PrRHOTRAL(r) (acebutolol hydrochloride) 100, 200, and 400 mg Tablets Antiyhypertensive and Anti-anginal Agent ATC Code: C07AB04 sanofi-aventis Canada Inc. Date of Revision: 2150 St. Elzear Blvd. West April 21, 2008 Laval, Quebec H7L 4A8 Submission Control No. : 119743

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 9 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 15 OVERDOSAGE 16 ACTION AND CLINICAL PHARMACOLOGY 17 STORAGE AND STABILITY 19 DOSAGE FORMS, COMPOSITION AND PACKAGING 19

PART II: SCIENTIFIC INFORMATION 20

PHARMACEUTICAL INFORMATION 20 DETAILED PHARMACOLOGY 20 TOXICOLOGY 22 REFERENCES 29

PART III: CONSUMER INFORMATION. 31

RHOTRAL(r)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

RHOTRAL(r) is indicated for the following: Treatment of mild to moderate hypertension. RHOTRAL(r) (acebutolol hydrochloride) 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 judgment of the physician, treatment should be started with a b-blocker rather than a diuretic. In patients with severe hypertension a b-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 RHOTRAL(r) with a diuretic or peripheral vasodilator has been found to be compatible and generally more effective than RHOTRAL(r) alone. Limited experience with other antihypertensive agents has not shown evidence of incompatibility. RHOTRAL(r) is not indicated in the emergency treatment of hypertensive crises. Long-term management of patients with angina pectoris due to ischemic heart disease. Geriatrics: RHOTRAL(r) 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 (see WARNINGS AND PRECAUTIONS, Special Populations). Pediatrics: There is no experience with RHOTRAL(r) in the treatment of pediatric age groups and therefore use in children is not recommended (see WARNINGS AND PRECAUTIONS, Special Populations).

CONTRAINDICATIONS

Patients who are hypersensitive to this drug, beta-blockers, or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph. Patients exhibiting sinus bradycardia. Patients with sinus syndrome. Patients with second and third degree A-V block. Patients with right ventricular failure secondary to pulmonary hypertension. Patients with congestive heart failure. Patients with cardiogenic shock. Patients with anesthesia with agents that produce myocardial depression, e.g. ether. Patients with severe peripheral circulatory disorders. Patients with phaeochromocytoma.

WARNINGS AND PRECAUTIONS

RHOTRAL(r) dosage should be individually adjusted when used concomitantly with other antihypertensive agents (see DOSAGE AND ADMINISTRATION). Cessation of therapy with a beta-blocker should be gradual (see WARNINGS AND PRECAUTIONS section, under 'Cardiovascular'). Dizziness and/or fatigue may occur with beta-blocker administration and this should be taken into account when driving or operating machinery.

Severe sinus bradycardia may occur with the use of RHOTRAL(r) from unopposed vagal activity remaining after blockade of beta1-adrenergic receptors; in such cases, dosage should be reduced. RHOTRAL(r) dosage should be individually adjusted when used concomitantly with other antihypertensive agents (see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS sections). Caution should be used in patients with Prinzmetal angina. RHOTRAL(r) may increase the number and duration of angina attacks in patients with Printzmetal's angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction. Therefore, RHOTRAL(r) should be used in these patients with the utmost care.

Special caution should be exercised when administering RHOTRAL(r) (acebutolol hydrochloride) to patients with a history of heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with b-blockade always carries the potential hazard of further depressing myocardial contractibility and precipitating cardiac failure. RHOTRAL(r) acts selectively without abolishing the inotropic action of digitalis on the heart 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 b-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 digitalised and/or given a diuretic and the response observed closely. If cardiac failure continues despite adequate digitalisation and diuretic therapy, RHOTRAL(r) therapy should be immediately withdrawn.

Abrupt cessation of therapy with RHOTRAL(r) Patients with angina or ischaemic heart disease should be warned against abrupt discontinuation of RHOTRAL(r). 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 b-blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of RHOTRAL(r) 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 RHOTRAL(r) be reinstituted promptly, at least temporarily (see DRUG INTERACTIONS).

The low lipid solubility and lack of accumulation in CNS tissues of acebutolol and its active metabolite reduce the likelihood of sleep disturbances, depression or other central effects and such occurrences are rare.

