectson peripheral vascular 2-receptors at restand after epinephrine stimulation than nonselective-antagonists. Bronchial Effects: In single-dose studies in asthmaticsexamining effects of various beta-blockers on pulmonaryfunction, low doses of acebutolol produce less evidence ofbronchoconstriction and less reduction of beta2agonist, bronchodilating effects, than nonselective agents likepropranolol but more than atenolol. ISA has been observed with Sectral in man, as shown by aslightly smaller (about beats per minute) decrease in restingheart rate when compared to equivalent -blocking dosesof propranolol, metoprolol or atenolol. Chronic therapy withSectral induced no significant alteration in the blood lipidprofile. Sectral has been shown to delay AV conduction time andto increase the refractoriness of the AV node withoutsignificantly affecting sinus node recovery time, atrialrefractory period, or the HV conduction time. Themembrane-stabilizing effect of Sectral is not manifest at thedoses used clinically. Significant reductions in resting and exercise heartrates and systolic blood pressures have been observed 1.5 hoursafter Sectral administration with maximal effects occurringbetween and hours postdosing in normal volunteers. Sectralhas demonstrated significant effect on exercise-inducedtachycardia 24 to 30 hours after drug administration. There are significant correlations between plasma levelsof acebutolol and both the reduction in resting heart rate andthe percent of -blockade of exercise-inducedtachycardia. The antihypertensive effect of Sectral has been shown indouble-blind controlled studies to be superior to placebo andsimilar to propranolol and hydrochlorothiazide. In addition,patients responding to Sectral administered twice daily had asimilar response whether the dosage regimen was changed to oncedaily administration or continued on b.i.d. regimen. Mostpatients responded to 400 to 800 mg per day in divided doses. The antiarrhythmic effect of Sectral was compared withplacebo, propranolol, and quinidine. Compared with placebo,Sectral significantly reduced mean total ventricular ectopicbeats (VEB), paired VEB, multiform VEB, R-on-T beats, andventricular tachycardia (VT). Both Sectral and propranololsignificantly reduced mean total and paired VEB and VT. Sectraland quinidine significantly reduced resting total and complexVEB; the antiarrhythmic efficacy of Sectral was also observedduring exercise. Pharmacokinetics and Metabolism. Sectral is well absorbed from the GI tract. It issubject to extensive first-pass hepatic biotransformation, withan absolute bioavailability of approximately 40% for the parentcompound. The major metabolite, an N-acetyl derivative(diacetolol), is pharmacologically active. This metabolite isequipotent to Sectral and in cats is more cardioselective thanSectral; therefore, this first-pass phenomenon does notattenuate the therapeutic effect of Sectral. Food intake doesnot have significant effect on the area under the plasmaconcentration-time curve (AUC) of Sectral although the rate ofabsorption and peak concentration decreased slightly. The plasma elimination half-life of Sectral isapproximately to hours, while that of its metabolite,diacetolol, is to 13 hours. The time to reach peakconcentration for Sectral is 2.5 hours and for diacetolol, afteroral administration of Sectral, 3.5 hours. Within the single oral dose range of 200 to 400 mg, thekinetics are dose proportional. However, this linearity is notseen at higher doses, probably due to saturation of hepaticbiotransformation sites. In addition, after multiple dosing thelack of linearity is also seen by AUC increases of approximately100% as compared to single oral dosing. Elimination via renalexcretion is approximately 30% to 40% and by nonrenal mechanisms50% to 60%, which includes excretion into the bile and directpassage through the intestinal wall. Sectral has low binding affinity for plasma proteins(about 26%). Sectral and its metabolite, diacetolol, arerelatively hydrophilic and, therefore, only minimal quantitieshave been detected in the cerebrospinal fluid (CSF). Drug interaction studies with tolbutamide and warfarinindicated no influence on the therapeutic effects of thesecompounds. Digoxin and hydrochlorothiazide plasma levels werenot affected by concomitant Sectral administration. The kineticsof Sectral were not significantly altered by concomitantadministration of hydrochlorothiazide, hydralazine,sulfinpyrazone, or oral contraceptives. In patients with renal impairment, there is no effect onthe elimination half-life of Sectral, but there is decreasedelimination of the metabolite, diacetolol, resulting in two-to three-fold increase in its half-life. For this reason, thedrug should be administered with caution in patients with renalinsufficiency (see PRECAUTIONS). Sectral and its major metabolite are dialyzable. Sectral crosses the placental barrier and is secreted inbreast milk. In geriatric patients, the bioavailability of Sectral andits metabolite is increased, approximately two-fold, probablydue to decreases in the first-pass metabolism and renal functionin the elderly.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Sectral is contraindicated in: 1) persistently severebradycardia; 2) second- and third-degree heart block; 3) overt cardiacfailure; and 4) cardiogenic shock. (See WARNINGS.).

