Acebutolol is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses acebutolol also inhibits beta2 adrenoreceptors, chiefly located in the bronchial and vascular musculature. It possesses some partial agonist activity (or intrinsic sympathomimetic activity - ISA). It is used in the treatment of hypertension and/or prophylaxis of angina pectoris. The mechanism of the antihypertensive effect has not been established. Among the factors that may be involved are:

The mechanism of the anti-anginal effect is also uncertain. An important factor may be the reduction of myocardial oxygen requirements by blocking catecholamine-induced increases in heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Acebutolol hydrochloride is well absorbed from the gastrointestinal tract. It undergoes extensive first-pass hepatic biotransformation, with an absolute bioavailability of approximately 40% for the parent compound. The major metabolite, an N-acetyl derivative (diacetolol), is pharmacologically active. This metabolite is equipotent to acebutolol and, in cats, is more cardioselective than acebutolol; therefore, this first-pass phenomenon does not attenuate the therapeutic effect of acebutolol. Food intake does not have a significant effect on the area under the plasma concentration time curve [AUC] of acebutolol although the rate of absorption and peak concentration decreased slightly. The plasma elimination half-life of acebutolol is approximately 3 to 4 hours, while that of its metabolite, diacetolol, is 8 to 13 hours. The time to reach peak concentration for acebutolol is 2.5 hours and for diacetolol, after oral administration of acebutolol, 3.5 hours. Within the single oral dose range of 200 to 400 mg, the kinetics are dose proportional. However, this linearity is not seen at higher doses, probably due to saturation of hepatic biotransformation sites. In addition, after multiple dosing the lack of linearity is also seen by AUC increases of approximately 100% as compared to single oral dosing. Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. Acebutolol has a low binding affinity for plasma proteins (about 26%). Acebutolol and its metabolite, diacetolol, are relatively hydrophilic and therefore only minimal quantities have been detected in the cerebrospinal fluid (CSF).

A comparative bioavailability study was performed using healthy human volunteers. The rate and extent of absorption of acebutolol were measured and compared after a single oral 400 mg dose of Rhoxal-acebutolol (one 400 mg tablet) and Monitan (one 400 mg tablet). The results are summarized as follows:

* For the Tmax and t1/2 parameters, these are the arithmetic means (standard deviations).

INDICATIONS AND CLINICAL USE

HYPERTENSION

: Rhoxal-acebutolol (acebutolol hydrochloride) is indicated in patients with mild to moderate hypertension. It is usually used in combination with other drugs, particularly a thiazide diuretic. However, it may be tried alone as an initial agent in those patients in whom, in the judgement of the physician, treatment should be started with a beta-blocker rather than a diuretic.

In patients with severe hypertension, a beta-adrenergic blocking agent may be used as part of a multiple drug regimen which would normally include a diuretic and a vasodilator. The combination of acebutolol with a diuretic or peripheral vasodilator has been found to be compatible and generally more effective than acebutolol alone. Limited experience with other antihypertensive agents has not shown evidence of incompatibility. Rhoxal-acebutolol is not indicated in the emergency treatment of hypertensive crises.

ANGINA PECTORIS

: Rhoxal-acebutolol is indicated in the long-term management of patients with angina pectoris due to ischemic heart disease.

CONTRAINDICATIONS

Rhoxal-acebutolol (acebutolol hydrochloride) should not be used in the presence of: sinus bradycardia, second and third degree A-V block, right ventricular failure secondary to pulmonary hypertension, congestive heart failure, cardiogenic shock, anesthesia with agents that produce myocardial depression, e.g., ether.

WARNINGS

muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effect of acebutolol hydrochloride when the two drugs are used concomitantly. The effects of beta-blockers and digitalis are additive in depressing A-V conduction. In patients without a history of cardiac failure, continued depression of myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic and the response observed closely. If cardiac failure continues despite adequate digitalization and diuretic therapy, Rhoxal-acebutolol therapy should be immediately withdrawn.

: Patients with angina should be warned against abrupt discontinuation of Rhoxal-acebutolol. There have been reports of severe exacerbation of angina, and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of beta-blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of Rhoxal-acebutolol is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about two weeks and the patient should be carefully observed. The same frequency of administration should be maintained. In situations of greater urgency, acebutolol hydrochloride therapy should be discontinued stepwise and under conditions of closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with Rhoxal-acebutolol be reinstituted promptly, at least temporarily.

Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including acebutolol. A severe syndrome (oculo-muco-cutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one beta-adrenergic blocking agent (practolol). This syndrome has not been observed with acebutolol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur. Severe sinus bradycardia may occur with the use of acebutolol from unopposed vagal activity remaining after blockade of beta1-adrenergic receptors; in such cases, dosage should be reduced. In patients with thyrotoxicosis, the possible deleterious effects from long-term use of acebutolol have not been adequately appraised. Rhoxal-acebutolol may give a false impression of improvement by masking the clinical signs of continuing hyperthyroidism or its complications. Therefore, abrupt withdrawal of Rhoxal-acebutolol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.

: Reproduction studies have been performed with acebutolol in rats and rabbits at doses of up to 60 mg/kg/day by the oral route and 18 mg/kg/day by the I.V. route. In one rabbit study where acebutolol was administered by the I.V. route, the following malformations were observed: rib defects, gastroschisis, ventricular septal defect, dysplasia of urogenital system and umbilical hernia. These results could not be confirmed in a repeat intravenous study and were not seen in a study using the oral route.

Studies have also been performed with diacetolol (the major metabolite of acebutolol in man) at doses of up to 450 mg/kg/day p.o. in rabbits and 1800 mg/kg/day p.o. in rats. There was a significant elevation of postimplantation loss in rabbit dams receiving 450 mg/kg/day, a level at which food consumption and body weight gain were reduced; a non- statistically significant increase in incidence of bilateral cataracts was also noticed in rat fetuses from dams treated with 1800 mg/kg/day. There has been no experience with the use of acebutolol in pregnant women; however, studies have shown that both acebutolol and diacetolol cross the placenta. Rhoxal- acebutolol should not be given to pregnant patients. Its use in women with child bearing potential requires that the anticipated benefit be cautiously weighed against possible hazards.

: Acebutolol and diacetolol appear in breast milk with a milk: plasma ratio of 7.1 and 12.2 respectively. Use in nursing mothers is not recommended.

PRECAUTIONS

Patients with bronchospastic disease should, in general, not receive a beta-blocker. Because of its relative beta1 selectivity, however, low doses of Rhoxal-acebutolol (acebutolol hydrochloride) may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate, alternative treatment. Since beta1 selectivity is not absolute and is dose-dependent, a beta2 stimulating agent should be administered concomitantly and the lowest possible dose of acebutolol should be used initially, preferably in divided doses to avoid the higher plasma levels associated with the longer dose interval. There may be increased difficulty in treating an allergic type reaction in patients on beta- blockers. In these patients, the reaction may be more severe due to pharmacological effects of beta-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive alpha-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart- block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of beta- agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm, and norepinephrine to overcome hypotension. Rhoxal-acebutolol should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycemia. Rhoxal-acebutolol should be administered with caution to patients with impaired renal function. Acebutolol hydrochloride is excreted through the G.I. tract, but the active metabolite diacetolol, is eliminated predominantly by the kidney. There is a linear relationship between renal clearance of diacetolol and creatinine clearance. The daily dose of Rhoxal-acebutolol should be reduced in patients with a creatinine clearance less than 50 mL/min. Acebutolol has been used in the elderly without specific adjustment of dosage. However, this patient population may require lower maintenance doses because the bioavailability of both acebutolol hydrochloride and its metabolite are approximately doubled in this age group. This increased bioavailability is probably due to decreases in first-pass metabolism and renal function in the elderly. Rhoxal-acebutolol dosage should be individually adjusted when used concomitantly with other antihypertensive agents (see DOSAGE AND ADMINSTRATION). Liver function tests should be performed at regular intervals during long-term treatment.

: The management of patients being treated with beta-blockers and undergoing elective or emergency surgery is controversial. Although beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically-mediated reflex stimuli, abrupt discontinuation of therapy with Rhoxal- acebutolol may be followed by severe complications (see WARNINGS). Some patients receiving beta-adrenergic blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients with angina undergoing elective surgery, Rhoxal-acebutolol should be withdrawn gradually following the recommendation given under Abrupt Cessation of Therapy (see WARNINGS). According to available evidence, all clinical and physiological effects of beta-blockade are no longer present 72 hours after cessation of medication.

In emergency surgery, since Rhoxal-acebutolol is a competitive inhibitor of beta- adrenergic receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol.

: There is no experience with Rhoxal-acebutolol in the treatment of pediatric age groups and therefore use in children is not recommended.

: Catecholamine-depleting drugs, such as reserpine, may have an additive effect when given with $-blocking agents. Patients treated with Rhoxal-acebutolol plus catecholamine depletors should, therefore be observed closely for evidence of marked bradycardia or hypotension which may present as vertigo, syncope/pre-syncope, or orthostatic changes in blood pressure without compensatory tachycardia.