In patients with thyrotoxicosis, the possible deleterious effects from long-term use of RHOTRAL(r) have not been adequately appraised. RHOTRAL(r) may give a false impression of improvement by masking the clinical signs of continuing hyperthyroidism or its complications. Therefore, abrupt withdrawal of RHOTRAL(r) may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.

Increase in antinuclear antibody (ANA) titer was observed in approximately 12.5% of patients on chronic acebutolol hydrochloride therapy. Rare instances (<1%) of a syndrome resembling lupus erythematosus have been reported with maintenance RHOTRAL(r) therapy. Similar symptoms were occasionally observed with some other b-blockers. In addition to increase ANA titers, polyarthralgia, myalgia and pleuritic pain were the main presenting symptoms. Symptoms and ANA titers appear reversible upon discontinuation of RHOTRAL(r) therapy (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests section). The drug should be withdrawn if symptoms appear or if the results of ANA testing are significantly positive. Patients should be followed up both clinically and serologically until resolution of symptoms.

Conjunctival xerosis (dry eyes) has been reported with b-blockers, including RHOTRAL(r). Cases of a severe syndrome (oculo-muco-cutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis were reported with the chronic use of one b-adrenergic-blocking agent (practolol). This syndrome has not been observed with RHOTRAL(r) 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.

: The management of patients being treated with b-blockers and undergoing elective or emergency surgery is controversial. Although

b-adrenergic-receptor blockade impairs the ability of the heart to respond to b-adrenergically- mediated reflex stimuli, abrupt discontinuation of therapy with RHOTRAL(r) may be followed by severe complications (see WARNINGS AND PRECAUTIONS section, under 'Cardiovascular'). Some patients receiving b-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, RHOTRAL(r) should be withdrawn gradually following the recommendation given under "Abrupt Cessation of Therapy" (see WARNINGS AND PRECAUTIONS section, under 'Cardiovascular'). According to available evidence, all clinical and physiological effects of b- blockade are no longer present 72 hours after cessation of medication. The patient may be protected against vagal reactions by intravenous administration of atropine. In emergency surgery, since RHOTRAL(r) is a competitive inhibitor of b-adrenergic-receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol.

Cases of serious pulmonary infiltration and pneumonitis complications have been reported during beta-blockage therapy. Cases of pneumonitis have been reported with acebutolol. Patients with bronchospastic disease should in general not receive a b-blocker. Because of its relative b1 selectivity, however, low doses of RHOTRAL(r) may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate, alternative treatment. Since b1 selectivity is not absolute and is dose-dependent, the lowest possible dose of RHOTRAL(r) should be used initially, preferably in divided doses to avoid the higher plasma levels associated with the longer dose-interval. A bronchodilator such as a theophylline or a b2- agonist should be made available in advance with instructions concerning its use. Drug-induced bronchospasm is usually at least partially reversible by the use of a suitable agonist. Although cardio-selective beta blockers may have less effect on lung function than non- selective beta blockers, as with all beta blockers, they should be avoided in patients with obstructive airways disease unless there are compelling clinical reasons for their use. Where such reasons exist, cardio-selective b-blockers should be used with the utmost care. Beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions. 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, reflux 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.

Various skin rashes have been reported with b-blockers, including RHOTRAL(r). Cases of a severe syndrome (oculo-muco-cutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis were reported with the chronic use of one b- adrenergic-blocking agent (practolol). Patients with known psoriasis should take beta-blockers only after careful consideration.

Pregnant Women: Reproduction studies have been performed with RHOTRAL(r) 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 RHOTRAL(r) 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 RHOTRAL(r) in man) at doses of up to 450 mg/kg/day p.o. in rabbits and 1,800 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 1,800 mg/kg/day. There has been no experience with the use of RHOTRAL(r) in pregnant women; however, studies have shown that both acebutolol and diacetolol cross the placenta. RHOTRAL(r) should not be given to pregnant patients. In animal studies beta blockers administered in late pregnancy gave rise to bradycardia, hypoglycaemia and cardiac or pulmonary complications in the fetus/neonate. Beta-blockers reduced placental perfusion, which resulted in intrauterine fetal death, immature and premature deliveries. The use of RHOTRAL(r) in women with child bearing potential requires that the anticipated benefit be cautiously weighed against possible hazards.