DESCRIPTION SECTION.

DESCRIPTION. Sectral (acebutolol HCl) is selective, hydrophilicbeta-adrenoreceptor blocking agent with mild intrinsic sympathomimeticactivity for use in treating patients with hypertension and ventriculararrhythmias. It is marketed in capsule form for oral administration.Sectral capsules are provided in two dosage strengths which contain 200or 400 mg of acebutolol as the hydrochloride salt. The inactiveingredients present are D&C Red 22, FD&C Blue 1,FD&C Yellow 6, gelatin, povidone, starch, stearic acid, andtitanium dioxide. The 200 mg dosage strength also contains D&CRed 28 and the 400 mg dosage strength also contains FD&C Red 40.Acebutolol HCl has the following structural formula: Acebutolol HCl is white or slightly off-white powder freelysoluble in water, and less soluble in alcohol. Chemically it is definedas the hydrochloride salt of (+-)N-[3-Acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl] butanamide. Image of chemical structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Hypertension. The initial dosage of Sectral in uncomplicatedmild-to-moderate hypertension is 400 mg. This can be given as asingle daily dose, but in occasional patients twice daily dosingmay be required for adequate 24-hour blood-pressure control. Anoptimal response is usually achieved with dosages of 400 to 800mg per day, although some patients have been maintained on aslittle as 200 mg per day. Patients with more severe hypertensionor who have demonstrated inadequate control may respond to atotal of 1200 mg daily (administered b.i.d.), or to the additionof second antihypertensive agent. Beta-1 selectivitydiminishes as dosage is increased. Ventricular Arrhythmia. The usual initial dose of Sectral is 400 mg daily givenas 200 mg b.i.d. Dosage should be increased gradually until anoptimal clinical response is obtained, generally at 600 to 1200mg per day. If treatment is to be discontinued, the dosageshould be reduced gradually over period of about two weeks.. Use in Older Patients. Older patients have an approximately 2-foldincrease in bioavailability and may require lowermaintenance doses. Doses above 800 mg/day should beavoided in the elderly.

DRUG INTERACTIONS SECTION.

Drug Interactions:. Catecholamine-depleting drugs, such as reserpine, may have anadditive effect when given with -blocking agents. Patientstreated with Sectral plus catecholamine depletors should, therefore, beobserved closely for evidence of marked bradycardia or hypotension whichmay present as vertigo, syncope/presyncope, or orthostatic changes inblood pressure without compensatory tachycardia. Exaggeratedhypertensive responses have been reported from the combined use of-adrenergic antagonists and -adrenergic stimulants,including those contained in proprietary cold remedies andvasoconstrictive nasal drops. Patients receiving -blockersshould be warned of this potential hazard. Blunting of the antihypertensive effect of beta-adrenoceptorblocking agents by nonsteroidal anti-inflammatory drugs has beenreported. No significant interactions with digoxin, hydrochlorothiazide,hydralazine, sulfinpyrazone, oral contraceptives, tolbutamide, orwarfarin have been observed. Both digitalis glycosides and beta-blockers slowatrioventricular conduction and decrease heart rate. Concomitant use canincrease the risk of bradycardia.

GENERAL PRECAUTIONS SECTION.