Exaggerated hypertensive responses have been reported from the combined use of b- adrenergic antagonists and "-adrenergic stimulants, including those contained in proprietary cold remedies and vasoconstrictive nasal drops. Patients receiving b-blockers should be warned of this potential hazard. No significant interactions of acebutolol with digoxin, hydrochlorothiazide, hydralazine, sulfinpyrazone, oral contraceptives, tolbutamide or warfarin have been observed. Should it be decided to discontinue therapy in patients receiving beta-blockers and clonidine concurrently, the beta-blocker should be discontinued several days before the gradual withdrawal of clonidine. It has been suggested that withdrawal of clonidine in the presence of beta-blockade may exaggerate the clonidine withdrawal syndrome (see also prescribing information for clonidine).

ADVERSE REACTIONS

The incidence of treatment-related side effects is derived from clinical trials in 3090 patients with hypertension, angina pectoris or arrhythmia. The most serious adverse reactions encountered with acebutolol hydrochloride are congestive heart failure, severe bradycardia and bronchospasm occurring in less than 1% of patients. The most common adverse reactions reported are fatigue (4%), dyspnea (2.5%), nausea (2%), dizziness (2%), hypotension (1%) and rashes (1%). Adverse reactions grouped by systems are as follows:

Cardiovascular

: Congestive heart failure (see WARNINGS); secondary effects of decreased cardiac output which include: syncope, vertigo, lightheadedness and postural hypotension; severe bradycardia, lengthening of PR interval, second and third degree A-V block , sinus arrest, palpitation, chest pain, cold extremities, Raynaud's phenomenon, hot flushes, pain in legs, edema.

Central Nervous System

: Headache, dizziness, mental depression, tiredness, drowsiness or somnolence, lightheadedness, anxiety, tinnitus, weakness, confusion, vivid dreams, paresthesia, insomnia.

Gastrointestinal

: Nausea and vomiting, heartburn, indigestion, flatulence, abdominal pain, diarrhea, constipation.

Respiratory

: Dyspnea, cough, shortness of breath, wheezing, bronchospasm.

Allergic/Dermatological

: (See WARNINGS): Urticaria, pruritus, sweating, exfoliative dermatitis, psoriasiform rash; Lupus-like syndrome with arthralgia, myalgia, dyspnea and pleuritic pain, reversible upon cessation of the drug.

EENT

: Blurred vision and non-specific visual disturbances, itching eyes, conjunctivitis.

Miscellaneous

: Weight gain, loss of appetite, decrease in libido, shivering, micturition (frequency), nocturia.

Laboratory tests

: Occasional reports of increased transaminase, alkaline phosphatase and lactic dehydrogenase values; positive antinuclear antibodies (see WARNINGS).

SYMPTOMS AND TREATMENT OF OVERDOSAGE

: The most common signs to be expected with a beta-adrenergic blocking agent are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia.

: If overdosage occurs, in all cases therapy with Rhoxal-acebutolol (acebutolol hydrochloride) should be discontinued and the patient observed closely. In addition, if required, the following therapeutic measures are suggested:

epinephrine rather than isoproterenol or norepinephrine may be useful in addition to atropine and digitalis. [See Precaution concerning the use of epinephrine in b-blocked patients.]

Rhoxal-acebutolol and its major metabolite are dialyzable. It should be remembered that Rhoxal-acebutolol is a competitive antagonist of isoproterenol and hence large doses of isoproterenol can be expected to reverse many of the effects of excessive doses of Rhoxal-acebutolol. However, the complications of excess isoproterenol should not be overlooked.

DOSAGE AND ADMINISTRATION

The dose of Rhoxal-acebutolol (acebutolol hydrochloride) must always be adjusted to the individual requirements of the patient in accordance with the following guidelines:

Rhoxal-acebutolol is usually used in conjunction with other antihypertensive agents, particularly thiazide diuretics but may be used alone (see INDICATIONS AND CLINICAL USE). Rhoxal-acebutolol treatment should be initiated with doses of 100 mg b.i.d. If an adequate response is not seen after one week, the dosage should be increased to 200 mg b.i.d. In some cases, the daily dosage may need further increments of 100 mg b.i.d. at intervals of not less than two weeks, up to the maximum of 400 mg b.i.d. The maintenance dose is within the range of 400 to 800 mg daily. Patients who show a satisfactory response at a daily dose of 400 mg or less may be given the total dose once daily in the morning. Daily doses above this should be divided into two equal doses.