Nursing Women:

7.1 and 12.2 respectively. The half-life of acebutolol in the neonate is double that in adults. The risks of hypoglycaemia and bradycardia occurring in the nursing infant have not been evaluated. Use in nursing mothers is not recommended. Diabetics: RHOTRAL(r) 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. b-adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycemia. Pediatrics: There is no experience with RHOTRAL(r) in the treatment of pediatric age groups and therefore use in children is not recommended. Geriatrics: RHOTRAL(r) 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 (see DOSAGE AND ADMINISTRATION section). Patients with Impaired Renal/Liver Function: RHOTRAL(r) 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 RHOTRAL(r) should be reduced in patients with a creatinine clearance less than 50 mL/min (see DOSAGE AND ADMINISTRATION section). Liver function tests should be performed at regular intervals during long-term treatment.

Increase in antinuclear antibody (ANA) titer was observed in approximately 12.5% of patients on chronic acebutolol hydrochloride therapy sometimes associated with clinical symptoms; when present, these clear promptly on discontinuation of treatment (see WARNINGS AND PRECAUTIONS, Immune section). Liver function tests should be performed at regular intervals during long-term treatment.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The incidence of side effects is derived from clinical trials in 3,090 patients with hypertension, angina pectoris or arrhythmia. The serious adverse reactions encountered with RHOTRAL(r) (acebutolol hydrochloride) are congestive heart failure, severe bradycardia and bronchospasm occurring in less than 1% of patients. Other serious adverse reactions encountered with RHOTRAL(r) (acebutolol hydrochloride) in clinical trials are third degree A-V block, syncope (in the context of decreased cardiac output), sinus arrest, lupus-like syndrome (with arthralgia, myalgia, dyspnea and pleuritic pain, reversible upon cessation of the drug [see WARNINGS AND PRECAUTIONS section]), hallucinations, psychoses and pneumonitis.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse

reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1 - Common Adverse Drug Reactions to RHOTRAL(r) in Patients with Hypertension, Angina Pectoris or Arrhythmia

System Organ Class Adverse Event	Frequency n = 3,090
Gastrointestinal disorders Nausea	2 %
General disorders and Administration Site Conditions Fatigue	4 %
Nervous System disorders Dizziness	2 %
Respiratory, Thoracic and Mediastinal disorders Dyspnea	2.5 %
Vascular disorders Hypotension	1 %
Skin and Subcutaneous Tissue disorders Rashes	1 %

Less Common Clinical Trial Adverse Drug Reactions

Adverse reactions grouped by systems are as follows:

Allergic-Dermatological:

(see WARNINGS AND PRECAUTIONS section) Exfoliative dermatitis Pruritus Psoriasiform rash Sweating Urticaria

Cardiovascular:

Chest pain Cold extremities Congestive heart failure (see WARNINGS AND PRECAUTIONS) Edema Hot flushes Intermittent claudication (pain in legs) Lengthening of PR interval Palpitation Raynaud's phenomenon Second degree A-V block Secondary effects of decreased cardiac output, which include: vertigo, lightheadedness and postural hypotension. Severe bradycardia Slowing of AV conduction or increase of existing AV block.

Central Nervous System:

Anxiety Confusion Dizziness Drowsiness or somnolence Headache Insomnia Lethargy Lightheadedness Mental depression Paresthesia Tinnitus Tiredness Vivid dreams Weakness

Ears, Eyes, Nose, and Throat:

Blurred vision and non-specific visual disturbances Conjunctival xerosis (dry eyes) Conjunctivitis Itching eyes

Gastrointestinal:

Abdominal pain Constipation Diarrhea Flatulence Heartburn Indigestion Nausea and vomiting

Laboratory Tests:

Reports of increased transaminase (SGOT, SGPT), alkaline phosphatase and lactic dehydrogenase (LDH) values. Positive antinuclear antibodies (see WARNINGS AND PRECAUTIONS section).

Respiratory:

Bronchospasm Cough Dyspnea Shortness of breath Wheezing

Metabolism:

Loss of appetite Weight gain

Urinary:

Micturition (frequency) Nocturia

Miscellaneous:

Cyanotic extremities Decrease in libido Shivering

Abnormal Hematologic and Clinical Chemistry Findings:

No data available.

Post-Market Adverse Drug Reactions

Investigations:

There have been reports of patients who have developed anti-nuclear factor titers, sometimes associated with clinical symptoms; when present, these clear promptly on discontinuation of treatment.

Musculoskeletal and Connective Tissue disorders:

During acebutolol therapy, cases of systemic lupus erythematosus (SLE) were identified. The events abated following discontinuation of acebutolol therapy within a period of a few days to 4 months. Based on this information, an association between SLE and acebutolol therapy cannot be excluded.