Risk of AnaphylacticReaction. While taking beta-blockers, patients with ahistory of severe anaphylactic reaction to variety ofallergens may be more reactive to repeated challenge,either accidental, diagnostic, or therapeutic. Suchpatients may be unresponsive to the usual doses ofepinephrine used to treat allergic reaction.. Impaired Renal or HepaticFunction. Studies on the effect of acebutolol in patientswith renal insufficiency have not been performed in theU.S. Foreign published experience shows that acebutololhas been used successfully in chronic renalinsufficiency. Acebutolol is excreted through the GItract, but the active metabolite, diacetolol, iseliminated predominantly by the kidney. There is alinear relationship between renal clearance ofdiacetolol and creatinine clearance. Therefore, thedaily dose of acebutolol should be reduced by 50% whenthe creatinine clearance is less than 50 mL/min and by75% when it is less than 25 mL/min. Sectral should beused cautiously in patients with impaired hepaticfunction. Sectral has been used successfully and withoutproblems in elderly patients in the U.S. clinical trialswithout specific adjustment of dosage. However, elderlypatients may require lower maintenance doses because thebioavailability of both Sectral and its metabolite areapproximately doubled in this age group. Information for Patients. Patients, especially those with evidence ofcoronary artery disease, should be warned againstinterruption or discontinuation of Sectral therapywithout physicians supervision. Although cardiacfailure rarely occurs in properly selected patients,those being treated with -adrenergic blockingagents should be advised to consult physician if theydevelop signs or symptoms suggestive of impending CHF,or unexplained respiratory symptoms. Patients should also be warned of possiblesevere hypertensive reactions from concomitant use of-adrenergic stimulants, such as the nasaldecongestants commonly used in OTC cold preparations andnasal drops.

GERIATRIC USE SECTION.

Geriatric Use. Clinical studies of Sectral and other reported clinicalexperience is inadequate to determine whether there are differences insafety or effectiveness between patients above or below age 65. Elderly subjects evidence greater bioavailability of acebutolol(see CLINICALPHARMACOLOGY--Pharmacokinetics and Metabolism), presumably because of age-related reduction in first-passmetabolism and renal function. Therefore, it may be appropriate to startelderly patients at the low end of the dosing range (see DOSAGE AND ADMINISTRATION--Use inOlder Patients).

HOW SUPPLIED SECTION.

HOW SUPPLIED. Sectral(R) (acebutolol HCl) is available inthe following dosage strengths: 200 mg, opaque purple and orange capsule marked RP 700 andSectral(R) 200NDC 67857-700-01, in bottlesof 100 capsules. 400 mg, opaque brown and orange capsule marked RP 701 andSectral(R) 400 NDC 67857-701-01, in bottlesof 100 capsules. Keep tightly closed Store at controlledroom temperature 20 to 25C (68 to 77F) Protect from lightDispense in light-resistant, tight container Use carton toprotect contents from light Distributed by:Promius Pharma, LLC Bridgewater, NJ 08807 Manufactured by:PATHEON, Puerto Rico, Inc. Manati, Puerto Rico 00674, USARevised April 2008.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Patients, especially those with evidence ofcoronary artery disease, should be warned againstinterruption or discontinuation of Sectral therapywithout physicians supervision. Although cardiacfailure rarely occurs in properly selected patients,those being treated with -adrenergic blockingagents should be advised to consult physician if theydevelop signs or symptoms suggestive of impending CHF,or unexplained respiratory symptoms. Patients should also be warned of possiblesevere hypertensive reactions from concomitant use of-adrenergic stimulants, such as the nasaldecongestants commonly used in OTC cold preparations andnasal drops.

LABOR & DELIVERY SECTION.

Labor and Delivery. The effect of Sectral on labor and delivery in pregnant women isunknown. Studies in animals have not shown any effect of Sectral on theusual course of labor and delivery.

NONTERATOGENIC EFFECTS SECTION.

Nonteratogenic Effects. Studies in humans have shown that both acebutolol anddiacetolol cross the placenta. Neonates of mothers who havereceived acebutolol during pregnancy have reduced birth weight,decreased blood pressure, and decreased heart rate. In thenewborn the elimination half-life of acebutolol was to 14hours, while the half-life of diacetolol was 24 to 30 hours forthe first 24 hours after birth, followed by half-life of 12 to16 hours. Adequate facilities for monitoring these infants atbirth should be available.

NURSING MOTHERS SECTION.

Nursing Mothers. Acebutolol and diacetolol also appear in breast milk with amilk:plasma ratio of 7.1 and 12.2, respectively. Use in nursing mothersis not recommended.

OVERDOSAGE SECTION.