The initial dose is 200 mg b.i.d. If after two weeks a satisfactory response has not been obtained, the dosage should be increased to a maximum of 300 mg b.i.d. The usual maintenance dose of Rhoxal-acebutolol in angina pectoris is in the range of 200 to 600 mg daily administered in two divided doses. In patients adequately controlled on 400 mg daily, a lower maintenance dose of 100 mg twice a day may be tried.

Older patients have an approximately 2-fold increase in bioavailability and are likely to require lower maintenance doses.

The daily dose of acebutolol hydrochloride should be reduced by 50% when creatinine clearance is less than 50 mL/min and by 75% when it is less than 25 mL/min (see PRECAUTIONS). Rhoxal-acebutolol and its metabolite are dialyzable.

PHARMACEUTICAL INFORMATION

Proper/Common Name: acebutolol hydrochloride Chemical Name: N-[3-acetyl-4-[2-hydroxy-3-[(1-methyl-ethyl)amino]propoxy]phenyl]- butanamide hydrochloride Structural Formula: Molecular Formula: C18H28N2O4 *HCl Molecular Weight: 372.89 Description: fine white, crystalline, non-hygroscopic, practically odourless powder. It is freely soluble in water at 22EC. The melting point is 141-145EC.

In addition to acebutolol hydrochloride, each film-coated tablet contains the non-medicinal ingredients dextrates, magnesium stearate, colloidal silicon dioxide, hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.

AVAILABILITY OF DOSAGE FORMS

: Each white, round, biconvex, film-coated tablet, scored and engraved "RXP" over "100" on one side, contains acebutolol hydrochloride equivalent to 100 mg acebutolol. Available in bottles of 100 and 500.

: Each white, oval, biconvex, film-coated tablet, scored and engraved "RXP 200" on one side contains acebutolol hydrochloride equivalent to 200 mg acebutolol. Available in bottles of 100 and 500.

: Each white, capsule-shaped, biconvex, film-coated tablet, scored and engraved "RXP 400" on one side contains acebutolol hydrochloride equivalent to 400 mg acebutolol. Available in bottles of 100 and 500.

PHARMACOLOGY

Administration of acebutolol hydrochloride to the cat and the dog has shown that low doses block isoproterenol-induced tachycardia (chronotropic action). Higher doses are required to block isoproterenol-induced hypotension. Similar findings were seen in the anesthetized cat and guinea pig. Doses of 5 mg intravenously and 100 mg orally blocked isoproterenol-induced tachycardia in man. The action of isoproterenol on the FEV was not changed. A dose-related inhibition of reflex tachycardia to passive tilting and to nitroglycerin-induced tachycardia was observed. Acebutolol hydrochloride markedly lowered exercise-induced hypertension and tachycardia. In the anesthetized dog high doses (10-20 mg/kg) of acebutolol hydrochloride infused slowly resulted in an increased PR interval and a decreased dP/dt. In man, oral or intravenous acebutolol hydrochloride usually caused a dose-related reduction in heart rate, cardiac index, dP/dt (left ventricular contractility) and cardiac output. Little or no effect was produced on blood pressure, peripheral vascular resistance or pulmonary functions (FEV and FVC). Acebutolol hydrochloride, in low doses (0.05-0.5 mg/kg), controls sympathetically-induced arrhythmias in several species. High intravenous and oral doses are effective in ouabain-induced arrhythmias (anesthetized dog and conscious rabbit). Ventricular arrhythmias in dogs with coronary ligation are reduced by acebutolol hydrochloride. Electrophysiological studies in man showed delayed AV conduction time and increased refractoriness of the AV node without significantly affecting sinus node recovery time, atrial refractory period, or the HV conduction time. Membrane stabilizing properties have been shown in three animal models. However this effect of acebutolol hydrochloride is not manifested at the doses used clinically. ISA was demonstrated in catecholamine-depleted rats by tachycardia induced by intravenous administration of the drug.

The effects on airway resistance (FEV and FVC) of single oral doses of 100 and 200 mg of acebutolol hydrochloride were assessed in 15 patients with bronchial asthma. Peak flow was measured in 9 of these patients. No bronchodilator was used. The drug did not have a significant effect on any of the pulmonary function tests. Clinically, one subject developed bronchospasm on the 100 mg dose but not on the 200 mg. In another study, 300 mg single doses were given to 10 patients with bronchial asthma. No bronchodilator was used. There was no significant difference on FEV, but specific airway conductance (SCAW) was reduced. When isoproterenol was subsequently administered, the bronchodilator response (rise in FEV1) was also decreased.

Acebutolol hydrochloride caused a significant decrease in plasma renin in hypertensive patients. This decrease was closely correlated to the decrease in blood pressure.

