PRODUCT MONOGRAPH

PrSECTRAL(r) (acebutolol hydrochloride) 100, 200, and 400 mg Tablets Antiyhypertensive and Anti-anginal Agent ATC Code: C07AB04 sanofi-aventis Canada Inc. 2150 St. Elzear Blvd. West Laval, Quebec H7L 4A8 Date of Revision: November 14, 2007 sanofi-aventis version 1.0 dated Submission Control No: 115977

Table of Contents

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 18 DOSAGE FORMS, COMPOSITION AND PACKAGING 19

PART II: SCIENTIFIC INFORMATION 20

PHARMACEUTICAL INFORMATION 20 DETAILED PHARMACOLOGY 20 TOXICOLOGY 22 REFERENCES 28

PART III: CONSUMER INFORMATION. 30

SECTRAL(r)

(acebutolol hydrochloride)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

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

General

SECTRAL(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.

Cardiovascular

Severe sinus bradycardia may occur with the use of SECTRAL(r) from unopposed vagal activity remaining after blockade of beta1-adrenergic receptors; in such cases, dosage should be reduced. SECTRAL(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. SECTRAL(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, SECTRAL(r) should be used in these patients with the utmost care.

Cardiac Failure

Special caution should be exercised when administering SECTRAL(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 -blockade always carries the potential hazard of further depressing myocardial contractibility and precipitating cardiac failure. SECTRAL(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 -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, SECTRAL(r) therapy should be immediately withdrawn. Abrupt cessation of therapy with SECTRAL(r) Patients with angina or ischaemic heart disease should be warned against abrupt discontinuation of SECTRAL(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 -blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of SECTRAL(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 SECTRAL(r) be reinstituted promptly, at least temporarily (see DRUG INTERACTIONS).

Central Nervous Sytem

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.

Endocrine and Metabolism

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

Immune

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 SECTRAL(r) therapy. Similar symptoms were occasionally observed with some other -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 SECTRAL(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.

Ophthalmologic

Conjunctival xerosis (dry eyes) has been reported with -blockers, including SECTRAL(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 -adrenergic-blocking agent (practolol). This syndrome has not been observed with SECTRAL(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.

Peri-Operative Considerations

In patients undergoing elective or emergency surgery

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

-adrenergic-receptor blockade impairs the ability of the heart to respond to -adrenergically- mediated reflex stimuli, abrupt discontinuation of therapy with SECTRAL(r) may be followed by severe complications (see WARNINGS AND PRECAUTIONS section, under 'Cardiovascular'). Some patients receiving -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, SECTRAL(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 - 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 SECTRAL(r) is a competitive inhibitor of -adrenergic-receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol.

Respiratory

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 -blocker. Because of its relative 1 selectivity, however, low doses of SECTRAL(r) may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate, alternative treatment. Since 1 selectivity is not absolute and is dose-dependent, the lowest possible dose of SECTRAL(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 2- 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 -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.

Skin

Various skin rashes have been reported with -blockers, including SECTRAL(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 - adrenergic-blocking agent (practolol) Patients with known psoriasis should take beta-blockers only after careful consideration.

Special Populations

Pregnant Women: Reproduction studies have been performed with SECTRAL(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 SECTRAL(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 SECTRAL(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 SECTRAL(r) in pregnant women; however, studies have shown that both acebutolol and diacetolol cross the placenta. SECTRAL(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 SECTRAL(r) in women with child bearing potential requires that the anticipated benefit be cautiously weighed against possible hazards.

Nursing Women:

Acebutolol and diacetolol appear in breast milk with a milk plasma ratio of

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: SECTRAL(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. -adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycemia. Pediatrics: There is no experience with SECTRAL(r) in the treatment of pediatric age groups and therefore use in children is not recommended. Geriatrics: SECTRAL(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: SECTRAL(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 SECTRAL(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.

Monitoring and Laboratory Tests

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.

DRUG INTERACTIONS

Overview

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.