OVERDOSAGE. No specific information on emergency treatment of overdosage isavailable for Sectral. However, overdosage with other-blocking agents has been accompanied by extreme bradycardia,advanced atrioventricular block, intraventricular conduction defects,hypotension, severe congestive heart failure, seizures, and insusceptible patients, bronchospasm and hypoglycemia. Although specificinformation on the emergency treatment of Sectral overdose is notavailable, on the basis of the pharmacological actions and theobservations in treating overdoses with other -blockers, thefollowing general measures should be considered: Empty stomach by emesis or lavage.Bradycardia: IV atropine (1 to mg in divided doses). Ifantivagal response is inadequate, administer isoproterenolcautiously since larger than usual doses of isoproterenol may berequired. Persistent hypotension in spite of correction of bradycardia:Administer vasopressor (e.g., epinephrine, levarterenol, dopamine,or dobutamine) with frequent monitoring of blood pressure and pulserate. Bronchospasm: theophylline derivative, such as aminophyllineand/or parenteral 2-stimulant, such asterbutaline. Cardiac failure: Digitalize the patient and/or administer adiuretic. It has been reported that glucagon is useful in thissituation. Sectral is dialyzable.. Empty stomach by emesis or lavage.. Bradycardia: IV atropine (1 to mg in divided doses). Ifantivagal response is inadequate, administer isoproterenolcautiously since larger than usual doses of isoproterenol may berequired. Persistent hypotension in spite of correction of bradycardia:Administer vasopressor (e.g., epinephrine, levarterenol, dopamine,or dobutamine) with frequent monitoring of blood pressure and pulserate. Bronchospasm: theophylline derivative, such as aminophyllineand/or parenteral 2-stimulant, such asterbutaline. Cardiac failure: Digitalize the patient and/or administer adiuretic. It has been reported that glucagon is useful in thissituation.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC-67857-700-01 100 CapsulesSECTRAL(R)(acebutolol HCL)equivalent to200 mgacebutololSEALED FOR YOUR PROTECTIONRx onlyPROMIUS PHARMA. image of 200 mg package label.

PEDIATRIC USE SECTION.

Pediatric Use. Safety and effectiveness in pediatric patients have not beenestablished.

PHARMACODYNAMICS SECTION.

Pharmacodynamics. 1-cardioselectivity has beendemonstrated in experimental animal studies. In anesthetizeddogs and cats, Sectral is more potent in antagonizingisoproterenol-induced tachycardia (1) thanin antagonizing isoproterenol-induced vasodilatation(2).In guinea pigs and cats, it is morepotent in antagonizing this tachycardia than in antagonizingisoproterenol- induced bronchodilatation(2). ISA of Sectral has been demonstratedin catecholamine-depleted rats by tachycardia induced byintravenous administration of this agent. membrane-stabilizingeffect has been detected in animals, but only with highconcentrations of Sectral. Clinical studies have demonstrated1-blocking activity at the recommendeddoses by: a) reduction in the resting heart rate and decrease inexercise-induced tachycardia; b) reduction in cardiac output atrest and after exercise; c) reduction of systolic and diastolicblood pressures at rest and postexercise; d) inhibition ofisoproterenol-induced tachycardia. The 1-selectivity of Sectral hasalso been demonstrated on the basis of the following vascularand bronchial effects: Vascular Effects: Sectral has less antagonistic effectson peripheral vascular 2-receptors at restand after epinephrine stimulation than nonselective-antagonists. Bronchial Effects: In single-dose studies in asthmaticsexamining effects of various beta-blockers on pulmonaryfunction, low doses of acebutolol produce less evidence ofbronchoconstriction and less reduction of beta2agonist, bronchodilating effects, than nonselective agents likepropranolol but more than atenolol. ISA has been observed with Sectral in man, as shown by aslightly smaller (about beats per minute) decrease in restingheart rate when compared to equivalent -blocking dosesof propranolol, metoprolol or atenolol. Chronic therapy withSectral induced no significant alteration in the blood lipidprofile. Sectral has been shown to delay AV conduction time andto increase the refractoriness of the AV node withoutsignificantly affecting sinus node recovery time, atrialrefractory period, or the HV conduction time. Themembrane-stabilizing effect of Sectral is not manifest at thedoses used clinically. Significant reductions in resting and exercise heartrates and systolic blood pressures have been observed 1.5 hoursafter Sectral administration with maximal effects occurringbetween and hours postdosing in normal volunteers. Sectralhas demonstrated significant effect on exercise-inducedtachycardia 24 to 30 hours after drug administration. There are significant correlations between plasma levelsof acebutolol and both the reduction in resting heart rate andthe percent of -blockade of exercise-inducedtachycardia. The antihypertensive effect of Sectral has been shown indouble-blind controlled studies to be superior to placebo andsimilar to propranolol and hydrochlorothiazide. In addition,patients responding to Sectral administered twice daily had asimilar response whether the dosage regimen was changed to oncedaily administration or continued on b.i.d. regimen. Mostpatients responded to 400 to 800 mg per day in divided doses. The antiarrhythmic effect of Sectral was compared withplacebo, propranolol, and quinidine. Compared with placebo,Sectral significantly reduced mean total ventricular ectopicbeats (VEB), paired VEB, multiform VEB, R-on-T beats, andventricular tachycardia (VT). Both Sectral and propranololsignificantly reduced mean total and paired VEB and VT. Sectraland quinidine significantly reduced resting total and complexVEB; the antiarrhythmic efficacy of Sectral was also observedduring exercise.