Respiratory, Thoracic and Mediastinal disorders:

Cases of serious pulmonary infiltration and pneumonitis complications have been reported during beta-blockage therapy. Cases of pneumonitis have been reported with acebutolol.

DRUG INTERACTIONS

Cross reactions due to displacement of other drugs from plasma protein binding sites are unlikely due to the degree of plasma protein binding exhibited by acebutolol (26%) and diacetolol.

The drug interactions discussed in this section are based on either drug interaction case reports, or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2 - Established or Predicted Drug-Drug Interactions Proper Name Ref Effect Clinical Comments a-adrenergic Stimulants

No significant interactions of RHOTRAL(r) with hydrochlorothiazide, hydralazine, sulfinpyrazone, oral contraceptives, tolbutamide or warfarin have been observed.

Food intake does not have a significant effect on the area under the plasma concentration time curve [AUC] of RHOTRAL(r) although the rate of absorption and peak concentration decreases slightly (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics-Absorption).

DOSAGE AND ADMINISTRATION

The following situations affect dosing with RHOTRAL(r) (see WARNINGS AND PRECAUTIONS): Hypertension Angina Pectoris Use in Geriatrics Use in Patients with Impaired Renal/Liver Function

The dose of RHOTRAL(r) (acebutolol hydrochloride) must always be adjusted to the individual requirements of the patient in accordance with the following guidelines.

Hypertension: RHOTRAL(r) is usually used in conjunction with other antihypertensive agents, particularly thiazide diuretics but may be used alone (see INDICATIONS AND CLINICAL USE). RHOTRAL(r) 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.

Angina Pectoris: 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 RHOTRAL(r) 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.

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

Use in Patients with Impaired Renal/Liver Function: 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 WARNINGS AND PRECAUTIONS section, under 'Special Populations'). RHOTRAL(r) and its metabolite are dialyzable.

OVERDOSAGE

: The most common signs to be expected with a b-adrenergic blocking agent are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia, cardiogenic shock, AV block, conduction defects, pulmonary edema, depressed level of consciousness, and rarely, hyperkalemia. Cases of bronchospasm have been reported during overdosage with acebutolol.

Treatment: If overdosage occurs, in all cases therapy with RHOTRAL(r) (acebutolol hydrochloride) should be discontinued and the patient observed closely (see WARNINGS AND PRECAUTIONS, Cardiovascular section). In addition, if required, the following therapeutic measures are suggested:

: One (1) mg atropine sulphate administered intravenously should be given without delay. If this is insufficient it should be followed by a slow intravenous injection of isoprenaline (5mg per minute) with constant monitoring until a response occurs. In severe cases of self-poisoning with circulatory collapse unresponsive to atropine and catecholamines the intravenous injection of glucagon (10-20 mg) may produce a dramatic improvement. Cardiac pacing may be employed if bradycardia becomes severe. Judicious use of vasopressors, diazepam, phenytoin, lidocaine, digoxin, and bronchodilators should be considered depending on the presentation of the patient.

: 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].

Hypoglycemia: intravenous glucose. RHOTRAL(r) and its major metabolite are dialyzable. It should be remembered that RHOTRAL(r) 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 RHOTRAL(r). However, the complications of excess isoproterenol should not be overlooked. For management of a suspected drug overdose contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

RHOTRAL(r) (acebutolol hydrochloride) is a b-adrenergic receptor blocking agent. In vitro and in vivo animal studies show it has a preferential effect on beta1 adrenoreceptors, mainly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, RHOTRAL(r) inhibits beta2 adrenoreceptors, mostly located in the bronchial and vascular musculature. Its peripheral effects are to reduce heart rate, especially on exercise, and to lower blood pressure in hypertensive subjects. RHOTRAL(r) and its equally active metabolite, diacetolol, have anti- arrhythmic activity, and possess some partial agonist activity (or intrinsic sympathomimetic activity - ISA). ISA of RHOTRAL(r) has been demonstrated in catecholamine-depleted rats by tachycardia induced by intravenous administration of this agent. The membrane-stabilizing effect of RHOTRAL(r) is not manifest at the doses used clinically. ISA has been observed with RHOTRAL(r) in man, as shown by a slightly smaller (about 3 beats per minute) decrease in resting heart rate when compared to equivalent b-blocking doses of propranolol, metoprolol or atenolol. This property ensures that some degree of stimulation of beta receptors is maintained. RHOTRAL(r) blocks the effects of excessive catecholamine stimulation resulting from stress, which are responsible for increases in heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. This reduces myocardial oxygen requirements, which may be an important factor in the mechanism of the anti-anginal effect. Other factors that may be involved in the mechanism of the antihypertensive effect are inhibition of renin release by the kidneys and inhibition of the vasomotor centres. RHOTRAL(r) is used in the treatment of hypertension and/or long-term management of angina pectoris. 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.