Drug-Drug Interactions

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

-adrenergic Stimulants

Anaesthetic Agents

Antiadrenergic Agents

Antidepressants

Proper Name Ref Effect Clinical Comments

Calcium Antagonists

Catecholamine Depletors

Class I Anti-arrhythmics

Digitalis Glycosides

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Other Drugs

Legend: C= Case Study; T= Theoretical

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

Drug-Food Interactions

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

Drug- Herb Interaction

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established

DOSAGE AND ADMINISTRATION

Dosing Considerations

The following situations affect dosing with SECTRAL(r) (see WARNINGS AND PRECAUTIONS):

• Hypertension

• Pectoris

• in Geriatrics

• in Patients with Impaired Renal/Liver Function

Recommended Dose and Dosage Adjustment

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

Hypertension: SECTRAL(r) is usually used in conjunction with other antihypertensive agents, particularly thiazide diuretics but may be used alone (see INDICATIONS AND CLINICAL USE). SECTRAL(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 SECTRAL(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'). SECTRAL(r) and its metabolite are dialyzable.

OVERDOSAGE

Symptoms

: The most common signs to be expected with a -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 SECTRAL(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:

1. Excess Bradycardia or Hypotension : 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 (5ug 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.

2. Bradycardia : atropine or another anticholinergic drug.

3. Heart block (second or third degree) : isoproterenol or transvenous cardiac pacemaker.

4. Congestive heart failure : conventional therapy.

5. Hypotension (depending on associated factors) : epinephrine rather than isoproterenol or norepinephrine may be useful in addition to atropine and digitalis [see Precaution concerning the use of epinephrine in -blocked patients].

6. Bronchospasm : aminophylline or isoproterenol.

7. Hypoglycemia: intravenous glucose. SECTRAL(r) and its major metabolite are dialyzable.

It should be remembered that SECTRAL(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 SECTRAL(r). However, the complications of excess isoproterenol should not be overlooked.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

SECTRAL(r) (acebutolol hydrochloride) is a -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, SECTRAL(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. SECTRAL(r) and its equally active metabolite, diacetolol, have anti- arrhythmic activity, and possess some partial agonist activity (or intrinsic sympathomimetic activity - ISA). ISA of SECTRAL(r) has been demonstrated in catecholamine-depleted rats by tachycardia induced by intravenous administration of this agent. The membrane-stabilizing effect of SECTRAL(r) is not manifest at the doses used clinically. ISA has been observed with Sectral in man, as shown by a slightly smaller (about 3 beats per minute) decrease in resting heart rate when compared to equivalent -blocking doses of propranolol, metoprolol or atenolol. This property ensures that some degree of stimulation of beta receptors is maintained. SECTRAL(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. SECTRAL(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.

Pharmacokinetics

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 SECTRAL(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 SECTRAL(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 SECTRAL(r) is 2.5 hours and for diacetolol, after oral administration of SECTRAL(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: SECTRAL(r) has a low binding affinity for plasma proteins (about 26%). SECTRAL(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 SECTRAL(r); therefore, this first-pass phenomenon does not attenuate the therapeutic effect of SECTRAL(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.

Special Populations and Conditions

Gender

: No data available.

Race:

No data available.

Hepatic Insufficiency:

No data available.

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

Genetic Polymorphism:

No data available.

STORAGE AND STABILITY

Store between 15-30degC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

SECTRAL(r) 100 mg, available in bottles of 100 and 500. White to off-white shield-shaped, film- coated tablet. One side is scored, debossed with "SECTRAL(r)" above scoreline and with "100" below the scoreline. Other side is debossed with "rPr" in a heart.

Non-medicinal ingredients

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

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

Non-medicinal ingredients

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

SECTRAL(r) 400 mg, available in bottles of 100. White to off-white shield-shaped, film-coated tablet. One side is scored, debossed with "SECTRAL(r)" above scoreline and with "400" below the scoreline. Other side is debossed with "rPr" in a heart.

Non-medicinal ingredients

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