PHARMACOKINETICS SECTION.

Pharmacokinetics and Metabolism. Sectral is well absorbed from the GI tract. It issubject to extensive first-pass hepatic biotransformation, withan absolute bioavailability of approximately 40% for the parentcompound. The major metabolite, an N-acetyl derivative(diacetolol), is pharmacologically active. This metabolite isequipotent to Sectral and in cats is more cardioselective thanSectral; therefore, this first-pass phenomenon does notattenuate the therapeutic effect of Sectral. Food intake doesnot have significant effect on the area under the plasmaconcentration-time curve (AUC) of Sectral although the rate ofabsorption and peak concentration decreased slightly. The plasma elimination half-life of Sectral isapproximately to hours, while that of its metabolite,diacetolol, is to 13 hours. The time to reach peakconcentration for Sectral is 2.5 hours and for diacetolol, afteroral administration of Sectral, 3.5 hours. Within the single oral dose range of 200 to 400 mg, thekinetics are dose proportional. However, this linearity is notseen at higher doses, probably due to saturation of hepaticbiotransformation sites. In addition, after multiple dosing thelack of linearity is also seen by AUC increases of approximately100% as compared to single oral dosing. Elimination via renalexcretion is approximately 30% to 40% and by nonrenal mechanisms50% to 60%, which includes excretion into the bile and directpassage through the intestinal wall. Sectral has low binding affinity for plasma proteins(about 26%). Sectral and its metabolite, diacetolol, arerelatively hydrophilic and, therefore, only minimal quantitieshave been detected in the cerebrospinal fluid (CSF). Drug interaction studies with tolbutamide and warfarinindicated no influence on the therapeutic effects of thesecompounds. Digoxin and hydrochlorothiazide plasma levels werenot affected by concomitant Sectral administration. The kineticsof Sectral were not significantly altered by concomitantadministration of hydrochlorothiazide, hydralazine,sulfinpyrazone, or oral contraceptives. In patients with renal impairment, there is no effect onthe elimination half-life of Sectral, but there is decreasedelimination of the metabolite, diacetolol, resulting in two-to three-fold increase in its half-life. For this reason, thedrug should be administered with caution in patients with renalinsufficiency (see PRECAUTIONS). Sectral and its major metabolite are dialyzable. Sectral crosses the placental barrier and is secreted inbreast milk. In geriatric patients, the bioavailability of Sectral andits metabolite is increased, approximately two-fold, probablydue to decreases in the first-pass metabolism and renal functionin the elderly.

PRECAUTIONS SECTION.

PRECAUTIONS. . Risk of AnaphylacticReaction. While taking beta-blockers, patients with ahistory of severe anaphylactic reaction to variety ofallergens may be more reactive to repeated challenge,either accidental, diagnostic, or therapeutic. Suchpatients may be unresponsive to the usual doses ofepinephrine used to treat allergic reaction.. Impaired Renal or HepaticFunction. Studies on the effect of acebutolol in patientswith renal insufficiency have not been performed in theU.S. Foreign published experience shows that acebutololhas been used successfully in chronic renalinsufficiency. Acebutolol is excreted through the GItract, but the active metabolite, diacetolol, iseliminated predominantly by the kidney. There is alinear relationship between renal clearance ofdiacetolol and creatinine clearance. Therefore, thedaily dose of acebutolol should be reduced by 50% whenthe creatinine clearance is less than 50 mL/min and by75% when it is less than 25 mL/min. Sectral should beused cautiously in patients with impaired hepaticfunction. Sectral has been used successfully and withoutproblems in elderly patients in the U.S. clinical trialswithout specific adjustment of dosage. However, elderlypatients may require lower maintenance doses because thebioavailability of both Sectral and its metabolite areapproximately doubled in this age group. Information for Patients. Patients, especially those with evidence ofcoronary artery disease, should be warned againstinterruption or discontinuation of Sectral therapywithout physicians supervision. Although cardiacfailure rarely occurs in properly selected patients,those being treated with -adrenergic blockingagents should be advised to consult physician if theydevelop signs or symptoms suggestive of impending CHF,or unexplained respiratory symptoms. Patients should also be warned of possiblesevere hypertensive reactions from concomitant use of-adrenergic stimulants, such as the nasaldecongestants commonly used in OTC cold preparations andnasal drops.