Absorption:

Following oral administration, acebutolol is rapidly and almost completely (90%) absorbed from the gastrointestinal tract.

Food intake does not have a significant effect on the area under the plasma concentration time curve [AUC] of RHOTRAL(r) (mean decrease = 6%) although the rate of absorption and peak concentration decreases slightly (mean decrease in Cmax = 10%). The plasma elimination half-life of RHOTRAL(r) under fasted conditions is approximately 3 to 4 hours, while that of its metabolite, diacetolol, is 8 to 13 hours. The time to reach peak concentration for RHOTRAL(r) is 2.5 hours and for diacetolol, after oral administration of RHOTRAL(r), 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. Distribution: RHOTRAL(r) has a low binding affinity for plasma proteins (about 26%). RHOTRAL(r) and its metabolite, diacetolol, are relatively hydrophilic and therefore only minimal quantities have been detected in the cerebrospinal fluid (CSF). Metabolism: It undergoes extensive first pass hepatic biotransformation, with an absolute bioavailability of approximately 40% for the parent compound. There is rapid formation of a major equiactive metabolite, N-acetyl derivative (diacetolol). This metabolite is equipotent to RHOTRAL(r) ; therefore, this first-pass phenomenon does not attenuate the therapeutic effect of RHOTRAL(r).

Excretion:

Within the single oral dose range of 200 to 400 mg, 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.

Gender

Race:

Hepatic Insufficiency:

Renal Insufficiency: (r)

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 RHOTRAL

should be reduced in patients with a creatinine clearance less than 50 mL/min (see DOSAGE AND ADMINISTRATION section).

Genetic Polymorphism:

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING

RHOTRAL(r) 100 mg, available in bottles of 100 and 500. White to creamy white shield-shaped, film-coated tablet. One side is scored, debossed with "RH" above scoreline and with "100" below scoreline. Other side is debossed with "RHOTRAL".

: microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10 aluminum lake, dibasic calcium phosphate, magnesium stearate, Opadry II White Y-22-7719, polyethylene glycol, povidone, talc.

RHOTRAL(r) 200 mg, available in bottles of 100 and 500. Blue shield-shaped, film-coated tablet. One side is scored, debossed with "RH" above scoreline and with "200" below scoreline. Other side is debossed with "RHOTRAL".

: microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, FD&C Blue No. 1 aluminum lake, magnesium stearate, Opadry II White Y-22-7719, polyethylene glycol, povidone, talc.

RHOTRAL(r) 400 mg, available in bottles of 100. White to creamy white shield-shaped, film- coated tablet. One side is scored, debossed with "RH" above scoreline and with "400" below scoreline. Other side is debossed with "RHOTRAL".

: colloidal silicon dioxide, cornstarch, D&C Yellow No. 10 aluminum lake, lactose, magnesium stearate, methylcellulose, Opadry II White Y-22-7719, polyethylene glycol, povidone, talc.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Oral	Tablet 100, 200, or 400 mg	For a complete listing see Dosage Forms, Composition and Packaging section.

Sympathomimetic and xanthine bronchodilators	T	\| bronchodilation	Acebutolol may antagonize the effects of sympathomimetic and xanthine bronchodilators.
Barbiturates Phenothiazines Tricyclic depressants Other antihypertensive agents	T	\| acebutolol hypotensive effects	Concomitant administration of tricyclic antidepressants, barbiturates and phenothiazines as well as other anti-hypertensive agents may increase the blood pressure lowering effects of beta-blockers.

Monoamine	T	hypertension	There is a theoretical risk that concurrent
Proper Name	Ref Effect		Clinical Comments
Oxidase Inhibitors			administration of monoamine oxidase inhibitors and high doses of beta-blockers, even if they are cardio-selective, can produce hypertension.

PRODUCT MONOGRAPH