In healthy volunteers acebutolol hydrochloride did not affect serum glucose, triglycerides or cholesterol. The release of free fatty acids following administration of isoproterenol was inhibited. The drug potentiated the initial insulin-induced hypoglycemia but did not delay the return of normoglycemia.

TOXICOLOGY

and increase in PR interval. Increase in serum potassium at 110 mg/kg. One dog also had elevated SGPT and SGOT levels on 110 mg/kg.
Dog	I.V.	0	4F	4 weeks	Dose-related unsteadiness,
		5	4M		retching and vomiting
		30			immediately after dosing. One female dog died on the high
					dose.

Groups of 50 male and 50 female albino rats of the CD F/Crl BR strain received, in the diet, respectively 0, 100 and 300 mg/kg/day of acebutolol hydrochloride for 78 weeks. All groups were then off medication until the study terminated at 106 weeks. Groups of 60 male and 60 female CFLP mice received 0, 20, 60 and 300 mg/kg/day of the drug for 87 weeks in a similar study. There were no overt signs of toxicity. The incidence of tumors in acebutolol hydrochloride treated animals was no greater than that for the controls. Diacetolol, the major metabolite of acebutolol hydrochloride in man, was tested for carcinogenicity in rats of the CD strain. Groups of 85 males and 85 females received, in the diet during 104 weeks, doses of 100, 500 or 3000 mg/kg/day; 145 animals of each sex were used as controls. No carcinogenic potential was observed. Acebutolol hydrochloride and diacetolol were shown to be devoid of mutagenic potential in the Ames Test.

* *Females: for 2 weeks prior to mating through gestation and lactation (2 generations).

Rats	F	I.V.	120	Sedation, ataxia, respiratory depression.
	M	I.V.	115
	F	P.O.	5200

Dogs	M/F	I.V.	> 40 to < 63	Retching and vomiting, ataxia, weak pulse,
	M/F	P.O.	>150 to <500	respiratory depression.

SPECIES	ROUTE	DOSE (mg/kg/day)	# ANIMALS/ DOSE LEVEL	DURATION	FINDINGS
Rat	Oral	0	40F	78 weeks	Reduced grooming activity,
		20	40M		decreased body weight gain
		60			and food intake in the
		300			300 mg/kg group.
Rat	I.V.	0	10F	4 weeks	Rats at 40 mg/kg collapsed
		5	10M		within 5 seconds of dosing; all
		15			recovered within 2 minutes.
		40			Increased urine output and spleen weight at 40 mg/kg.
					Mild inflammatory reaction at
					injection sites.
Dog	Oral	0	4F	52 weeks	Occasional vomiting at all dose
		20	4M		levels. Sedation and salivation
		40			mainly in dogs receiving 110
		110			mg/kg. Prolonged, dose- related reduction in heart rate
		DOSE	# ANIMALS/
SPECIES	ROUTE	(mg/kg/day)	DOSE LEVEL	DURATION	FINDINGS

Rat	Oral	0	16	Days 6-16 of	No teratogenicity or
		12	17	gestation	embryotoxicity seen.
		60	17
Rat	I.V.	0	15	Days 5-17 of	No teratogenicity or
		2	16	gestation	embryotoxicity seen.
		6	15
		18	15
Rabbit	Oral	0	15	Days 6-16 of	No teratogenicity or
		12	16	gestation	embryotoxicity seen.
		60	17
Rabbit	I.V.	0	15	Days 5-20 of	Fetal abnormalities, not
		2	14	gestation	previously encountered in the
		6	15		strain of rabbits used, were
		18	14		observed at 6 and 18 mg/kg: rib defects, gastroschisis,
					ventricular septal defect,
					dysplasia of urogenital system
					and umbilical hernia.
Rabbit	I.V.	0	11	Days 5-20 of	Mean live fetal weight
		6	15	gestation	significantly reduced at 6
		18	17		mg/kg. No teratogenicity or embryotoxicity seen.

Rat	Oral	0	25	Days 5-17 of	Non-statistically significant
		50		gestation	increase in incidence of
		300			bilateral cataracts in fetuses
		1800			from dams treated with 1800 mg/kg/day.
Rabbit	Oral	0	18	Days 5-20 of	Increase in post- implantation
		50	18	gestation	loss (reduced food
		150	18		consumption and weight gain)
		450	19		at 450 mg/kg/day. No teratogenicity seen.

PRODUCT MONOGRAPH

THERAPEUTIC CLASSIFICATION

ACTIONS AND CLINICAL PHARMACOLOGY