PREGNANCY SECTION.

Pregnancy. Teratogenic Effects. Pregnancy Category B: Reproduction studies have beenperformed with Sectral in rats (up to 630 mg/kg/day) and rabbits(up to 135 mg/kg/day). These doses are equivalent toapproximately 31.5 and 6.8 times the maximum recommendedtherapeutic dose in 60-kg human, respectively. The compoundwas not teratogenic in either species. In the rabbit, however,doses of 135 mg/kg/day caused slight fetal growth retardation;this effect was considered to be result of maternal toxicity,as evidenced by reduced food intake, lowered rate of bodyweight gain, and mortality. Studies have also been performed inthese species with diacetolol (at doses of up to 450 mg/kg/dayin rabbits and up to 1800 mg/kg/day in rats). Other than asignificant elevation in postimplantation loss with 450mg/kg/day diacetolol, level at which food consumption and bodyweight gain were reduced in rabbit dams and nonstatisticallysignificant increase in incidence of bilateral cataract in ratfetuses from dams treated with 1800 mg/kg/day diacetolol, therewas no evidence of harm to the fetus. There are no adequate andwell-controlled trials in pregnant women. Because animalteratology studies are not always predictive of the humanresponse, Sectral should be used during pregnancy only if thepotential benefit justifies the risk to the fetus. Nonteratogenic Effects. Studies in humans have shown that both acebutolol anddiacetolol cross the placenta. Neonates of mothers who havereceived acebutolol during pregnancy have reduced birth weight,decreased blood pressure, and decreased heart rate. In thenewborn the elimination half-life of acebutolol was to 14hours, while the half-life of diacetolol was 24 to 30 hours forthe first 24 hours after birth, followed by half-life of 12 to16 hours. Adequate facilities for monitoring these infants atbirth should be available.

SPL UNCLASSIFIED SECTION.

Clinical Laboratory Findings. Sectral(R), like other -blockers,has been associated with the development of antinuclear antibodies(ANA). In prospective clinical trials, patients receiving Sectral had adose-dependent increase in the development of positive ANA titers, andthe overall incidence was higher than that observed with propranolol.Symptoms (generally persistent arthralgias and myalgias) related to thislaboratory abnormality were infrequent (less than 1% with both drugs).Symptoms and ANA titers were reversible upon discontinuation oftreatment.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects. Pregnancy Category B: Reproduction studies have beenperformed with Sectral in rats (up to 630 mg/kg/day) and rabbits(up to 135 mg/kg/day). These doses are equivalent toapproximately 31.5 and 6.8 times the maximum recommendedtherapeutic dose in 60-kg human, respectively. The compoundwas not teratogenic in either species. In the rabbit, however,doses of 135 mg/kg/day caused slight fetal growth retardation;this effect was considered to be result of maternal toxicity,as evidenced by reduced food intake, lowered rate of bodyweight gain, and mortality. Studies have also been performed inthese species with diacetolol (at doses of up to 450 mg/kg/dayin rabbits and up to 1800 mg/kg/day in rats). Other than asignificant elevation in postimplantation loss with 450mg/kg/day diacetolol, level at which food consumption and bodyweight gain were reduced in rabbit dams and nonstatisticallysignificant increase in incidence of bilateral cataract in ratfetuses from dams treated with 1800 mg/kg/day diacetolol, therewas no evidence of harm to the fetus. There are no adequate andwell-controlled trials in pregnant women. Because animalteratology studies are not always predictive of the humanresponse, Sectral should be used during pregnancy only if thepotential benefit justifies the risk to the fetus.

USE IN SPECIFIC POPULATIONS SECTION.

Use in Older Patients. Older patients have an approximately 2-foldincrease in bioavailability and may require lowermaintenance doses. Doses above 800 mg/day should beavoided in the elderly.

WARNINGS SECTION.

WARNINGS. Cardiac Failure. Sympathetic stimulation may be essential for support ofthe circulation in individuals with diminished myocardialcontractility, and its inhibition by -adrenergicreceptor blockade may precipitate more severe failure. Although-blockers should be avoided in overt cardiac failure,Sectral can be used with caution in patients with history ofheart failure who are controlled with digitalis and/ordiuretics. Both digitalis and Sectral impair AV conduction. Ifcardiac failure persists, therapy with Sectral should bewithdrawn. In Patients Without History of Cardiac Failure. In patients with aortic or mitral valve disease orcompromised left ventricular function, continued depression ofthe myocardium with -blocking agents over period oftime may lead to cardiac failure. At the first signs of failure,patients should be digitalized and/or be given diuretic andthe response observed closely. If cardiac failure continuesdespite adequate digitalization and/or diuretic, Sectral therapyshould be withdrawn. Exacerbation of Ischemic Heart Disease Following AbruptWithdrawal. Following abrupt cessation of therapy with certain-blocking agents in patients with coronary arterydisease, exacerbation of angina pectoris and, in some cases,myocardial infarction and death have been reported. Therefore,such patients should be cautioned against interruption oftherapy without physicians advice. Even in the absence ofovert ischemic heart disease, when discontinuation of Sectral isplanned, the patient should be carefully observed, and should beadvised to limit physical activity to minimum while Sectral isgradually withdrawn over period of about two weeks. (Iftherapy with an alternative -blocker is desired, thepatient may be transferred directly to comparable doses ofanother agent without interruption of -blockingtherapy.) If an exacerbation of angina pectoris occurs,antianginal therapy should be restarted immediately in fulldoses and the patient hospitalized until his conditionstabilizes. Peripheral Vascular Disease. Treatment with -antagonists reduces cardiacoutput and can precipitate or aggravate the symptoms of arterialinsufficiency in patients with peripheral or mesenteric vasculardisease. Caution should be exercised with such patients, andthey should be observed closely for evidence of progression ofarterial obstruction. Bronchospastic Disease. PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL,NOT RECEIVE -BLOCKER. Because of its relative1-selectivity, however, low doses ofSectral may be used with caution in patients with bronchospasticdisease who do not respond to, or who cannot tolerate,alternative treatment. Since 1-selectivityis not absolute and is dose-dependent, the lowest possible doseof Sectral should be used initially, preferably in divided dosesto avoid the higher plasma levels associated with the longerdose-interval. bronchodilator, such as theophylline or a2- stimulant, should be made availablein advance with instructions concerning its use. Anesthesia and Major Surgery. The necessity, or desirability, of withdrawal of -blocking therapy prior to major surgery is controversial.-adrenergic receptor blockade impairs the ability of the heartto respond to -adrenergically mediated reflex stimuli. Whilethis might be of benefit in preventing arrhythmic response, therisk of excessive myocardial depression during generalanesthesia may be enhanced and difficulty in restarting andmaintaining the heart beat has been reported with beta-blockers.If treatment is continued, particular care should be taken whenusing anesthetic agents which depress the myocardium, such asether, cyclopropane, and trichlorethylene, and it is prudent touse the lowest possible dose of Sectral. Sectral, like other-blockers, is competitive inhibitor of -receptor agonists, andits effect on the heart can be reversed by cautiousadministration of such agents (e.g., dobutamine orisoproterenol--see OVERDOSAGE). Manifestations of excessive vagal tone (e.g.,profound bradycardia, hypotension) may be corrected Diabetes and Hypoglycemia. -blockers may potentiate insulin-inducedhypoglycemia and mask some of its manifestations such astachycardia; however, dizziness and sweating are usually notsignificantly affected. Diabetic patients should be warned ofthe possibility of masked hypoglycemia. Thyrotoxicosis. -adrenergic blockade may mask certain clinicalsigns (tachycardia) of hyperthyroidism. Abrupt withdrawal of-blockade may precipitate thyroid storm; therefore,patients suspected of developing thyrotoxicosis from whomSectral therapy is to be withdrawn should be monitored closely.